**Meet the editor**

Branislav Baskot MD PhD Ass Prof; was born 1958 in Ruma, Serbia. Medicine Faculty finishes in Sarajevo BiH, specialization of Nuclear Medicine finish 1994 on Military Medical Academy Belgrade Serbia. The main occupation in the field of Nuclear medicine was nuclear cardiology. Doctoral degree 2005; "Determination of culprit lesion before and after percutaneous coronary

intervention by myocardial perfusion imaging". In the 2003 finished Master's Degree; "Myocardial perfusion imaging with 99mTc-Tetrofosmin in the diagnosis ischemic heart disease".

Contents

**Preface IX**

**Disease? 3**

and Teresa Pinheiro

**Artery Disease 53**

Jasmin Čaluk

Hakeem

Dino Bodini

Chapter 3 **Radiation Principles and Safety 55**

**Section 1 Something About Prevence of Coronary Heart Disease 1**

Chapter 2 **Relationship Between Ox–LDL, Immune Cells, Atheroma**

**Dimensions and Angiographic Measurements Assessed by Coronary Angiography and Intravascular Ultrasound 29** Catarina Ramos, Patrícia Napoleão, Rui Cruz Ferreira, Cristina Fondinho, Mafalda Selas, Miguel Mota Carmo, Ana Maria Crespo

Massimo Cocchi and Giovanni Lercker

**Section 2 Noninvasive Diagnostic Approach in Coronary**

Chapter 4 **Noninvasive Modalities for Coronary Angiography 75**

Chapter 5 **Non-Invasive Study of Coronary Circulation by Means of a**

**Coronary Flow Reserve Evaluation 109**

G.J. Pelgrim, M. Oudkerk and R. Vliegenthart

Karthikeyan Ananthasubramaniam, Sabha Bhatti and Abdul

**Transthoracic Dipyridamole Stress Echocardiography with**

Maurizio Turiel, Luigi Gianturco, Vincenzo Gianturco and Bruno

Chapter 6 **Computed Tomography Imaging of the Coronary Arteries 119**

Chapter 1 **Reduced Consumption of Olive Oil: A Risk for Ischemic Heart**

## Contents

## **Preface XIII**

Dino Bodini


Chapter 6 **Computed Tomography Imaging of the Coronary Arteries 119** G.J. Pelgrim, M. Oudkerk and R. Vliegenthart


Chapter 17 **Contrast-Induced Nephropathy in Coronary Angiography and**

Contents **VII**

**Implication, Diagnostics Approach, Prevention 375** Frantisek Kovar, Milos Knazeje and Marian Mokan

Chia-Ter Chao, Vin-Cent Wu and Yen-Hung Lin

Mohamed Bamoshmoosh and Paolo Marraccini

Chapter 20 **Percutaneous. Recanalization of Chronic Total Occlusion (CTO)**

**Coronary Arteries: Looking Back and Moving Forward 431** Simona Giubilato, Salvatore Davide Tomasello and Alfredo Ruggero

Chapter 18 **Contrast-Induced Nephropathy: Risk Factors, Clinical**

Chapter 19 **Myocardial Bridges in the ERA of Non-Invasive**

**Intervention 349**

**Angiography 413**

Galassi


Chapter 7 **Clinical and Research Applications of Optical Coherence**

Chapter 9 **A Noninvasive Alternative to Coronary Angiography:**

Chapter 10 **Nuclear Cardiology — In the Era of the Interventional**

Obradovic, Nenad Ratkovic and Miodrag Zivkovic

**Section 3 Invasive Approach and Interventional Cardiology 227**

Chapter 13 **Improving the Utility of Coronary Angiography: The Use of**

Chapter 14 **Coronary Angiography – Technical Recommendations and**

Chapter 15 **Transradial Versus Transfemoral Coronary Angiography 307**

Christopher Raffel and Darren L. Walters

**Adjuvant Imaging and Physiological Assessment 257** Alexander Incani, Anthony C. Camuglia, Karl K. Poon, O.

**as a Gate Way to Myocardial Contrast**

**Echocardiography Map 187**

Takao Hasegawa and Kenei Shimada

**Artery Bypass Graft 153**

Bong Gun Song

**VI** Contents

Ri-ichiro Kakihara

**Cardiology 203**

Chapter 11 **Coronary Angiography 229** Azarisman Mohd Shah

Chapter 12 **Coronary Angiography (IJECCE) 235**

**Radiation Protection 291** Maria Anna Staniszewska

Amir Farhang Zand Parsa

Chapter 16 **Contrast-Induced Nephropathy 321**

Omer Toprak

Chiu-Lung Wu and Chi-Wen Juan

**Tomography Imaging in Coronary Artery Disease 143**

Chapter 8 **Multidector CT Imaging of Coronary Artery Stent and Coronary**

**Myocardial Contrast Echocardiography Following Strain Map**

Branislav Baskot, Igor Ivanov, Dragan Kovacevic, Slobodan

Chapter 20 **Percutaneous. Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward 431** Simona Giubilato, Salvatore Davide Tomasello and Alfredo Ruggero Galassi

Preface

myocardial infarction as well as revascularization.

experts and investigators in medical imaging.

patients with coronary artery disease.

The mortality from ischemic heart disease has decreased in recent years. The better under‐ standing of risk factors associated with development of coronary artery disease (CAD) has significantly contributed to this decline. Preventive measures such as aggressive therapy of arterial hypertension, diabetes mellitus, and lipid disorders and by campaigning against the smoking are important components of this medical success. Furthermore, improvements in medical and interventional therapy have reduced the complications associated with acute

This book brings together contributions from around the world, investigators who are clini‐ cal versus imaging science in their orientation, and representatives from academic medical centers and the imaging industry. Each article is written to be accessible to those with a basic knowledge of coronary imaging but also to be stimulating and educational to those who are

This book covers where advances have been dramatic in the past two decades and shows the major contributions of the imaging scientists and engineers from both academia and in‐ dustry. Patients with know or suspected coronary artery disease who are asymptomatic or who have stable symptoms are often evaluated noninvasive. Functional test, such as stress electrocardiography, stress echocardiography, and stress nuclear perfusion imaging, detect and quantity the presence of ischemia based on electrical, mechanical, or perfusion abnor‐ malities, indirectly, but nuclear perfusion imaging directly, establishing the burden of coro‐ nary artery disease. Nuclear cardiology imaging (MPI) is well establishment imaging techniques and is already integral part of the management of CAD, and is included in a number of professional guidelines. Coronary angiography, considered the "gold standard" for the diagnosis of CAD, often does not provide information about the functional signifi‐ cance of coronary stenosis, especially in borderline lesions. Andres Gruentzig said; *when cor‐ onary angiography founded coronary narrowing, I would like to have some kind of diagnostic procedure who gives me functional significance that lesion.* Nuclear cardiology imaging is very important diagnostic tool for the diagnosis culprit lesions, and indicating for cardiovascular intervention (PCI or ACBP). *The predominant theme* is that MPI finding can serve as the gate‐ keeper for more costly and more risky invasive strategies in the evaluation and treatment of

This book includes a series of articles that provide a state-of-the-art summary of the current clinical applications of cardiac CT, reviews data that support the accuracy and the prognos‐ tic use of CT coronary angiography and reports of the newest technologic advances and promising future applications of these imaging modalities. Its also provide other diagnostic approach like functional test, which finding helps to make decision about invasive strategies

## Preface

The mortality from ischemic heart disease has decreased in recent years. The better under‐ standing of risk factors associated with development of coronary artery disease (CAD) has significantly contributed to this decline. Preventive measures such as aggressive therapy of arterial hypertension, diabetes mellitus, and lipid disorders and by campaigning against the smoking are important components of this medical success. Furthermore, improvements in medical and interventional therapy have reduced the complications associated with acute myocardial infarction as well as revascularization.

This book brings together contributions from around the world, investigators who are clini‐ cal versus imaging science in their orientation, and representatives from academic medical centers and the imaging industry. Each article is written to be accessible to those with a basic knowledge of coronary imaging but also to be stimulating and educational to those who are experts and investigators in medical imaging.

This book covers where advances have been dramatic in the past two decades and shows the major contributions of the imaging scientists and engineers from both academia and in‐ dustry. Patients with know or suspected coronary artery disease who are asymptomatic or who have stable symptoms are often evaluated noninvasive. Functional test, such as stress electrocardiography, stress echocardiography, and stress nuclear perfusion imaging, detect and quantity the presence of ischemia based on electrical, mechanical, or perfusion abnor‐ malities, indirectly, but nuclear perfusion imaging directly, establishing the burden of coro‐ nary artery disease. Nuclear cardiology imaging (MPI) is well establishment imaging techniques and is already integral part of the management of CAD, and is included in a number of professional guidelines. Coronary angiography, considered the "gold standard" for the diagnosis of CAD, often does not provide information about the functional signifi‐ cance of coronary stenosis, especially in borderline lesions. Andres Gruentzig said; *when cor‐ onary angiography founded coronary narrowing, I would like to have some kind of diagnostic procedure who gives me functional significance that lesion.* Nuclear cardiology imaging is very important diagnostic tool for the diagnosis culprit lesions, and indicating for cardiovascular intervention (PCI or ACBP). *The predominant theme* is that MPI finding can serve as the gate‐ keeper for more costly and more risky invasive strategies in the evaluation and treatment of patients with coronary artery disease.

This book includes a series of articles that provide a state-of-the-art summary of the current clinical applications of cardiac CT, reviews data that support the accuracy and the prognos‐ tic use of CT coronary angiography and reports of the newest technologic advances and promising future applications of these imaging modalities. Its also provide other diagnostic approach like functional test, which finding helps to make decision about invasive strategies with best benefit for patients. Finally, the next decades should see even greater advances in the field, and such breakthroughs will be instrumental in further enhancing the information that can be derived from functional testing for the assessment of myocardial blood flow, car‐ diac function, and myocardial viability.

Readers of *Coronary Angiography* will enjoy in this section and will find the information and expert opinions very useful to their clinical practice.

#### **Branislav G. Baskot MD PhD Ass Prof**

**Section 1**

**Something About Prevence of Coronary Heart**

**Disease**

Department of Nuclear Medicine Imaging "Dr Baskot"

**Something About Prevence of Coronary Heart Disease**

with best benefit for patients. Finally, the next decades should see even greater advances in the field, and such breakthroughs will be instrumental in further enhancing the information that can be derived from functional testing for the assessment of myocardial blood flow, car‐

Readers of *Coronary Angiography* will enjoy in this section and will find the information and

**Branislav G. Baskot MD PhD Ass Prof**

Department of Nuclear Medicine Imaging "Dr Baskot"

diac function, and myocardial viability.

X Preface

expert opinions very useful to their clinical practice.

**Chapter 1**

**Reduced Consumption**

**for Ischemic Heart Disease?**

Massimo Cocchi and Giovanni Lercker

lence of classical cardiovascular risk factors [2].

Additional information is available at the end of the chapter

Comparing the nutritional content of food to individual health status, there are several con‐ siderations that can be informative and raise troubling concerns. For many decades, re‐ searchers have investigated the relationships between health status and consumption of extra virgin olive oil. Extra virgin olive oil (and oleic acid) is considered important for the prevention and coronary heart disease. While the biomolecular aspects involving G protein need further research, oleic acid levels in platelets may be a discriminating factor, together with linoleic and arachidonic acid, for coronary heart disease. There is still a huge debate

Coronary Heart Disease (CHD) is the main cause of death and morbidity in industrialized countries. The incidence of myocardial infarction, however, is highly variable, with lower rates in Mediterranean countries compared to those in northern Europe, USA, or Australia [1]. Paradoxically, the low incidence of myocardial infarction occurs in spite of a high preva‐

Olive oil is the primary source of fat in the Mediterranean diet. The beneficial effects of olive oil on CHD have now been recognized, and are often attributed to the high levels of mono‐ unsaturated fatty acids (MUFA) [3]. Indeed, in November 2004, the US Federal Drug Ad‐ ministration (FDA) allowed a claim on olive oil labels concerning "the benefits on the risk of coronary heart disease of eating about two tablespoons (23 g) of olive oil daily, due to the

and reproduction in any medium, provided the original work is properly cited.

© 2013 Cocchi and Lercker; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

regarding the effects of oleic acid alone or in combination with antioxidants.

**of Olive Oil: A Risk**

http://dx.doi.org/10.5772/54035

**1. Introduction**

MUFA in olive oil" [4].

**Chapter 1**

## **Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?**

Massimo Cocchi and Giovanni Lercker

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54035

## **1. Introduction**

Comparing the nutritional content of food to individual health status, there are several con‐ siderations that can be informative and raise troubling concerns. For many decades, re‐ searchers have investigated the relationships between health status and consumption of extra virgin olive oil. Extra virgin olive oil (and oleic acid) is considered important for the prevention and coronary heart disease. While the biomolecular aspects involving G protein need further research, oleic acid levels in platelets may be a discriminating factor, together with linoleic and arachidonic acid, for coronary heart disease. There is still a huge debate regarding the effects of oleic acid alone or in combination with antioxidants.

Coronary Heart Disease (CHD) is the main cause of death and morbidity in industrialized countries. The incidence of myocardial infarction, however, is highly variable, with lower rates in Mediterranean countries compared to those in northern Europe, USA, or Australia [1]. Paradoxically, the low incidence of myocardial infarction occurs in spite of a high preva‐ lence of classical cardiovascular risk factors [2].

Olive oil is the primary source of fat in the Mediterranean diet. The beneficial effects of olive oil on CHD have now been recognized, and are often attributed to the high levels of mono‐ unsaturated fatty acids (MUFA) [3]. Indeed, in November 2004, the US Federal Drug Ad‐ ministration (FDA) allowed a claim on olive oil labels concerning "the benefits on the risk of coronary heart disease of eating about two tablespoons (23 g) of olive oil daily, due to the MUFA in olive oil" [4].

© 2013 Cocchi and Lercker; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **2. A crucial element for a healthy heart: oleic acid and platelets**

Oleic acid, and especially that obtained from pressing olives, is a crucial element in the pre‐ vention of ischemic cardiovascular disease, as has been demonstrated by a series of interna‐ tional scientific activity. Fatty acids other than n-3 Polyunsaturated Fatty Acids (PUFAs) can interact with the metabolism of eicosanoids and potentially influence platelet function. For example, there is evidence that diets rich in unsaturated fatty acids, such as linoleic acid and oleic acid, can also decrease thromboembolic risk by replacing arachidonic acid in platelet phospholipids, decreasing, at least in vitro, the production of thromboxane A2 [TXA2] and platelet aggregation. However, there is little conclusive evidence that platelet function in vivo is affected by diet [5].

Oleic acid has been found to be a potent inhibitor of platelet aggregating factor (PAF) and serotonin secretion. Consequently, in order to understand the molecular mechanisms of ole‐ ic acid action, the effects of this fatty acid on several biochemical events associated with pla‐ telet aggregation induced by PAF have been investigated. In particular, it has been found that oleic acid causes a decrease in the levels of phosphatidyl inositide phosphate (PIP) and PIP2, which is associated with an inhibition of platelet aggregation induced by PAF. These results suggest that inhibition of the PAF response by oleic acid may be at least one of the steps involved in signal transduction [6].

Several literature reports have further suggested that olive oil may inhibit platelet function. This possible effect is of interest for two reasons. First, it may contribute to the apparent an‐ ti-atherogenic effects of olive oil, and second, it may invalidate the use of olive oil as an inert placebo in studies of platelet function. After exposure to olive oil, platelet aggregation and TXA2 release decreased, and the content of platelet membrane oleic acid increased signifi‐ cantly; platelet membrane arachidonic acid content was found to significantly decrease. This suggests that excess of oleic acid impairs the incorporation of arachidonic acid into platelet phospholipids.

**Figure 1.** Description of selected biochemical and biomolecular events potentially involved in psychiatric disorders.

such a mechanism.

In figure 1, the molecular depression hypothesis described by Cocchi et al. [10], Donati et al. [11] and Hameroff and Penrose [12] is shown. Because of the possible similarity of the plate‐ let to neurons, membrane viscosity can modify Gsα protein status. The Gsα protein is asso‐ ciated with tubulin. Depending on local membrane lipid composition, tubulin may serve as a positive or negative regulator of phosphatidylinositol bisphosphate hydrolysis (PIP2) simi‐ lar to G proteins. Tubulin is known to form high-affinity complexes with certain G proteins. The formation of these complexes allows tubulin to activate Gsα protein and creates a sys‐ tem whereby elements of the cytoskeleton can influence G-protein signaling. Rapid changes in membrane lipid composition or the cytoskeleton can modify neuronal signaling through

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?

http://dx.doi.org/10.5772/54035

5

Protein kinase C (PKC) activation (Figure 2) is preceded by a number of steps, originating from the binding of an extracellular ligand that activates a G-protein on the cytosolic side of the plasma membrane. This G-protein, using guanosine triphosphate (GTP) as an energy source, then activates protein kinase C (PKC) via the phosphatidylinositol bisphosphate (PIP2) intermediate, which is shown as the diacylglycerol DAG/IP3 complex. Several studies have shown that a reduced functionality of the serotonin (5-HT) transporter in some psychi‐ atric disorders, such as obsessive-compulsive disorder (OCD), may be related to alterations

Olive oil also has an inhibitory effect on various aspects of platelet function, which might be associated with decreased risk for heart disease, although fish intake also plays a protective role [7].

The beneficial effects of olive oil can be attributed to its high content of oleic acid (70-80%). The consumption of olive oil increases the levels of oleic acid in cell membranes, which helps to regulate the structure of membrane lipids through the control of signal-mediated Gprotein, causing a reduction in blood pressure [8].

In rats, cardiovascular tissues treated with 2-OHOA (hydroxy oleic acid) show activation of cAMP in response to activation of Gsα protein, which can be attributed to increased expres‐ sion of Gsα proteins. As a result, there is significant reduction in systolic blood pressure [9]. The involvement of Gs alpha protein is also of interest considering the hypothesis forward‐ ed by Cocchi, Tonello, Rasenick and Hameroff in psychiatric disorders as depression, sui‐ cide etc. (private meeting, 2008). In light of the below model, the role of Gsα protein in ischemic heart disease merits further investigation.

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease? http://dx.doi.org/10.5772/54035 5

**2. A crucial element for a healthy heart: oleic acid and platelets**

4 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

vivo is affected by diet [5].

phospholipids.

role [7].

steps involved in signal transduction [6].

protein, causing a reduction in blood pressure [8].

ischemic heart disease merits further investigation.

Oleic acid, and especially that obtained from pressing olives, is a crucial element in the pre‐ vention of ischemic cardiovascular disease, as has been demonstrated by a series of interna‐ tional scientific activity. Fatty acids other than n-3 Polyunsaturated Fatty Acids (PUFAs) can interact with the metabolism of eicosanoids and potentially influence platelet function. For example, there is evidence that diets rich in unsaturated fatty acids, such as linoleic acid and oleic acid, can also decrease thromboembolic risk by replacing arachidonic acid in platelet phospholipids, decreasing, at least in vitro, the production of thromboxane A2 [TXA2] and platelet aggregation. However, there is little conclusive evidence that platelet function in

Oleic acid has been found to be a potent inhibitor of platelet aggregating factor (PAF) and serotonin secretion. Consequently, in order to understand the molecular mechanisms of ole‐ ic acid action, the effects of this fatty acid on several biochemical events associated with pla‐ telet aggregation induced by PAF have been investigated. In particular, it has been found that oleic acid causes a decrease in the levels of phosphatidyl inositide phosphate (PIP) and PIP2, which is associated with an inhibition of platelet aggregation induced by PAF. These results suggest that inhibition of the PAF response by oleic acid may be at least one of the

Several literature reports have further suggested that olive oil may inhibit platelet function. This possible effect is of interest for two reasons. First, it may contribute to the apparent an‐ ti-atherogenic effects of olive oil, and second, it may invalidate the use of olive oil as an inert placebo in studies of platelet function. After exposure to olive oil, platelet aggregation and TXA2 release decreased, and the content of platelet membrane oleic acid increased signifi‐ cantly; platelet membrane arachidonic acid content was found to significantly decrease. This suggests that excess of oleic acid impairs the incorporation of arachidonic acid into platelet

Olive oil also has an inhibitory effect on various aspects of platelet function, which might be associated with decreased risk for heart disease, although fish intake also plays a protective

The beneficial effects of olive oil can be attributed to its high content of oleic acid (70-80%). The consumption of olive oil increases the levels of oleic acid in cell membranes, which helps to regulate the structure of membrane lipids through the control of signal-mediated G-

In rats, cardiovascular tissues treated with 2-OHOA (hydroxy oleic acid) show activation of cAMP in response to activation of Gsα protein, which can be attributed to increased expres‐ sion of Gsα proteins. As a result, there is significant reduction in systolic blood pressure [9]. The involvement of Gs alpha protein is also of interest considering the hypothesis forward‐ ed by Cocchi, Tonello, Rasenick and Hameroff in psychiatric disorders as depression, sui‐ cide etc. (private meeting, 2008). In light of the below model, the role of Gsα protein in

**Figure 1.** Description of selected biochemical and biomolecular events potentially involved in psychiatric disorders.

In figure 1, the molecular depression hypothesis described by Cocchi et al. [10], Donati et al. [11] and Hameroff and Penrose [12] is shown. Because of the possible similarity of the plate‐ let to neurons, membrane viscosity can modify Gsα protein status. The Gsα protein is asso‐ ciated with tubulin. Depending on local membrane lipid composition, tubulin may serve as a positive or negative regulator of phosphatidylinositol bisphosphate hydrolysis (PIP2) simi‐ lar to G proteins. Tubulin is known to form high-affinity complexes with certain G proteins. The formation of these complexes allows tubulin to activate Gsα protein and creates a sys‐ tem whereby elements of the cytoskeleton can influence G-protein signaling. Rapid changes in membrane lipid composition or the cytoskeleton can modify neuronal signaling through such a mechanism.

Protein kinase C (PKC) activation (Figure 2) is preceded by a number of steps, originating from the binding of an extracellular ligand that activates a G-protein on the cytosolic side of the plasma membrane. This G-protein, using guanosine triphosphate (GTP) as an energy source, then activates protein kinase C (PKC) via the phosphatidylinositol bisphosphate (PIP2) intermediate, which is shown as the diacylglycerol DAG/IP3 complex. Several studies have shown that a reduced functionality of the serotonin (5-HT) transporter in some psychi‐ atric disorders, such as obsessive-compulsive disorder (OCD), may be related to alterations in its regulation at an intracellular level. PKC has also been reported to provoke a decrease in the number of 5-HT transporter proteins. The increased activity of PKC in OCD may be the result of increased activity of the phosphatidylinositol pathway.

Monocytes and macrophages are critical cells present in all stages of atherosclerosis. In addi‐ tion to promoting LDL oxidation through free radical production, they also secrete proin‐ flammatory cytokines such as IL-1 and Tumor Necrosis Factor (TNF), which stimulate the expression of adhesion molecules such as intercellular cell adhesion molecule-1 (ICAM-1), vascular-cell adhesion molecule-1 (VCAM-1), and E-selectin [25]. Circulating monocytes are attracted by these molecules and adhere to the endothelium, from which they transmigrate to the subendothelial space. Once within the endothelium, monocytes differentiate into mac‐ rophages, which in turn scavenge oxidized LDL, thus becoming foam cells and lead to pla‐

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?

http://dx.doi.org/10.5772/54035

7

The proinflammatory response releases a principal messenger from macrophages, namely cytokine IL6. After engagement of its receptor on the liver, IL6 promotes the secretion of C Reactive Protein (CRP), a prototypic marker of inflammation [28, 29]. Serum IL6 and CRP have been shown to be predictive of CHD. Altered levels of serum CRP, IL6, and ICAM-1 have been associated with progression of atherosclerosis, and IL6 has been shown to be a

The inflammatory protection of diets rich in oleic acid has been attributed to a decrease in the content of LDL linoleic acid [32]. The low susceptibility of oleic acid to oxidation, and the scavenging capacity of minor compounds in olive oil, can decrease the activation of proinflammatory transcription factors, such as nuclear factor-kappa B (NFkB), through a reduc‐ tion of reactive oxygen spices and peroxyl radicals [33]. In this regard, it has been reported that consumption of meals enriched in olive oil do not activate NFkB in monocytes in con‐ trast to meals rich in butter and walnut-enriched meals [34]. Studies on oleic acid enriched liposomes and vascular endothelium exposed to oleic acid, however, suggest a protective mechanism of oleic acid on free radical generation, oxidative damage to lipids, and inflam‐

Recent data suggest that oleic acid is not the only agent responsible for the anti-inflammato‐ ry properties of olive oil. In experimental studies, minor components of the unsaponifiable fraction of olive oil, such as alfa-tocopherol, beta-sitosterol, and triterpenes, in addition to phenolic compounds, have all been shown to have both anti-inflammatory and anti-endo‐ thelial activation properties [37]. The results of a meta-analysis of 14 studies carried out dur‐ ing 1983–1994 showed that the replacement of SFA by oils enriched in MUFA or PUFA had similar effects on total, LDL, and HDL cholesterol, whereas PUFA-enriched oil had a slight triglyceride-lowering effect [38]. Dubois et al. [39] showed that increasing the amount of fat up to 50 g led to stepwise increases in the postprandial rise of serum triglycerides, while the ingestion of 15 g fat had no effect on postprandial lipemia or lipoproteins in healthy adults. A meal containing 31 g of fat induced considerably less variations in lipemia, chylomicrons, and lipoproteins than a 42 g fat meal [39]. A single dose of 25 mL olive oil was not found to promote postprandial lipemia [40], in contrast to 40 mL and 50 mL doses [41, 42] with no

Abia et al. [43] reported that virgin olive oil intake resulted in lower postprandial triacylgly‐ ceride-rich-lipoprotein (TRL) levels and a faster disappearance of TRL-TG from blood, com‐ pared to intake of sunflower oil with a high content of oleic acid. Chylomicrons produced

good predictor of progressive peripheral atherosclerosis [30, 31].

que formation.

matory activity [35, 36].

effect on the phenolic content of the olive oil.

**Figure 2.** Description of PKC activation. Adapted from Alberts et al. [13].

The exclusive use of olive oil during food preparation seems to offer significant protection against ischemic heart disease, in spite of poor clinical conditions, lifestyle and other charac‐ teristics of individuals [14]. In addition, several historical papers have reported on the posi‐ tive effects of olive oil on CHD.

In 1985, Mattson and Grundy [15] reported that olive oil reduces HDL cholesterol, which plays a protective, anti-atherogenic function, favoring the elimination of LDL-cholesterol. In 1986, Sirtori et al. [16] have shown that in addition to its effects on cholesterol and athero‐ sclerosis, olive oil has preventive action on thrombosis and platelet aggregation. High intake of olive oil is not harmful, and reduces the levels of LDL-cholesterol, but not HDL [17 - 25].

## **3. Oleic acid and Atherogenesis**

Atherosclerosis is considered to be an inflammatory disease [26], and endothelial dysfunc‐ tion occurs early in the development of the pathology. Traditional risk factors for atheroscle‐ rosis promote endothelium activation, which induces adhesion and trans-endothelial migration of monocytes [26]. Several inflammatory mediators are released by the endotheli‐ um such as the eicosanoids derived from n-6 PUFA arachidonic acid. These include prosta‐ glandin E2 (PGE2), leukotriene B4, a chemoattractant and neutrophile activator, thromboxane, a potent vasoconstrictor, and platelet-aggregating factor [27].

Monocytes and macrophages are critical cells present in all stages of atherosclerosis. In addi‐ tion to promoting LDL oxidation through free radical production, they also secrete proin‐ flammatory cytokines such as IL-1 and Tumor Necrosis Factor (TNF), which stimulate the expression of adhesion molecules such as intercellular cell adhesion molecule-1 (ICAM-1), vascular-cell adhesion molecule-1 (VCAM-1), and E-selectin [25]. Circulating monocytes are attracted by these molecules and adhere to the endothelium, from which they transmigrate to the subendothelial space. Once within the endothelium, monocytes differentiate into mac‐ rophages, which in turn scavenge oxidized LDL, thus becoming foam cells and lead to pla‐ que formation.

in its regulation at an intracellular level. PKC has also been reported to provoke a decrease in the number of 5-HT transporter proteins. The increased activity of PKC in OCD may be

6 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The exclusive use of olive oil during food preparation seems to offer significant protection against ischemic heart disease, in spite of poor clinical conditions, lifestyle and other charac‐ teristics of individuals [14]. In addition, several historical papers have reported on the posi‐

In 1985, Mattson and Grundy [15] reported that olive oil reduces HDL cholesterol, which plays a protective, anti-atherogenic function, favoring the elimination of LDL-cholesterol. In 1986, Sirtori et al. [16] have shown that in addition to its effects on cholesterol and athero‐ sclerosis, olive oil has preventive action on thrombosis and platelet aggregation. High intake of olive oil is not harmful, and reduces the levels of LDL-cholesterol, but not HDL [17 - 25].

Atherosclerosis is considered to be an inflammatory disease [26], and endothelial dysfunc‐ tion occurs early in the development of the pathology. Traditional risk factors for atheroscle‐ rosis promote endothelium activation, which induces adhesion and trans-endothelial migration of monocytes [26]. Several inflammatory mediators are released by the endotheli‐ um such as the eicosanoids derived from n-6 PUFA arachidonic acid. These include prosta‐ glandin E2 (PGE2), leukotriene B4, a chemoattractant and neutrophile activator,

thromboxane, a potent vasoconstrictor, and platelet-aggregating factor [27].

the result of increased activity of the phosphatidylinositol pathway.

**Figure 2.** Description of PKC activation. Adapted from Alberts et al. [13].

tive effects of olive oil on CHD.

**3. Oleic acid and Atherogenesis**

The proinflammatory response releases a principal messenger from macrophages, namely cytokine IL6. After engagement of its receptor on the liver, IL6 promotes the secretion of C Reactive Protein (CRP), a prototypic marker of inflammation [28, 29]. Serum IL6 and CRP have been shown to be predictive of CHD. Altered levels of serum CRP, IL6, and ICAM-1 have been associated with progression of atherosclerosis, and IL6 has been shown to be a good predictor of progressive peripheral atherosclerosis [30, 31].

The inflammatory protection of diets rich in oleic acid has been attributed to a decrease in the content of LDL linoleic acid [32]. The low susceptibility of oleic acid to oxidation, and the scavenging capacity of minor compounds in olive oil, can decrease the activation of proinflammatory transcription factors, such as nuclear factor-kappa B (NFkB), through a reduc‐ tion of reactive oxygen spices and peroxyl radicals [33]. In this regard, it has been reported that consumption of meals enriched in olive oil do not activate NFkB in monocytes in con‐ trast to meals rich in butter and walnut-enriched meals [34]. Studies on oleic acid enriched liposomes and vascular endothelium exposed to oleic acid, however, suggest a protective mechanism of oleic acid on free radical generation, oxidative damage to lipids, and inflam‐ matory activity [35, 36].

Recent data suggest that oleic acid is not the only agent responsible for the anti-inflammato‐ ry properties of olive oil. In experimental studies, minor components of the unsaponifiable fraction of olive oil, such as alfa-tocopherol, beta-sitosterol, and triterpenes, in addition to phenolic compounds, have all been shown to have both anti-inflammatory and anti-endo‐ thelial activation properties [37]. The results of a meta-analysis of 14 studies carried out dur‐ ing 1983–1994 showed that the replacement of SFA by oils enriched in MUFA or PUFA had similar effects on total, LDL, and HDL cholesterol, whereas PUFA-enriched oil had a slight triglyceride-lowering effect [38]. Dubois et al. [39] showed that increasing the amount of fat up to 50 g led to stepwise increases in the postprandial rise of serum triglycerides, while the ingestion of 15 g fat had no effect on postprandial lipemia or lipoproteins in healthy adults. A meal containing 31 g of fat induced considerably less variations in lipemia, chylomicrons, and lipoproteins than a 42 g fat meal [39]. A single dose of 25 mL olive oil was not found to promote postprandial lipemia [40], in contrast to 40 mL and 50 mL doses [41, 42] with no effect on the phenolic content of the olive oil.

Abia et al. [43] reported that virgin olive oil intake resulted in lower postprandial triacylgly‐ ceride-rich-lipoprotein (TRL) levels and a faster disappearance of TRL-TG from blood, com‐ pared to intake of sunflower oil with a high content of oleic acid. Chylomicrons produced after olive oil [44, 45] or n-3 PUFA [46] ingestion seem to enter the circulation more rapidly, and cleared at a faster rate, in comparison to those produced after intake of fats rich in SFA or PUFA. Although fat intake appears to be the major nutritional determinant of the post‐ prandrial triglyceride response, it is also influenced by other dietary components, including fiber, glucose, starch, and alcohol in a meal [47].

tack), was submitted to a classic complete functional cardiovascular investigation which re‐ sulted negative. The subject is a heavy smoker, cholesterol: 230 mg/dl, HDL: 84 mg/dl. Framingham score: 13 (low risk score). Platelet levels of oleic acid, linoleic acid and arachi‐ donic acid were analyzed using the SOM designed for ischemic patients, and the concentra‐ tions of those fatty acids were entered in the SOM. The subject detailed information on the study and provided informed consent. The patient's fatty acid triplet, tested in the SOM,

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?

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**Figure 3.** SOM classification of depressive subjects (red) against normal subjects (green). Platelet arachidonic acid

**Figure 4.** SOM classification of ischemic subjects (red) against normal subjects (green). Platelet oleic acid (C18:1), arachi‐

donic acid (C20:4), linoleic acid (C18:2) can discriminate ischemia and have diagnostic power.

(C20:4), palmitic acid (C16:0), and linoleic acid (C18:2) can discriminate depression and have diagnostic power.

gave the following result (Figure 5).

The oxidative modification of LDL plays a key role in development of atherosclerosis and CHD. Oxidation of lipids and lipoproteins present in LDL leads to a change in the lipoprotein conformation by which LDL are more facilitated to enter the monocyte/macrophage system of the arterial wall, and promote the atherosclerotic process [48]. It is currently believed that oxi‐ dized LDL are more damaging to the arterial wall than native LDL [49]. Elevated concentra‐ tions of circulating oxidized LDL show a positive relationship with the severity of acute coronary events [50, 51]. They are also independently associated with carotid intima-media thickness [52] and are predictors for CHD both in CHD patients [53] and the general popula‐ tion [54]. Several studies have been performed comparing the effects of MUFA-rich diets on the susceptibility of LDL to oxidation with those of PUFA- or carbohydrate-rich diets. Oleaterich LDL have been shown to be less susceptible to oxidation than linoleate rich LDL [55-61].

## **4. Depression and Ischemic Heart Disease: a common role for oleic acid?**

Because of the particular role of platelets on depressive and thrombogenetic risk, our group has investigated the platelet fatty acid profile in three groups of subjects: healthy (n=60), is‐ chemic (n= 50) and depressive (n= 84). The aim of the study was to understand which fatty acid could be utilized as markers of ischemic cardiovascular pathology and depressive dis‐ order, and to classify subjects using an artificial neural network (ANN). All the ANNs tested gave essentially the same result. However, one type of ANN, known as Self-Organizing Map (SOM), [62, 63, 64], gave additional information by allowing the results to be described in a two-dimensional plane with potentially informative border areas. The central property of the SOM is that it forms a nonlinear projection of a high-dimensional data manifold on a regular, low-dimensional (usually 2D) grid.

A series of repeated and independent SOM simulations, with the input parameters being changed each time, led to the finding that the best discriminating map was that obtained by inclusion of the following three fatty acids: palmitic acid (C16:0), linoleic acid (C18:2 *n*-6) and arachidonic acid (C20:4 *n*-6) for depressive subjects and oleic acid (C18:1), linoleic acid and arachidonic acid for ischemic subjects [10, 65-67] (Figures 3, 4).

### **5. A case study**

A 42-year-old female with a very high familial risk for ischemic cardiovascular disease (one sister 34 years old died of heart attack; another sister, 48 years old, heart attack; uncle, two infarctions; mother, 69 years old, died of heart attack; aunt, 59 years old, died of heart at‐ tack), was submitted to a classic complete functional cardiovascular investigation which re‐ sulted negative. The subject is a heavy smoker, cholesterol: 230 mg/dl, HDL: 84 mg/dl. Framingham score: 13 (low risk score). Platelet levels of oleic acid, linoleic acid and arachi‐ donic acid were analyzed using the SOM designed for ischemic patients, and the concentra‐ tions of those fatty acids were entered in the SOM. The subject detailed information on the study and provided informed consent. The patient's fatty acid triplet, tested in the SOM, gave the following result (Figure 5).

after olive oil [44, 45] or n-3 PUFA [46] ingestion seem to enter the circulation more rapidly, and cleared at a faster rate, in comparison to those produced after intake of fats rich in SFA or PUFA. Although fat intake appears to be the major nutritional determinant of the post‐ prandrial triglyceride response, it is also influenced by other dietary components, including

8 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The oxidative modification of LDL plays a key role in development of atherosclerosis and CHD. Oxidation of lipids and lipoproteins present in LDL leads to a change in the lipoprotein conformation by which LDL are more facilitated to enter the monocyte/macrophage system of the arterial wall, and promote the atherosclerotic process [48]. It is currently believed that oxi‐ dized LDL are more damaging to the arterial wall than native LDL [49]. Elevated concentra‐ tions of circulating oxidized LDL show a positive relationship with the severity of acute coronary events [50, 51]. They are also independently associated with carotid intima-media thickness [52] and are predictors for CHD both in CHD patients [53] and the general popula‐ tion [54]. Several studies have been performed comparing the effects of MUFA-rich diets on the susceptibility of LDL to oxidation with those of PUFA- or carbohydrate-rich diets. Oleaterich LDL have been shown to be less susceptible to oxidation than linoleate rich LDL [55-61].

**4. Depression and Ischemic Heart Disease: a common role for oleic acid?**

Because of the particular role of platelets on depressive and thrombogenetic risk, our group has investigated the platelet fatty acid profile in three groups of subjects: healthy (n=60), is‐ chemic (n= 50) and depressive (n= 84). The aim of the study was to understand which fatty acid could be utilized as markers of ischemic cardiovascular pathology and depressive dis‐ order, and to classify subjects using an artificial neural network (ANN). All the ANNs tested gave essentially the same result. However, one type of ANN, known as Self-Organizing Map (SOM), [62, 63, 64], gave additional information by allowing the results to be described in a two-dimensional plane with potentially informative border areas. The central property of the SOM is that it forms a nonlinear projection of a high-dimensional data manifold on a

A series of repeated and independent SOM simulations, with the input parameters being changed each time, led to the finding that the best discriminating map was that obtained by inclusion of the following three fatty acids: palmitic acid (C16:0), linoleic acid (C18:2 *n*-6) and arachidonic acid (C20:4 *n*-6) for depressive subjects and oleic acid (C18:1), linoleic acid

A 42-year-old female with a very high familial risk for ischemic cardiovascular disease (one sister 34 years old died of heart attack; another sister, 48 years old, heart attack; uncle, two infarctions; mother, 69 years old, died of heart attack; aunt, 59 years old, died of heart at‐

fiber, glucose, starch, and alcohol in a meal [47].

regular, low-dimensional (usually 2D) grid.

**5. A case study**

and arachidonic acid for ischemic subjects [10, 65-67] (Figures 3, 4).

**Figure 3.** SOM classification of depressive subjects (red) against normal subjects (green). Platelet arachidonic acid (C20:4), palmitic acid (C16:0), and linoleic acid (C18:2) can discriminate depression and have diagnostic power.

**Figure 4.** SOM classification of ischemic subjects (red) against normal subjects (green). Platelet oleic acid (C18:1), arachi‐ donic acid (C20:4), linoleic acid (C18:2) can discriminate ischemia and have diagnostic power.

acteristics of the triplets previously highlighted, which were all different from one another

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**Figure 6.** Simultaneous classification, using the SOM, of three groups of subjects (normal, depressive and ischemic). In the right corner of the map, ischemic and depressive subjects are mixed and have, in common, a low level of platelet

As shown by the SOM, it is possible that reduced amounts of oleic acid not only are critical in the biochemical classification of ischemic heart disease, but are also common to a condi‐ tion that characterizes a relationship between depression and ischemia [69]. It seems possi‐ ble that levels of C18:1 in platelets dominate in ischemia, and are linked to depression. Furthermore, it can be conjectured that there are two different types of depression, namely classical and ischemia-induced according to the findings of different platelet membrane vis‐ cosity and its effect at the biomolecular level. [10-12, 70]. The relationships between depres‐ sion and ischemic heart disease have been widely studied [71, 72]. Interestingly, Weyers and Colquhoun [73] reported improvements in depressive symptoms in patients with CHD after

The question then arises as to whether there is sufficient consumption of olive oil and oleic acid in the Italian population. Knowing that oleic acid can significantly change the composition of platelet fatty acids, which are crucial in the genesis of plaque formation, and can significantly alter the amount of oleic acid in platelet membranes, an experiment on a large group of pigs (80 Duroc x Large White) was performed [74]. Four groups of pigs were studied, 20 animals each,

Diet 1: corn oil (low linoleic acid.), diet 2: corn oil (medium linoleic acid.), diet 3: sunflower oil (high oleic acid.), diet 4: sunflower oil (high oleic acid) + palm oil (high palmitic acid). The di‐ ets fed to animals, to meet the needs for growth, had the following lipid composition (Table 1):

[68] (Figure 6).

oleic acid.

consumption of olive oil.

**7. Do we eat enough extra virgin olive oil?**

which received four diets containing different lipid fractions, as follows:

**Figure 5.** Position of the patient according to the three fatty acids (oleic, linoleic and arachidonic) on the SOM, which classifies ischemic patients.

This result was compared with the SOM classification of normal and pathologic subjects, as shown in figure 4. The patient was asked to submit herself to a Coronary TAC and the im‐ ages showed "Interventricular Anterior (IVA) branch: small mixed plaque in the proximal tract, 33% of the lumen" (radiological diagnosis). The result suggests the opportunity to se‐ lect young high risk subjects to evaluate not only the diagnostic power of the SOM, but also the possibility for early diagnosis of plaque formation. A large trial is necessary to validate this result, but based on the classical rules of Evidence Based Medicine, it is very difficult to obtain approval from an ethic's committee.

Medical science has not yet fully understood or accepted the use of the ANN mathematic models in relation to experimental conditions, which are still strongly linked to traditional protocols. The task of finding biomarkers according to the rules dictated by Evidence Based Medicine requires the elimination of selection bias, and leads to selection of a population that may be clinically unrealistic. The characteristics of the above-described method none‐ theless allow the analysis to be carried out, and permit to find differences among subsets of the population.

The first fundamental consequence of the use of fatty acids is that an extremely effective and practical diagnostic tool can be obtained, with a strong tolerance to "noise". Secondly, the choice of specific fatty acids and their relative strength in the classification by the SOM al‐ lows investigating more in-depth investigation of the problem and helps in understanding the disease from the biochemical point of view.

## **6. Commonalities between CHD and depression**

To demonstrate the powerful grouping capacity of the SOM, we created a new network where all three groups were inserted and grouped simultaneously on the basis of the char‐ acteristics of the triplets previously highlighted, which were all different from one another [68] (Figure 6).

**Figure 6.** Simultaneous classification, using the SOM, of three groups of subjects (normal, depressive and ischemic). In the right corner of the map, ischemic and depressive subjects are mixed and have, in common, a low level of platelet oleic acid.

As shown by the SOM, it is possible that reduced amounts of oleic acid not only are critical in the biochemical classification of ischemic heart disease, but are also common to a condi‐ tion that characterizes a relationship between depression and ischemia [69]. It seems possi‐ ble that levels of C18:1 in platelets dominate in ischemia, and are linked to depression. Furthermore, it can be conjectured that there are two different types of depression, namely classical and ischemia-induced according to the findings of different platelet membrane vis‐ cosity and its effect at the biomolecular level. [10-12, 70]. The relationships between depres‐ sion and ischemic heart disease have been widely studied [71, 72]. Interestingly, Weyers and Colquhoun [73] reported improvements in depressive symptoms in patients with CHD after consumption of olive oil.

## **7. Do we eat enough extra virgin olive oil?**

**Figure 5.** Position of the patient according to the three fatty acids (oleic, linoleic and arachidonic) on the SOM, which

10 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

This result was compared with the SOM classification of normal and pathologic subjects, as shown in figure 4. The patient was asked to submit herself to a Coronary TAC and the im‐ ages showed "Interventricular Anterior (IVA) branch: small mixed plaque in the proximal tract, 33% of the lumen" (radiological diagnosis). The result suggests the opportunity to se‐ lect young high risk subjects to evaluate not only the diagnostic power of the SOM, but also the possibility for early diagnosis of plaque formation. A large trial is necessary to validate this result, but based on the classical rules of Evidence Based Medicine, it is very difficult to

Medical science has not yet fully understood or accepted the use of the ANN mathematic models in relation to experimental conditions, which are still strongly linked to traditional protocols. The task of finding biomarkers according to the rules dictated by Evidence Based Medicine requires the elimination of selection bias, and leads to selection of a population that may be clinically unrealistic. The characteristics of the above-described method none‐ theless allow the analysis to be carried out, and permit to find differences among subsets of

The first fundamental consequence of the use of fatty acids is that an extremely effective and practical diagnostic tool can be obtained, with a strong tolerance to "noise". Secondly, the choice of specific fatty acids and their relative strength in the classification by the SOM al‐ lows investigating more in-depth investigation of the problem and helps in understanding

To demonstrate the powerful grouping capacity of the SOM, we created a new network where all three groups were inserted and grouped simultaneously on the basis of the char‐

classifies ischemic patients.

the population.

obtain approval from an ethic's committee.

the disease from the biochemical point of view.

**6. Commonalities between CHD and depression**

The question then arises as to whether there is sufficient consumption of olive oil and oleic acid in the Italian population. Knowing that oleic acid can significantly change the composition of platelet fatty acids, which are crucial in the genesis of plaque formation, and can significantly alter the amount of oleic acid in platelet membranes, an experiment on a large group of pigs (80 Duroc x Large White) was performed [74]. Four groups of pigs were studied, 20 animals each, which received four diets containing different lipid fractions, as follows:

Diet 1: corn oil (low linoleic acid.), diet 2: corn oil (medium linoleic acid.), diet 3: sunflower oil (high oleic acid.), diet 4: sunflower oil (high oleic acid) + palm oil (high palmitic acid). The di‐ ets fed to animals, to meet the needs for growth, had the following lipid composition (Table 1):


**Figure 7.** By increasing the oleic acid content in diets is possible to move pig platelets, in agreement with the fatty

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?

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It is feasible to obtain similar results in humans. If one considers the characteristics descri‐ bed for the pig model of atherosclerosis [75], and applying similar characteristics to humans, it can be assumed that we should consume a quantity of oleic acid, and consequently, extra virgin olive oil, that is at least twice that of current levels. To demonstrate this, we made simple considerations based on the purchase of olive oil in Italy (Data provided by the Isti‐

Based on data provided and taking into account that the value derived from the table should be increased by 40%, since about 40% of purchase data were excluded, the consump‐ tion of extra virgin olive oil for each Italian is on average, about 11.76 grams of oleic acid daily, considering that olive oil is on average value about 70% oleic acid. This value is even likely to be less, as much oil is also used for frying, and therefore cannot be included as part of raw consumption. While this quantity is very small, there are also regional differences be‐

This observation is also related to the observation that current eating behavior does not al‐ low large consumption of olive oil. It should be remembered that meals eaten out of the household, often consisting of a sandwich, make it difficult to consume extra virgin olive oil in larger quantities. While the eating habits of rural areas may still be able to compensate this situation, there is an increasing trend to gradually move away from such traditions.

Recently, we investigated the consumption of olive oil in a restaurant in the Center-North of Italy, (2750 subjects in one month). The average consumption of olive oil was 1.8 g per cus‐ tomer per month, which corresponds to about 1.26 g of oleic acid. Together with the above cited data, this results confirms that olive oil is not consumed in large quantities. Given this, as Ancel Keys pointed out, one wonders if the Mediterranean diet is still a model of health,

acid triplet [66, 67], from the pathologic (red area) to the normal (green area) area.

tuto di Servizi per il Mercato Agricolo Alimentare (ISMEA).

considering the consumption of extra virgin olive oil.

tween the north and south of Italy.

**Table 1.** Ether extract (% dry Matter) and fatty acid composition of lipid fractions


**Table 2.** Mean values ± SD of platelet fatty acids in the different treatment groups

The platelet fatty acids (Table 2) were plotted as for ischemic and normal human subjects in the SOM for ischemia (Figure 7).

**Period (kg) Diet EE C16:0 C18:0 C18:1n9 C18:2n6 C18:3n3**

12 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

50 - 90 1 2.70 13.13 2.05 31.07 50.90 2.59 50 - 90 2 2.86 14.37 2.04 26.40 54.54 2.42 50 - 90 3 5.30 8.91 2.39 56.47 30.23 1.27 50 - 90 4 5.37 18.67 8.36 39.99 30.86 1.40 90 - 120 1 2.63 12.83 1.72 31.60 51.15 2.38 90 - 120 2 2.57 14.16 1.94 25.76 54.96 2.55 90 - 120 3 5.56 8.81 2.44 57.12 29.73 1.26 90 - 120 4 5.62 20.02 9.26 39.41 29.59 1.12 120 - 160 1 2.83 13.32 1.69 30.46 52.00 2.41 120 - 160 2 2.89 13.75 1.88 25.65 56.29 2.35 120 - 160 3 5.74 8.54 2.10 57.18 30.91 1.07 120 - 160 4 5.76 19.71 9.25 39.16 30.25 1.17

**Fatty Acids C16:0 C18:0 C18:1n9 C18:2n6 C18:3n3 C20:4**

28.51a 32.00 17.38 B 9.30 0.63a 12.19 AB

1.84 10.70 5.63 3.40 0.36 5.18

27.73 ab 29.01 18.0 B 9.07 0.48ab 15.6 A

1.47 8.48 3.17 2.88 0.29 4.52

27.00ab 27.78 24.93 A 9.37 0.34b 10.59B

2.07 8.12 6.78 3.10 0.25 4.48

26.51b 32.04 19.36 B 9.32 0.51ab 12.25AB

2.63 11.07 5.43 3.64 0.32 4.27

P <0.05 n.s. <0.01 n.s. <0.05 <0.01

The platelet fatty acids (Table 2) were plotted as for ischemic and normal human subjects in

**Table 1.** Ether extract (% dry Matter) and fatty acid composition of lipid fractions

**Table 2.** Mean values ± SD of platelet fatty acids in the different treatment groups

Diet 1 Media s.d.

Diet 2 Media s.d.

Diet 3 Media s.d.

Diet 4 Media s.d.

the SOM for ischemia (Figure 7).

**Figure 7.** By increasing the oleic acid content in diets is possible to move pig platelets, in agreement with the fatty acid triplet [66, 67], from the pathologic (red area) to the normal (green area) area.

It is feasible to obtain similar results in humans. If one considers the characteristics descri‐ bed for the pig model of atherosclerosis [75], and applying similar characteristics to humans, it can be assumed that we should consume a quantity of oleic acid, and consequently, extra virgin olive oil, that is at least twice that of current levels. To demonstrate this, we made simple considerations based on the purchase of olive oil in Italy (Data provided by the Isti‐ tuto di Servizi per il Mercato Agricolo Alimentare (ISMEA).

Based on data provided and taking into account that the value derived from the table should be increased by 40%, since about 40% of purchase data were excluded, the consump‐ tion of extra virgin olive oil for each Italian is on average, about 11.76 grams of oleic acid daily, considering that olive oil is on average value about 70% oleic acid. This value is even likely to be less, as much oil is also used for frying, and therefore cannot be included as part of raw consumption. While this quantity is very small, there are also regional differences be‐ tween the north and south of Italy.

This observation is also related to the observation that current eating behavior does not al‐ low large consumption of olive oil. It should be remembered that meals eaten out of the household, often consisting of a sandwich, make it difficult to consume extra virgin olive oil in larger quantities. While the eating habits of rural areas may still be able to compensate this situation, there is an increasing trend to gradually move away from such traditions.

Recently, we investigated the consumption of olive oil in a restaurant in the Center-North of Italy, (2750 subjects in one month). The average consumption of olive oil was 1.8 g per cus‐ tomer per month, which corresponds to about 1.26 g of oleic acid. Together with the above cited data, this results confirms that olive oil is not consumed in large quantities. Given this, as Ancel Keys pointed out, one wonders if the Mediterranean diet is still a model of health, considering the consumption of extra virgin olive oil.

**8. Chemical and technological considerations about oleic acid**

melting point (see Table 3), with very few exceptions.

**Table 4.** Fatty acid solubility in water at 20°C (in grams per liter)

less functionality (permeability).

Fatty acids have different functions in living organisms, including the structural one, which are determined by the length of their hydrocarbon chain and the presence or absence of double bonds. Hydrocarbon chain length, in the same conditions of unsaturation, is directly proportional to the melting point (as well as the boiling point) (Table 3). The solubility in water (Table 4) and unsaturation, for the same chain length, is inversely proportional to the

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?

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**Carbon number Solubility 2** Infinite **4** Infinite **6** 9.7 **8** 0.7 **10** 0.15 **12** 0.055 **14** 0.02 **16** 0.007 **18** 0.003

These chemical differences are determined in large part by chemical and physical interac‐ tions that exist when molecules are close enough to unsaturate them. In the case of fatty acids, the possibility to join molecules depends only on the hydrocarbon chain (Van der Waals forces), which is facilitated when it is saturated and more difficult when unsaturated (especially at the point of unsaturation). The longer and more linear the chain, the greater the interaction, and the more unsaturated it will be, consequently, the interaction will be lower. When fatty acids are part of a triglyceride or phospholipid, the effect occurs in a simi‐ lar manner and therefore, in biological membranes, a greater or lesser chance of interaction corresponds to greater or lesser "fluidity" of the membrane, which is proportional to more or

At room temperature, in terms of membrane structure, fatty acids are important, and the ones that are more widespread in nature are those with 18 total carbon atoms, especially un‐ saturated. Modulation of proper membrane fluidity requires that some fatty acids are rela‐ tively "rigid", such as palmitic and stearic acid, with a preference for the former since it has a

One of the most important aspects of biological systems that protect themselves through membranes is the preservation of integrity of the membrane itself, which is subject to con‐

lower melting point and thus is more effective in bringing about small changes.


(see: http://216.239.59.104/search?q=cache:qTHq\_xfePkIJ:www.cyberlipid.org/fa/acid0001.htm+Aitzetm %C3%BCller+K&hl=it)

**Table 3.** Selected chemical and physical characteristics of fatty acids

## **8. Chemical and technological considerations about oleic acid**

Fatty acids have different functions in living organisms, including the structural one, which are determined by the length of their hydrocarbon chain and the presence or absence of double bonds. Hydrocarbon chain length, in the same conditions of unsaturation, is directly proportional to the melting point (as well as the boiling point) (Table 3). The solubility in water (Table 4) and unsaturation, for the same chain length, is inversely proportional to the melting point (see Table 3), with very few exceptions.


**Table 4.** Fatty acid solubility in water at 20°C (in grams per liter)

**Systematic name Trivial name**

butanoic butyric 4:0 88.1 -7.9 pentanoic valeric 5:0 102,1 -19 hexanoic caproic 6:0 116.1 -3.4 octanoic caprylic 8:0 144.2 16.7 nonanoic pelargonic 9:0 158.2 12.5 decanoic capric 10:0 172.3 31.6 dodecanoic lauric 12:0 200.3 44.2 tetradecanoic myristic 14:0 228.4 53.9 hexadecanoic palmitic 16:0 256.4 63.1 heptadecanoic margaric (daturic) 17:0 270.4 61.3 octadecanoic stearic 18:0 284.4 69.6 eicosanoic arachidic 20:0 312.5 75.3 docosanoic behenic 22:0 340.5 79.9 tetracosanoic lignoceric 24:0 368.6 84.2 *cis*-9-hexadecenoic palmitoleic 16:1(n-7) 254.4 0.5 *cis*-9-octadecenoic oleic 18:1(n-9) 282.4 16.2 *trans*-9-octadecenoic elaidic tr18:1(n-9) 282.4 43.7 *cis*-11-octadecenoic *cis*-vaccenic (asclepic) 18:1(n-7) 282.4 39 *cis*-9-eicosenoic gadoleic 20:1(n-11) 310.5 25 *cis*-13-docosenoic erucic 22:1(n-9) 338.6 33.4 9,12-octadecadienoic linoleic 18:2(n-6) 280.4 -5

14 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

6,9,12-octadecatrienoic γ-linolenic 18:3(n-6) 278.4

8,11,14-eiosatrienoic dihomo-γ-linolenic 20:3(n-6) 306.5

7,10,13,16,19-docosapentaenoi DPA 22:5(n-3) 330.6

**Table 3.** Selected chemical and physical characteristics of fatty acids

%C3%BCller+K&hl=it)

9,12,15-octadecatrienoic α-linolenic 18:3(n-3) 278.4 -11

5,8,11,14-eicosatetraenoic arachidonic 20:4(n-6) 304. -50 6,912,15-octadecatetraenoic stearidonic 18:4(n-3) 276.4 -57 5,8,11,14,17-eicosapentaenoic EPA 20:5(n-3) 302.5 -54

4,7,10,13,16,19-docosahexaenoic DHA 22:6(n-3) 328.6 -44

(see: http://216.239.59.104/search?q=cache:qTHq\_xfePkIJ:www.cyberlipid.org/fa/acid0001.htm+Aitzetm

**Shorthand designation** **Molecular**

**weight Melting point (°C)**

These chemical differences are determined in large part by chemical and physical interac‐ tions that exist when molecules are close enough to unsaturate them. In the case of fatty acids, the possibility to join molecules depends only on the hydrocarbon chain (Van der Waals forces), which is facilitated when it is saturated and more difficult when unsaturated (especially at the point of unsaturation). The longer and more linear the chain, the greater the interaction, and the more unsaturated it will be, consequently, the interaction will be lower. When fatty acids are part of a triglyceride or phospholipid, the effect occurs in a simi‐ lar manner and therefore, in biological membranes, a greater or lesser chance of interaction corresponds to greater or lesser "fluidity" of the membrane, which is proportional to more or less functionality (permeability).

At room temperature, in terms of membrane structure, fatty acids are important, and the ones that are more widespread in nature are those with 18 total carbon atoms, especially un‐ saturated. Modulation of proper membrane fluidity requires that some fatty acids are rela‐ tively "rigid", such as palmitic and stearic acid, with a preference for the former since it has a lower melting point and thus is more effective in bringing about small changes.

One of the most important aspects of biological systems that protect themselves through membranes is the preservation of integrity of the membrane itself, which is subject to con‐ tact with chemical reactive oxygen species (ROS), and capable of chemically attacking the unsaturated zone of the molecule. Greater effectiveness is related to a greater level of unsa‐ turation, leading to subsequent breakage of the molecule with increased membrane fragility. For these reasons, the membrane is associated with a series of antioxidants, whose action is linked to their position in the membrane [75]. Oleic acid is the least oxidizable among unsa‐ turated fatty acids (Table 5), and is also not too fluid or too rigid, and is thus suitable for prolonging membrane stability [76, 77].

**Fat or Oil source Fatty acid position 14:0 16:0 18:0 18:1 18:2 18:3 20:0 22:0**

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?

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1 3.2 16.1 15.0 46.1 11 0.4 2 7.3 58.2 3.3 12.7 7.3 0.6 3 7.1 6.2 2.0 49.7 2.0 1.6

1 18.2 20.0 73.9 42.5 33.3 15.4 2 41.5 72.3 16.3 11.7 22.1 23.1 3 40.3 7.7 9.9 45.8 44.5 61.5

1 11 36 15 21 1 2 20 33 6 14 3 3 7 10 4 15 <1

1 1 10 30 51 6 2 4 72 2 13 3 3 7 73 8

1 34 50 12 1 2 2 2 87 9

3 37 53 9

1 4 41 17 20 4 1 2 9 17 9 41 5 1 3 1 22 24 37 5 1

1 18 3 27 50 1 2 2 <1 26 70 <1 3 13 3 31 51 1

1 14 6 23 48 9 2 1 1 21 70 7 3 13 6 28 45 8

1 13 3 72 10 <1 2 1 - 83 14 1 3 7 4 74 5 1

\*Relative GC area % (http://www.cyberlipid.org/index.htm); \*\* Sørensen A.D.M. et al., 2010 [78]

**Table 6.** Main fatty acid (mol %) distribution in the three positions of glycerine molecule of the corresponding

1 14 5 59 18 1 - 2 1 <1 58 39 - - 3 11 5 57 10 4 6

Women milk\*

Women milk

Cow milk

Pig

Cow

Cocoa butter

Groundnut

Corn

Soya

Olive

Mol % = molar percentage

triacylglycerols (triglycerides) of several fats and oils.


\*\* Hypothesis based on physical-chemical behavior

**Table 5.** Oxidation rate of several unsaturated fatty acids [Modified from Gunstone et al. [76]]

The rate of oxidation between various unsaturated fatty acids shown in Table 5 appears in‐ creased between oleic acid (monoenes) and linoleic acid (dienes), but upon increasing the unsaturation (trienes), the variation is much less pronounced. In biological systems, the po‐ sition of the fatty acid in glycerides or phospholipids [77] appears to influence the rate of oxidation, and is slower when inserted in position 2, or in the β position of the molecule. In the case of olive oil, as in all vegetable fats (Table 6), the 2 position is occupied by unsaturat‐ ed fatty acids, and is more available in that position because it can directly cross the intesti‐ nal wall of the 2-monoglycerides, resulting from digestion of glycerides by pancreatic lipase. In particular, on a molar basis, 83% of unsaturated fatty acids, in position 2 of triglycerides in olive oil, is occupied by oleic acid.

For extra virgin olive oil, its total unsaturation makes it particularly stable (Table 7) [79, 80] so that appropriate conservation, which is further prolonged by the presence of numerous and effective natural antioxidants (biophenol), is still present after refining, in contrast to other oils.

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease? http://dx.doi.org/10.5772/54035 17


Mol % = molar percentage

tact with chemical reactive oxygen species (ROS), and capable of chemically attacking the unsaturated zone of the molecule. Greater effectiveness is related to a greater level of unsa‐ turation, leading to subsequent breakage of the molecule with increased membrane fragility. For these reasons, the membrane is associated with a series of antioxidants, whose action is linked to their position in the membrane [75]. Oleic acid is the least oxidizable among unsa‐ turated fatty acids (Table 5), and is also not too fluid or too rigid, and is thus suitable for

16 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**PHOTOSENSITIZED OXIDATION (PHOTOXIDATION)**

prolonging membrane stability [76, 77].

**SATURATED** 1 1

\* In brackets ratio between photoxidation and autoxidation is shown

\*\* Hypothesis based on physical-chemical behavior

in olive oil, is occupied by oleic acid.

other oils.

TETRAENES\*\* 300

PENTAENES\*\* 400

HESAENES\*\* 500

**FATTY ACID 1) AUTOXIDATION 2) AUTOXIDATION**

**MONOENES** 10 100 1.1 (32,000)\*

**DIENES** 100 1200 2.9 (1600)\*

**TRIENES** 200 2500 3.5

**Table 5.** Oxidation rate of several unsaturated fatty acids [Modified from Gunstone et al. [76]]

The rate of oxidation between various unsaturated fatty acids shown in Table 5 appears in‐ creased between oleic acid (monoenes) and linoleic acid (dienes), but upon increasing the unsaturation (trienes), the variation is much less pronounced. In biological systems, the po‐ sition of the fatty acid in glycerides or phospholipids [77] appears to influence the rate of oxidation, and is slower when inserted in position 2, or in the β position of the molecule. In the case of olive oil, as in all vegetable fats (Table 6), the 2 position is occupied by unsaturat‐ ed fatty acids, and is more available in that position because it can directly cross the intesti‐ nal wall of the 2-monoglycerides, resulting from digestion of glycerides by pancreatic lipase. In particular, on a molar basis, 83% of unsaturated fatty acids, in position 2 of triglycerides

For extra virgin olive oil, its total unsaturation makes it particularly stable (Table 7) [79, 80] so that appropriate conservation, which is further prolonged by the presence of numerous and effective natural antioxidants (biophenol), is still present after refining, in contrast to

\*Relative GC area % (http://www.cyberlipid.org/index.htm); \*\* Sørensen A.D.M. et al., 2010 [78]

**Table 6.** Main fatty acid (mol %) distribution in the three positions of glycerine molecule of the corresponding triacylglycerols (triglycerides) of several fats and oils.


ministration (FDA) has stated (November 1, 2004) that U.S. consumption of 23 g of olive oil

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?

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19

Today, there are other sources of oil high in oleic acid, such as safflower, sunflower and can‐ ola (the new name for rapeseed oil low in erucic acid), and therefore based solely on the con‐ tent of oleic acid, these sources would also be optimal in this regard. However, the reputation of olive oil as a healthy product is most likely due to the presence of the numer‐ ous "minor elements" contained within [82, 83]. Among these minor components, several compounds are worthy of mention including biophenols, which consists of phenols and pol‐ yphenols with high antioxidant and antiradical activity, some triterpene alcohols, phytoster‐ ols, squalene, and tocopherols. These latter are considered important because of the content of vitamin E, and for their ability to facilitate the assimilation of polyunsaturated fatty acids:

The discovery of health effects from the minor components in olive oil has led to a large gap in the nutritional properties of edible oils. In fact, oils from seeds, subject to refining, loose many minor components and do not have the health properties that the corresponding ma‐ trix has. The technology for olive processing influences the quality and organoleptic charac‐ teristics of the final product, which is not always considered by industrial operators as much of the scientific knowledge is particularly new. The olive oil is encapsulated in small drops (10-30 micrometers) within vacuoles with a polysaccharide wall: oil droplets, during proc‐ essing, are released in crushing and come into contact with the other components of olives during grinding of the paste. It is the prolonged contact with the oil-pasta that allows join‐ ing of small droplets such that they can then leave the dough during the separation process

Therefore, time and temperature of processing can also affect the final product, and even if the starting characteristics of the olives are similar they can yield very different products. Moreover, during the same oil-paste stage, enzyme activities are capable of forming the fra‐ grance of the oil through a series of biochemical steps that, in part, may reduce the antioxi‐ dant ability of biophenol components and their effects on health. Therefore, choices made

There are several hundred olive cultivars grown in Italy, which can produce many oils that have a very different composition, although all can be considered of excellent quality. In particular, the richness in antioxidants (especially biophenols) can affect characteristics of the oil in terms of taste, storage stability, and health properties. Even if much scientific knowledge has been learned about olive production and processing technology, there are still many questions that must be answered in order to improve the quality, especially those

The ability to transform, by the action of delta9-desaturase, stearic acid to oleic acid, and vice versa makes oleic acid very useful for the modulation of the fluidity (and functionality)

during the processing of olives should take these effects into consideration.

related to health, of the oils obtained by processing olives

**9. Conclusion**

each day (about two tablespoons) helps in prevention of cardiovascular diseases [4].

1 mg allows the assimilation of 1 g of polyunsaturated fatty acids [84].

that emulsifies all the minor components in oil.

<sup>a</sup> Total unsaturation is calculated as the relative percentage of single fatty acid for a different factor, for each unsatura‐ tion, the degree is proportional to the oxidative instability. The factors utilized were: 1 for monounsaturated, 10 for diunsaturated and 20 for triunsaturated fatty acids. HO =high oleic. ND = not detectable

**Table 7.** Main fatty acid composition of fats and oils

Not all olive oils have the same concentration of oleic acid. The International Olive Oil Council (IOOC) has dictated that the content of oleic acid in olive oils can vary from 55% to 83% of total fatty acids [81]. The regulations of the European Community do not indicate the amount of oleic acid in olive oil, but simply indicate the specifications of several other pa‐ rameters that are useful for detecting fraud and require the distinction between various commercial products obtained from olive processing.

Among these, extra virgin oils are those that must have the highest quality. Extra virgin olive oils with the highest content of oleic acid have always been regarded as those with the highest quality, but only because of their higher stability during storage, as a consequence of the low reactivity of oleic acid compared with polyunsaturated fats. The Food and Drug Ad‐ ministration (FDA) has stated (November 1, 2004) that U.S. consumption of 23 g of olive oil each day (about two tablespoons) helps in prevention of cardiovascular diseases [4].

Today, there are other sources of oil high in oleic acid, such as safflower, sunflower and can‐ ola (the new name for rapeseed oil low in erucic acid), and therefore based solely on the con‐ tent of oleic acid, these sources would also be optimal in this regard. However, the reputation of olive oil as a healthy product is most likely due to the presence of the numer‐ ous "minor elements" contained within [82, 83]. Among these minor components, several compounds are worthy of mention including biophenols, which consists of phenols and pol‐ yphenols with high antioxidant and antiradical activity, some triterpene alcohols, phytoster‐ ols, squalene, and tocopherols. These latter are considered important because of the content of vitamin E, and for their ability to facilitate the assimilation of polyunsaturated fatty acids: 1 mg allows the assimilation of 1 g of polyunsaturated fatty acids [84].

The discovery of health effects from the minor components in olive oil has led to a large gap in the nutritional properties of edible oils. In fact, oils from seeds, subject to refining, loose many minor components and do not have the health properties that the corresponding ma‐ trix has. The technology for olive processing influences the quality and organoleptic charac‐ teristics of the final product, which is not always considered by industrial operators as much of the scientific knowledge is particularly new. The olive oil is encapsulated in small drops (10-30 micrometers) within vacuoles with a polysaccharide wall: oil droplets, during proc‐ essing, are released in crushing and come into contact with the other components of olives during grinding of the paste. It is the prolonged contact with the oil-pasta that allows join‐ ing of small droplets such that they can then leave the dough during the separation process that emulsifies all the minor components in oil.

Therefore, time and temperature of processing can also affect the final product, and even if the starting characteristics of the olives are similar they can yield very different products. Moreover, during the same oil-paste stage, enzyme activities are capable of forming the fra‐ grance of the oil through a series of biochemical steps that, in part, may reduce the antioxi‐ dant ability of biophenol components and their effects on health. Therefore, choices made during the processing of olives should take these effects into consideration.

There are several hundred olive cultivars grown in Italy, which can produce many oils that have a very different composition, although all can be considered of excellent quality. In particular, the richness in antioxidants (especially biophenols) can affect characteristics of the oil in terms of taste, storage stability, and health properties. Even if much scientific knowledge has been learned about olive production and processing technology, there are still many questions that must be answered in order to improve the quality, especially those related to health, of the oils obtained by processing olives

## **9. Conclusion**

**Fattyacids**

Oil from:

Rapeseed (0 erucic)

Fat from:

**Caprylic (C8:0)**

**Capric (C10:0)**

**Lauric (C12:0)** **Mirystic (C14:0)**

**Palmitic (C16:0)**

18 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Stearic (C18:0)**

Groundnut ND-0.1 8.0-14.0 1.0-4.5 35.0-69.0 12.0-43.0 0-0.3 0.7-1.7 200-481 86-107

Safflower ND-0.2 5.3-8.0 1.9-2.9 8.4-21.3 67.8-83.2 ND-0.1 0.1-0.3 700-740 136-148 Safflower (HO) ND-0.2 3.6-6.0 1.5-2.4 70.0-83.7 9.0-19.9 ND-0.2 0.1-0.5 175-270 80-100 Sunflower ND-0.1 ND-0.2 5.0-7.6 2.7-6.5 14.0-39.4 48.3-74.0 0-0.3 0-0.3 531-766 118-141 Sunflower (HO) ND-0.1 2.6-5.0 2.9-6.2 70.0-90.7 2.1-20.0 ND-3.0 0.1-0.5 118-270 78-90 Corn ND-0.3 ND-0.3 8.6-14.0 ND-3.3 20.0-42.0 34.0-65.6 0-1.2 0.2-0.6 400-481 103-135 Olive (CODEX) 7.5-20.0 55.0-83.0 3.5-21.0 Max 1.0 Max 0.4 163-285 75-94 Soya Bean ND-0.1 ND-0.2 8.0-13.5 2.5-5.4 17.0-30.0 48.0-59.0 4.5-11.0 0-0.5 600-840 124-139 Grape seed ND-0.3 5.5-11.0 3.0-6.5 12.0-28.0 58.0-78.0 0-1.0 0-0.3 596-802 128-150

Cocoa butter 22.6-30.4 30.2-36.0 29.2-36.4 1.3-4.0 ND-0.5 370-380 34-40 Coconut 4.6-10 5.0-8.0 45.1-53.2 16.8-21.0 7.5-10.2 2.0-4.0 5.0-10.0 1.0-2.5 ND-0.2 ND-0.2 24-34 6.3-10.6 Palm ND-0.5 0.5-2.0 39.3-47.5 3.5-6.0 36.3-44.0 9.0-12.0 ND-0.5 ND-0.4 130-391 50.0-55.0 *Palm olein* 0.1-0.5 0.5-1.5 38.0-43.5 3.5-5.0 39.8-46.0 10.0-13.5 ND-0.6 ND-04 158-187 56 *Palm stearin* 0.1-0.5 1.0-2.0 48.0-74.0 3.9-6.0 15.5-36.0 3.0-10.0 ND-0.5 ND-0.4 76-270 33 *Palm kernel* 2.4-6.2 2.6-5.0 45.0-55.0 14.0-18.0 6.5-10.0 1.0-3.0 12.0-19.0 1.0-3.5 ND-0.2 ND-0.2 33-51 14.1-21.0

<sup>a</sup> Total unsaturation is calculated as the relative percentage of single fatty acid for a different factor, for each unsatura‐ tion, the degree is proportional to the oxidative instability. The factors utilized were: 1 for monounsaturated, 10 for

Not all olive oils have the same concentration of oleic acid. The International Olive Oil Council (IOOC) has dictated that the content of oleic acid in olive oils can vary from 55% to 83% of total fatty acids [81]. The regulations of the European Community do not indicate the amount of oleic acid in olive oil, but simply indicate the specifications of several other pa‐ rameters that are useful for detecting fraud and require the distinction between various

Among these, extra virgin oils are those that must have the highest quality. Extra virgin olive oils with the highest content of oleic acid have always been regarded as those with the highest quality, but only because of their higher stability during storage, as a consequence of the low reactivity of oleic acid compared with polyunsaturated fats. The Food and Drug Ad‐

diunsaturated and 20 for triunsaturated fatty acids. HO =high oleic. ND = not detectable

**Table 7.** Main fatty acid composition of fats and oils

commercial products obtained from olive processing.

**Oleic (C18:1)** **Linoleic (C18:2)**

ND-0.2 2.5-7.0 0.8-3.0 51.0-70.0 15.0-30.0 5.0-14.0 0.1-4.3 320-630 105-126

**Linolenic (C18:3)**

**Eicosenoic (C20:1)**

**Total Unsaturationa (unstability factor)**

**Iodine number**

> The ability to transform, by the action of delta9-desaturase, stearic acid to oleic acid, and vice versa makes oleic acid very useful for the modulation of the fluidity (and functionality)

of cell membranes. Recalling that the fatty acid composition of platelets can be correlated with depression and also with ischemia [85], we can consider the oil obtained from olive processing such as the lipid substrate better balanced with respect to the fatty acid unsatura‐ tions, for the platelet membrane composition of normal individuals.

populations. Monitoring trends and determinants in cardiovascular disease. Lancet,

Reduced Consumption of Olive Oil: A Risk for Ischemic Heart Disease?

http://dx.doi.org/10.5772/54035

21

[2] Masia, R. Pena, A Marrugat, J. Sala, J. Vila, J. Pavesi, Covas, M. Aubo, Elosua, C. R. High prevalence of cardiovascular risk factors in Gerona, Spain, a province with low myocardial infarction incidence. REGICOR Investigators. J Epidemiol Community

[3] Covas, MI. Olive oil and the cardiovascular system. Pharmacological Research, 2007,

[4] US Food and Drug Administration. Press Release P04-100. November 1, 2004. http:// www.fda.gov/bbs/topics/news/2004/NEW01129.htlm. Accessed on October 28, 2006.

[5] Kris-Etherton, P M.; Mustad V. Derr J.A. Effects of dietary stearic acid on plasma lip‐

[6] Nunez, J Randon, C Gandhi, A Siafaka-Kapadai, MS Olson and DJ Hanahan: The in‐ hibition of platelet-activating factor-induced platelet activation by oleic acid is associ‐ ated with a decrease in polyphosphoinositide metabolism, Journal of Biological

[7] Barradas, M.A. Christofides, J.A. Jeremy, J.Y. Mikhailidis, D.P. Fry, D.E. Dandona, P. The Effect of Olive Oil Supplementation on Human Platelet Function, Serum Choles‐ terol-Related Variables and Plasma Fibrinogen Concentrations: A Pilot Study, Nutri‐

[8] Teres, S. Barcelo-Coblijn, G. Benet, M. Alvarez, R. A, Bressani, R. Halver, J. E. Escriba, P. V. Oleic acid content is responsible for the reduction in blood pressure induced by

[9] Alemany R. Terés S., Baamonde C., Benet M., Vögler O., Escribá P. V. 2-Hydroxyoleic

[10] Cocchi, M., Tonello, L. Tsaluchidu, S. Puri, B.K. The use of artificial neural networks to study fatty acids in neuropsychiatric disorders. BMC Psychiatry. 2008, 8(Suppl.

[11] Donati, R.J. Dwivedi, Y. Roberts, R.C. Conley, R.R. Pandey, G.N. Rasenick, M.M. Postmortem Brain Tissue of Depressed Suicides Reveals Increased Gs Localization in Lipid Raft Domains Where It Is Less Likely to Activate Adenylyl Cyclase. J. Neuro‐

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55: 175–186.

We must remember that the presence of high concentrations of oleic acid from olive oil is one of the stabilizing factors against oxidative modification, in both cases, for the oil itself and for cell membranes. Furthermore, the oil from olives when is classified as extra virgin, possesses a wealth of biophenols, powerful antioxidants predominantly of antiradical type, which further increase the stability of the oil and, more or less directly, even of the mem‐ brane lipids.

Olive oil, and, particularly an extra virgin olive oil-rich diet, decreases prothrombotic activi‐ ty, and modify platelet adhesion, coagulation, and fibrinolysis. The wide range of antia‐ therogenic effects associated with olive oil consumption can help to justify the low rate of cardiovascular mortality found in southern European Mediterranean countries, in compari‐ son with other western countries, despite a high prevalence of CHD risk factors. Experimen‐ tal evidence confirms a critical role of reduced levels of oleic acid in platelets in ischemic subjects with a diagnostic discriminant capacity from normal subjects [85]. At present, al‐ though traditional cardiovascular risk factors are under revision, a new field of research in platelets, and in particular oleic acid and its relationship with linoleic and arachidonic acid, should be pursued. The mechanisms by which olive oil exerts its beneficial effects merit fur‐ ther investigation, and additional studies are required to document the benefits of olive oil consumption on primary endpoints for cardiovascular disease. In this regard, consumption of extra virgin olive oil and daily intake of oleic acid should, however, be promoted.

## **Author details**

Massimo Cocchi1,2 and Giovanni Lercker3

1 "Paolo Sotgiu" Institute for research in Quantitative & Quantum Psychiatry & Cardiology, L.U.de.S University, Lugano, Switzerland

2 Department of Medical Veterinary Sciences, University of Bologna, Italy

3 DISA, University of Bologna, Italy

#### **References**

[1] Tunstall-Pedoe, H. Kuulasmaa, K. Mahonen, M. Tolonen, H. Ruokokoski, E. Amouyel, P. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet, 1999, 353: 1547–57.

of cell membranes. Recalling that the fatty acid composition of platelets can be correlated with depression and also with ischemia [85], we can consider the oil obtained from olive processing such as the lipid substrate better balanced with respect to the fatty acid unsatura‐

20 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

We must remember that the presence of high concentrations of oleic acid from olive oil is one of the stabilizing factors against oxidative modification, in both cases, for the oil itself and for cell membranes. Furthermore, the oil from olives when is classified as extra virgin, possesses a wealth of biophenols, powerful antioxidants predominantly of antiradical type, which further increase the stability of the oil and, more or less directly, even of the mem‐

Olive oil, and, particularly an extra virgin olive oil-rich diet, decreases prothrombotic activi‐ ty, and modify platelet adhesion, coagulation, and fibrinolysis. The wide range of antia‐ therogenic effects associated with olive oil consumption can help to justify the low rate of cardiovascular mortality found in southern European Mediterranean countries, in compari‐ son with other western countries, despite a high prevalence of CHD risk factors. Experimen‐ tal evidence confirms a critical role of reduced levels of oleic acid in platelets in ischemic subjects with a diagnostic discriminant capacity from normal subjects [85]. At present, al‐ though traditional cardiovascular risk factors are under revision, a new field of research in platelets, and in particular oleic acid and its relationship with linoleic and arachidonic acid, should be pursued. The mechanisms by which olive oil exerts its beneficial effects merit fur‐ ther investigation, and additional studies are required to document the benefits of olive oil consumption on primary endpoints for cardiovascular disease. In this regard, consumption

of extra virgin olive oil and daily intake of oleic acid should, however, be promoted.

1 "Paolo Sotgiu" Institute for research in Quantitative & Quantum Psychiatry & Cardiology,

[1] Tunstall-Pedoe, H. Kuulasmaa, K. Mahonen, M. Tolonen, H. Ruokokoski, E. Amouyel, P. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project

2 Department of Medical Veterinary Sciences, University of Bologna, Italy

tions, for the platelet membrane composition of normal individuals.

brane lipids.

**Author details**

**References**

Massimo Cocchi1,2 and Giovanni Lercker3

L.U.de.S University, Lugano, Switzerland

3 DISA, University of Bologna, Italy


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**Chapter 2**

**Relationship Between Ox–LDL, Immune Cells,**

**Measurements Assessed by Coronary Angiography and**

In this chapter we report on the relationship between angiographic findings, measured by coronary angiography (CA) and intravascular ultrasound virtual histology (IVUS-VH) mo‐ dalities, and indicators of vascular inflammation in the context of coronary artery disease (CAD). We sought to explore *in vivo* the relationship between patient demographics, anthro‐ pometric measures, risk factors, soluble biomarkers and plaque composition or its morpho‐

The interplay of inflammatory cells, cytokines and indicators of cell death may concur to the plaque phenotype in the context of coronary artery disease. Therefore, the lymphocyte pop‐ ulations expressing CD4 and CD8, the circulating levels of oxidized low density lipoprotein (ox-LDL), which may be primarily originated in the atheroma, the levels of tumour necrosis factor alpha (TNF- α) and of soluble Fas ligand (sFasL), which may reflect the inflammatory

These biomarkers would provide useful tools to improve medical diagnosis of the clinical atheroma. Noninvasive identification of high-risk/vulnerable coronary atherosclerotic pla‐ ques is one of the ultimate goals of coronary imaging and would dramatically improve risk

and reproduction in any medium, provided the original work is properly cited.

© 2013 Ramos et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Atheroma Dimensions and Angiographic**

Rui Cruz Ferreira, Cristina Fondinho, Mafalda Selas,

Miguel Mota Carmo, Ana Maria Crespo and

Additional information is available at the end of the chapter

response and vascular apoptosis, were studied.

**Intravascular Ultrasound**

Catarina Ramos, Patrícia Napoleão,

Teresa Pinheiro

**1. Introduction**

logical characteristics.

http://dx.doi.org/10.5772/54084

**Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by Coronary Angiography and Intravascular Ultrasound**

Catarina Ramos, Patrícia Napoleão, Rui Cruz Ferreira, Cristina Fondinho, Mafalda Selas, Miguel Mota Carmo, Ana Maria Crespo and Teresa Pinheiro

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54084

## **1. Introduction**

In this chapter we report on the relationship between angiographic findings, measured by coronary angiography (CA) and intravascular ultrasound virtual histology (IVUS-VH) mo‐ dalities, and indicators of vascular inflammation in the context of coronary artery disease (CAD). We sought to explore *in vivo* the relationship between patient demographics, anthro‐ pometric measures, risk factors, soluble biomarkers and plaque composition or its morpho‐ logical characteristics.

The interplay of inflammatory cells, cytokines and indicators of cell death may concur to the plaque phenotype in the context of coronary artery disease. Therefore, the lymphocyte pop‐ ulations expressing CD4 and CD8, the circulating levels of oxidized low density lipoprotein (ox-LDL), which may be primarily originated in the atheroma, the levels of tumour necrosis factor alpha (TNF- α) and of soluble Fas ligand (sFasL), which may reflect the inflammatory response and vascular apoptosis, were studied.

These biomarkers would provide useful tools to improve medical diagnosis of the clinical atheroma. Noninvasive identification of high-risk/vulnerable coronary atherosclerotic pla‐ ques is one of the ultimate goals of coronary imaging and would dramatically improve risk

© 2013 Ramos et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

stratification of both symptomatic and asymptomatic patients [1]. Therefore, correlations be‐ tween plaque composition, bio-indicators and the severity of cardiac events may provide unique information about plaque type to enhance the precision of clinical and laboratory variables used to assess patients at risk of CAD.

The ox-LDL has been described as a relevant pro-atherogenic autoantigen and its inflammatory and immunogenic activity has been implicated in atherosclerosis development and CAD [14,24]. Experimental data showed that ox-LDL is formed in the arterial wall where it is internalized by macrophages to form foam cells, contributing to the plaque progression [14]. The co-localization of ox-LDL with lymphocytes and monocyte-derived cells in the human atherosclerotic lesions reinforce the pro-atherogenic and immunogenic properties of ox-LDL, which was verified *in vi‐ tro* [24]. Eventually, ox-LDL formed in the arterial wall is released in the circulation [13], being their circulating levels strongly associated with angiographically documented coronary artery disease [25]. The proximity of ox-LDL and inflammatory cells, such as lymphocyte populations, in the atherosclerotic plaque may accelerate macrophage activity and therefore promote athero‐ genesis [26]. The T-cells expressing CD4 surface marker recognize antigens presented by den‐ dritic cells and macrophages. The T-cell expressing CD8 when activated are capable of killing smooth muscle cells and macrophages. Both CD4 and CD8 T cells share the capacity to recognize

Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by…

http://dx.doi.org/10.5772/54084

31

Thus, the *in vivo* identification of plaque vulnerability whether by characterizing its compo‐ nents or by providing measures of plaque-related oxidative and inflammation markers may improve diagnostic and eventually allow the detection of vulnerable atheroma before rupture.

Since its implementation over 30 years ago, invasive coronary angiography has become the standard clinical method for describing the coronary arteries and the "gold standard" for di‐ agnosing CAD. The use of contrast-enhanced coronary angiography has been introduced for stenosis detection and for assessing blood flow in the epicardial arteries. The approach based on edge-detection algorithms has also been proposed as an emerging tool for the de‐

The increased understanding of atherosclerosis has highlighted inherent limitations of coro‐ nary angiography as a technique for the assessment of coronary atherosclerotic plaques. An‐ giography provides a 2-dimensional view of the arterial lumen, but with no visualization of the vessel wall. Atherosclerosis primarily affects the arterial wall and since only the lumen is displayed, angiography does not provide extensive information about the plaque [28,29] and may obscure the true plaque burden, leading to an underestimation of plaque severity [3]. Also, the atherosclerotic plaque initially grows in an outwardly manner, expanding to the vessel wall, a process denominated positive remodeling. Therefore, as a result of posi‐ tive remodeling, angiography frequently fails to detect the early stages of atherosclerosis. Although positively remodeled lesions do not restrict blood flow, they may be unstable and may contribute to the onset of acute coronary syndromes [30]. Furthermore, because puta‐ tive sites of stenosis are compared with an apparently normal arterial segment, angiography often fails to detect diffuse disease in which a large portion of the artery is impacted by athe‐ rosclerotic disease. Both positive remodeling and diffuse disease are common in atheroscler‐

Also, the assessment of angiograms is solely visual and, consequently, subject to significant variation in image interpretation (observer bias) which may lead to a significant underesti‐

tection, characterization, and quantification of coronary atherosclerotic plaques [11].

otic progression and may be determinants of clinical outcome.

protein antigens bound to histocompatibility molecules on cell surfaces [27].

**1.2. Coronary angiography**

mation of lesion severity [30].

#### **1.1. Coronary artery disease**

Coronary artery disease is still the main cause of death worldwide and coronary athero‐ thrombosis is the leading cause of death in the United States and Europe [2,3]. A large num‐ ber of individuals who die suddenly of CAD due to atherosclerosis have no previous symptoms [4].

Atherosclerosis is a chronic pathological process of the vasculature characterized by focal arte‐ rial wall inflammation that leads to plaque build-up, intraluminal narrowing, and athero‐ thrombotic stenosis or occlusion with distal organ damage [5,6]. The atherosclerotic lesion is a thickening of the artery intima that consists of inflammatory and smooth muscle cells [7], as well as connective-tissue, lipids and debris [8]. The atheroma formation is initiated by an accu‐ mulation of lipid-laden cells beneath the endothelium, denominated fatty streak [9,10]. As atherosclerosis progresses from a benign phenotype, the atheroma becomes fibrotic, with a large necrotic core. Also, the plaque becomes more inflamed, resulting in an infiltration of mac‐ rophages and T-lymphocytes to the metabolically active fibrous cap [3]. Disintegration of foam cells and production of matrix metalloproteinases by activated leukocytes have detrimental consequences leading to the destabilization of lipid rich cores and the thinning of the fibrous cap [8]. This leads to a rupture-prone thin-cap fibroatheroma. The plaque rupture may cause arterial thrombosis, which results in a clinical spectrum of presentations ranging from sudden cardiac death, due to coronary occlusion, to an asymptomatic event with plaque progression [3]. In fact, the rupture of vulnerable atherosclerotic plaque is the cause of most acute coronary syndromes, e.g. myocardial infarction and unstable angina [8,11].

Atherosclerotic plaque stability is related to histological composition however biomarkers for the disease severity are still lacking today [12-14]. Multiple evidences link risk factors for atherosclerosis and its complications with altered histology, including the operation of both innate and adaptive immunity and the balance of stimulatory and inhibitory pathways that regulate their participation in atheroma formation and complication [15].

The early involvement of monocytes and macrophages in atherosclerosis is initiated with endothelial cell activation. Several protein mediators, specifically cytokines and chemokines, and LDL oxidative modification [16], direct monocyte migration to the intima and promote their maturation into macrophages, which are retained in the lesion [17,18]. These pro-in‐ flammatory monocytes propagate the innate response by expressing high levels of pro-in‐ flammatory cytokines and other macrophages mediators including metalloproteinases [6,19,20]. Dendritic cells that populate atherosclerotic plaques can present antigens to T-cells, which mount a cellular immune response [21]. These immune cells are also involved in thrombosis. Coagulation proteins elicit the expression of pro-inflammatory cytokines and mediators that interact with toll-like receptors of immune cells. These events promote endo‐ thelial cell apoptosis [22,23].

The ox-LDL has been described as a relevant pro-atherogenic autoantigen and its inflammatory and immunogenic activity has been implicated in atherosclerosis development and CAD [14,24]. Experimental data showed that ox-LDL is formed in the arterial wall where it is internalized by macrophages to form foam cells, contributing to the plaque progression [14]. The co-localization of ox-LDL with lymphocytes and monocyte-derived cells in the human atherosclerotic lesions reinforce the pro-atherogenic and immunogenic properties of ox-LDL, which was verified *in vi‐ tro* [24]. Eventually, ox-LDL formed in the arterial wall is released in the circulation [13], being their circulating levels strongly associated with angiographically documented coronary artery disease [25]. The proximity of ox-LDL and inflammatory cells, such as lymphocyte populations, in the atherosclerotic plaque may accelerate macrophage activity and therefore promote athero‐ genesis [26]. The T-cells expressing CD4 surface marker recognize antigens presented by den‐ dritic cells and macrophages. The T-cell expressing CD8 when activated are capable of killing smooth muscle cells and macrophages. Both CD4 and CD8 T cells share the capacity to recognize protein antigens bound to histocompatibility molecules on cell surfaces [27].

Thus, the *in vivo* identification of plaque vulnerability whether by characterizing its compo‐ nents or by providing measures of plaque-related oxidative and inflammation markers may improve diagnostic and eventually allow the detection of vulnerable atheroma before rupture.

#### **1.2. Coronary angiography**

stratification of both symptomatic and asymptomatic patients [1]. Therefore, correlations be‐ tween plaque composition, bio-indicators and the severity of cardiac events may provide unique information about plaque type to enhance the precision of clinical and laboratory

30 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Coronary artery disease is still the main cause of death worldwide and coronary athero‐ thrombosis is the leading cause of death in the United States and Europe [2,3]. A large num‐ ber of individuals who die suddenly of CAD due to atherosclerosis have no previous

Atherosclerosis is a chronic pathological process of the vasculature characterized by focal arte‐ rial wall inflammation that leads to plaque build-up, intraluminal narrowing, and athero‐ thrombotic stenosis or occlusion with distal organ damage [5,6]. The atherosclerotic lesion is a thickening of the artery intima that consists of inflammatory and smooth muscle cells [7], as well as connective-tissue, lipids and debris [8]. The atheroma formation is initiated by an accu‐ mulation of lipid-laden cells beneath the endothelium, denominated fatty streak [9,10]. As atherosclerosis progresses from a benign phenotype, the atheroma becomes fibrotic, with a large necrotic core. Also, the plaque becomes more inflamed, resulting in an infiltration of mac‐ rophages and T-lymphocytes to the metabolically active fibrous cap [3]. Disintegration of foam cells and production of matrix metalloproteinases by activated leukocytes have detrimental consequences leading to the destabilization of lipid rich cores and the thinning of the fibrous cap [8]. This leads to a rupture-prone thin-cap fibroatheroma. The plaque rupture may cause arterial thrombosis, which results in a clinical spectrum of presentations ranging from sudden cardiac death, due to coronary occlusion, to an asymptomatic event with plaque progression [3]. In fact, the rupture of vulnerable atherosclerotic plaque is the cause of most acute coronary

Atherosclerotic plaque stability is related to histological composition however biomarkers for the disease severity are still lacking today [12-14]. Multiple evidences link risk factors for atherosclerosis and its complications with altered histology, including the operation of both innate and adaptive immunity and the balance of stimulatory and inhibitory pathways that

The early involvement of monocytes and macrophages in atherosclerosis is initiated with endothelial cell activation. Several protein mediators, specifically cytokines and chemokines, and LDL oxidative modification [16], direct monocyte migration to the intima and promote their maturation into macrophages, which are retained in the lesion [17,18]. These pro-in‐ flammatory monocytes propagate the innate response by expressing high levels of pro-in‐ flammatory cytokines and other macrophages mediators including metalloproteinases [6,19,20]. Dendritic cells that populate atherosclerotic plaques can present antigens to T-cells, which mount a cellular immune response [21]. These immune cells are also involved in thrombosis. Coagulation proteins elicit the expression of pro-inflammatory cytokines and mediators that interact with toll-like receptors of immune cells. These events promote endo‐

variables used to assess patients at risk of CAD.

syndromes, e.g. myocardial infarction and unstable angina [8,11].

regulate their participation in atheroma formation and complication [15].

**1.1. Coronary artery disease**

thelial cell apoptosis [22,23].

symptoms [4].

Since its implementation over 30 years ago, invasive coronary angiography has become the standard clinical method for describing the coronary arteries and the "gold standard" for di‐ agnosing CAD. The use of contrast-enhanced coronary angiography has been introduced for stenosis detection and for assessing blood flow in the epicardial arteries. The approach based on edge-detection algorithms has also been proposed as an emerging tool for the de‐ tection, characterization, and quantification of coronary atherosclerotic plaques [11].

The increased understanding of atherosclerosis has highlighted inherent limitations of coro‐ nary angiography as a technique for the assessment of coronary atherosclerotic plaques. An‐ giography provides a 2-dimensional view of the arterial lumen, but with no visualization of the vessel wall. Atherosclerosis primarily affects the arterial wall and since only the lumen is displayed, angiography does not provide extensive information about the plaque [28,29] and may obscure the true plaque burden, leading to an underestimation of plaque severity [3]. Also, the atherosclerotic plaque initially grows in an outwardly manner, expanding to the vessel wall, a process denominated positive remodeling. Therefore, as a result of posi‐ tive remodeling, angiography frequently fails to detect the early stages of atherosclerosis. Although positively remodeled lesions do not restrict blood flow, they may be unstable and may contribute to the onset of acute coronary syndromes [30]. Furthermore, because puta‐ tive sites of stenosis are compared with an apparently normal arterial segment, angiography often fails to detect diffuse disease in which a large portion of the artery is impacted by athe‐ rosclerotic disease. Both positive remodeling and diffuse disease are common in atheroscler‐ otic progression and may be determinants of clinical outcome.

Also, the assessment of angiograms is solely visual and, consequently, subject to significant variation in image interpretation (observer bias) which may lead to a significant underesti‐ mation of lesion severity [30].

Assessing the atheroma dimensions by coronary angiography (CA) has been more recently surpassed by new methods for cardiovascular imaging using ultrasound [28,29,31] and mul‐ tislice CT [32-34], which allow a more accurate and complete imaging of atherosclerotic cor‐ onary vessels.

tion of plaques with a high risk of spontaneous rupture [31]. However, coronary angiogra‐ phy is still regarded by many as the principal imaging technique for guiding coronary interventions. Recently, the correlation of coronary artery geometric measurements using both CA and IVUS has been reported [41-43], calling the attention for the value of IVUS alone or in conjugation with VH as precise measurements of plaque geometric parameters

Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by…

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33

Individual data and blood samples were obtained from patients enrolled in a prospective study performed at the Cardiology Service of Santa Marta Hospital (CHLC, Lisbon, Portu‐ gal). The study was designed to investigate the association of circulating levels of ox-LDL, TNF-α, sFasL and T-lymphocytes with angiographic data and atherosclerotic plaque mor‐

Patients, men and women aged between 56 and 71 years old with suspected and known coro‐ nary artery disease were included in the study. A total of 35 subjects were eligible to partici‐ pate: 4 patients with ST-elevation myocardial infarction (STEMI), 7 patients with non-ST elevation myocardial infarction (NSTEMI), 11 stable angina (SA) patients, 10 unstable angina (UA) patients and 3 silent ischemia patients (SI). All patients underwent standard diagnostic procedures and treated accordingly. Acute coronary syndrome patients were enrolled in the first 24 hours of hospital admission, although the time period from the onset of chest pain to the intervention was less than 9 hours for the majority of them. Demographic information and his‐ tory, including traditional risk factors for CAD were obtained at study entry. Evaluations in‐ cluded cardiac testing and imaging, cardiac characteristics and procedures, such as angioplasty and stenting. Coronary angiography and IVUS-VH data was recorded. One prespecified study lesion was identified in each patient. An anatomical segment containing the en‐ tirety of the study lesion was then selected, which could be easily identified based on standard anatomical landmarks on two modalities (CA and IVUS-VH). All patients received standard

care therapy after discharge including dual antiplatelet therapy after angioplasty.

signed an informed consent accepting their participation before study enrollment.

All subjects were characterized demographically, clinically and biochemically (Table I).

ble if coronary anatomy was inappropriate for IVUS.

**2.2. Patient characterization**

Subjects with age above 85, significant co-morbidities as peripheral artery disease or carotid artery disease, known antecedents of malignance or infectious diseases, chronic renal insuf‐ ficiency, concurrent inflammatory disorders, malignant neoplasm or infection and previous myocardial infarction in the previous 5 years were not enrolled. Also, patients were ineligi‐

The study protocol was approved by the CHLC Ethical Committee board and all patients

and tissue histological characteristics can be obtained with this modality.

**2. Methods**

**2.1. Study design and participants**

phological and biological characteristics.

#### **1.3. Intravascular ultrasound**

Intravascular ultrasound (IVUS), a catheter-based technique that provides high resolution cross-sectional images of the coronary vessel in vivo, is a tomographic technique that per‐ mits two-dimensional visualization of the arterial wall and allows further characterization of its individual layers. Thus, IVUS is a unique imaging modality for the direct examination of vessel dimensions and arterial wall characteristics in live subjects.

The coronary artery is inspected by a catheter incorporating a miniature ultrasound trans‐ ducer, which emits high-frequency ultrasound, usually in the range of 20 to 50 MHz provid‐ ing an axial resolution of about 100–200 μm. Lateral resolution of the ultrasonic waves is less specific and may vary depending on imaging depth and beam width, averaging around 250 μm [35].

Given their proximity to the plaque, intravascular catheters have the inherent advantage of a high signal-to-noise ratio [3]. The information obtained through IVUS imaging depicts the morphological characteristics of the atheromatous plaque and is used to illustrate the geomet‐ rical configuration of its layers and architecture. Most clinical centers use a pullback system to withdraw the catheter at a constant rate of 0.5 mm/s following its initial deployment distal to the area of interest. As the transducer is moved through the artery, ultrasonic reflections are electronically converted to cross-sectional images [31]. This IVUS modality is called "virtual histology" IVUS (IVUS-VH) and allows the identification of the composition of atherosclerotic plaques by discriminating varying echolucent regions within the atheroma [12]. Four plaque components, fibrotic, fibro-fatty, calcification and necrotic core, can be identified as they exhib‐ it a defined radiofrequency spectrum, which can be analyzed and mathematically transformed into a color-coded representation of the plaque composition [36].

Therefore, IVUS imaging delivers precise geometric measurements of the coronary wall and lumen and enables the identification of different types of plaques according to their content in lipid, fibrin calcium and necrotic tissues [12,32,37,38]. The evaluation of lipid deposits contents commonly associated to vulnerable plaques and positive remodeling has been used to assess lesion severity [39]. In addition, three-dimensional IVUS image reconstruction is possible and is essential for proper assessment of the longitudinal distribution of the plaque [36], because multiple plaque morphologies varying from a fibrotic stable plaque to sites containing large lipids/necrotic cores can be found in a single arterial segment.

Because of its methodology, IVUS is not subject to the same limitations as angiography. Not only is IVUS more sensitive than angiography for the detection of stenosis, it can also identi‐ fy diffuse disease and positive remodeling of the vessel wall. Furthermore, since IVUS al‐ lows the identification of morphologic characteristics of vulnerable plaques, it may be helpful in the characterization of atherosclerotic plaque formation [31,40] and in the detec‐ tion of plaques with a high risk of spontaneous rupture [31]. However, coronary angiogra‐ phy is still regarded by many as the principal imaging technique for guiding coronary interventions. Recently, the correlation of coronary artery geometric measurements using both CA and IVUS has been reported [41-43], calling the attention for the value of IVUS alone or in conjugation with VH as precise measurements of plaque geometric parameters and tissue histological characteristics can be obtained with this modality.

## **2. Methods**

Assessing the atheroma dimensions by coronary angiography (CA) has been more recently surpassed by new methods for cardiovascular imaging using ultrasound [28,29,31] and mul‐ tislice CT [32-34], which allow a more accurate and complete imaging of atherosclerotic cor‐

32 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Intravascular ultrasound (IVUS), a catheter-based technique that provides high resolution cross-sectional images of the coronary vessel in vivo, is a tomographic technique that per‐ mits two-dimensional visualization of the arterial wall and allows further characterization of its individual layers. Thus, IVUS is a unique imaging modality for the direct examination of

The coronary artery is inspected by a catheter incorporating a miniature ultrasound trans‐ ducer, which emits high-frequency ultrasound, usually in the range of 20 to 50 MHz provid‐ ing an axial resolution of about 100–200 μm. Lateral resolution of the ultrasonic waves is less specific and may vary depending on imaging depth and beam width, averaging around 250

Given their proximity to the plaque, intravascular catheters have the inherent advantage of a high signal-to-noise ratio [3]. The information obtained through IVUS imaging depicts the morphological characteristics of the atheromatous plaque and is used to illustrate the geomet‐ rical configuration of its layers and architecture. Most clinical centers use a pullback system to withdraw the catheter at a constant rate of 0.5 mm/s following its initial deployment distal to the area of interest. As the transducer is moved through the artery, ultrasonic reflections are electronically converted to cross-sectional images [31]. This IVUS modality is called "virtual histology" IVUS (IVUS-VH) and allows the identification of the composition of atherosclerotic plaques by discriminating varying echolucent regions within the atheroma [12]. Four plaque components, fibrotic, fibro-fatty, calcification and necrotic core, can be identified as they exhib‐ it a defined radiofrequency spectrum, which can be analyzed and mathematically transformed

Therefore, IVUS imaging delivers precise geometric measurements of the coronary wall and lumen and enables the identification of different types of plaques according to their content in lipid, fibrin calcium and necrotic tissues [12,32,37,38]. The evaluation of lipid deposits contents commonly associated to vulnerable plaques and positive remodeling has been used to assess lesion severity [39]. In addition, three-dimensional IVUS image reconstruction is possible and is essential for proper assessment of the longitudinal distribution of the plaque [36], because multiple plaque morphologies varying from a fibrotic stable plaque to sites

Because of its methodology, IVUS is not subject to the same limitations as angiography. Not only is IVUS more sensitive than angiography for the detection of stenosis, it can also identi‐ fy diffuse disease and positive remodeling of the vessel wall. Furthermore, since IVUS al‐ lows the identification of morphologic characteristics of vulnerable plaques, it may be helpful in the characterization of atherosclerotic plaque formation [31,40] and in the detec‐

containing large lipids/necrotic cores can be found in a single arterial segment.

vessel dimensions and arterial wall characteristics in live subjects.

into a color-coded representation of the plaque composition [36].

onary vessels.

μm [35].

**1.3. Intravascular ultrasound**

### **2.1. Study design and participants**

Individual data and blood samples were obtained from patients enrolled in a prospective study performed at the Cardiology Service of Santa Marta Hospital (CHLC, Lisbon, Portu‐ gal). The study was designed to investigate the association of circulating levels of ox-LDL, TNF-α, sFasL and T-lymphocytes with angiographic data and atherosclerotic plaque mor‐ phological and biological characteristics.

Patients, men and women aged between 56 and 71 years old with suspected and known coro‐ nary artery disease were included in the study. A total of 35 subjects were eligible to partici‐ pate: 4 patients with ST-elevation myocardial infarction (STEMI), 7 patients with non-ST elevation myocardial infarction (NSTEMI), 11 stable angina (SA) patients, 10 unstable angina (UA) patients and 3 silent ischemia patients (SI). All patients underwent standard diagnostic procedures and treated accordingly. Acute coronary syndrome patients were enrolled in the first 24 hours of hospital admission, although the time period from the onset of chest pain to the intervention was less than 9 hours for the majority of them. Demographic information and his‐ tory, including traditional risk factors for CAD were obtained at study entry. Evaluations in‐ cluded cardiac testing and imaging, cardiac characteristics and procedures, such as angioplasty and stenting. Coronary angiography and IVUS-VH data was recorded. One prespecified study lesion was identified in each patient. An anatomical segment containing the en‐ tirety of the study lesion was then selected, which could be easily identified based on standard anatomical landmarks on two modalities (CA and IVUS-VH). All patients received standard care therapy after discharge including dual antiplatelet therapy after angioplasty.

Subjects with age above 85, significant co-morbidities as peripheral artery disease or carotid artery disease, known antecedents of malignance or infectious diseases, chronic renal insuf‐ ficiency, concurrent inflammatory disorders, malignant neoplasm or infection and previous myocardial infarction in the previous 5 years were not enrolled. Also, patients were ineligi‐ ble if coronary anatomy was inappropriate for IVUS.

The study protocol was approved by the CHLC Ethical Committee board and all patients signed an informed consent accepting their participation before study enrollment.

#### **2.2. Patient characterization**

All subjects were characterized demographically, clinically and biochemically (Table I).

Diabetes was diagnosed on the basis of fasting plasma glucose concentration ≥7.0 mmol/l (126 mg/dl) or 2h plasma glucose ≥11.1 mmol/l (200 mg/dl) or confirmed as clinically known and treated diabetes mellitus. Subjects were diagnosed hypertensive if they were documented to have systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or were already on anti-hypertensive therapy. Dyslipidaemia was identified in subjects who had total serum cholesterol level ≥190 mg/dl and/or serum triglycerides ≥180 mg/dl or were on lipidlowering medication. Smoking was defined as the inhaled use of cigarettes, cigars or pipes in any quantity. Subjects who smoked within the previous year were also defined as smokers.

**2.3. Percutaneous angiography**

Diseased vessels (n, %)

Lesions (n, %)

Culprit vessel (n, %)

TIMI score (n, %)

Lesion type (n, %)

Lesion morphology (n, %)

All patients were clinically evaluated for the extension of coronary artery disease through the characterization of lesion morphology to define the coronary stenosis, the number of dis‐ eased vessels, the thrombolysis in myocardial infarction (TIMI) risk score, which refers to the level of coronary blood flow assessed during coronary angiography (ranging from 3 – complete perfusion, to 0 – total occlusion), lesion length and the presence of calcium and/or thrombi in the lesions. The number and type of stents positioned in patients undergoing cor‐ onary angiography were also recorded. A coronary stenosis was considered clinically signif‐ icant (high-grade) as a ≥70% narrowing in the luminal diameter. Multivessel disease was defined when more than one major coronary artery presented high-grade stenosis: left ante‐ rior descending artery (LAD); right coronary artery (RCA); left circumflex artery (LCX).

Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by…

**Patients angiographic characterization**

**Table 2.** Patients angiographic characterization. Results are presented in median (Q25 – Q75) unless otherwise specified.

The extent (severity) of CAD was assessed following a graded angiographic system based on previous reports by others [43, 44]. The number of diseased vessels, number of lesions, culprit lesion and TIMI were the contributing parameters. The severity score was calculated on the basis of the sum of individual scores assigned to each parameter assuming normal

Stenosis (%) 87.5 (70 – 91) Lesion length (mm) 18.5 (13– 28) Multivessel (n, %) 6, 19

> 0 4, 11 1 20, 57 2 7, 20 3 2, 6

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0 4, 11 1 17, 49 2 6, 17 3 2, 6 4 4, 11

LAD / TC 20, 61 RCA 11, 31 LCX 2, 6

0 1, 3 3 26, 74

A 3, 9 B 17, 49 C 2, 6

Concentric 5, 14 Eccentric 20, 57


**Table 1.** Patients demographic, clinical and biochemical characterization. Results are presented in median (Q25 – Q75) unless otherwise specified.

#### **2.3. Percutaneous angiography**

Diabetes was diagnosed on the basis of fasting plasma glucose concentration ≥7.0 mmol/l (126 mg/dl) or 2h plasma glucose ≥11.1 mmol/l (200 mg/dl) or confirmed as clinically known and treated diabetes mellitus. Subjects were diagnosed hypertensive if they were documented to have systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or were already on anti-hypertensive therapy. Dyslipidaemia was identified in subjects who had total serum cholesterol level ≥190 mg/dl and/or serum triglycerides ≥180 mg/dl or were on lipidlowering medication. Smoking was defined as the inhaled use of cigarettes, cigars or pipes in any quantity. Subjects who smoked within the previous year were also defined as smokers.

34 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Patients characterization**

**Table 1.** Patients demographic, clinical and biochemical characterization. Results are presented in median (Q25 – Q75)

Male sex (n, %) 23, 66 Age (y) 63 (56 – 71) Weight (kg) 75 (67 – 80) Height (m) 1.7 (1.6 – 1.7) BMI (kg/m2) 27.3 (23.7 – 29)

Smoking (n, %) 6, 34 Hypercholesterolemia (n, %) 25, 71 Arterial hypertension (n, %) 25, 71 Diabetes mellitus (n, %) 8, 23

Aspirin (n, %) 18, 51 ACE Inhibitors (n, %) 16, 46 Anti-platelets (n, %) 14, 40 β - blockers (n, %) 15, 43 Statins (n, %) 25, 7

Total cholesterol (mg/dl) 156 (133 – 188) LDL (mg/dl) 104 (82 – 127) HDL (mg/dl) 36 (27 – 45) Triglycerides (mg/dl) 85 (59 – 127) Glucose (mg/dl) 111 (95 – 137) Leucocytes (x103/µl) 6.8 (5.4 – 8.5) Neutrophils (x103/µl) 4.4 (3.3 – 5.7) Lymphocytes (x103/µl) 1.8 (1.3 – 2.7) Monocytes (x103/µl) 0.5 (0.3 – 0.8) Platelets (x103/µl) 190 (156 – 235) CK (U/l) 84 (47 – 169) CRP (mg/l) 5.3 (2.5 – 18.4) Pro-BNP (pg/ml) 203 (64 – 916)

**Demographics**

**Risk factors / Comorbidities**

**Previous medication**

**Biochemical analysis**

unless otherwise specified.

All patients were clinically evaluated for the extension of coronary artery disease through the characterization of lesion morphology to define the coronary stenosis, the number of dis‐ eased vessels, the thrombolysis in myocardial infarction (TIMI) risk score, which refers to the level of coronary blood flow assessed during coronary angiography (ranging from 3 – complete perfusion, to 0 – total occlusion), lesion length and the presence of calcium and/or thrombi in the lesions. The number and type of stents positioned in patients undergoing cor‐ onary angiography were also recorded. A coronary stenosis was considered clinically signif‐ icant (high-grade) as a ≥70% narrowing in the luminal diameter. Multivessel disease was defined when more than one major coronary artery presented high-grade stenosis: left ante‐ rior descending artery (LAD); right coronary artery (RCA); left circumflex artery (LCX).


**Table 2.** Patients angiographic characterization. Results are presented in median (Q25 – Q75) unless otherwise specified.

The extent (severity) of CAD was assessed following a graded angiographic system based on previous reports by others [43, 44]. The number of diseased vessels, number of lesions, culprit lesion and TIMI were the contributing parameters. The severity score was calculated on the basis of the sum of individual scores assigned to each parameter assuming normal arteries as grade "0": a) each vessel with ≥70% stenosis lesions contributed as 2, and vessels with <70% stenosis lesions contributed as 1; b) each lesion treated contributed as 1; c) the most severe lesions were graded 3 when occurring in LAD, 2 in RCA and 1 in LCX; d) the TIMI values contributed as 0 = no occlusion to 3 = total occlusion.

Lymphocyte populations were analyzed by flow cytometry (FASCalibur, BD) in whole blood lysed with lysing solution (BD). The following antibodies were used: PerCP mouse anti-human CD45 (2D1, BD Pharmigen), FITC mouse anti-human CD3 (HIT3a, BD Pharmi‐ gen), APC mouse anti-human CD4 (RPA-T4, BD Pharmigen), PE mouse anti-human CD8

Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by…

**Atherosclerotic plaque characterization**

Larger stenosis region 77.6 (65 – 84) Proximal region 49 (40 – 58) Distal region 48.1 (37 – 59.5)

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Larger stenosis region 58.5 (51 – 75) Proximal region 61.7 (48 – 75.5) Distal region 59 (43 – 74.5)

Larger stenosis region 9.6 (6.4 – 18) Proximal region 13 (5 – 17.5) Distal region 9 (4.7 – 20)

Larger stenosis region 11 (2.7 – 17) Proximal region 6 (0.3 – 14.2) Distal region 12.8 (0.5 – 22)

Larger stenosis region 16.5 (8 – 22) Proximal region 17.4 (8 – 24) Distal region 16.5 (10 – 24)

area (mm2) 3.8 (2.9 – 5.1)

area (mm2) 17.2 (15 – 19)

Plaque area (mm2) 13 (10 – 15) Plaque burden (%) 77.4 (65 – 84)

**Table 3.** Atherosclerotic plaque measurements obtained by IVUS-VH. Results of the plaque morphology and

Data were summarized and represented (box-plots) as median and inter-quartiles 25% and 75% (Q25-Q75) for continuous variables and as proportions for categorical variables. Non-continuous variables were analyzed using a 2x2 table and χ2 test. Continuous varia‐

Minimum 2.1 (1.8 – 2.3) Maximum 2.4 (2.1 – 3) Median 2.2 (1.9 – 2.7)

Minimum 4.3 (4 – 4.6) Maximum 4.9 (4.5 – 5.1) Median 4.6 (4.2 – 4.9)

(RPA-T8, BD Pharmigen).

Stenosis (%)

Fibrotic tissue (%)

Fibro-fatty tissue (%)

Calcified tissue (%)

Necrotic core (%)

composition are presented in median (Q25 – Q75).

diameter (mm)

diameter (mm)

Lumen

External elastic lamina

**2.6. Statistical analysis**

#### **2.4. Intravascular ultrasound (IVUS)**

The IVUS-VH acquisition was performed using a EagleEye catheter (20 MHz) at pullback speed of 0.5 mm/sec. The IVUS data was recorded for the reconstruction of the radiofre‐ quency backscatter information using In-Vision gold commercial software (Volcano Cor‐ poration, USA).

For each lesion, vessel and lumen area data were obtained for every cross-section through‐ out the region of interest and lesion borders were established using the leading edges of ex‐ ternal elastic lamina (EEL) and the luminal contour. Minimal lumen diameter and reference diameter were measured and percentage of diameter stenosis was calculated. The composi‐ tion of coronary atheroma was assessed using spectral analysis of backscatter RF signals. The percentages of fibrotic, fibro-fatty, calcified and necrotic core were assessed. Atheroma area and volume and were obtained after EEL and lumen diameter (LD) measures were completed at the lumen/plaque boundary and at the media/adventitia boundary in each cross-section forming the region of interest.

Atheroma or plaque area (PA) was determined as the difference between EEL and lumen areas. The plaque burden was calculated as the plaque cross sectional area divided by the EEL area and multiplying by 100. IVUS measurements were recorded at three different re‐ gions-of-interest of the selected lesion: larger stenosis region cross-section and distal and proximal cross-sections. Median values and 25% and 75% quartile intervals for the various parameters measured and/or calculated are listed in Table 3.

#### **2.5. Blood sampling and laboratory assays**

Peripheral blood was drawn from all patients into blood collection tubes (Vacuette) with ap‐ propriate anti-coagulant, and centrifuged at 2500 rpm for 10 minutes. Serum and plasma were collected and stored at -80ºC until analysis, for a period not exceeding 6 months. Sam‐ ples were thawed only once.

Levels of glucose, creatinine kinase, troponin T, N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), blood cells count and lipid profile were routine‐ ly measured in the hospital. Plasma concentrations of ox-LDL and sFasL and serum concen‐ trations of TNF-α were measured by enzyme-linked immunosorbent assays (ELISA) commercial kits (R&D Systems).

All the assays were performed according to the manufacturer's recommendations. Each sample was measured in duplicate; intra-assay variation among the duplicates for all sam‐ ples was <10%.

Lymphocyte populations were analyzed by flow cytometry (FASCalibur, BD) in whole blood lysed with lysing solution (BD). The following antibodies were used: PerCP mouse anti-human CD45 (2D1, BD Pharmigen), FITC mouse anti-human CD3 (HIT3a, BD Pharmi‐ gen), APC mouse anti-human CD4 (RPA-T4, BD Pharmigen), PE mouse anti-human CD8 (RPA-T8, BD Pharmigen).


**Table 3.** Atherosclerotic plaque measurements obtained by IVUS-VH. Results of the plaque morphology and composition are presented in median (Q25 – Q75).

#### **2.6. Statistical analysis**

arteries as grade "0": a) each vessel with ≥70% stenosis lesions contributed as 2, and vessels with <70% stenosis lesions contributed as 1; b) each lesion treated contributed as 1; c) the most severe lesions were graded 3 when occurring in LAD, 2 in RCA and 1 in LCX; d) the

36 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The IVUS-VH acquisition was performed using a EagleEye catheter (20 MHz) at pullback speed of 0.5 mm/sec. The IVUS data was recorded for the reconstruction of the radiofre‐ quency backscatter information using In-Vision gold commercial software (Volcano Cor‐

For each lesion, vessel and lumen area data were obtained for every cross-section through‐ out the region of interest and lesion borders were established using the leading edges of ex‐ ternal elastic lamina (EEL) and the luminal contour. Minimal lumen diameter and reference diameter were measured and percentage of diameter stenosis was calculated. The composi‐ tion of coronary atheroma was assessed using spectral analysis of backscatter RF signals. The percentages of fibrotic, fibro-fatty, calcified and necrotic core were assessed. Atheroma area and volume and were obtained after EEL and lumen diameter (LD) measures were completed at the lumen/plaque boundary and at the media/adventitia boundary in each

Atheroma or plaque area (PA) was determined as the difference between EEL and lumen areas. The plaque burden was calculated as the plaque cross sectional area divided by the EEL area and multiplying by 100. IVUS measurements were recorded at three different re‐ gions-of-interest of the selected lesion: larger stenosis region cross-section and distal and proximal cross-sections. Median values and 25% and 75% quartile intervals for the various

Peripheral blood was drawn from all patients into blood collection tubes (Vacuette) with ap‐ propriate anti-coagulant, and centrifuged at 2500 rpm for 10 minutes. Serum and plasma were collected and stored at -80ºC until analysis, for a period not exceeding 6 months. Sam‐

Levels of glucose, creatinine kinase, troponin T, N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), blood cells count and lipid profile were routine‐ ly measured in the hospital. Plasma concentrations of ox-LDL and sFasL and serum concen‐ trations of TNF-α were measured by enzyme-linked immunosorbent assays (ELISA)

All the assays were performed according to the manufacturer's recommendations. Each sample was measured in duplicate; intra-assay variation among the duplicates for all sam‐

TIMI values contributed as 0 = no occlusion to 3 = total occlusion.

**2.4. Intravascular ultrasound (IVUS)**

cross-section forming the region of interest.

**2.5. Blood sampling and laboratory assays**

ples were thawed only once.

commercial kits (R&D Systems).

ples was <10%.

parameters measured and/or calculated are listed in Table 3.

poration, USA).

Data were summarized and represented (box-plots) as median and inter-quartiles 25% and 75% (Q25-Q75) for continuous variables and as proportions for categorical variables. Non-continuous variables were analyzed using a 2x2 table and χ2 test. Continuous varia‐ bles, such as plaque measures at proximal, distal and larger stenosis region cross-sec‐ tions of the plaque, transformed into categorical variables based on median values. Differences between classes of variables were compared using a Mann-Whitney test. As‐ sociations between variables, angiographic data and IVUS measures were evaluated us‐ ing non-parametric Spearman correlations.

However, when the plaque components were analyzed relative to the calcified tissue con‐ tent of plaques (cut-point and median value of 11%) only the plaque fibrotic content could be discriminated in the larger stenosis region (Q25-Q75=58.8-77.5% fibrotic tissue for calci‐

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39

**Figure 1.** Correlation of necrotic core (a and b) and calcified tissue (c and d) with fibrotic tissue (r=-0.677, p<0.001 and r=-0.743, p<0.001, respectively) and fibro-fatty tissue (r=-0.562, p<0.001, r=-0.421 and p=0.012, respectively) in the larger stenosis region. Solid line represents the linear regression, black dashed lines represent 95% confidence bands

**Figure 2.** Box-plots of plaque content in fibrotic (a), fibro-fatty (b) and calcified (c) tissues according to the necrotic

and grey dashed lines represent prediction bands.

core levels <16.5% and ≥16.5% in the larger stenosis region.

fied tissue <11%; Q25-Q75=33.1-58.7% fibrotic tissue for calcified tissue ≥11%; p<0.001).

The calculations were performed using SPSS (v. 19.0, IBM 2010) and linear regressions were made using OriginLab (v. 7.5 SR6, OriginaLab Comp, 2006).

## **3. Results**

The atherosclerotic plaque physical characteristics and composition obtained by IVUS were studied and related with the severity of CAD following CA scores. These parameters were also associated with plaque-related oxidative and inflammation bio-indicators measured in the blood. The inter-relations between the parameters measured are described below.

#### **3.1. Analysis of plaque components along the lesion**

The composition of the plaque along its length in terms of fibrotic, fibro-fatty, necrotic and calcified tissues assessed by IVUS-VH can be inferred from data listed in Table 3. Measure‐ ments were carried out along the plaque at three plaque regions. Therefore, larger stenosis region, proximal and distal cross-sections were studied.

The variations observed between proximal, distal and larger stenosis region cross-sections did not reach statistical significance, although major variations were also observed in fibrofatty and calcified tissues. To further analyze the plaque composition, the associations be‐ tween the fibrotic, fibro-fatty, calcified and necrotic components of the plaque were assessed.

In the overall, high fibrotic and fibro-fatty tissue contents were correlated to low content of calcified tissue and low necrotic core (Fig. 1).

The necrotic core content was positively correlated with calcified tissue (r=0.675, p<0.001). The correlation values were more representative in the region with larger stenosis, although the associations were observed in proximal and distal cross-sections.

Categorizing the plaque necrotic core and calcified tissue contents by the median value, it was confirmed that these two components were significantly associated with the fibrot‐ ic and fibro-fatty tissues. Plaques with large areas of necrotic core (≥16.5%) had low per‐ centage of fibrotic (p=0.001) and fibro-fatty (p=0.002) tissues and these levels were significantly different from those in plaques with necrotic core <16.5%. Moreover, the percentage of calcium content increased in plaques with necrotic core content ≥16.5% rel‐ ative to plaques with necrotic core below 16.5% (p=0.001) (Fig. 2). These differences were valid and equally significant along the plaque length, i.e. for distal, proximal and larger stenosis region cross-sections.

However, when the plaque components were analyzed relative to the calcified tissue con‐ tent of plaques (cut-point and median value of 11%) only the plaque fibrotic content could be discriminated in the larger stenosis region (Q25-Q75=58.8-77.5% fibrotic tissue for calci‐ fied tissue <11%; Q25-Q75=33.1-58.7% fibrotic tissue for calcified tissue ≥11%; p<0.001).

bles, such as plaque measures at proximal, distal and larger stenosis region cross-sec‐ tions of the plaque, transformed into categorical variables based on median values. Differences between classes of variables were compared using a Mann-Whitney test. As‐ sociations between variables, angiographic data and IVUS measures were evaluated us‐

38 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The calculations were performed using SPSS (v. 19.0, IBM 2010) and linear regressions were

The atherosclerotic plaque physical characteristics and composition obtained by IVUS were studied and related with the severity of CAD following CA scores. These parameters were also associated with plaque-related oxidative and inflammation bio-indicators measured in the blood. The inter-relations between the parameters measured are described below.

The composition of the plaque along its length in terms of fibrotic, fibro-fatty, necrotic and calcified tissues assessed by IVUS-VH can be inferred from data listed in Table 3. Measure‐ ments were carried out along the plaque at three plaque regions. Therefore, larger stenosis

The variations observed between proximal, distal and larger stenosis region cross-sections did not reach statistical significance, although major variations were also observed in fibrofatty and calcified tissues. To further analyze the plaque composition, the associations be‐ tween the fibrotic, fibro-fatty, calcified and necrotic components of the plaque were

In the overall, high fibrotic and fibro-fatty tissue contents were correlated to low content of

The necrotic core content was positively correlated with calcified tissue (r=0.675, p<0.001). The correlation values were more representative in the region with larger stenosis, although

Categorizing the plaque necrotic core and calcified tissue contents by the median value, it was confirmed that these two components were significantly associated with the fibrot‐ ic and fibro-fatty tissues. Plaques with large areas of necrotic core (≥16.5%) had low per‐ centage of fibrotic (p=0.001) and fibro-fatty (p=0.002) tissues and these levels were significantly different from those in plaques with necrotic core <16.5%. Moreover, the percentage of calcium content increased in plaques with necrotic core content ≥16.5% rel‐ ative to plaques with necrotic core below 16.5% (p=0.001) (Fig. 2). These differences were valid and equally significant along the plaque length, i.e. for distal, proximal and larger

the associations were observed in proximal and distal cross-sections.

ing non-parametric Spearman correlations.

**3. Results**

assessed.

made using OriginLab (v. 7.5 SR6, OriginaLab Comp, 2006).

**3.1. Analysis of plaque components along the lesion**

region, proximal and distal cross-sections were studied.

calcified tissue and low necrotic core (Fig. 1).

stenosis region cross-sections.

**Figure 1.** Correlation of necrotic core (a and b) and calcified tissue (c and d) with fibrotic tissue (r=-0.677, p<0.001 and r=-0.743, p<0.001, respectively) and fibro-fatty tissue (r=-0.562, p<0.001, r=-0.421 and p=0.012, respectively) in the larger stenosis region. Solid line represents the linear regression, black dashed lines represent 95% confidence bands and grey dashed lines represent prediction bands.

**Figure 2.** Box-plots of plaque content in fibrotic (a), fibro-fatty (b) and calcified (c) tissues according to the necrotic core levels <16.5% and ≥16.5% in the larger stenosis region.

#### **3.2. Association between plaque components and plaque morphology**

Measures of the EEL diameter and area, lumen diameter and area, plaque area and plaque burden were related with the plaque composition in order to assess whether the correlations between these parameters could identify plaque types. It was observed that associations be‐ tween morphology and components of the plaque varied along the lesion. The relationship between the plaque content in calcified and fibrotic tissues and plaque morphology was on‐ ly verified in proximal cross-sections of the plaques.

**3.3. Coronary angiography data versus IVUS measures**

95% confidence bands and grey dashed lines represent prediction bands.

measures and angiographic data and severity score.

as fibrotic, fibro-fatty and necrotic core, with CD4+

**measures**

point.

markers and plaque type.

The IVUS-derived measures of coronary atherosclerotic plaques were evaluated having into account the severity score established with angiographic data. Severity of CAD was found to be unambiguously associated to vessel lumen decrease and increased plaque burden. The severity score was negatively correlated with the plaque geometry IVUS VH-derived meas‐ ures, such as lumen diameter (r=-0.402, p=0.038) and lumen area (r=-0.419, p=0.03), and posi‐

Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by…

**Figure 5.** Correlation of angiographic severity with IVUS-derived measures of the atherosclerotic plaque: a) lumen di‐ ameter; b) lumen area; and c) plaque burden. Solid line represents the linear regression, black dashed lines represent

**3.4. Association of soluble biomarkers and T-cells with IVUS and angiography derived**

The relationship between the levels of indicators of oxidation and inflammation in the blood circulation with IVUS- and angiography-derived measures of the atherosclerotic plaque was examined with the aim of establishing relevant associations between bio‐

Indicators of the inflammatory process associated to cell activation and apoptosis, such as TNF-α and sFasL, were determined. Also the concentration of ox-LDL in circulation was as‐ sessed as a measure of plaque outflow and inflammation. The variations observed in the concentration levels of these parameters were studied relative to the plaque IVUS-derived

Several associations were observed between the plaque morphology and components, such

sFasL and ox-LDL concentrations in the blood circulation. Due to the limited number of pa‐ tients enrolled in this prospective study and to improve statistical results enabling the con‐ current evaluation of IVUS and angiographic data, including the severity score, IVUS variables (see variables listed in Table 3) were categorized using the median value as cut-off

and CD8+ T-cell populations and TNF-α,

http://dx.doi.org/10.5772/54084

41

tively correlated with plaque burden (r=0.496, p=0.009) as can be depicted in Fig. 5.

It was observed that the calcified tissue content was positively correlated with the EEL di‐ ameter (r=0.525, p=0.001), the EEL area (r=0.478, p=0.004) and plaque area (r=0.442, p=0.008) in proximal cross-sections (see Fig. 3).

**Figure 3.** Correlation of calcified tissue content in the proximal region with EEL maximum diameter (a) and plaque area (b). Solid line represents the linear regression, black dashed lines represent 95% confidence bands and grey dash‐ ed lines represent prediction bands.

Also in the proximal region of the plaques, the fibrotic content discriminated plaque sizes as expressed by the EEL diameter and area. Both EEL diameter and area were significantly higher for fibrotic tissue percentages below median value (<59%) by report to plaques with fibrotic tissue percentages above median (p=0.041) (Fig. 4).

**Figure 4.** Variations of EEL diameter (a) and area (b) according to fibrotic content <59% and ≥59% in the proximal region.

#### **3.3. Coronary angiography data versus IVUS measures**

**3.2. Association between plaque components and plaque morphology**

40 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

ly verified in proximal cross-sections of the plaques.

fibrotic tissue percentages above median (p=0.041) (Fig. 4).

in proximal cross-sections (see Fig. 3).

ed lines represent prediction bands.

Measures of the EEL diameter and area, lumen diameter and area, plaque area and plaque burden were related with the plaque composition in order to assess whether the correlations between these parameters could identify plaque types. It was observed that associations be‐ tween morphology and components of the plaque varied along the lesion. The relationship between the plaque content in calcified and fibrotic tissues and plaque morphology was on‐

It was observed that the calcified tissue content was positively correlated with the EEL di‐ ameter (r=0.525, p=0.001), the EEL area (r=0.478, p=0.004) and plaque area (r=0.442, p=0.008)

**Figure 3.** Correlation of calcified tissue content in the proximal region with EEL maximum diameter (a) and plaque area (b). Solid line represents the linear regression, black dashed lines represent 95% confidence bands and grey dash‐

Also in the proximal region of the plaques, the fibrotic content discriminated plaque sizes as expressed by the EEL diameter and area. Both EEL diameter and area were significantly higher for fibrotic tissue percentages below median value (<59%) by report to plaques with

**Figure 4.** Variations of EEL diameter (a) and area (b) according to fibrotic content <59% and ≥59% in the proximal region.

The IVUS-derived measures of coronary atherosclerotic plaques were evaluated having into account the severity score established with angiographic data. Severity of CAD was found to be unambiguously associated to vessel lumen decrease and increased plaque burden. The severity score was negatively correlated with the plaque geometry IVUS VH-derived meas‐ ures, such as lumen diameter (r=-0.402, p=0.038) and lumen area (r=-0.419, p=0.03), and posi‐ tively correlated with plaque burden (r=0.496, p=0.009) as can be depicted in Fig. 5.

**Figure 5.** Correlation of angiographic severity with IVUS-derived measures of the atherosclerotic plaque: a) lumen di‐ ameter; b) lumen area; and c) plaque burden. Solid line represents the linear regression, black dashed lines represent 95% confidence bands and grey dashed lines represent prediction bands.

#### **3.4. Association of soluble biomarkers and T-cells with IVUS and angiography derived measures**

The relationship between the levels of indicators of oxidation and inflammation in the blood circulation with IVUS- and angiography-derived measures of the atherosclerotic plaque was examined with the aim of establishing relevant associations between bio‐ markers and plaque type.

Indicators of the inflammatory process associated to cell activation and apoptosis, such as TNF-α and sFasL, were determined. Also the concentration of ox-LDL in circulation was as‐ sessed as a measure of plaque outflow and inflammation. The variations observed in the concentration levels of these parameters were studied relative to the plaque IVUS-derived measures and angiographic data and severity score.

Several associations were observed between the plaque morphology and components, such as fibrotic, fibro-fatty and necrotic core, with CD4+ and CD8+ T-cell populations and TNF-α, sFasL and ox-LDL concentrations in the blood circulation. Due to the limited number of pa‐ tients enrolled in this prospective study and to improve statistical results enabling the con‐ current evaluation of IVUS and angiographic data, including the severity score, IVUS variables (see variables listed in Table 3) were categorized using the median value as cut-off point.

Following this procedure, and in what concerns soluble biomarkers, it was observed that sFasL, TNF-α and ox-LDL levels in circulation were strongly associated to the median val‐ ues of lumen and plaque dimensions.

significantly lowered TNF-α concentrations (p=0.016) observed in plaques with large necrot‐

Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by…

**Figure 8.** Box-plot representation of TNF-α concentrations according to the necrotic core categories in the larger

In what concerns T-cell CD3+ populations expressing CD4 and CD8, it was observed that the percentage of T-cells expressing CD3CD8 were associated with the plaque dimensions (T-

CD8<sup>+</sup>

and fibro-fatty tissue components along the plaque length, i.e. from distal to proximal re‐

**Figure 9.** Correlation between plaque fibro-fatty and fibrotic tissue content and CD4+ and CD8+ T lymphocytes. Solid line represents the linear regression, black dashed lines represent 95% confidence bands and grey dashed lines repre‐

CD8<sup>+</sup>

lymphocytes were positively correlated with fibrotic tissue

CD8<sup>+</sup> cells were negatively correlated (r=-0.481, p=0.037) (see

, were correlated with the plaque fibrotic

vs EEL area r=-0.530,

http://dx.doi.org/10.5772/54084

43

vs EEL diameter r=-0.518, p=0.019; T-cell CD3<sup>+</sup>

and CD3+

CD4+

CD4+

ic cores (≥16.5%) (Fig. 8)

stenosis region, <16.5 % and ≥16.5 %.

CD8<sup>+</sup>

gions. Likely, CD3<sup>+</sup>

Fig. 9 a and c).

sent prediction bands.

p=0.016). T-cells, both CD3<sup>+</sup>

(r=0.579, p=0.009) whereas CD3<sup>+</sup>

cell CD3+

The concentration of TNF-α significantly increased for large plaque areas, as expressed by EEL diameter and area (p=0.05 in both cases), whereas sFasL concentrations increased with diminished lumen diameters (p=0.017), as can be depicted in Fig. 6.

**Figure 6.** Box-plot representation of the TNF-α and sFasL concentrations relative to indicators of plaque dimensions: a) EEL diameter categories <4.6 mm and ≥4.6 mm; b) EEL area categories <17.2 mm2 and ≥17.2mm2; c) Lumen diameter categories <2.1 mm and ≥2.1 mm

The concentrations of ox-LDL in plasma were significantly associated with plaque area as can be depicted in Fig. 7. Large plaque areas, above median value (area ≥13 mm2 ), were as‐ sociated with high ox-LDL concentrations whereas plaque areas below 13 mm2 were associ‐ ated with low ox-LDL concentrations, and the differences between median concentration values of ox-LDL in the two groups were significant (p=0.039).

**Figure 7.** Box-plot representation of ox-LDL concentrations according to plaque area categories <13 mm2 and ≥13 mm2.

Concerning the plaque components, only the necrotic content assessed in the plaque region with larger stenosis could be associated with TNF-α concentration in circulation. High con‐ centrations of TNF-α were associated with low necrotic core contents contrasting with the significantly lowered TNF-α concentrations (p=0.016) observed in plaques with large necrot‐ ic cores (≥16.5%) (Fig. 8)

Following this procedure, and in what concerns soluble biomarkers, it was observed that sFasL, TNF-α and ox-LDL levels in circulation were strongly associated to the median val‐

42 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The concentration of TNF-α significantly increased for large plaque areas, as expressed by EEL diameter and area (p=0.05 in both cases), whereas sFasL concentrations increased with

**Figure 6.** Box-plot representation of the TNF-α and sFasL concentrations relative to indicators of plaque dimensions: a) EEL diameter categories <4.6 mm and ≥4.6 mm; b) EEL area categories <17.2 mm2 and ≥17.2mm2; c) Lumen diameter

The concentrations of ox-LDL in plasma were significantly associated with plaque area as

sociated with high ox-LDL concentrations whereas plaque areas below 13 mm2 were associ‐ ated with low ox-LDL concentrations, and the differences between median concentration

**Figure 7.** Box-plot representation of ox-LDL concentrations according to plaque area categories <13 mm2 and ≥13

Concerning the plaque components, only the necrotic content assessed in the plaque region with larger stenosis could be associated with TNF-α concentration in circulation. High con‐ centrations of TNF-α were associated with low necrotic core contents contrasting with the

), were as‐

can be depicted in Fig. 7. Large plaque areas, above median value (area ≥13 mm2

values of ox-LDL in the two groups were significant (p=0.039).

diminished lumen diameters (p=0.017), as can be depicted in Fig. 6.

ues of lumen and plaque dimensions.

categories <2.1 mm and ≥2.1 mm

mm2.

**Figure 8.** Box-plot representation of TNF-α concentrations according to the necrotic core categories in the larger stenosis region, <16.5 % and ≥16.5 %.

In what concerns T-cell CD3+ populations expressing CD4 and CD8, it was observed that the percentage of T-cells expressing CD3CD8 were associated with the plaque dimensions (Tcell CD3+ CD8<sup>+</sup> vs EEL diameter r=-0.518, p=0.019; T-cell CD3<sup>+</sup> CD8<sup>+</sup> vs EEL area r=-0.530, p=0.016). T-cells, both CD3<sup>+</sup> CD4+ and CD3+ CD8<sup>+</sup> , were correlated with the plaque fibrotic and fibro-fatty tissue components along the plaque length, i.e. from distal to proximal re‐ gions. Likely, CD3<sup>+</sup> CD4+ lymphocytes were positively correlated with fibrotic tissue (r=0.579, p=0.009) whereas CD3<sup>+</sup> CD8<sup>+</sup> cells were negatively correlated (r=-0.481, p=0.037) (see Fig. 9 a and c).

**Figure 9.** Correlation between plaque fibro-fatty and fibrotic tissue content and CD4+ and CD8+ T lymphocytes. Solid line represents the linear regression, black dashed lines represent 95% confidence bands and grey dashed lines repre‐ sent prediction bands.

An opposite relationship was found between fibro-fatty tissue component and CD3+ CD4+ lymphocytes (Fig. 9 b and d). The CD3+ CD4+ lymphocytes were negatively correlated with fibro-fatty tissue (r =-0.671, p=0.002) and CD3+ CD8+ were positively correlated (r=0.698, p=0.001).

the extent of vascular inflammation. Also the relationship found between TNF-α concentra‐ tion in blood and the percentage of necrotic core area suggests an association between an exacerbation of inflammation and the thinning of the fibrous cap with increases of fibrous

Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by…

In addition the process of apoptosis is an important mechanism in the pathophysiology of atherosclerosis. Atherosclerotic plaques include large numbers of apoptotic cells and related receptors, such as FasL, which is a type II membrane protein that induces apoptosis when it binds to its membrane receptor Fas. FasL is expressed by activated T lymphocytes, as well as endothelial cells [49]. It was observed in this study that decreases of lumen diameter as oc‐ curring in disease exacerbation, favored the elevation of sFasL in circulation. This supports the view that one of the control mechanisms elicited by FasL in CAD may be the prevention of inflammation by destruction of the activated inflammatory cells invading vascular tissues via FasL/Fas-mediated apoptosis [49,50]. In fact, in this study the percentage of T-cells ex‐ pressing CD4 and CD8 were associated to the percentage of fibrous and fibro-fatty area rein‐ forcing the notion that Th1 cellular immunity is taking place during the disease process [6].

plaque percentage of fibrous and fibro-fatty areas, as observed in this study call the atten‐ tion for the balanced action of these immune cells in CAD. However, the role of specific im‐ mune responses has remained unclear. Evidence is accumulating that T-cells homing the vessel wall contribute to inflammation [6,9] and that T-cell expressing CD4 promote athero‐ sclerosis particularly when activated by LDL modified by oxidative processes [26,27]. The T-

produce different effectors molecules and then effect different cells and pathways, although redundancy of mechanisms has been described pointing to the importance of lymphocyte

The positive association of plaque area with ox-LDL concentrations in plasma can also be considered a marker of plaque instability and/or plaque rupture [51,52] in addition to dis‐ ease severity. Extensive experimental data shows that ox-LDL is formed in the arterial wall [14,16] contributing to the plaque progression. It is accepted that ox-LDL in circulation is ori‐ ginated in the vessel wall, being their circulating levels strongly associated to angiographi‐ cally documented CAD [25]. Increases in plaque area, and therefore in regions where lumen decreases relative to circumferential EEL, may favor plaque outflow. In these regions the vessel wall is exposed to shear stress that may contribute to endothelial denuding and pla‐

The current forms of imaging enable atherosclerosis assessment at the later stage when the vascular morphology has changed dramatically. However, the evaluation of plaque charac‐ teristics by angiography and IVUS-VH was associated to circulating biomarkers levels, and these indicators may reflect plaque vulnerability. The *in vivo* identification of plaque vulner‐ ability whether by characterizing its components or by providing measures of oxidative and inflammation markers may improve diagnostic and eventually allow the detection of vul‐ nerable atheroma before rupture. The relations among the plaque components – fibrotic, fi‐ bro-fatty calcified and necrotic core – and plaque dimensions, may be important in the

cells expressing CD8, when activated, trigger caspase pathways. However, CD4+

and CD8+

T-cells and the

http://dx.doi.org/10.5772/54084

45

and CD8+

T

and fibro-fatty areas as plaque evolves [30,31].

homeostasis in disease.

que cap erosion [47].

Also, the opposite relationship between the percentage of CD4+

### **4. Discussion**

This prospective study showed that plaque composition is related to plaque morphology and these characteristics were associated with the concentration of biomarkers in blood circulation.

Plaques with higher content in necrotic core showed lower fibrotic and fibro-fatty contents and larger areas of calcified tissue. Increased EEL diameter and area were associated to larg‐ er fibrotic and calcium contents, linking these two components to plaques protruding in the vessel wall rather than high-stenosis regions. Together these observations suggest that pla‐ que vulnerability is not strictly linked to high-grade stenosis. Also the angiographic disease severity score was associated with plaque burden. This is in agreement with previous stud‐ ies demonstrating that plaque ruptures typically occur in large and complex plaques [1,30], and that coronary calcification is associated to acute coronary syndromes [37] and independ‐ ently predicts all-cause mortality in CAD in addition to traditional risk factors [46]. Prior studies reported that shear stress and circumferential wall stress play an important role in plaque rupture [47]. Sano *et al.* [31] demonstrated that the percentage of fibrous area was the most sensitive parameter for classifying the plaques causing acute coronary syndrome. Also the percentage of lipid area was significant in the classification of vulnerable plaques [31]. Evidences are accumulating by coronary angiography and IVUS and other imaging modali‐ ties showing that plaque complexity associates to vulnerable plaques [11,31,37]. Therefore, to differentiate vulnerable plaques from stable plaques, the fragile part of the atheromatous plaque is of major interest and both tissue characteristics of coronary plaques and mechani‐ cal stresses on coronary plaques should be taken into account.

Plaque rupture is related to the process in which fibrous caps over lipid core become fragile [3]. Several *in vitro* studies support that continuous inflammatory stimulus in the plaque driven by the infiltration of monocytes, macrophages and T-lymphocytes in the lesion, ulti‐ mately lead to disintegration of foam cells, and release of cytokines, such as TNF-α, and ma‐ trix metalloproteinases [6,7,18-20]. All this causes the destabilization of plaque lipid rich cores and the thinning of the fibrous cap [3,8].

We have preciously demonstrated [48] that the susceptibility of a plaque to rupture is not strictly linked to significant stenosis. This prospective study supports our previous findings as positive associations between plaque dimensions i.e., EEL diameter and area independent of high-stenosis regions, and the concentrations of TNF-α were found. TNF-α is involved in endothelial cells activation and in the inflammatory response amplification [9,20]. Increasing levels of this pro-inflammatory cytokine promote a continuous systemic inflammatory stim‐ ulation that can trigger and/or amplify local inflammatory responses and therefore express the extent of vascular inflammation. Also the relationship found between TNF-α concentra‐ tion in blood and the percentage of necrotic core area suggests an association between an exacerbation of inflammation and the thinning of the fibrous cap with increases of fibrous and fibro-fatty areas as plaque evolves [30,31].

An opposite relationship was found between fibro-fatty tissue component and CD3+

44 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

This prospective study showed that plaque composition is related to plaque morphology and these characteristics were associated with the concentration of biomarkers in blood

Plaques with higher content in necrotic core showed lower fibrotic and fibro-fatty contents and larger areas of calcified tissue. Increased EEL diameter and area were associated to larg‐ er fibrotic and calcium contents, linking these two components to plaques protruding in the vessel wall rather than high-stenosis regions. Together these observations suggest that pla‐ que vulnerability is not strictly linked to high-grade stenosis. Also the angiographic disease severity score was associated with plaque burden. This is in agreement with previous stud‐ ies demonstrating that plaque ruptures typically occur in large and complex plaques [1,30], and that coronary calcification is associated to acute coronary syndromes [37] and independ‐ ently predicts all-cause mortality in CAD in addition to traditional risk factors [46]. Prior studies reported that shear stress and circumferential wall stress play an important role in plaque rupture [47]. Sano *et al.* [31] demonstrated that the percentage of fibrous area was the most sensitive parameter for classifying the plaques causing acute coronary syndrome. Also the percentage of lipid area was significant in the classification of vulnerable plaques [31]. Evidences are accumulating by coronary angiography and IVUS and other imaging modali‐ ties showing that plaque complexity associates to vulnerable plaques [11,31,37]. Therefore, to differentiate vulnerable plaques from stable plaques, the fragile part of the atheromatous plaque is of major interest and both tissue characteristics of coronary plaques and mechani‐

Plaque rupture is related to the process in which fibrous caps over lipid core become fragile [3]. Several *in vitro* studies support that continuous inflammatory stimulus in the plaque driven by the infiltration of monocytes, macrophages and T-lymphocytes in the lesion, ulti‐ mately lead to disintegration of foam cells, and release of cytokines, such as TNF-α, and ma‐ trix metalloproteinases [6,7,18-20]. All this causes the destabilization of plaque lipid rich

We have preciously demonstrated [48] that the susceptibility of a plaque to rupture is not strictly linked to significant stenosis. This prospective study supports our previous findings as positive associations between plaque dimensions i.e., EEL diameter and area independent of high-stenosis regions, and the concentrations of TNF-α were found. TNF-α is involved in endothelial cells activation and in the inflammatory response amplification [9,20]. Increasing levels of this pro-inflammatory cytokine promote a continuous systemic inflammatory stim‐ ulation that can trigger and/or amplify local inflammatory responses and therefore express

lymphocytes (Fig. 9 b and d). The CD3+

(r=0.698, p=0.001).

**4. Discussion**

circulation.

with fibro-fatty tissue (r =-0.671, p=0.002) and CD3+

cal stresses on coronary plaques should be taken into account.

cores and the thinning of the fibrous cap [3,8].

CD4+

CD4+ lymphocytes were negatively correlated

CD8+ were positively correlated

In addition the process of apoptosis is an important mechanism in the pathophysiology of atherosclerosis. Atherosclerotic plaques include large numbers of apoptotic cells and related receptors, such as FasL, which is a type II membrane protein that induces apoptosis when it binds to its membrane receptor Fas. FasL is expressed by activated T lymphocytes, as well as endothelial cells [49]. It was observed in this study that decreases of lumen diameter as oc‐ curring in disease exacerbation, favored the elevation of sFasL in circulation. This supports the view that one of the control mechanisms elicited by FasL in CAD may be the prevention of inflammation by destruction of the activated inflammatory cells invading vascular tissues via FasL/Fas-mediated apoptosis [49,50]. In fact, in this study the percentage of T-cells ex‐ pressing CD4 and CD8 were associated to the percentage of fibrous and fibro-fatty area rein‐ forcing the notion that Th1 cellular immunity is taking place during the disease process [6]. Also, the opposite relationship between the percentage of CD4+ and CD8+ T-cells and the plaque percentage of fibrous and fibro-fatty areas, as observed in this study call the atten‐ tion for the balanced action of these immune cells in CAD. However, the role of specific im‐ mune responses has remained unclear. Evidence is accumulating that T-cells homing the vessel wall contribute to inflammation [6,9] and that T-cell expressing CD4 promote athero‐ sclerosis particularly when activated by LDL modified by oxidative processes [26,27]. The Tcells expressing CD8, when activated, trigger caspase pathways. However, CD4+ and CD8+ T produce different effectors molecules and then effect different cells and pathways, although redundancy of mechanisms has been described pointing to the importance of lymphocyte homeostasis in disease.

The positive association of plaque area with ox-LDL concentrations in plasma can also be considered a marker of plaque instability and/or plaque rupture [51,52] in addition to dis‐ ease severity. Extensive experimental data shows that ox-LDL is formed in the arterial wall [14,16] contributing to the plaque progression. It is accepted that ox-LDL in circulation is ori‐ ginated in the vessel wall, being their circulating levels strongly associated to angiographi‐ cally documented CAD [25]. Increases in plaque area, and therefore in regions where lumen decreases relative to circumferential EEL, may favor plaque outflow. In these regions the vessel wall is exposed to shear stress that may contribute to endothelial denuding and pla‐ que cap erosion [47].

The current forms of imaging enable atherosclerosis assessment at the later stage when the vascular morphology has changed dramatically. However, the evaluation of plaque charac‐ teristics by angiography and IVUS-VH was associated to circulating biomarkers levels, and these indicators may reflect plaque vulnerability. The *in vivo* identification of plaque vulner‐ ability whether by characterizing its components or by providing measures of oxidative and inflammation markers may improve diagnostic and eventually allow the detection of vul‐ nerable atheroma before rupture. The relations among the plaque components – fibrotic, fi‐ bro-fatty calcified and necrotic core – and plaque dimensions, may be important in the characterization of the plaque and in the assessment of its development. Also, circulating ox-LDL, sFasL, TNF-α and lymphocyte populations may be viable targets to follow as they may reflect the global extend of atherosclerosis and may provide useful information on pa‐ tient's evolution, together with quantitative angiography-derived plaque parameters. The approach may be incorporated in carefully designed clinical studies for the assessment of coronary atherosclerosis.

**Acknowledgements**

**Author details**

Catarina Ramos1

tugal

Miguel Mota Carmo4

tral, Lisboa, Portugal

Lisboa, Lisboa, Portugal

**References**

This work was supported by Fundação para a Ciência e Tecnologia (PIC/IC/82734/2007 and

Relationship Between Ox–LDL, Immune Cells, Atheroma Dimensions and Angiographic Measurements Assessed by…

, Rui Cruz Ferreira3

1 IST/ITN Instituto Superior Técnico, Universidade Técnica de Lisboa, Sacavém, Portugal

2 Unidade de Biologia Microvascular e Inflamação, Instituto de Medicina Molecular, Facul‐

3 Serviço Cardiologia, Hospital Santa Marta, Centro Hospitalar Lisboa Central, Lisboa, Por‐

4 Centro de Estudos de Doenças Crónicas, Faculdade de Ciências Médicas, Universidade Nova de Lisboa & Serviço Cardiologia, Hospital Santa Marta Centro Hospitalar Lisboa Cen‐

CESAM & Departamento de Biologia Animal, Faculdade de Ciências da Universidade de

[1] Hoffmann U, Moselewski F, Nieman K, Jang IK, Ferencik M, Rahman AM, Cury RC, Abbara S, Joneidi-Jafari H, Achenbach S, Brady TJ, Noninvasive Assessment of Pla‐ que Morphology and Composition in Culprit and Stable Lesions in Acute Coronary Syndrome and Stable Lesions in Stable Angina by Multidetector Computed Tomog‐

[2] Red-Horse K, Ueno H, Weissman IL, Krasnow MA, Coronary arteries form by devel‐

[3] Stone GW, Maehara A, Mintz GS, The Reality of Vulnerable Plaque Detection, JACC:

[4] Roger VL, Go AS, Lloyd-Jones DM, Adams RJ,. Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G,. Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ,. Hail‐

opmental reprogramming of venous cells, Nature 2010; 464: 549-553

and Teresa Pinheiro1\*

, Cristina Fondinho3

, Mafalda Selas3

http://dx.doi.org/10.5772/54084

,

47

SFRM/BPD/6308/2009); and by Liga dos Amigos do Hospital de Santa Marta.

, Patrícia Napoleão2

\*Address all correspondence to: murmur@itn.pt

, Ana Maria Crespo4

dade de Medicina da Universidade de Lisboa, Lisboa, Portugal

raphy, Am Coll Cardiol 2006; 47: 1655– 62

Cardiovascular Imaging 2011; 4: 902-904

#### **5. Study limitations**

This prospective study is a single-centre study that has a number of limitations. The small number of patients enrolled did not allow association of parameters with clinical presenta‐ tion. The measurements of biomarkers that entered into the study do not reflect chronic cir‐ culating levels, as more than 50% of patients presented with acute coronary syndromes (STEMI, NSTEMI and UA), which transiently alters levels of inflammatory biomarkers. Some of the measurements may be confounded by concomitant treatments (medication, stenting, etc.), which could not be estimated due to the reduced number of patients. We also wish to emphasize that all angiography and IVUS studies are limited to the analysis of a rel‐ atively short segment of coronary arterial tree that does not fully reflect disease characteris‐ tics elsewhere. The results obtained of plaque components were not confirmed by histology or other diagnostic modalities, such as optical coherent tomography.

#### **6. Conclusions**

The present study using angiography and IVUS-VH revealed that the atherosclerotic plaque components and dimensions were related to the concentration of biomarkers in the blood circulation. We reported on the vascular tissue characteristics that may be associated with vulnerable plaques and the incremental value of biomarkers in addition to invasive imaging modalities.

The association of ox-LDL, sFasL and TNF-α circulating levels with lumen dimension and plaque dimension suggest that these indicators may express not only plaque rupture but plaque vulnerability as well. Also the association of TNF-α and T lymphocytes expressing CD4 and CD8 with plaque percentage of fibrous, fibro-fatty, and necrotic core areas may contribute to an in vivo assessment of vascular inflammation and vulnerable plaques and their detection before rupture.

The results suggest that these biomarkers have clinical implications for identifying vul‐ nerable plaques as well as vulnerable patients. Further studies are needed to evaluate the impact of these biomarkers and angiography and IVUS-VH derived measures on clinical presentation.

## **Acknowledgements**

characterization of the plaque and in the assessment of its development. Also, circulating ox-LDL, sFasL, TNF-α and lymphocyte populations may be viable targets to follow as they may reflect the global extend of atherosclerosis and may provide useful information on pa‐ tient's evolution, together with quantitative angiography-derived plaque parameters. The approach may be incorporated in carefully designed clinical studies for the assessment of

46 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

This prospective study is a single-centre study that has a number of limitations. The small number of patients enrolled did not allow association of parameters with clinical presenta‐ tion. The measurements of biomarkers that entered into the study do not reflect chronic cir‐ culating levels, as more than 50% of patients presented with acute coronary syndromes (STEMI, NSTEMI and UA), which transiently alters levels of inflammatory biomarkers. Some of the measurements may be confounded by concomitant treatments (medication, stenting, etc.), which could not be estimated due to the reduced number of patients. We also wish to emphasize that all angiography and IVUS studies are limited to the analysis of a rel‐ atively short segment of coronary arterial tree that does not fully reflect disease characteris‐ tics elsewhere. The results obtained of plaque components were not confirmed by histology

The present study using angiography and IVUS-VH revealed that the atherosclerotic plaque components and dimensions were related to the concentration of biomarkers in the blood circulation. We reported on the vascular tissue characteristics that may be associated with vulnerable plaques and the incremental value of biomarkers in addition to invasive imaging

The association of ox-LDL, sFasL and TNF-α circulating levels with lumen dimension and plaque dimension suggest that these indicators may express not only plaque rupture but plaque vulnerability as well. Also the association of TNF-α and T lymphocytes expressing CD4 and CD8 with plaque percentage of fibrous, fibro-fatty, and necrotic core areas may contribute to an in vivo assessment of vascular inflammation and vulnerable plaques and

The results suggest that these biomarkers have clinical implications for identifying vul‐ nerable plaques as well as vulnerable patients. Further studies are needed to evaluate the impact of these biomarkers and angiography and IVUS-VH derived measures on clinical

or other diagnostic modalities, such as optical coherent tomography.

coronary atherosclerosis.

**5. Study limitations**

**6. Conclusions**

modalities.

presentation.

their detection before rupture.

This work was supported by Fundação para a Ciência e Tecnologia (PIC/IC/82734/2007 and SFRM/BPD/6308/2009); and by Liga dos Amigos do Hospital de Santa Marta.

## **Author details**

Catarina Ramos1 , Patrícia Napoleão2 , Rui Cruz Ferreira3 , Cristina Fondinho3 , Mafalda Selas3 , Miguel Mota Carmo4 , Ana Maria Crespo4 and Teresa Pinheiro1\*

\*Address all correspondence to: murmur@itn.pt

1 IST/ITN Instituto Superior Técnico, Universidade Técnica de Lisboa, Sacavém, Portugal

2 Unidade de Biologia Microvascular e Inflamação, Instituto de Medicina Molecular, Facul‐ dade de Medicina da Universidade de Lisboa, Lisboa, Portugal

3 Serviço Cardiologia, Hospital Santa Marta, Centro Hospitalar Lisboa Central, Lisboa, Por‐ tugal

4 Centro de Estudos de Doenças Crónicas, Faculdade de Ciências Médicas, Universidade Nova de Lisboa & Serviço Cardiologia, Hospital Santa Marta Centro Hospitalar Lisboa Cen‐ tral, Lisboa, Portugal

CESAM & Departamento de Biologia Animal, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal

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**Section 2**

**Noninvasive Diagnostic Approach in Coronary**

**Artery Disease**


**Noninvasive Diagnostic Approach in Coronary Artery Disease**

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E161.

**Chapter 3**

**Radiation Principles and Safety**

Additional information is available at the end of the chapter

Interventional cardiology today without the use of x-ray technology cannot even be imag‐ ined. This is also true for medicine in general. The radiology era begins with the discovery of the x-rays by Wilhelm Conrad Röntgen, on the November 8th 1895 (following the translit‐ eration conventions for the characters accentuated by 'umlaut', "Röntgen" is in English spel‐ led "Roentgen", and with that spelling is most often found in the literature). On that day he produced and detected for the first time the electromagnetic radiation in the wavelengths today known as the x-rays, for which he received the Nobel prize for physics in 1901 [1]. This was the start of radiology, which has developed tremendously over the years. In time, radiology adopted other forms of human body imaging (magnetic resonance, positron emis‐ sion tomography etc.), but even today the most radiologic studies in the world are per‐ formed using the x-rays, whether in the form of classic x-ray imaging, computer tomography, or various forms of fluoroscopy and/or fluorography, which is used in inter‐ ventional cardiology. The term 'fluoroscopy' depicts viewing of structures in real time, while 'fluorography' means that different methods of image aquisition and storage for later review

X-ray radiation is a form of electromagnetic radiation. X-rays are electromagnetic waves with a wavelength in the range of 0.01 to 10 nanometers, which corresponds to frequencies in the range 30 petahertz to 30 exahertz (3×1016 Hz to 3×1019 Hz) and energies in the range 120 eV to 120 keV. X-rays are shorter in wavelength than ultra-violet rays and longer than gamma rays. In many languages, X-radiation is called Röntgen radiation, after Wilhelm Conrad Röntgen, who is usually credited as its discoverer, and who had actually named it

X-ray input doses for fluorography are generally 10-fold higher than those used for fluo‐ roscopy. This is why fluorography is the major source of the radiation dose [2]. Proce‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Čaluk; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

X-radiation to signify the up to then unknown type of radiation [1].

Jasmin Čaluk

**1. Introduction**

are being used.

http://dx.doi.org/10.5772/54033

## **Chapter 3**

## **Radiation Principles and Safety**

Jasmin Čaluk

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54033

## **1. Introduction**

Interventional cardiology today without the use of x-ray technology cannot even be imag‐ ined. This is also true for medicine in general. The radiology era begins with the discovery of the x-rays by Wilhelm Conrad Röntgen, on the November 8th 1895 (following the translit‐ eration conventions for the characters accentuated by 'umlaut', "Röntgen" is in English spel‐ led "Roentgen", and with that spelling is most often found in the literature). On that day he produced and detected for the first time the electromagnetic radiation in the wavelengths today known as the x-rays, for which he received the Nobel prize for physics in 1901 [1]. This was the start of radiology, which has developed tremendously over the years. In time, radiology adopted other forms of human body imaging (magnetic resonance, positron emis‐ sion tomography etc.), but even today the most radiologic studies in the world are per‐ formed using the x-rays, whether in the form of classic x-ray imaging, computer tomography, or various forms of fluoroscopy and/or fluorography, which is used in inter‐ ventional cardiology. The term 'fluoroscopy' depicts viewing of structures in real time, while 'fluorography' means that different methods of image aquisition and storage for later review are being used.

X-ray radiation is a form of electromagnetic radiation. X-rays are electromagnetic waves with a wavelength in the range of 0.01 to 10 nanometers, which corresponds to frequencies in the range 30 petahertz to 30 exahertz (3×1016 Hz to 3×1019 Hz) and energies in the range 120 eV to 120 keV. X-rays are shorter in wavelength than ultra-violet rays and longer than gamma rays. In many languages, X-radiation is called Röntgen radiation, after Wilhelm Conrad Röntgen, who is usually credited as its discoverer, and who had actually named it X-radiation to signify the up to then unknown type of radiation [1].

X-ray input doses for fluorography are generally 10-fold higher than those used for fluo‐ roscopy. This is why fluorography is the major source of the radiation dose [2]. Proce‐

© 2013 Čaluk; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

dures which include the use of x-rays are associated with the exposure of the patients to a certain amount of x-ray radiation, and in some cases, especially in interventional cardi‐ ology, the staff is also exposed to this form of radiation. The constant evolution of inter‐ ventional cardiology, with ever more complex procedures demanding prolonged fluoroscopy and fluorography time, as well as the demands for better imaging of small structures (guidewires, angioplasty balloon- and stent-markers, stents themselves, intra‐ vascular ultrasound probes, etc.) associated with higher exposures to larger amounts of x-ray radiation, have all raised the question of radiation protection, both for the patients and the staff inside the catheterization laboratory (cath lab). Occupational doses of radia‐ tion in interventional cardiology procedures guided by fluoroscopy are the highest doses registered among medical staff using x-rays. The use of ionizing radiation increases the risk of malignant disease occurrence and can cause skin or eye damage to both the pa‐ tient and the personnel [3].

the anode is being rotated, the focal spot is actually the already described circular track on the anode disc. The size of the focal spot affects the image quality in different ways. If it is smaller, the images are sharper, but if it is larger, it can produce more x-rays. The cathode is a tungsten wire, and is the source of electrons which are accelerated towards the anode. The cathode is heated to high temperatures by passing the current through it, and is maintained at a large negative voltage relative to the anode. The electrons are 'fired away' from it and accelerate toward the anode, hitting it as they reach their maxi‐

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 57

**Figure 1.** The x-ray tube. Legend: A – housing; B – oil bath for cooling; C – cathode; D – electron beam; E – collimators;

F – filters; G – x-rays; H – anode; I – engine for anode rotation (illustration: J. Čaluk).

mum energy, which is 60 kV to 120 kV.

#### **2. How the x-ray radiation is produced**

#### **2.1. The x-ray tube**

The principle of generating the x-rays is basically the same in all x-ray machines. The source of x-rays is the x-ray tube (fig.1, fig. 2). Within it are the cathode and the anode (fig. 1). The electrically positive tungsten anode is bombarded with accelerated electrons originating from the electrically negative cathode. When the high-velocity electrons col‐ lide with the anode, they lose most of their energy (~99%) as heat, and a small fraction (~1%) as x-rays. Since the electrons are slowed down within the anode by different seg‐ ments of atoms and mostly multiple interactions with several atoms within the material itself, they release a variety of x-ray energies. However, when all of the electron's ener‐ gy is lost in a single interaction, the resultant emitted x-ray has the highest possible en‐ ergy, equivalent to the voltage applied across the tube. That is reffered to as the kVp, or 'peak kilovoltage' of the emitted x-rays. A typical x-ray tube ranges from 60 kV to 120 kV. The tube current, measured in milliamperes (mA) is defined as the number of elec‐ trons that arc from the cathode to the anode per second [4]. Modern x-ray tubes gener‐ ate the radiation in pulses rather than in a continuous form, and those pulses are synchronized with the other components in the fluoroscopic/fluorographic system. The duration of the time during which the electrons hit the anode is the pulse width, and is measured in milliseconds (ms).

The anode is made of tungsten because this material can withstand very high tempera‐ tures without melting. As stated before, some 99% of the energy which the electron beam is losing when hitting the anode is heat. The anode is constructed as a disc, and to reduce the heat strain even more, it is constantly rotated at speeds up to 10,000 rpm (fig. 1). This way, the area bombarded by the small electron beam is not actually a single spot, but a circle track. The small area of the anode which is being bombarded by the electron beam, and from which the x-rays are emitted is called the 'focal spot', and since the anode is being rotated, the focal spot is actually the already described circular track on the anode disc. The size of the focal spot affects the image quality in different ways. If it is smaller, the images are sharper, but if it is larger, it can produce more x-rays. The cathode is a tungsten wire, and is the source of electrons which are accelerated towards the anode. The cathode is heated to high temperatures by passing the current through it, and is maintained at a large negative voltage relative to the anode. The electrons are 'fired away' from it and accelerate toward the anode, hitting it as they reach their maxi‐ mum energy, which is 60 kV to 120 kV.

dures which include the use of x-rays are associated with the exposure of the patients to a certain amount of x-ray radiation, and in some cases, especially in interventional cardi‐ ology, the staff is also exposed to this form of radiation. The constant evolution of inter‐ ventional cardiology, with ever more complex procedures demanding prolonged fluoroscopy and fluorography time, as well as the demands for better imaging of small structures (guidewires, angioplasty balloon- and stent-markers, stents themselves, intra‐ vascular ultrasound probes, etc.) associated with higher exposures to larger amounts of x-ray radiation, have all raised the question of radiation protection, both for the patients and the staff inside the catheterization laboratory (cath lab). Occupational doses of radia‐ tion in interventional cardiology procedures guided by fluoroscopy are the highest doses registered among medical staff using x-rays. The use of ionizing radiation increases the risk of malignant disease occurrence and can cause skin or eye damage to both the pa‐

56 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The principle of generating the x-rays is basically the same in all x-ray machines. The source of x-rays is the x-ray tube (fig.1, fig. 2). Within it are the cathode and the anode (fig. 1). The electrically positive tungsten anode is bombarded with accelerated electrons originating from the electrically negative cathode. When the high-velocity electrons col‐ lide with the anode, they lose most of their energy (~99%) as heat, and a small fraction (~1%) as x-rays. Since the electrons are slowed down within the anode by different seg‐ ments of atoms and mostly multiple interactions with several atoms within the material itself, they release a variety of x-ray energies. However, when all of the electron's ener‐ gy is lost in a single interaction, the resultant emitted x-ray has the highest possible en‐ ergy, equivalent to the voltage applied across the tube. That is reffered to as the kVp, or 'peak kilovoltage' of the emitted x-rays. A typical x-ray tube ranges from 60 kV to 120 kV. The tube current, measured in milliamperes (mA) is defined as the number of elec‐ trons that arc from the cathode to the anode per second [4]. Modern x-ray tubes gener‐ ate the radiation in pulses rather than in a continuous form, and those pulses are synchronized with the other components in the fluoroscopic/fluorographic system. The duration of the time during which the electrons hit the anode is the pulse width, and is

The anode is made of tungsten because this material can withstand very high tempera‐ tures without melting. As stated before, some 99% of the energy which the electron beam is losing when hitting the anode is heat. The anode is constructed as a disc, and to reduce the heat strain even more, it is constantly rotated at speeds up to 10,000 rpm (fig. 1). This way, the area bombarded by the small electron beam is not actually a single spot, but a circle track. The small area of the anode which is being bombarded by the electron beam, and from which the x-rays are emitted is called the 'focal spot', and since

tient and the personnel [3].

measured in milliseconds (ms).

**2.1. The x-ray tube**

**2. How the x-ray radiation is produced**

**Figure 1.** The x-ray tube. Legend: A – housing; B – oil bath for cooling; C – cathode; D – electron beam; E – collimators; F – filters; G – x-rays; H – anode; I – engine for anode rotation (illustration: J. Čaluk).

The thickest filters would therefore be used for smaller patients, and the thinnest ones for large patients. Since the filters primarily eliminate the useless part of the x-ray beam, but also do attenuate even a part of the useful beam, the goal of filtration is to produce

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 59

In order to adjust the shape and the size of the x-ray field emerging from the tube, lead collimators which completely absorb the x-ray beam are used. They actually limit the ex‐ posure of the patient only within the region of interest, and thus reduce the unneccessa‐ ry exposure to both the patient and the staff. The collimators can be manipulated as to further reduce the port of the x-ray tube (fig. 1) and by that, to reduce the irradiated area. The edges of the collimator blades are then visible in the imaging field as shad‐ ows. The amount of absorbed and scattered radiation can be reduced by an adequate collimation –the entrance surface area of the x-ray beam on the patient's skin should be

The x-ray generator provides the electric power to heat the cathode, to accelerate the electrons from the cathode to the anode thus generating the x-ray beam, and to turn the x-ray pulses on and off. It automatically adjusts the tube voltage, current, and pulse width to maintain a certain image quality. In interventional cardiology, there is a de‐ mand for generators able to provide up to 100 kW of power across all the voltages in the diagnostic range. The modulation of variables of x-ray beams is automated, and it maintains constant brightness at the image receptor as the thickness of patient's tissues varies with different projections and angulations. Very oblique angulations mean that the tissue thickness is bigger, and more powerful radiation is required to generate the image in comparison to less or non-angulated tube positions. Also, the image quality must be maintained regardless of the patient's built, so bigger patients are exposed to higher amounts of radiation, because stronger x-ray beams are required to penetrate their bodies [8,9]. Image brightness at the oputput of the imaging chain is rapidly sam‐ pled. The measurements are sent back to the generator to modulate the above men‐ tioned variables and provide the desired image brightness. Beside the pulse width, the voltage, and the current, the parameters which can be altered are camera aperture and

The x-ray beam directed towards the patient is considered to be uniform. After interact‐ ing with different tissues which attenuate it to a variable degree, a non-uniform x-ray beam exits the patient. Its non-uniformity, generated by the process of x-ray absorption in the patient, is the basis for obtaining an x-ray image. The degree of 'darkness' in the

the best possible compromise between image quality and radiation dose.

reduced to the smallest possible/needed size [5,6,7].

**2.3. Collimators**

**2.4. X-ray generators**

electronic amplification gain.

**3. X-ray image formation**

**Figure 2.** X-ray tube

#### **2.2. Filters**

As the electrons are slowed down by the anode, there occurs a spectrum of different wavelength x-rays called the brake-radiation (in German: Bremsstrahlung), with spikes of x-ray energies at characteristic wavelengths when all the energy of an electron is lost at a single collision, as noted earlier. The brake-radiation is mostly of low photon ener‐ gies (<25-30 keV), and would be mostly absorbed in the patient's superfitial tissues. Therefore, the brake-radiation would not contribute to generating the x-ray image, but would, on the other hand, increase the amount of radiation to which the patient is ex‐ posed. This is why these x-rays are filtered in the beam exit port, and the filters applied selectively absorb the x-ray photons from this region of the energy spectrum [4]. Mod‐ ern systems usually use copper filters 0.2 – 0.9 mm thick. Since these filters attenuate the x-ray beam (fig. 1), this requires an increased tube output, and when this is accomplish‐ ed, the greater energy output occurs in the energy range of interest. Filters are basically simple, small metal sheets. In addition to the permanent beam filtration that is usually equivalent to 3 mm of aluminium, all cardio-angiographic equipment should have heavi‐ ly filtered x-ray sources. The number and the mode of filter use differs among manufac‐ turers, but optional filters of 0.1 mm, 0.2 mm, 0.3 mm, etc. should be available to order with the machine. In some products, users can employ different dose-management modes, and these filters might be incorporated into those modes, selectable by the user. The thickest filters would therefore be used for smaller patients, and the thinnest ones for large patients. Since the filters primarily eliminate the useless part of the x-ray beam, but also do attenuate even a part of the useful beam, the goal of filtration is to produce the best possible compromise between image quality and radiation dose.

#### **2.3. Collimators**

In order to adjust the shape and the size of the x-ray field emerging from the tube, lead collimators which completely absorb the x-ray beam are used. They actually limit the ex‐ posure of the patient only within the region of interest, and thus reduce the unneccessa‐ ry exposure to both the patient and the staff. The collimators can be manipulated as to further reduce the port of the x-ray tube (fig. 1) and by that, to reduce the irradiated area. The edges of the collimator blades are then visible in the imaging field as shad‐ ows. The amount of absorbed and scattered radiation can be reduced by an adequate collimation –the entrance surface area of the x-ray beam on the patient's skin should be reduced to the smallest possible/needed size [5,6,7].

#### **2.4. X-ray generators**

**Figure 2.** X-ray tube

As the electrons are slowed down by the anode, there occurs a spectrum of different wavelength x-rays called the brake-radiation (in German: Bremsstrahlung), with spikes of x-ray energies at characteristic wavelengths when all the energy of an electron is lost at a single collision, as noted earlier. The brake-radiation is mostly of low photon ener‐ gies (<25-30 keV), and would be mostly absorbed in the patient's superfitial tissues. Therefore, the brake-radiation would not contribute to generating the x-ray image, but would, on the other hand, increase the amount of radiation to which the patient is ex‐ posed. This is why these x-rays are filtered in the beam exit port, and the filters applied selectively absorb the x-ray photons from this region of the energy spectrum [4]. Mod‐ ern systems usually use copper filters 0.2 – 0.9 mm thick. Since these filters attenuate the x-ray beam (fig. 1), this requires an increased tube output, and when this is accomplish‐ ed, the greater energy output occurs in the energy range of interest. Filters are basically simple, small metal sheets. In addition to the permanent beam filtration that is usually equivalent to 3 mm of aluminium, all cardio-angiographic equipment should have heavi‐ ly filtered x-ray sources. The number and the mode of filter use differs among manufac‐ turers, but optional filters of 0.1 mm, 0.2 mm, 0.3 mm, etc. should be available to order with the machine. In some products, users can employ different dose-management modes, and these filters might be incorporated into those modes, selectable by the user.

58 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**2.2. Filters**

The x-ray generator provides the electric power to heat the cathode, to accelerate the electrons from the cathode to the anode thus generating the x-ray beam, and to turn the x-ray pulses on and off. It automatically adjusts the tube voltage, current, and pulse width to maintain a certain image quality. In interventional cardiology, there is a de‐ mand for generators able to provide up to 100 kW of power across all the voltages in the diagnostic range. The modulation of variables of x-ray beams is automated, and it maintains constant brightness at the image receptor as the thickness of patient's tissues varies with different projections and angulations. Very oblique angulations mean that the tissue thickness is bigger, and more powerful radiation is required to generate the image in comparison to less or non-angulated tube positions. Also, the image quality must be maintained regardless of the patient's built, so bigger patients are exposed to higher amounts of radiation, because stronger x-ray beams are required to penetrate their bodies [8,9]. Image brightness at the oputput of the imaging chain is rapidly sam‐ pled. The measurements are sent back to the generator to modulate the above men‐ tioned variables and provide the desired image brightness. Beside the pulse width, the voltage, and the current, the parameters which can be altered are camera aperture and electronic amplification gain.

## **3. X-ray image formation**

The x-ray beam directed towards the patient is considered to be uniform. After interact‐ ing with different tissues which attenuate it to a variable degree, a non-uniform x-ray beam exits the patient. Its non-uniformity, generated by the process of x-ray absorption in the patient, is the basis for obtaining an x-ray image. The degree of 'darkness' in the x-ray image, which forms the x-ray 'shadow', is determined by the energy of the origi‐ nal x-ray beam generated by the tube, the thickness of the exposed object (patient's tis‐ sues), and the elemental makeup of the object (patient's tissues). The removal of the xray beam as a function of the object thickness is exponential, but the elemental makeup of the tissue is characteristic for the tissue itself, and as a function is characterized by a linear attenuation coefficient. Half-value layer (HVL) is the parameter defined as the thickness of a tissue sample that absorbes (removes from the beam) one-half of the beam intensity. Regarding the beam energies used in interventional cardiology, HVL for mus‐ cle would be 3.2 cm, for bone is 1.5 cm, for iodine is 0.01 cm (100%), and as a compari‐ son, for the lead, the HVL is 0.01 cm [4].

the image intensifier is to convert the x-ray intensity information into the visible light spec‐ trum and expose photographic film or a video camera. The details of the process taking place within the image intensifier are beyond the scope of this chapter and are discussed

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 61

However, recently a novel technology has been introduced and its use in cardio-angiog‐ raphy is constantly increasing: the digital flat-panel detector (fig. 4), which consists of (simply speaking) several layers of material. The x-ray photons, upon leaving the pa‐ tient, hit the input phosphor layer of the detector, and it produces light photons. Behind that layer is the photodiode and the thin-film transistor layer. The generated light pho‐ tons produce electric signals within this layer, and those signals are captured as voltages in the discrete flat-panel elements [4]. A typical panel consists of 1024 x 1024 elements over a rectangle-shaped field of view. Each flat-panel element's voltage signal is convert‐ ed from an analogue voltage to a digital representation. The digital image produced like this is represented using a fixed number of values, and those are distributed over a lim‐ ited set of co-ordinates. This information can then be stored or copied. For viewing, it is fed through conversion system and into the viewing monitor, and we percieve it as an image, with monitor pixels corresponding to flat panel detector's elements which re‐ ceived the beam. In order to standardize the digital communication within the medical community, the DICOM (Digital Imaging Communications in Medicine) system has been introduced. It is used for organizing the image data in such a way that other users of the DICOM system can review those data accurately, and is currently the standard-one

elsewhere.

**Figure 4.** Digital flat-panel detector

in medicine.

**Figure 3.** Image intensifier

When a non-uniform x-ray beam leaves the patient's body, its spatial distribution is the ba‐ sis for forming an x-ray image. It contains the information on the anatomy of the scanned region, and if it is taken within a defined time-frame, it can also be used for the assessment of the patient's physiology. But, since the spectrum of x-rays cannot be detected by the hu‐ man eyes, it must be 'translated' into visible information. There are several technologies cur‐ rently in use for that purpose, and the most common being used in interventional cardiology today are image intensifier and digital flat-panel detector technology, both of which are digital. Although our senses use the analogue method to percieve the reality, for the purpose of securely storing the information and being possible to make exact copies, and later review the information without quality loss, that information needs to be digitalized. The digital-flat panel detectors are the state of the art now, but still the vast majority of the systems currently in use employ the image intensifier technology (fig. 3). The main role of the image intensifier is to convert the x-ray intensity information into the visible light spec‐ trum and expose photographic film or a video camera. The details of the process taking place within the image intensifier are beyond the scope of this chapter and are discussed elsewhere.

**Figure 4.** Digital flat-panel detector

x-ray image, which forms the x-ray 'shadow', is determined by the energy of the origi‐ nal x-ray beam generated by the tube, the thickness of the exposed object (patient's tis‐ sues), and the elemental makeup of the object (patient's tissues). The removal of the xray beam as a function of the object thickness is exponential, but the elemental makeup of the tissue is characteristic for the tissue itself, and as a function is characterized by a linear attenuation coefficient. Half-value layer (HVL) is the parameter defined as the thickness of a tissue sample that absorbes (removes from the beam) one-half of the beam intensity. Regarding the beam energies used in interventional cardiology, HVL for mus‐ cle would be 3.2 cm, for bone is 1.5 cm, for iodine is 0.01 cm (100%), and as a compari‐

60 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

When a non-uniform x-ray beam leaves the patient's body, its spatial distribution is the ba‐ sis for forming an x-ray image. It contains the information on the anatomy of the scanned region, and if it is taken within a defined time-frame, it can also be used for the assessment of the patient's physiology. But, since the spectrum of x-rays cannot be detected by the hu‐ man eyes, it must be 'translated' into visible information. There are several technologies cur‐ rently in use for that purpose, and the most common being used in interventional cardiology today are image intensifier and digital flat-panel detector technology, both of which are digital. Although our senses use the analogue method to percieve the reality, for the purpose of securely storing the information and being possible to make exact copies, and later review the information without quality loss, that information needs to be digitalized. The digital-flat panel detectors are the state of the art now, but still the vast majority of the systems currently in use employ the image intensifier technology (fig. 3). The main role of

son, for the lead, the HVL is 0.01 cm [4].

**Figure 3.** Image intensifier

However, recently a novel technology has been introduced and its use in cardio-angiog‐ raphy is constantly increasing: the digital flat-panel detector (fig. 4), which consists of (simply speaking) several layers of material. The x-ray photons, upon leaving the pa‐ tient, hit the input phosphor layer of the detector, and it produces light photons. Behind that layer is the photodiode and the thin-film transistor layer. The generated light pho‐ tons produce electric signals within this layer, and those signals are captured as voltages in the discrete flat-panel elements [4]. A typical panel consists of 1024 x 1024 elements over a rectangle-shaped field of view. Each flat-panel element's voltage signal is convert‐ ed from an analogue voltage to a digital representation. The digital image produced like this is represented using a fixed number of values, and those are distributed over a lim‐ ited set of co-ordinates. This information can then be stored or copied. For viewing, it is fed through conversion system and into the viewing monitor, and we percieve it as an image, with monitor pixels corresponding to flat panel detector's elements which re‐ ceived the beam. In order to standardize the digital communication within the medical community, the DICOM (Digital Imaging Communications in Medicine) system has been introduced. It is used for organizing the image data in such a way that other users of the DICOM system can review those data accurately, and is currently the standard-one in medicine.

## **4. Radiation management and safety**

X-ray radiation is a carcinogen [10]. No dose of radiation may be considered safe or harm‐ less [11]. It can also cause severe injury called radiation burns, but the likelihood of that is extremely low when the fluoroscopy/fluorography is adequately managed. Doctors, nurses, technicians, and other medical staff working in radiation environment, who have accumu‐ lated significant doses of radiation through their careers have been shown to develop some form of radiation-induced health-problems, the most important being cancer, cataracts, and skin injury [12,13]. Interventional cardiologists, working at very low distances from x-ray tubes, and the patients who are also the sources of scattered radiation, are at particular health risk.

ally an erythema, or a 'radiation burn') and a previous interventional cardiology procedure,

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 63

In order to understand and quantify the effects of radiation on humans, different units of measurement have been developed. It is necessary to know these units as to be able to apply the safety measures in radiation environment, as well as to compare the health-risks of dif‐

Absorbed dose is the amount of radiation energy absorbed by a particular tissue. The x-ray radiation interacts with living tissues upon entering them, and its energy causes molecular changes, and therefore has the potential to have biologic effects. The unit of absorbed dose is gray (Gy), meaning that 1 Gy is the radiation energy of one joule (1 J) concentrated in one

Equivalent dose is an estimate of the biologic potency which a form of radiation might have for an absorbed dose, and is determined by the properties of the radiation itself. Therefore, for different kinds of radiation, the equivalent doses can be different, although the absorbed doses can be the same. This is actually a safety term that can be used to compare the biologic potency of different kinds of radiation. The unit for equivalent dose is sievert (Sv). In inter‐

Effective dose is the estimate of a hypothetic dose which would have to be delivered to an interventionist's entire body to have the same risk for the radiation adverse effects as the non-uniform doses which are actually delivered. The need for establishing this unit of measurement occurred because during the procedures in the cath lab (or similar radi‐ ation environments), some of the body parts are better protected (e.g. internal organs), while other body parts are less, or not at all protected (e.g. head and limbs), under the assumption that they are less radiosensitive. Therefore, the spatial distribution of radia‐ tion exposure is non-uniform. Effective dose eliminates this complexity in radiation risk assessment. The unit to measure the effective dose is sievert (Sv), and in interventional cardiology 1 Sv can be considered to be equal to 1 Gy of x-ray radiation absorbed uni‐

There are, of course, the proposed limits to which personnel in the radiation environment can be exposed. Regarding the effective dose, the limit for the staff is 100 mSv in a consecu‐ tive five year period, subject to a maximum effective dose of 50 mSv in any single year. The equivalent dose for the lenses of the eye should be limited to 150 mSv in a year. The limit on equivalent dose for the skin should be 500 mSv in a year, and the dose for the hands, fore‐

The basic rule which can be applied regarding radiation protection is: 'what is good for the patient is also good for the staff'. For this reason, radiation protection measures will be dis‐

ventional cardiology, 1 Sv is considered to be equivalent to 1 Gy [10].

arms, feet, and ankles should be limited to 500 mSv in a year [11].

**4.3. Limiting the exposure to radiation**

because of this time delay – usually several weeks.

**4.2. Units of measurement of x-ray radiation**

ferent forms of radiation.

kilogram (1 kg) of tissue.

formly in the body.

#### **4.1. Radiation effects**

Effects of radiation can be generally divided into two basic groups: the stochastic effects, and the deterministic effects. Both groups are very important for the pathological conse‐ quences on the human body.

Stochastic effect occurs within a single cell and makes it adversely functional. This happens because of an alteration of an important macromolecule (such as the DNA) and can result upon a single interaction with radiation. It is therefore logical to assume that this kind of ef‐ fects may occur with any radiation dose, but in practice, low doses of radiation carry an ex‐ tremely low risk of stochastic effects on the body. The most important stochastic effects in the clinical sense are the occurrence of radiation-induced tumors and heritable changes in reproductive cells. The risk of these effects occurring rises with the rise of the amount of ra‐ diation to which a person is exposed, so the induced cancer becomes measurable in exposed adults at doses over some 100 mSv. In children, and in fetus (if a pregnant woman is ex‐ posed to radiation), even lower doses have been defined as carcinogenic. The stochastic risk of inducing malignant disease associated with radiation is small but definite [14].

Deterministic effects are the result of damage to a large number of cells, therefore a certain dose of radiation has to be applied for these effects to take place. This minimal dose for a deterministic effect is called the threshold dose. The higher the dose (above the threshold), the more severe the effects. Some examples of deterministic effects are: skin erythema, epila‐ tion, dry or moist desquamation, secondary ulceration, ischemic dermal necrosis, various stages of dermal atrophy, induration, teleangiectasia, late dermal necrosis, vision-impairing cataract [10]. Some authors propose that skin cancer can also be considered to be a determin‐ istic effect of radiation.

For both of these groups of radiation effects there exists a time delay between the exposure to radiation and the clinical manifestation of the effect itself. This delay ranges from days to weeks to months for deterministic effects, and for malignant diseases, from as little as 2 years, to as long as many decades. In many cases, neither the patient, nor the physician (usu‐ ally a dermatologists or a general practitioner) grasps the connection of a skin disorder (usu‐ ally an erythema, or a 'radiation burn') and a previous interventional cardiology procedure, because of this time delay – usually several weeks.

### **4.2. Units of measurement of x-ray radiation**

**4. Radiation management and safety**

health risk.

**4.1. Radiation effects**

quences on the human body.

istic effect of radiation.

X-ray radiation is a carcinogen [10]. No dose of radiation may be considered safe or harm‐ less [11]. It can also cause severe injury called radiation burns, but the likelihood of that is extremely low when the fluoroscopy/fluorography is adequately managed. Doctors, nurses, technicians, and other medical staff working in radiation environment, who have accumu‐ lated significant doses of radiation through their careers have been shown to develop some form of radiation-induced health-problems, the most important being cancer, cataracts, and skin injury [12,13]. Interventional cardiologists, working at very low distances from x-ray tubes, and the patients who are also the sources of scattered radiation, are at particular

62 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Effects of radiation can be generally divided into two basic groups: the stochastic effects, and the deterministic effects. Both groups are very important for the pathological conse‐

Stochastic effect occurs within a single cell and makes it adversely functional. This happens because of an alteration of an important macromolecule (such as the DNA) and can result upon a single interaction with radiation. It is therefore logical to assume that this kind of ef‐ fects may occur with any radiation dose, but in practice, low doses of radiation carry an ex‐ tremely low risk of stochastic effects on the body. The most important stochastic effects in the clinical sense are the occurrence of radiation-induced tumors and heritable changes in reproductive cells. The risk of these effects occurring rises with the rise of the amount of ra‐ diation to which a person is exposed, so the induced cancer becomes measurable in exposed adults at doses over some 100 mSv. In children, and in fetus (if a pregnant woman is ex‐ posed to radiation), even lower doses have been defined as carcinogenic. The stochastic risk

of inducing malignant disease associated with radiation is small but definite [14].

Deterministic effects are the result of damage to a large number of cells, therefore a certain dose of radiation has to be applied for these effects to take place. This minimal dose for a deterministic effect is called the threshold dose. The higher the dose (above the threshold), the more severe the effects. Some examples of deterministic effects are: skin erythema, epila‐ tion, dry or moist desquamation, secondary ulceration, ischemic dermal necrosis, various stages of dermal atrophy, induration, teleangiectasia, late dermal necrosis, vision-impairing cataract [10]. Some authors propose that skin cancer can also be considered to be a determin‐

For both of these groups of radiation effects there exists a time delay between the exposure to radiation and the clinical manifestation of the effect itself. This delay ranges from days to weeks to months for deterministic effects, and for malignant diseases, from as little as 2 years, to as long as many decades. In many cases, neither the patient, nor the physician (usu‐ ally a dermatologists or a general practitioner) grasps the connection of a skin disorder (usu‐ In order to understand and quantify the effects of radiation on humans, different units of measurement have been developed. It is necessary to know these units as to be able to apply the safety measures in radiation environment, as well as to compare the health-risks of dif‐ ferent forms of radiation.

Absorbed dose is the amount of radiation energy absorbed by a particular tissue. The x-ray radiation interacts with living tissues upon entering them, and its energy causes molecular changes, and therefore has the potential to have biologic effects. The unit of absorbed dose is gray (Gy), meaning that 1 Gy is the radiation energy of one joule (1 J) concentrated in one kilogram (1 kg) of tissue.

Equivalent dose is an estimate of the biologic potency which a form of radiation might have for an absorbed dose, and is determined by the properties of the radiation itself. Therefore, for different kinds of radiation, the equivalent doses can be different, although the absorbed doses can be the same. This is actually a safety term that can be used to compare the biologic potency of different kinds of radiation. The unit for equivalent dose is sievert (Sv). In inter‐ ventional cardiology, 1 Sv is considered to be equivalent to 1 Gy [10].

Effective dose is the estimate of a hypothetic dose which would have to be delivered to an interventionist's entire body to have the same risk for the radiation adverse effects as the non-uniform doses which are actually delivered. The need for establishing this unit of measurement occurred because during the procedures in the cath lab (or similar radi‐ ation environments), some of the body parts are better protected (e.g. internal organs), while other body parts are less, or not at all protected (e.g. head and limbs), under the assumption that they are less radiosensitive. Therefore, the spatial distribution of radia‐ tion exposure is non-uniform. Effective dose eliminates this complexity in radiation risk assessment. The unit to measure the effective dose is sievert (Sv), and in interventional cardiology 1 Sv can be considered to be equal to 1 Gy of x-ray radiation absorbed uni‐ formly in the body.

There are, of course, the proposed limits to which personnel in the radiation environment can be exposed. Regarding the effective dose, the limit for the staff is 100 mSv in a consecu‐ tive five year period, subject to a maximum effective dose of 50 mSv in any single year. The equivalent dose for the lenses of the eye should be limited to 150 mSv in a year. The limit on equivalent dose for the skin should be 500 mSv in a year, and the dose for the hands, fore‐ arms, feet, and ankles should be limited to 500 mSv in a year [11].

#### **4.3. Limiting the exposure to radiation**

The basic rule which can be applied regarding radiation protection is: 'what is good for the patient is also good for the staff'. For this reason, radiation protection measures will be dis‐ cussed in general, with additional comments regarding the staff or the patient when neces‐ sary. The four basic methods of limiting exposure to radiation can be remembered by using the mnemonic TIDS, which stands for: time, intensity, distance, and shielding [10].

tient's position and size (fig. 5, fig. 6). These shields protect the operator and the assist‐ ing staff from the radiation scattered from the patient's body. Some cardio-angiographic tables have the lower shields attached at the table sides, and the angulation of those shields can be altered to provide the best possible operator and staff protection from the scattered radiation off the posterior aspect of the supine patient, but also from the radia‐ tion generated by the tube, which is located beneath the patient (fig. 5, fig. 6). These shielding drapes significantly protect the operator from scattered radiation [19,20]. In some cases these shields are not connected to the tables themselves, but are free-stand‐ ing. These shields protect the operator's legs and feet, which are among the most ex‐ posed body parts of the operator. There is further shielding in the walls, floors, and the

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 65

**Figure 5.** Patient position and shielding in the cath lab. Legend: A – digital flat panel detector mounted on C-arm; B – ceiling-mounted articulated protection screen; C – monitors; D – patient; E – C-arm and image contriol panel; F – table-

side protective shielding.

ceiling of the cath lab in order to protect the people outside the cath lab.

The time of fluoroscopy/fluorography should be limited to the necessary minimum. A good measure for orientation regarding this is fluoroscopy time recorded by most ma‐ chines used for cardio-angiography today. Although, most devices show only fluorosco‐ py time, and the operator must also think about the fluorography time, knowing that the amount of radiation for the same amount of time is in fluorography 10-fold of that in fluoroscopy. Some devices have the ability to show fluorography time, or a complete beam-on time. In addition, a trend towards less fluoroscopy time is obvious with more experienced operators. However, more experienced operators are more often involved in complex procedures, which actually prolong the fluoroscopy time. Regardless of that, all operators have to be aware that they must reduce the beam-on time to a minimum pro‐ vided that they can visualize the structures of interest and complete the procedure safe‐ ly. Complex procedures, such as multivessel interventions, treating chronic total occlusions, or bifurcation lesions demand more procedure time than the simple interven‐ tions, and this leads to increased radiation dose when treating more complex coronary disease [16]. Some practical advices: when documenting balloon inflation, just a short single shot should be enough, there is no need to prolong the shot of an inflated bal‐ loon; there is no reason to record or observe the gradual balloon deflation, this can be checked with short beam-on shots; the operator's foot should be kept away from the flu‐ oropedal when not actually using fluorography, as to not accidentally step on the pedal and produce unnecessary radiation; a diagnostic fluorography can in most cases (but not always) be limited to a single cardiac cyclus; direct stenting can also be used and is pro‐ ven to reduce beam-on time [17,18].

Intensity of radiation should also be minimized. This can be done in several ways. As noted earlier, the tube current and voltage can be modulated up to a point. An easier way to re‐ duce the intensity would be by reducing the pulse rate, in some devices marked as 'frame rate'. This can also be done to a point where the radiation is minimal, while the images are adequate for performing the procedure.

Distance from the source of radiation must be maximized. It is advisable for the operator to stand away from the tube as much as possible, while being able to operate the equipment, the catheters, syringes, etc. Regarding the other staff in the cath lab, anyone who is not need‐ ed inside the room should leave the room, but be readily available to enter as soon as they are needed. All the members of the staff who must stay inside the cath lab should keep their distance from the radiation source at all times, but be ready to attend the patient, or assist the operator on demand. Even small increase of distance from the source of radiation is im‐ portant, because for each doubling of distance from the source, the intensity of radiation is reduced 4-fold.

Shielding of personnel from the radiation is also of utmost importance. The radiation shields come in several types. The ones above the patient are connected to an anchor point in the ceiling and should be moveable, so that they can be adjusted to the pa‐ tient's position and size (fig. 5, fig. 6). These shields protect the operator and the assist‐ ing staff from the radiation scattered from the patient's body. Some cardio-angiographic tables have the lower shields attached at the table sides, and the angulation of those shields can be altered to provide the best possible operator and staff protection from the scattered radiation off the posterior aspect of the supine patient, but also from the radia‐ tion generated by the tube, which is located beneath the patient (fig. 5, fig. 6). These shielding drapes significantly protect the operator from scattered radiation [19,20]. In some cases these shields are not connected to the tables themselves, but are free-stand‐ ing. These shields protect the operator's legs and feet, which are among the most ex‐ posed body parts of the operator. There is further shielding in the walls, floors, and the ceiling of the cath lab in order to protect the people outside the cath lab.

cussed in general, with additional comments regarding the staff or the patient when neces‐ sary. The four basic methods of limiting exposure to radiation can be remembered by using

The time of fluoroscopy/fluorography should be limited to the necessary minimum. A good measure for orientation regarding this is fluoroscopy time recorded by most ma‐ chines used for cardio-angiography today. Although, most devices show only fluorosco‐ py time, and the operator must also think about the fluorography time, knowing that the amount of radiation for the same amount of time is in fluorography 10-fold of that in fluoroscopy. Some devices have the ability to show fluorography time, or a complete beam-on time. In addition, a trend towards less fluoroscopy time is obvious with more experienced operators. However, more experienced operators are more often involved in complex procedures, which actually prolong the fluoroscopy time. Regardless of that, all operators have to be aware that they must reduce the beam-on time to a minimum pro‐ vided that they can visualize the structures of interest and complete the procedure safe‐ ly. Complex procedures, such as multivessel interventions, treating chronic total occlusions, or bifurcation lesions demand more procedure time than the simple interven‐ tions, and this leads to increased radiation dose when treating more complex coronary disease [16]. Some practical advices: when documenting balloon inflation, just a short single shot should be enough, there is no need to prolong the shot of an inflated bal‐ loon; there is no reason to record or observe the gradual balloon deflation, this can be checked with short beam-on shots; the operator's foot should be kept away from the flu‐ oropedal when not actually using fluorography, as to not accidentally step on the pedal and produce unnecessary radiation; a diagnostic fluorography can in most cases (but not always) be limited to a single cardiac cyclus; direct stenting can also be used and is pro‐

Intensity of radiation should also be minimized. This can be done in several ways. As noted earlier, the tube current and voltage can be modulated up to a point. An easier way to re‐ duce the intensity would be by reducing the pulse rate, in some devices marked as 'frame rate'. This can also be done to a point where the radiation is minimal, while the images are

Distance from the source of radiation must be maximized. It is advisable for the operator to stand away from the tube as much as possible, while being able to operate the equipment, the catheters, syringes, etc. Regarding the other staff in the cath lab, anyone who is not need‐ ed inside the room should leave the room, but be readily available to enter as soon as they are needed. All the members of the staff who must stay inside the cath lab should keep their distance from the radiation source at all times, but be ready to attend the patient, or assist the operator on demand. Even small increase of distance from the source of radiation is im‐ portant, because for each doubling of distance from the source, the intensity of radiation is

Shielding of personnel from the radiation is also of utmost importance. The radiation shields come in several types. The ones above the patient are connected to an anchor point in the ceiling and should be moveable, so that they can be adjusted to the pa‐

the mnemonic TIDS, which stands for: time, intensity, distance, and shielding [10].

64 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

ven to reduce beam-on time [17,18].

adequate for performing the procedure.

reduced 4-fold.

**Figure 5.** Patient position and shielding in the cath lab. Legend: A – digital flat panel detector mounted on C-arm; B – ceiling-mounted articulated protection screen; C – monitors; D – patient; E – C-arm and image contriol panel; F – tableside protective shielding.

increase the protection of the gonads (fig. 7). Since eyes can be affected when exposed to ra‐ diation over a prolonged period of time, it is advisable to wear leaded eyeglasses, or facemasks which are secured on the head (fig. 7). Protective eyewear must have at least the equivalent of protection of 0.5 mm of lead. Some recent investigations on the head exposure to radiation have resulted in a recommendation that leaded caps should also be worn.

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 67

**Figure 7.** Personal protection for members of the staff in the cath lab. Legend: A –thyroid protection collar; B – outside personal dosimeter (in the pocket); C – protective eyeglasses; D – radiation panoramic full face mask for face shielding

A cap with only 0.5 mm lead equivalence was proven to be more protective than a ceil‐ ing-mounted shield with 1.0 mm lead equivalence [21] This indicates that a significant amount of secondary scatter radiation, reflected from the walls of the cath lab, may reach

(preffered to eyeglasses); E – protective one-piece apron; F – additional protection for the gonads.

**Figure 6.** Radiation shields. Legend: A – image intensifier; B – Articulated, ceiling-mounted radiation protection screen; C – patient position; D – table-side shields.

The staff inside the cath lab must also wear the personal protection (fig. 7), which comes in several types and sizes. It is very important that one wears an adequate size protection gar‐ ments. Firstly, lead apron should be worn. They come in different lead- or lead-equivalent thickness, and can weigh some 15 kg. It is advisable to wear the aprons which cover both the front and the back of the person. Because they may be heavy and put strain to the skeletal system, belts are used to take the weight off the shoulders. The minimum of protection is the equivalent of 0.5 mm of lead at the front. A two piece (blouse-plus-skirt design) is preferred by some operators. Another shield can be worn around the neck to protect the thyroid and neck tissues and organs (fig. 7). An additional small apron can be worn around the waist to increase the protection of the gonads (fig. 7). Since eyes can be affected when exposed to ra‐ diation over a prolonged period of time, it is advisable to wear leaded eyeglasses, or facemasks which are secured on the head (fig. 7). Protective eyewear must have at least the equivalent of protection of 0.5 mm of lead. Some recent investigations on the head exposure to radiation have resulted in a recommendation that leaded caps should also be worn.

**Figure 7.** Personal protection for members of the staff in the cath lab. Legend: A –thyroid protection collar; B – outside personal dosimeter (in the pocket); C – protective eyeglasses; D – radiation panoramic full face mask for face shielding (preffered to eyeglasses); E – protective one-piece apron; F – additional protection for the gonads.

**Figure 6.** Radiation shields. Legend: A – image intensifier; B – Articulated, ceiling-mounted radiation protection

66 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The staff inside the cath lab must also wear the personal protection (fig. 7), which comes in several types and sizes. It is very important that one wears an adequate size protection gar‐ ments. Firstly, lead apron should be worn. They come in different lead- or lead-equivalent thickness, and can weigh some 15 kg. It is advisable to wear the aprons which cover both the front and the back of the person. Because they may be heavy and put strain to the skeletal system, belts are used to take the weight off the shoulders. The minimum of protection is the equivalent of 0.5 mm of lead at the front. A two piece (blouse-plus-skirt design) is preferred by some operators. Another shield can be worn around the neck to protect the thyroid and neck tissues and organs (fig. 7). An additional small apron can be worn around the waist to

screen; C – patient position; D – table-side shields.

A cap with only 0.5 mm lead equivalence was proven to be more protective than a ceil‐ ing-mounted shield with 1.0 mm lead equivalence [21] This indicates that a significant amount of secondary scatter radiation, reflected from the walls of the cath lab, may reach the interventionist's head, despite the presence of a ceiling mounted lead glass shield, and this shield is actually designed to protect the operator's head from the primary scat‐ ter radiation from the patient. The annual head dose sustained by interventional cardiolo‐ gists can be quite high, raising the issue of not only the cataract, but also brain tumors. The head dose may reach 60 mSv a year, and may in some cases exceed the occupational limit of 150 mSv a year recommended for the lens of the eye [22]. This information is the cause of the current consideration of the risks of radiation induced cataracts and malig‐ nancy, particularly brain cancer [23,24]. Primary scatter to the operator's unprotected head is highest for left anterior oblique (LAO) tube angulations [21]. However, some ar‐ gue that a careful use of the lead glass shield provides similar protection of the opera‐ tor's brain [20,25].

The equipment used in cardio-angiology is some of the most sophisticated and complex used in medicine today. It must be well-maintained and the users must be well trained in using it. As stated before, in all modern cardiology units, each fluoroscopic image is cap‐ tured using a short pulse of x-ray beam. The pulse itself lasts for 3-10 ms. Longer pulses would appear blurry since structures observed in cardiology move. The pulse rate is identi‐ cal to the image capture rate, and between pulses no radiation is being produced. At pulse rate of 30 images per second, the human eye perceives the series of fast changing images as a seemingly continuous motion. However, the amount of radiation at this pulse rate might be excessive. Reducing the pulse rate by half reduces (roughly by half) the amount of radia‐ tion to the exposed persons, and slightly affects the sequence quality, but usually not as much as to negatively affect the procedure. For large patients who require larger amounts of radiation to penetrate their bodies, reduction of pulse rate can mean the difference between no skin injury and the occurrence of radiation burns. Dose-rate control can also be achieved through modulating pulse width, tube current, beam energy, and filtration, but not all of these parameters can be controlled by the operator sometimes. The optimal control of these parameters means that the interventionist will choose the dose-rate mode which gives the smallest amount of radiation, while at the same time enabling adequate image quality.

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 69

A very important factor in determining the amount of radiation which will be used is the size of the patients. Smaller patients demand less radiation, and the image is brighter, crisp‐ er, and with better contrast. Bigger patients, however, demand larger amounts of radiation to obtain the same image quality. That amount is further increased with steeply angulated projections, so the operator must be aware of this while working with larger patients, and choose the projections wisely, to adequately display the region of interest while, at the same time, maintain the lowest radiation dose possible. When the lesions are difficult to treat, that prolongs the beam-on time and doses can be extremely high. Positioning the patient on car‐ dio-angiographic table also plays a role in radiation exposure. To protect the patient against radiation burns, and oneself from scattered radiation, the operator is advised to keep the pa‐ tient higher, farther away from the radiation source, and at the same time closer to the im‐

Today, the modern cardio-angiographic devices are equipped with dose-monitoring sys‐ tems which record the amount of radiation and calculate the exposure of the patient. There are also simpler methods, such as film-monitoring in which a film layer is posi‐ tioned beneath the patient, roughly at the site of the beam entrance. The film is sensitive to radiation and becomes darker with higher doses. It is examined after the procedure (or during the procedure if necessary), and a simple device estimates the exposure based on the degree of the film darkening. This method is very good for estimating the skin expo‐ sure when the beam enters from posterior, but lacks preciseness if very angulated or lat‐

Automated devices for exposure measurement usually measure air kerma. The unit of measurement is Gy. It is the sum of initial kinetic energies of all charged particles liberat‐

age receptor [5,6,7].

**4.4. Radiation dose monitoring**

eral projections are used.

The exposure of the operator in general is higher when LAO projections are used, as op‐ posed to RAO projections. The RAO positions are better regarding the operator dose, be‐ cause the x-ray entrance point into the patient is kept away from the operator [3]. The RAO 90°, for example, exposes the interventionist to some three times less less scattered radiation than the usually used LAO 90° projection [26].

Even the line of interventonist's vision is important in this regard. The monitors in the cath lab are usually placed so that the patient can also follow the procedure, meaning that the monitors are to the interventionist's left front field of vision. For the operator, even leaning the head to the left increases the radiation exposure, and also the whole body posture is af‐ fected by this – the interventionist then stands closer to the x-ray tube, and to the source of scattered radiation. Just looking towards the tube exposes the lower parts of the face to lev‐ els 4–10 times greater than does looking rightwards [21]. Knowing that the monitor position typically determines the operator's predominant line of vision in interventional cardiology, it is advisable to place the monitors to the operator's right front side. By placing the moni‐ tors into the interventionist's right front part of the field of vision (fig. 5), radiation exposure of the interventonist's head can be dramatically reduced. This way, regardless of tube angu‐ lation, the lowest scatter towards the operator's head will occur in a line of vision toward the foot of the table. This means that in order to protect the eye lenses and the brain, interven‐ tional cardiologists should try to work with monitors positioned to the right [21]. Since the operator's hands might sometimes be directly under an x-ray beam, there are even sets of sterile leaded gloves (for single use, of course) that can be worn, although the material is ob‐ viously thicker than that used for normal sterile gloves, and the tactile feeling in the hands and at the operator's fingertips is not very precise.

The cath lab should be in a room of adequate size. Large rooms of some 60 m2 are preferred not only because they are comfortable to work in, but also because in such rooms it is easy to employ the 'distance' and the 'shielding' principles of radiation protection [10]. A certain amount of space is also required for the ceiling-mounted radiation shields. Since the amount of radiation is reduced by the square distance from the source, in large rooms it is easy to distance and therefore protect oneself from radiation much better than in small rooms with limited space to move or stand. By staying inside the cath lab at the same time, assisting per‐ sonnel can be readily available to attend the patient when needed.

The equipment used in cardio-angiology is some of the most sophisticated and complex used in medicine today. It must be well-maintained and the users must be well trained in using it. As stated before, in all modern cardiology units, each fluoroscopic image is cap‐ tured using a short pulse of x-ray beam. The pulse itself lasts for 3-10 ms. Longer pulses would appear blurry since structures observed in cardiology move. The pulse rate is identi‐ cal to the image capture rate, and between pulses no radiation is being produced. At pulse rate of 30 images per second, the human eye perceives the series of fast changing images as a seemingly continuous motion. However, the amount of radiation at this pulse rate might be excessive. Reducing the pulse rate by half reduces (roughly by half) the amount of radia‐ tion to the exposed persons, and slightly affects the sequence quality, but usually not as much as to negatively affect the procedure. For large patients who require larger amounts of radiation to penetrate their bodies, reduction of pulse rate can mean the difference between no skin injury and the occurrence of radiation burns. Dose-rate control can also be achieved through modulating pulse width, tube current, beam energy, and filtration, but not all of these parameters can be controlled by the operator sometimes. The optimal control of these parameters means that the interventionist will choose the dose-rate mode which gives the smallest amount of radiation, while at the same time enabling adequate image quality.

A very important factor in determining the amount of radiation which will be used is the size of the patients. Smaller patients demand less radiation, and the image is brighter, crisp‐ er, and with better contrast. Bigger patients, however, demand larger amounts of radiation to obtain the same image quality. That amount is further increased with steeply angulated projections, so the operator must be aware of this while working with larger patients, and choose the projections wisely, to adequately display the region of interest while, at the same time, maintain the lowest radiation dose possible. When the lesions are difficult to treat, that prolongs the beam-on time and doses can be extremely high. Positioning the patient on car‐ dio-angiographic table also plays a role in radiation exposure. To protect the patient against radiation burns, and oneself from scattered radiation, the operator is advised to keep the pa‐ tient higher, farther away from the radiation source, and at the same time closer to the im‐ age receptor [5,6,7].

#### **4.4. Radiation dose monitoring**

the interventionist's head, despite the presence of a ceiling mounted lead glass shield, and this shield is actually designed to protect the operator's head from the primary scat‐ ter radiation from the patient. The annual head dose sustained by interventional cardiolo‐ gists can be quite high, raising the issue of not only the cataract, but also brain tumors. The head dose may reach 60 mSv a year, and may in some cases exceed the occupational limit of 150 mSv a year recommended for the lens of the eye [22]. This information is the cause of the current consideration of the risks of radiation induced cataracts and malig‐ nancy, particularly brain cancer [23,24]. Primary scatter to the operator's unprotected head is highest for left anterior oblique (LAO) tube angulations [21]. However, some ar‐ gue that a careful use of the lead glass shield provides similar protection of the opera‐

68 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The exposure of the operator in general is higher when LAO projections are used, as op‐ posed to RAO projections. The RAO positions are better regarding the operator dose, be‐ cause the x-ray entrance point into the patient is kept away from the operator [3]. The RAO 90°, for example, exposes the interventionist to some three times less less scattered radiation

Even the line of interventonist's vision is important in this regard. The monitors in the cath lab are usually placed so that the patient can also follow the procedure, meaning that the monitors are to the interventionist's left front field of vision. For the operator, even leaning the head to the left increases the radiation exposure, and also the whole body posture is af‐ fected by this – the interventionist then stands closer to the x-ray tube, and to the source of scattered radiation. Just looking towards the tube exposes the lower parts of the face to lev‐ els 4–10 times greater than does looking rightwards [21]. Knowing that the monitor position typically determines the operator's predominant line of vision in interventional cardiology, it is advisable to place the monitors to the operator's right front side. By placing the moni‐ tors into the interventionist's right front part of the field of vision (fig. 5), radiation exposure of the interventonist's head can be dramatically reduced. This way, regardless of tube angu‐ lation, the lowest scatter towards the operator's head will occur in a line of vision toward the foot of the table. This means that in order to protect the eye lenses and the brain, interven‐ tional cardiologists should try to work with monitors positioned to the right [21]. Since the operator's hands might sometimes be directly under an x-ray beam, there are even sets of sterile leaded gloves (for single use, of course) that can be worn, although the material is ob‐ viously thicker than that used for normal sterile gloves, and the tactile feeling in the hands

tor's brain [20,25].

than the usually used LAO 90° projection [26].

and at the operator's fingertips is not very precise.

The cath lab should be in a room of adequate size. Large rooms of some 60 m2

sonnel can be readily available to attend the patient when needed.

not only because they are comfortable to work in, but also because in such rooms it is easy to employ the 'distance' and the 'shielding' principles of radiation protection [10]. A certain amount of space is also required for the ceiling-mounted radiation shields. Since the amount of radiation is reduced by the square distance from the source, in large rooms it is easy to distance and therefore protect oneself from radiation much better than in small rooms with limited space to move or stand. By staying inside the cath lab at the same time, assisting per‐

are preferred

Today, the modern cardio-angiographic devices are equipped with dose-monitoring sys‐ tems which record the amount of radiation and calculate the exposure of the patient. There are also simpler methods, such as film-monitoring in which a film layer is posi‐ tioned beneath the patient, roughly at the site of the beam entrance. The film is sensitive to radiation and becomes darker with higher doses. It is examined after the procedure (or during the procedure if necessary), and a simple device estimates the exposure based on the degree of the film darkening. This method is very good for estimating the skin expo‐ sure when the beam enters from posterior, but lacks preciseness if very angulated or lat‐ eral projections are used.

Automated devices for exposure measurement usually measure air kerma. The unit of measurement is Gy. It is the sum of initial kinetic energies of all charged particles liberat‐ ed by the x-rays per mass of air. This measures the amount of radiation at a point in space and can assess the level of hazard at the specified location. Most modern devices used in interventional cardiology have a built-in monitor of total accumulation of air ker‐ ma at a reference point, and this point in interventional cardiology approximates the po‐ sition of the skin where the beam enters the patient. It adds up the radiation from all projections, making it in this sense more convenient than the film monitor, but it approxi‐ mates, so the true result might be different from the measured value. Some machines have the possibility to measure kerma-area product and dose-area product. The logic of these devices is based on the fact that the beam area increases with the distance from the source, and the air kerma decreases. Theoretically, the product of these values is the same at all positions along the beam. This is primarily a quality control measurement, and if one wants to calculate the dose to the patient, usually a medical physicist must be con‐ sulted, because such calculations can be quite complicated.

If a member of the staff is pregnant, different regulatory bodies define different forms of radiologic protection for the woman and the fetus. In some countries, the recommenda‐ tions are that the fetus must be protected, while not interfering with the future mother's ability to do her job. The employees, both men and women, must be introduced to radia‐ tion safety measures in connection with reproductive issues. Usually, there is also a rec‐ ommendation that all female employees of childbearing potential carry a whole-body dosimeter on the outside of the protective apron, as well as a dosimeter worn under the apron, at the abdominal level. The readings on these dosimeters must not exceed 0.25 mGy per month, thus ensuring that the conceptus receives less than a half of a maxi‐ mum allowed dose recommended by the professional agencies (which is 0.5 mGy). A pregnant employee must be provided with an option to wear an additional pelvic shield of 0.25 to 0.5 mm of lead equivalent material. The employee should also be provided with duties involving less radiation exposure, if at all possible. In some countries, as is the case in the author's country, the pregnant employee who works in a medical radia‐ tion environment has the right to start pregnancy-leave at the very beginning of the preg‐ nancy, and continue with it up to one year postpartum. It is the author's firm belief that all pregnant employees must be given an option to take pregnancy-leave as soon as they learn they are pregnant, so no unnecessary radiation risks, small as they might be, are

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 71

When there is a pregnant patient in the cath lab, it is usually a patient with an acute coro‐ nary syndrome (ACS). Although pregnant women rarely have ACS, this is possible and the staff must be prepared for such an event. With general population, percutaneous coronary intervention (PCI) is the preferred treatment modality for an acute myocardial infarction. On the other hand, PCI in pregnancy includes the exposure of fetus to ionizing radiation. High doses of radiation carry the risk of a spontaneous abortion, fetal organ deformities, fe‐ tal mental retardation and a higher incidence of childhood cancer. However, radiation doses received by fetus during a PCI on a pregnant woman are completely acceptable and PCI can and must be performed in a pregnant woman with an ACS. Before the introduction of the practice of ACS treatment by using PCI, ACS mortality in pregnancy was as high as 20% [28]. Today, by using PCI in the treatment of ACS, the mortality from ACS in pregnancy is reduced to only 5% [29]. During the invasive cardiologic procedures, the x-ray beam is di‐ rected to the patient's chest. Some of the radiation does penetrate even to the fetus, and a part of it is scattered radiation from the mother's body. Contemporary cardio-angiography machines, with excellent beam collimation and a precise beam direction, have very little pri‐ mary beam dissipation. Since that kind of radiation is still theoretically possible, it is manda‐ tory to protect the pregnant patient's abdomen with protective leaded aprons. The mean exposure of a fetus during a PCI procedure is 0.02 mSv, and in very difficult and time-con‐ suming procedures can reach up to 0.1 mSv. These doses are acceptable, and are even rela‐ tively small when compared to computer tomography (CT) scan of the abdomen (8 mSv on average, to a maximum of 49 mSv), pelvic CT scan (25 mSv on average, to a maximum of 79 mSv), abdominal radiography (1.4 mSv on average, with a maximum of up to 4.2 mSv), or even a CT-scan of the thorax (0.06 mSv on average, to a maximum of 0.96 mSv). Doses over 50-100 mSv increase the incidence of fetal malformation. The radiation which is scattered

imposed on the fetus and the pregnant mother-to-be.

As for the staff, radiation monitors must be worn at all times during the procedure. This way the exposure of the staff can be measured. It is necessary for interventional cardiolo‐ gists and other personnel employed in the cath lab to wear personal radiation exposure monitors (dosimeters) on a regular basis, although sometimes this is not the case. Sometimes dosimeters are not worn because of a lack of awareness of risks associated with radiation and/or lack of education in radiation protection [27]. In some institutions or countries, regu‐ latory bodies demand that the monitors are placed outside the protective aprons, while oth‐ ers demand that they must be worn underneath the protection garments. In some hospitals (as is the case in the hospital in which the author works), two monitors must be worn per person: one on the outside, and the other one beneath the protective apron. The one outside records the exposure of the unprotected areas (fig. 7). If only that one is worn, it can be ap‐ proximated that the dose underneath 0.5 mm of lead equivalent is 0.5% of the dose meas‐ ured on the outside monitor. Wearing only under-the-apron monitor may give the operator a false sense of security and lead to potentially heavy exposure of the unprotected body parts. Also, the monitoring of the exposure at the hands and legs/feet should be considered, at least periodically. Beside wearing the monitors, the staff working inside the radiation en‐ vironment must undergo periodical clinical examinations to evaluate the state of their skin, to detect vision impairment, to do blood tests, and to check for chromosomal abnormalities, and possibly other diagnostic measures, as defined by the responsible regulatory bodies. Sometimes, if the doses of radiation exposure found in an employee are larger than recom‐ mended, the employee will be ordered to be removed from the radiation environment, tem‐ porarily or permanently.

#### **5. Pregnancy and x-ray radiation in the cath lab**

There are two ways in which the pregnancy can affect radiologic procedures in a cath lab: either one of the staff is pregnant, or the patient is pregnant. Both situations warrant a care‐ ful approach and need to be mentioned.

If a member of the staff is pregnant, different regulatory bodies define different forms of radiologic protection for the woman and the fetus. In some countries, the recommenda‐ tions are that the fetus must be protected, while not interfering with the future mother's ability to do her job. The employees, both men and women, must be introduced to radia‐ tion safety measures in connection with reproductive issues. Usually, there is also a rec‐ ommendation that all female employees of childbearing potential carry a whole-body dosimeter on the outside of the protective apron, as well as a dosimeter worn under the apron, at the abdominal level. The readings on these dosimeters must not exceed 0.25 mGy per month, thus ensuring that the conceptus receives less than a half of a maxi‐ mum allowed dose recommended by the professional agencies (which is 0.5 mGy). A pregnant employee must be provided with an option to wear an additional pelvic shield of 0.25 to 0.5 mm of lead equivalent material. The employee should also be provided with duties involving less radiation exposure, if at all possible. In some countries, as is the case in the author's country, the pregnant employee who works in a medical radia‐ tion environment has the right to start pregnancy-leave at the very beginning of the preg‐ nancy, and continue with it up to one year postpartum. It is the author's firm belief that all pregnant employees must be given an option to take pregnancy-leave as soon as they learn they are pregnant, so no unnecessary radiation risks, small as they might be, are imposed on the fetus and the pregnant mother-to-be.

ed by the x-rays per mass of air. This measures the amount of radiation at a point in space and can assess the level of hazard at the specified location. Most modern devices used in interventional cardiology have a built-in monitor of total accumulation of air ker‐ ma at a reference point, and this point in interventional cardiology approximates the po‐ sition of the skin where the beam enters the patient. It adds up the radiation from all projections, making it in this sense more convenient than the film monitor, but it approxi‐ mates, so the true result might be different from the measured value. Some machines have the possibility to measure kerma-area product and dose-area product. The logic of these devices is based on the fact that the beam area increases with the distance from the source, and the air kerma decreases. Theoretically, the product of these values is the same at all positions along the beam. This is primarily a quality control measurement, and if one wants to calculate the dose to the patient, usually a medical physicist must be con‐

70 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

As for the staff, radiation monitors must be worn at all times during the procedure. This way the exposure of the staff can be measured. It is necessary for interventional cardiolo‐ gists and other personnel employed in the cath lab to wear personal radiation exposure monitors (dosimeters) on a regular basis, although sometimes this is not the case. Sometimes dosimeters are not worn because of a lack of awareness of risks associated with radiation and/or lack of education in radiation protection [27]. In some institutions or countries, regu‐ latory bodies demand that the monitors are placed outside the protective aprons, while oth‐ ers demand that they must be worn underneath the protection garments. In some hospitals (as is the case in the hospital in which the author works), two monitors must be worn per person: one on the outside, and the other one beneath the protective apron. The one outside records the exposure of the unprotected areas (fig. 7). If only that one is worn, it can be ap‐ proximated that the dose underneath 0.5 mm of lead equivalent is 0.5% of the dose meas‐ ured on the outside monitor. Wearing only under-the-apron monitor may give the operator a false sense of security and lead to potentially heavy exposure of the unprotected body parts. Also, the monitoring of the exposure at the hands and legs/feet should be considered, at least periodically. Beside wearing the monitors, the staff working inside the radiation en‐ vironment must undergo periodical clinical examinations to evaluate the state of their skin, to detect vision impairment, to do blood tests, and to check for chromosomal abnormalities, and possibly other diagnostic measures, as defined by the responsible regulatory bodies. Sometimes, if the doses of radiation exposure found in an employee are larger than recom‐ mended, the employee will be ordered to be removed from the radiation environment, tem‐

There are two ways in which the pregnancy can affect radiologic procedures in a cath lab: either one of the staff is pregnant, or the patient is pregnant. Both situations warrant a care‐

sulted, because such calculations can be quite complicated.

**5. Pregnancy and x-ray radiation in the cath lab**

ful approach and need to be mentioned.

porarily or permanently.

When there is a pregnant patient in the cath lab, it is usually a patient with an acute coro‐ nary syndrome (ACS). Although pregnant women rarely have ACS, this is possible and the staff must be prepared for such an event. With general population, percutaneous coronary intervention (PCI) is the preferred treatment modality for an acute myocardial infarction. On the other hand, PCI in pregnancy includes the exposure of fetus to ionizing radiation. High doses of radiation carry the risk of a spontaneous abortion, fetal organ deformities, fe‐ tal mental retardation and a higher incidence of childhood cancer. However, radiation doses received by fetus during a PCI on a pregnant woman are completely acceptable and PCI can and must be performed in a pregnant woman with an ACS. Before the introduction of the practice of ACS treatment by using PCI, ACS mortality in pregnancy was as high as 20% [28]. Today, by using PCI in the treatment of ACS, the mortality from ACS in pregnancy is reduced to only 5% [29]. During the invasive cardiologic procedures, the x-ray beam is di‐ rected to the patient's chest. Some of the radiation does penetrate even to the fetus, and a part of it is scattered radiation from the mother's body. Contemporary cardio-angiography machines, with excellent beam collimation and a precise beam direction, have very little pri‐ mary beam dissipation. Since that kind of radiation is still theoretically possible, it is manda‐ tory to protect the pregnant patient's abdomen with protective leaded aprons. The mean exposure of a fetus during a PCI procedure is 0.02 mSv, and in very difficult and time-con‐ suming procedures can reach up to 0.1 mSv. These doses are acceptable, and are even rela‐ tively small when compared to computer tomography (CT) scan of the abdomen (8 mSv on average, to a maximum of 49 mSv), pelvic CT scan (25 mSv on average, to a maximum of 79 mSv), abdominal radiography (1.4 mSv on average, with a maximum of up to 4.2 mSv), or even a CT-scan of the thorax (0.06 mSv on average, to a maximum of 0.96 mSv). Doses over 50-100 mSv increase the incidence of fetal malformation. The radiation which is scattered from the directly irradiated body part reaches the fetus, but this is only a small fraction of the radiation dose reaching the pregnant patient's thorax [5]. Although it protects from a di‐ rect beam, the leaded apron at the patient's abdomen will not protect the fetus from the scat‐ tered radiation within the patient's (pregnant woman's) body. Taken into account the spectre of causes of an acute myocardial infarction during pregnancy, PCI will in most cases be the treatment of choice during pregnancy. Not only that it treats the thromboembolic processes, but their causes can be treated also, namely the coronary dissection, which is a disproportionally common cause of ACS in pregnancy, probably because of the alterations in the connective tissue structure (including that within the coronary artery walls) mediated by pregnancy hormones. Once again, PCI is considered to be relatively safe during pregnan‐ cy, both for the pregnant patient and for the fetus and it must be employed as the first line of treatment for ACS in pregnancy because it dramatically reduces ACS mortality for pregnant women.

[4] Cusma JT. X-Ray Cinefluorographic Systems. In: King SB & Yeung AC (eds.) Inter‐

Radiation Principles and Safety http://dx.doi.org/10.5772/54033 73

[5] Hirshfeld JW, Balter S, Brinker et al.: ACCF/AHA/SCAI Clinical competence state‐ ment on physician knowledge to optimize patient safety and image quality in fluoro‐ scopically guided invasive cardiovascular procedures. Circulation 2005;111:511–532.

[6] Kuon E, Dahm JB, Robinson DM, et al: Radiation-reducing planning of cardiac cathe‐

[7] Bashore TM: Radiation safety in the catherization laboratory. Am. Heart J

[8] Vano E, Gonzales L, Fernandez JM, et al: Influence of patient thickness and operation modes on occupational and patient radiation doses in interventional cardiology. Ra‐

[9] Reay J, Chapple CL, Kotre CJ: Is patient size important in dose determination and

[10] Wagner LK. Operational Radiation Management for Patients and Staff. In: King SB & Yeung AC (eds.) Interventional Cardiology. The McGraw-Hill Companies, Inc,

[11] Miller SW, Castronovo FP. Radiation exposure and protection in cardiac catheterisa‐

[12] Yoshinaga S, Mabuchi K, Sigurdson AJ, et al. Cancer risks among radiologists and ra‐ diologic technologists: review of epidemiologic studies. Radiology 2004;233(2):

[13] Wagner LK. Overconfidence, overexposure, and overprotection. Radiology.

[14] Venneri L, Rossi F, Botto N et al.: Cancer risk from professional exposure in staff working in cardiac catheterization laboratory: insights from the National Research Council's Biological Effects of Ionizising Radiation VII Report. Am. Heart J

[15] International Commission on Radiological Protection. ICRP Publication 85. Avoid‐ ance of radiation injuries from medical interventional procedures. Annals ICRP

[16] Mercuri M, Xie C, Levy M, et al: Predictors of increased radiation dose during percu‐

[17] Caluk J, Osmanovic E, Barakovic F, et al. Direct coronary stenting in reducing radia‐

taneous coronary intervention. Am. J. Cardiol 2009;104:1241–1244.

tion and radiocontrast consumption. Radiol Oncol 2010; 44(3): 153-157.

optimization in cardiology? Phys. Med. Biol 2003;48:3843–3850.

ventional Cardiology. The McGraw-Hill Companies, Inc, 2007.p109-119.

rization. Z. Kardiol 2005; 94: 663–673.

diat. Prot. Dosimetry 2006;118:325–330.

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2004;147:375–378.

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313-21.

2004;233(2):307-8.

2009;157:118–124.

#### **6. Conclusion**

In conclusion, although the discovery of the x-ray radiation is more than 100 years old, the x-ray technology is developing as fast as ever. As much as we need to learn about its useful‐ ness and the different forms of its application, we must always be aware of its dangers, risks, and limitations, and use it with care and adequately protect ourselves and our pa‐ tients.

#### **Author details**

#### Jasmin Čaluk

BH Heart Center, Department of interventional cardiology, Tuzla, Bosnia and Herzegovina

#### **References**


[4] Cusma JT. X-Ray Cinefluorographic Systems. In: King SB & Yeung AC (eds.) Inter‐ ventional Cardiology. The McGraw-Hill Companies, Inc, 2007.p109-119.

from the directly irradiated body part reaches the fetus, but this is only a small fraction of the radiation dose reaching the pregnant patient's thorax [5]. Although it protects from a di‐ rect beam, the leaded apron at the patient's abdomen will not protect the fetus from the scat‐ tered radiation within the patient's (pregnant woman's) body. Taken into account the spectre of causes of an acute myocardial infarction during pregnancy, PCI will in most cases be the treatment of choice during pregnancy. Not only that it treats the thromboembolic processes, but their causes can be treated also, namely the coronary dissection, which is a disproportionally common cause of ACS in pregnancy, probably because of the alterations in the connective tissue structure (including that within the coronary artery walls) mediated by pregnancy hormones. Once again, PCI is considered to be relatively safe during pregnan‐ cy, both for the pregnant patient and for the fetus and it must be employed as the first line of treatment for ACS in pregnancy because it dramatically reduces ACS mortality for pregnant

72 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

In conclusion, although the discovery of the x-ray radiation is more than 100 years old, the x-ray technology is developing as fast as ever. As much as we need to learn about its useful‐ ness and the different forms of its application, we must always be aware of its dangers, risks, and limitations, and use it with care and adequately protect ourselves and our pa‐

BH Heart Center, Department of interventional cardiology, Tuzla, Bosnia and Herzegovina

[1] Novelline R. Squire's Fundamentals of Radiology. Harvard University Press. 5th edi‐

[2] Tsapaki V, Maniatis PN, Magginas A et al.: What are the clinical and technical factors that influence the kerma-area product in percutaneous coronary intervention? Br. J.

[3] Saunamaki KI. Radiation Protection in the Cardiac Catheterization Laboratory. In‐

women.

tients.

**6. Conclusion**

**Author details**

Jasmin Čaluk

**References**

tion. 1997.

Radiol 2008;81:949–945.

terv Cardiol 2010;2(5):667-672.


[18] Larrazet F, Dibie A, Philippe F, et al: Factors influencing fluoroscopy time and dose– area product values during ad hoc one-vessel percutaneous coronary angioplasty. Br. J. Radiol 2003;76:473–477.

**Chapter 4**

**Noninvasive Modalities for Coronary Angiography**

Optimal diagnostic quality non-invasive alternatives for visualization of the coronary arteries has been a major goal with the advent of newer cardiovascular imaging mo‐ dalities such as coronary computed tomography angiography (CCTA) and magnetic resonance coronary angiography (MRCA). The challenges in imaging coronaries are ob‐ vious. The technology must be capable of visualizing arteries as small as 1.5 mm to delineate luminal and wall pathology which becomes challenging as many of the arter‐ ies are engulfed in tissue of similar composition. Coronary arteries exhibit rapid mo‐ tion which poses major issues with blurring of images due to substantial limitations of temporal resolution. Invasive coronary angiography current enjoys the best temporal resolution (less than 20 msec ) for real time visualization of coronaries and its branch‐ es but comes with its obvious limitations. CCTA has rapidly risen to this challenge and is already widely employed using 64 slice detector technology and is outstanding for exclusion of CAD with substantial advances in radiation reduction and speed of acquisition. MRCA has made significant improvements in technology which has made coronary imaging less challenging using navigator gating, whole heart imaging and us‐ ing 3Tesla magnets, with the big advantage of no radiation and capability of non-con‐ trast coronary imaging and most of all the promise of a true " one stop " comprehensive assessment. However, it is still suboptimal compared to CCTA as dis‐ cussed subsequently in detail. This chapters aims to discuss MRCA and CCTA with regards to coronary imaging and compare and contrast both these imaging modalities with one another and also highlight some emerging comparisons of CCTA to invasive

> © 2013 Ananthasubramaniam et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

Karthikeyan Ananthasubramaniam, Sabha Bhatti and Abdul Hakeem

coronary luminal assessment technologies.

properly cited.

http://dx.doi.org/10.5772/54082

**1. Introduction**

Additional information is available at the end of the chapter


## **Noninvasive Modalities for Coronary Angiography**

Karthikeyan Ananthasubramaniam, Sabha Bhatti and Abdul Hakeem

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54082

## **1. Introduction**

[18] Larrazet F, Dibie A, Philippe F, et al: Factors influencing fluoroscopy time and dose– area product values during ad hoc one-vessel percutaneous coronary angioplasty. Br.

74 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

[19] Miller DL, Vano E, Bartal G et al.: Occupational radiation protection in interventional radiology: a Joint Guideline of the Cardiovascular and and Interventional Radiology Society of Europe and the Society of Interventional Radiology. J Vasc Interv Radiol

[20] Shortt CP, Al-Hashimi H, Malone L, Lee MJ: Staff radiation doses to the lower ex‐ tremities in interventional radiology. Cardiovasc. Interv. Radiol 2007;30:1206–1209.

[21] Kuon E, Birkel J, Schmitt M, Dahm JB. Radiation exposure benefit of a lead cap in in‐

[22] Renaud L. A 5-year follow up of the radiation exposure to in-room personnel during

[23] Folkerts KH, Münz A, Jung S. Estimation of radiation exposure and radiation risk to

[24] Finkelstein MM. Is brain cancer an occupational disease of cardiologists? Can J Car‐

[25] Maeder M, Brunner-La Rocca HP, Wolber T et al.: Impact of lead glass screen on scat‐ ter radiation to eyes and hands in interventional cardiologists. Catheter. Cardiovasc.

[26] Kuon E, Dahm JB, Empen K, et al: Identification of less-irradiating tube angulations

[27] Niklason LT, Marx MV, Chan HP. Interventional radiologists: occupational radiation

[28] Roth A, Elkayam U. Acute myocardial infarction associated with pregnancy. Ann In‐

[29] James AH, Jamison MG, Biswas MS et al.: Acute myocardial infarction in pregnancy: a United States population-based study. Circulation 2006;113(12):1564-1571.

staff of cardiac catheterization laboratories. Z Kardiol 1997;86:258–63.

in invasive cardiology. J. Am. Coll. Cardiol 2004;44:1420–1428.

J. Radiol 2003;76:473–477.

vasive cardiology. Heart 2003;89:1205–1210.

doses and risks. Radiology 1993;187:729–33.

cardiac catheterization. Health Phys 1992;62:10–15.

2010;21(5):607-15.

diol 1998;14:1385–8.

Interv 2006;67:18–23.

tern Med. 1996;125(9):751-62.

Optimal diagnostic quality non-invasive alternatives for visualization of the coronary arteries has been a major goal with the advent of newer cardiovascular imaging mo‐ dalities such as coronary computed tomography angiography (CCTA) and magnetic resonance coronary angiography (MRCA). The challenges in imaging coronaries are ob‐ vious. The technology must be capable of visualizing arteries as small as 1.5 mm to delineate luminal and wall pathology which becomes challenging as many of the arter‐ ies are engulfed in tissue of similar composition. Coronary arteries exhibit rapid mo‐ tion which poses major issues with blurring of images due to substantial limitations of temporal resolution. Invasive coronary angiography current enjoys the best temporal resolution (less than 20 msec ) for real time visualization of coronaries and its branch‐ es but comes with its obvious limitations. CCTA has rapidly risen to this challenge and is already widely employed using 64 slice detector technology and is outstanding for exclusion of CAD with substantial advances in radiation reduction and speed of acquisition. MRCA has made significant improvements in technology which has made coronary imaging less challenging using navigator gating, whole heart imaging and us‐ ing 3Tesla magnets, with the big advantage of no radiation and capability of non-con‐ trast coronary imaging and most of all the promise of a true " one stop " comprehensive assessment. However, it is still suboptimal compared to CCTA as dis‐ cussed subsequently in detail. This chapters aims to discuss MRCA and CCTA with regards to coronary imaging and compare and contrast both these imaging modalities with one another and also highlight some emerging comparisons of CCTA to invasive coronary luminal assessment technologies.

properly cited.

© 2013 Ananthasubramaniam et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **2. Magnetic Resonance Coronary Angiography (MRCA)**

**Introduction:** MRCA has been performed for close to 20 years with numerous advances in technical and imaging aspects during this period although slower than CCTA explaining its slower adoption [1]. Initially 2 dimensional k space segmented imaging was done, but most centers now use whole heart free breathing navigator coronary MRI or targeted 3D imaging to enable better reconstruction capabilities. Published studies from experienced centers have shown excellent accuracy and superiority to conventional coronary angiography (CA) using 2 and 3 dimensional k space gradient echo MRCA (Table 1)[2]..

**3. Challenges for MRCA**

clearance prior to scanning.

50-150 milliseconds per cardiac cycle [8, 9].

latter is the most widely used [10].

**MRCA Acquisition Methods:**

**2. Acquisition strategies:**

lowed by a 1800

heart imaging have been developed.

mined by the T2 relaxation time.

**1. Pulse sequences:**

Achieving optimal spatial and temporal resolution, accurate motion compensation, wide anatomical coverage, and high signal and contrast to noise ratios are inherent challenges in MRCA. Improvement in one parameter occurs at the expense of another. Other factors that limit its widespread application in the acute setting include longer exam time, limited clini‐ cal monitoring in the scanner, device implants and other metallic objects that may need

Noninvasive Modalities for Coronary Angiography

http://dx.doi.org/10.5772/54082

77

Cardiac motion compensation deserves special mention. Since the heart moves due to both inherent motion and due to diaphragmatic movement and as the magnitude of this motion is greater than the diameter of the coronary vessels substantial blurring occurs if motion suppression techniques are not utilized [7]. A regular cardiac rhythm and reliable ECG gat‐ ing is crucial for cardiac motion suppression techniques to work. Also time intervals of ac‐ quisition has to be determined in advance to plan the preparatory pulses which is a limitation. Acquisition is usually in mid-diastole due to least coronary motion and lasts for

As breath holds may be long during coronary imaging and impossible for some patients free breathing MRCA is an alternative and numerous correction techniques such as multiple averaging, chest wall bellows and navigator techniques have been attempted of which the

Pulse sequence design has evolved from black blood spin echo sequences to bright blood se‐ quences such as gradient echo and steady state free precession (SSFP) imaging. Currently

This includes k-space acquisition, contrast –enhanced (intrinsic and extrinsic) MRCA, 2D and 3D acquisitions. Despite many advances, the speed of acquisition and signal to noise ra‐ tio (SNR) remain limited. New strategies such as real time, parallel, time resolved and whole

**2.** 2D SEGMENTED k SPACE GRADIENT ECHO MRI: The most widely available MRCA sequence is a 2D segmented k-space gradient echo acquisition usually performed in a single breath hold of fewer than 12 heartbeats. Thick slices and breath hold variability can limit registration of images from slice to slice however this sequence is adequate for

pulse which refocuses the dephased spins up to a decay curve deter‐

RF pulse fol‐

GRE is the chosen acquisition scheme in the majority of MRCA studies.

**1.** CONVENTIONAL SPIN ECHO MRI: A spin echo signal results from a 900

applications such as evaluation for anomalous coronaries.

Although whole heart MRCA was initially performed with 4 channel cardiac coils and a parallel imaging factor of 2 [3, 4] it has been limited due longer acquisition times and image deterioration from diaphragmatic drift. Thirty two channel cardiac coils and higher parallel imaging factor of 4 [5] has potential for enhanced coronary imaging with whole heart MRCA. 3T MRCA gives higher signal to noise ratio (approximately 30%) but has its own limitations such as constructive/destructive interference in images causing dark and bright areas due to inherent in-homogeneities which worsen with strong magnetic fields [6]. Also specific absorption rates can increase upto 4 fold with 3T systems limiting use of certain imaging sequences. There are multiple components of MRCA namely cardiac triggering to suppress cardiac motion, respiratory motion suppression (navigator, breath hold) pre-pulses to enhance contrast noise ratio and image acquisition to enhance coronary arterial image quality. Overall image sequences for coronaries include black blood (fast spin echo and dual inversion) bright blood (segmented k space gradient echo and SSFP) all of which can be used either with 2D or 3D imaging.


Abbreviations: BH, breath hold; GRE, gradient echo; LAD, left anterior descending coronary artery; LCX, left circumflex cor‐ onary artery; LM, left main coronary artery; PRO Nav GAC, prospective navigator gating with correction; RCA, right coro‐ nary artery; Retro Nav, retrospective navigator gating; Seg EPL, segmented EPI; SSFP, steady state free precession, 3D

**Table 1.** Successful visualization of native coronary arteries using 2 and 3 dimensional k space gradient echo MRCA [2].Obtained with permission

## **3. Challenges for MRCA**

**2. Magnetic Resonance Coronary Angiography (MRCA)**

76 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

2 and 3 dimensional k space gradient echo MRCA (Table 1)[2]..

**Compensation**

Manning, 1993 2D GRE BH 25 100% 96% 100% 76% Pennell, 1993 2D GRE BH 26 95% 95% 91% 76% Duerinckx, 1994 2D GRE BH 20 100% 95% 86% 77% Sakuma, 1994 2D GRE cine BH 18 100% 100% 100% 67% Masui, 1995 2D GRE BH 13 85% 92% 100% 92% Davis, 1996 2D GRE BH 33\* 100% 100% 100% 100% Li, 1993 3D GRE Multiple Averages 14 100% 100% 86% 93% Post, 1996 3D GRE Retro Nav G 20 100% 100% 100% 100% Wielopoiski, 1998 3D Seg EPI BH 32 100% 100% 100% 100% Botnar, 1999 3D GRE Pro Nav G/C 13 97% 100% 100% 97% Weber, 2003 3D SSFP Pro Nav G/C 12 100% 100% 100% 100% Abbreviations: BH, breath hold; GRE, gradient echo; LAD, left anterior descending coronary artery; LCX, left circumflex cor‐ onary artery; LM, left main coronary artery; PRO Nav GAC, prospective navigator gating with correction; RCA, right coro‐ nary artery; Retro Nav, retrospective navigator gating; Seg EPL, segmented EPI; SSFP, steady state free precession, 3D

**Table 1.** Successful visualization of native coronary arteries using 2 and 3 dimensional k space gradient echo MRCA

used either with 2D or 3D imaging.

[2].Obtained with permission

**Investigator Technique Respiratory**

**Introduction:** MRCA has been performed for close to 20 years with numerous advances in technical and imaging aspects during this period although slower than CCTA explaining its slower adoption [1]. Initially 2 dimensional k space segmented imaging was done, but most centers now use whole heart free breathing navigator coronary MRI or targeted 3D imaging to enable better reconstruction capabilities. Published studies from experienced centers have shown excellent accuracy and superiority to conventional coronary angiography (CA) using

Although whole heart MRCA was initially performed with 4 channel cardiac coils and a parallel imaging factor of 2 [3, 4] it has been limited due longer acquisition times and image deterioration from diaphragmatic drift. Thirty two channel cardiac coils and higher parallel imaging factor of 4 [5] has potential for enhanced coronary imaging with whole heart MRCA. 3T MRCA gives higher signal to noise ratio (approximately 30%) but has its own limitations such as constructive/destructive interference in images causing dark and bright areas due to inherent in-homogeneities which worsen with strong magnetic fields [6]. Also specific absorption rates can increase upto 4 fold with 3T systems limiting use of certain imaging sequences. There are multiple components of MRCA namely cardiac triggering to suppress cardiac motion, respiratory motion suppression (navigator, breath hold) pre-pulses to enhance contrast noise ratio and image acquisition to enhance coronary arterial image quality. Overall image sequences for coronaries include black blood (fast spin echo and dual inversion) bright blood (segmented k space gradient echo and SSFP) all of which can be

> **Number of Subjects**

**RCA LM LAD LCX**

Achieving optimal spatial and temporal resolution, accurate motion compensation, wide anatomical coverage, and high signal and contrast to noise ratios are inherent challenges in MRCA. Improvement in one parameter occurs at the expense of another. Other factors that limit its widespread application in the acute setting include longer exam time, limited clini‐ cal monitoring in the scanner, device implants and other metallic objects that may need clearance prior to scanning.

Cardiac motion compensation deserves special mention. Since the heart moves due to both inherent motion and due to diaphragmatic movement and as the magnitude of this motion is greater than the diameter of the coronary vessels substantial blurring occurs if motion suppression techniques are not utilized [7]. A regular cardiac rhythm and reliable ECG gat‐ ing is crucial for cardiac motion suppression techniques to work. Also time intervals of ac‐ quisition has to be determined in advance to plan the preparatory pulses which is a limitation. Acquisition is usually in mid-diastole due to least coronary motion and lasts for 50-150 milliseconds per cardiac cycle [8, 9].

As breath holds may be long during coronary imaging and impossible for some patients free breathing MRCA is an alternative and numerous correction techniques such as multiple averaging, chest wall bellows and navigator techniques have been attempted of which the latter is the most widely used [10].

#### **MRCA Acquisition Methods:**

#### **1. Pulse sequences:**

Pulse sequence design has evolved from black blood spin echo sequences to bright blood se‐ quences such as gradient echo and steady state free precession (SSFP) imaging. Currently GRE is the chosen acquisition scheme in the majority of MRCA studies.

#### **2. Acquisition strategies:**

This includes k-space acquisition, contrast –enhanced (intrinsic and extrinsic) MRCA, 2D and 3D acquisitions. Despite many advances, the speed of acquisition and signal to noise ra‐ tio (SNR) remain limited. New strategies such as real time, parallel, time resolved and whole heart imaging have been developed.


**3.** 3D MRI: The use of navigator respiratory gating has given access to three-dimensional (3D) coronary magnetic resonance imaging techniques, allowing a 3D dataset to be ob‐ tained in a single acquisition. It provides higher spatial resolution and is less operator dependent. However, it relies on a reproducible respiratory pattern, which is not al‐ ways present. Furthermore, 3D techniques are hampered by the saturation of blood sig‐ nal, which decreases the signal to-noise ratio and the contrast of blood to myocardium.

**2.** Coronary Artery Disease:

tion is shown in Figures 1A and 1B

2009-01-2

Clinical studies have produced variable results. Kim et al [20] performed the first multicen‐ ter trial in 109 patients with suspected CAD. Overall sensitivity and specificity was 93 and 42%, respectively. 84% of coronary segments were of diagnostic quality. Table 1 shows the comparative sensitivities of MRCA to CA. An example of MRCA coronary artery delinea‐

Noninvasive Modalities for Coronary Angiography

http://dx.doi.org/10.5772/54082

79

Sakuma et al [21] evaluated over 130 patients with significant CAD and found an overall ac‐

**Figure 1.** Sliding partial MIP images of 3 T whole heart coronary MRA acquired with a patient-specific narrow acquisi‐ tion window (50 ms) in the cardiac cycle Journal of Cardiovascular Magnetic Resonance **Vol.** 11 **Issue** Suppl 1

**Introduction:** CCTA has been rapidly adopted in a short time span by institutions across the world as the most widely used anatomic noninvasive imaging modality for coronary artery assessment. A major reason for this is the existing wide use of CT for non-cardiac applica‐ tions and most institutions have access to a CT scanner. Thus, investing in a state of the art

**4. Coronary Computed Tomoraphy Angiography (CCTA)**

curacy of 87%, per patient sensitivity of 82% and specificity of 90%


#### **Clinical Applications:**

**1.** Anomalous coronary arteries:

C-MRA provides a 3D spatial relationship to great vessels, allowing evaluation of the origin and course of anomalous coronary arteries. Accurate delineation of proximal course has been shown with a sensitivity of 88-100% and specificity of 100% [14-19] MRI can often provide a definitive diagnosis in patients in whose X ray angiography is inconclusive. See Table 2


**Table 2.** Anomalous coronary assessment by MRCA.[2] (reproduced with permission)

#### **2.** Coronary Artery Disease:

**3.** 3D MRI: The use of navigator respiratory gating has given access to three-dimensional (3D) coronary magnetic resonance imaging techniques, allowing a 3D dataset to be ob‐ tained in a single acquisition. It provides higher spatial resolution and is less operator dependent. However, it relies on a reproducible respiratory pattern, which is not al‐ ways present. Furthermore, 3D techniques are hampered by the saturation of blood sig‐ nal, which decreases the signal to-noise ratio and the contrast of blood to myocardium.

78 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**4.** CONTRAST ENHANCED CORONARY MRI: The use of interstitial paramagnetic con‐ trast agents allows an improvement of signal and contrast. The disadvantage is the rap‐ id leakage out of the intravascular space, amounting to 50% during the first pass. Multiple injections are necessary to cover the whole coronary artery tree. With the in‐ troduction of intravascular paramagnetic contrast agents [11, 12], the signal from blood no longer relies on inflow of blood but rather on the presence of the contrast agent itself. The imaging time can be prolonged with potential increased signal and in contrast, al‐

**5.** 3T MRI: Imaging at higher field strength can enhance signal-to-noise ratio (SNR) and enable higher spatial resolution. However, image quality may be hampered by in‐ creased susceptibility artifacts and RF inhomogeneity which may be addressed by shortening the TE and acquisition time. High-field imaging at 3 Tenhances spiral MRCA. A number of research groups already have demonstrated the feasibility of car‐ diac imaging at 7 T and beyond and have shown improved contrast between blood and epicardial fat, better coronary vessel sharpness, and increased blood signal intensity of

C-MRA provides a 3D spatial relationship to great vessels, allowing evaluation of the origin and course of anomalous coronary arteries. Accurate delineation of proximal course has been shown with a sensitivity of 88-100% and specificity of 100% [14-19] MRI can often provide a definitive diagnosis in patients in whose X ray angiography

**Investigator Number of patients Correctly Classified Anomalous Vessels**

McConnell, 1995 15 14 (93%) Post, 1995 19 19 (100%) Vilegen, 1997 12 11 (92%) Taylor, 2000 25 24 (96%) Bunce, 2003 26 26 (100%) Razmi, 2001 12 12 (100%)

**Table 2.** Anomalous coronary assessment by MRCA.[2] (reproduced with permission)

lowing a larger volume coverage and higher resolution.

the coronaries are obtained at 7 T than at 3 T [13].

**Clinical Applications:**

**1.** Anomalous coronary arteries:

is inconclusive. See Table 2

Clinical studies have produced variable results. Kim et al [20] performed the first multicen‐ ter trial in 109 patients with suspected CAD. Overall sensitivity and specificity was 93 and 42%, respectively. 84% of coronary segments were of diagnostic quality. Table 1 shows the comparative sensitivities of MRCA to CA. An example of MRCA coronary artery delinea‐ tion is shown in Figures 1A and 1B

Sakuma et al [21] evaluated over 130 patients with significant CAD and found an overall ac‐ curacy of 87%, per patient sensitivity of 82% and specificity of 90%

**Figure 1.** Sliding partial MIP images of 3 T whole heart coronary MRA acquired with a patient-specific narrow acquisi‐ tion window (50 ms) in the cardiac cycle Journal of Cardiovascular Magnetic Resonance **Vol.** 11 **Issue** Suppl 1 2009-01-2

## **4. Coronary Computed Tomoraphy Angiography (CCTA)**

**Introduction:** CCTA has been rapidly adopted in a short time span by institutions across the world as the most widely used anatomic noninvasive imaging modality for coronary artery assessment. A major reason for this is the existing wide use of CT for non-cardiac applica‐ tions and most institutions have access to a CT scanner. Thus, investing in a state of the art CT scanner serves multiple purposes and makes financial sense with opportunity for cardiac and non-cardiac use. Although initially limited to electron beam scanners in the 1980's where imaging of the heart arteries took several seconds and processing several hours, with the advent of multi-detector coronary computed CT technology (MDCT or multi slice (MSCT)) in the late 1990's, rapid advancement in scanner technology has enabled rapid whole heart acquisitions in a few seconds. With such scanners post processing capabilities on a 3D dataset is usually achievable in about 15-20 minutes.

antecubital IV that is at least 18-gauge is preferred. If heart rate is not low enough with oral

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Two types of ECG gating are possible, prospective and retrospective. Prospective is where the scanner emits radiation only at a predefined point after the R wave. Mid-di‐ astole occurs at 70-75% of the R-R interval and during this time in the cardiac cycle, there is minimum amount of motion enabling better coronary imaging. The CT beam is off during all other points in the cycle. This requires a regular heart rate and is the preferred method of imaging because of the low radiation dose. In retrospective trig‐ gering a continuous heart scan is utilized. Imaging is performed throughout systole and diastole. Left ventricular function data is hence available. This method of gating is used if the patient's heart rate is irregular or not low enough for 64 slice CT scanners.

**Radiation Exposure:** Reported CTA effective radiation dose is higher than many other car‐ diac diagnostic procedures as described by the International Commission on Radiological Protection (ICRP) 60 [23]. The rapid expansion of CCTA magnifies the importance of dose reduction within the population. The clinical acceptance of CCTA will partially depend on the radiation exposure and its consequences, particularly if it is going to be used at an earlier

stage of CAD detection. Some commonly used dose reduction strategies include:

Figure 2 below shows the different modes of CCCT acquisition [22].

beta-blockers, IV beta-blockers may be useful.

**Figure 2.** Reproduced under permission from [22]

**Data Acquisition:**

CCTA requires high temporal resolution to minimize motion artifacts caused by cardiac mo‐ tion and breathing. This requires a fast gantry rotation with multiple detectors. Because the coronaries are seen best when there is least motion, the diastolic phase is most optimal for imaging and thus the temporal resolution must be less than the length of the diastolic phase. High spatial resolution is also necessary to allow imaging of the coronary arteries which are small and tortuous. At present, 64-detector row CT systems are the most widely employed platform for performing CCTA. The 64 detectors allow an x-,y- axis (in-plane) spatial resolu‐ tion of near 0.4mm and the z-axis spatial resolution or slice thickness is almost 0.6mm. Fast contiguous coverage of the heart is required to allow imaging of the entire heart in one breath hold. This requires the multi-slice helical CT technique, each slice of the heart is col‐ lected in one or more heartbeats. There is a 30%-50% overlap between each slice. The scan must be triggered to the heartbeat to allow gating so that imaging in multiple slices occurs across multiple heartbeats. Table 3 below, is a summary of the state of art 64 slice CT scan‐ ners with their various technical specifications [22].


**Table 3.** Reproduced under permission from [22]

#### **Patient preparation:**

On the day of the test, patients should take medications as scheduled especially betablock‐ ers. Metformin should be avoided because of the potential adverse effects when used con‐ comitantly with iodinated contrast agents. Phosphodiesterase inhibitors should be avoided 48 hours before a CCTA because nitrates are needed to dilate the coronary arteries. Premedi‐ cation with mucomyst and hydration are recommended if the creatinine is elevated. If a con‐ trast allergy is present, premedication with steroids and antihistamines is required. A right antecubital IV that is at least 18-gauge is preferred. If heart rate is not low enough with oral beta-blockers, IV beta-blockers may be useful.

#### **Data Acquisition:**

CT scanner serves multiple purposes and makes financial sense with opportunity for cardiac and non-cardiac use. Although initially limited to electron beam scanners in the 1980's where imaging of the heart arteries took several seconds and processing several hours, with the advent of multi-detector coronary computed CT technology (MDCT or multi slice (MSCT)) in the late 1990's, rapid advancement in scanner technology has enabled rapid whole heart acquisitions in a few seconds. With such scanners post processing capabilities

80 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

CCTA requires high temporal resolution to minimize motion artifacts caused by cardiac mo‐ tion and breathing. This requires a fast gantry rotation with multiple detectors. Because the coronaries are seen best when there is least motion, the diastolic phase is most optimal for imaging and thus the temporal resolution must be less than the length of the diastolic phase. High spatial resolution is also necessary to allow imaging of the coronary arteries which are small and tortuous. At present, 64-detector row CT systems are the most widely employed platform for performing CCTA. The 64 detectors allow an x-,y- axis (in-plane) spatial resolu‐ tion of near 0.4mm and the z-axis spatial resolution or slice thickness is almost 0.6mm. Fast contiguous coverage of the heart is required to allow imaging of the entire heart in one breath hold. This requires the multi-slice helical CT technique, each slice of the heart is col‐ lected in one or more heartbeats. There is a 30%-50% overlap between each slice. The scan must be triggered to the heartbeat to allow gating so that imaging in multiple slices occurs across multiple heartbeats. Table 3 below, is a summary of the state of art 64 slice CT scan‐

On the day of the test, patients should take medications as scheduled especially betablock‐ ers. Metformin should be avoided because of the potential adverse effects when used con‐ comitantly with iodinated contrast agents. Phosphodiesterase inhibitors should be avoided 48 hours before a CCTA because nitrates are needed to dilate the coronary arteries. Premedi‐ cation with mucomyst and hydration are recommended if the creatinine is elevated. If a con‐ trast allergy is present, premedication with steroids and antihistamines is required. A right

on a 3D dataset is usually achievable in about 15-20 minutes.

ners with their various technical specifications [22].

**Table 3.** Reproduced under permission from [22]

**Patient preparation:**

Two types of ECG gating are possible, prospective and retrospective. Prospective is where the scanner emits radiation only at a predefined point after the R wave. Mid-di‐ astole occurs at 70-75% of the R-R interval and during this time in the cardiac cycle, there is minimum amount of motion enabling better coronary imaging. The CT beam is off during all other points in the cycle. This requires a regular heart rate and is the preferred method of imaging because of the low radiation dose. In retrospective trig‐ gering a continuous heart scan is utilized. Imaging is performed throughout systole and diastole. Left ventricular function data is hence available. This method of gating is used if the patient's heart rate is irregular or not low enough for 64 slice CT scanners. Figure 2 below shows the different modes of CCCT acquisition [22].

**Figure 2.** Reproduced under permission from [22]

**Radiation Exposure:** Reported CTA effective radiation dose is higher than many other car‐ diac diagnostic procedures as described by the International Commission on Radiological Protection (ICRP) 60 [23]. The rapid expansion of CCTA magnifies the importance of dose reduction within the population. The clinical acceptance of CCTA will partially depend on the radiation exposure and its consequences, particularly if it is going to be used at an earlier stage of CAD detection. Some commonly used dose reduction strategies include:

**1.** Restricting scan field to anatomy of interest (~1 cm above left main to ~1 cm below heart)

**1. Anomalous coronary arteries:** CTA provides a 3D spatial relationship to great vessels, allowing evaluation of the origin and course of anomalous coronary arteries in a non– invasive manner. It is the "gold standard" test for evaluating anomalous coronary arter‐

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**Figure 3.** 40 year old male with syncope during exercise. CCTA shows anomalous left main coronary artery take off

**i. Detection of Coronary Stenosis:** With ongoing technical development, the diag‐

nostic performance of CT with respect to detection and quantification of obstruc‐ tive CAD is steadily improving. The confidence and accuracy to assess stenosis is better in larger branches and in the absence of extensive coronary calcification. For the assessment of individual coronary segments, the sensitivity to detect significant coronary artery stenosis ranges between 64-99%, the specificity between 84- 98%, with pooled average sensitivity of 87% and specificity of 96%. The positive predic‐ tive value is approximately 80% whereas the negative predictive value has been consistently high in all the studies with a pooled average of 98%. Calcified coro‐ nary disease causes blooming artifacts, which increases apparent stenosis severity of a lesion. The ability to quantify coronary stenosis severity has been modest com‐

from right coronary cusp between aorta and RVOT

**2. Coronary artery disease**

ies and has the highest level of appropriateness use for this indication.


With regards to radiation exposure numerous algorithms and acquisition techniques have been developed as discussed previously to reduce exposure specifically prospective trig‐ gered acquisition [24] and high pitch acquisition with dual source CCTA [25].

## **5. Limitations**

There are several limitations with CCTA. Patients unable to cooperate with scanning in‐ structions should be considered for other imaging modalities. Uncontrollable arrhythmias can result in significant motion artifacts and multiple uninterpretable coronary segments. Contraindications to iodinated contrast use include pregnancy, prior severe/anaphylactic contrast reaction and renal insufficiency (but end-stage renal disease is not a contraindica‐ tion) for contrast-induced nephropathy. Certain conditions should raise concerns for the use of pre-scan beta-blocker (chronic obstructive pulmonary disease/asthma, decompensated heart failure, and advanced atrioventricular block) and nitroglycerin (severe aortic stenosis, hypertrophic cardiomyopathy, recent phosphodiesterase-5 inhibitor use). Metallic objects such as pacemakers, intra-cardiac defibrillator leads, prosthetic valves cause beam-harden‐ ing and streaking artifact over adjacent coronary arteries. Dense concentric coronary calcifi‐ cation causes a blooming artifact, which often leads to overestimation of degree of stenosis.

#### **Clinical Applications:**

#### **Most Important Appropriate indications for CCTA**

**Chest pain evaluation after an uninterpretable or equivocal stress test**

**Chest pain evaluation in patients with an intermediate probability, an uninterpretable EKG and unable to exercise**

**Acute chest pain evaluation, an intermediate pretest probability, no EKG changes, and serial enzymes negative**

**Suspected coronary anomalies in symptomatic patients**

**Coronary evaluation in new onset heart failure**

**Table 4.**

**1. Anomalous coronary arteries:** CTA provides a 3D spatial relationship to great vessels, allowing evaluation of the origin and course of anomalous coronary arteries in a non– invasive manner. It is the "gold standard" test for evaluating anomalous coronary arter‐ ies and has the highest level of appropriateness use for this indication.

**Figure 3.** 40 year old male with syncope during exercise. CCTA shows anomalous left main coronary artery take off from right coronary cusp between aorta and RVOT

#### **2. Coronary artery disease**

**1.** Restricting scan field to anatomy of interest (~1 cm above left main to ~1 cm below

82 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**2.** Reducing peak mAs based on body size (non-contrast scout films may be used to esti‐

**3.** Using ECG dependant current modulation with lowest mAs during systole. Narrowing

With regards to radiation exposure numerous algorithms and acquisition techniques have been developed as discussed previously to reduce exposure specifically prospective trig‐

There are several limitations with CCTA. Patients unable to cooperate with scanning in‐ structions should be considered for other imaging modalities. Uncontrollable arrhythmias can result in significant motion artifacts and multiple uninterpretable coronary segments. Contraindications to iodinated contrast use include pregnancy, prior severe/anaphylactic contrast reaction and renal insufficiency (but end-stage renal disease is not a contraindica‐ tion) for contrast-induced nephropathy. Certain conditions should raise concerns for the use of pre-scan beta-blocker (chronic obstructive pulmonary disease/asthma, decompensated heart failure, and advanced atrioventricular block) and nitroglycerin (severe aortic stenosis, hypertrophic cardiomyopathy, recent phosphodiesterase-5 inhibitor use). Metallic objects such as pacemakers, intra-cardiac defibrillator leads, prosthetic valves cause beam-harden‐ ing and streaking artifact over adjacent coronary arteries. Dense concentric coronary calcifi‐ cation causes a blooming artifact, which often leads to overestimation of degree of stenosis.

**Chest pain evaluation in patients with an intermediate probability, an uninterpretable EKG and unable to**

**Acute chest pain evaluation, an intermediate pretest probability, no EKG changes, and serial enzymes negative**

gered acquisition [24] and high pitch acquisition with dual source CCTA [25].

heart)

**5. Limitations**

**Clinical Applications:**

**exercise**

**Table 4.**

**Most Important Appropriate indications for CCTA**

**Suspected coronary anomalies in symptomatic patients**

**Coronary evaluation in new onset heart failure**

**Chest pain evaluation after an uninterpretable or equivocal stress test**

mate image noise)

the width of the peak mAs phase

**5.** Use prospective gating if available.

**4.** Reducing kV to 100 if body Wt is <85 kg

**i. Detection of Coronary Stenosis:** With ongoing technical development, the diag‐ nostic performance of CT with respect to detection and quantification of obstruc‐ tive CAD is steadily improving. The confidence and accuracy to assess stenosis is better in larger branches and in the absence of extensive coronary calcification. For the assessment of individual coronary segments, the sensitivity to detect significant coronary artery stenosis ranges between 64-99%, the specificity between 84- 98%, with pooled average sensitivity of 87% and specificity of 96%. The positive predic‐ tive value is approximately 80% whereas the negative predictive value has been consistently high in all the studies with a pooled average of 98%. Calcified coro‐ nary disease causes blooming artifacts, which increases apparent stenosis severity of a lesion. The ability to quantify coronary stenosis severity has been modest com‐ pared to invasive angiography given the limited spatial resolution of CT and blooming artifacts of calcified lesions. There are numerous single-center [26-34] and three multicenter studies [35-37] using different scanner technologies (Table 4) [35-37] in symptomatic patients with suspected CAD.

**ii. Stents:** CCTA is not optimal for the evaluation of coronary stents because the spa‐

**Figure 5.** Shows multiplanar reformats of the left anterior descending coronary artery with clear visualization of pat‐

**iii. Bypass Graft Analysis:** CCTA may be used to assess bypass graft patency as well

as to evaluate the patient undergoing repeat bypass surgery. In repeat bypass sur‐ gery CCTA is utilized to identify the location of a previously utilized graft. Clips may often create challenges in assessing bypass grafts because of beam hardening artifact and their potential to obscure the graft lumen or anastomosis point. Below is an example of a 3d surface rendering of patient with prior coronary artery by‐ pass surgery (Figure 6) [40]. The saphenous vein graft (SVG) to the right coronary artery is seen taking off from the aorta and inserting into the RCA. The origins of 2 other SVG are also noted adjacent to the SVG to RCA going to the left coronary sys‐ tem. The maximum intensity projection reveals a significant stenosis in the inser‐

ent stents and normal right and left circumflex coronary arteries. Reproduced from Cademartiri et al [39].

tion site of the SVG to RCA [40].

stents >3.5-4.0 mm may be adequately assessed [39].

tial resolution is not quite good enough to visualize the intrastent lumen, thus should not be routinely used for the evaluation of coronary stents. Small stents tend to cause blooming and beam hardening issues leading to poor delineation of lumen. Lack of contrast in lumen is a sign of in-stent restenosis. Currently, larger

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**Table 5.** Adapted with permission from Chang et al [38].

**Figure 4.** CCTA of a 60 year old smoker with atypical chest pain and sub-maximal negative stress echo. Thick maxi‐ mum intensity projection (MIP) images and multiplanar reconstruction images (MPR) are shown showing focal high grade stenosis in proximal-mid RCA accompanied by scattered calcified plaques throughout RCA, Coronary angio‐ gram was performed confirming CCTA findings.

**ii. Stents:** CCTA is not optimal for the evaluation of coronary stents because the spa‐ tial resolution is not quite good enough to visualize the intrastent lumen, thus should not be routinely used for the evaluation of coronary stents. Small stents tend to cause blooming and beam hardening issues leading to poor delineation of lumen. Lack of contrast in lumen is a sign of in-stent restenosis. Currently, larger stents >3.5-4.0 mm may be adequately assessed [39].

pared to invasive angiography given the limited spatial resolution of CT and blooming artifacts of calcified lesions. There are numerous single-center [26-34] and three multicenter studies [35-37] using different scanner technologies (Table 4)

**Figure 4.** CCTA of a 60 year old smoker with atypical chest pain and sub-maximal negative stress echo. Thick maxi‐ mum intensity projection (MIP) images and multiplanar reconstruction images (MPR) are shown showing focal high grade stenosis in proximal-mid RCA accompanied by scattered calcified plaques throughout RCA, Coronary angio‐

[35-37] in symptomatic patients with suspected CAD.

84 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Table 5.** Adapted with permission from Chang et al [38].

gram was performed confirming CCTA findings.

**Figure 5.** Shows multiplanar reformats of the left anterior descending coronary artery with clear visualization of pat‐ ent stents and normal right and left circumflex coronary arteries. Reproduced from Cademartiri et al [39].

**iii. Bypass Graft Analysis:** CCTA may be used to assess bypass graft patency as well as to evaluate the patient undergoing repeat bypass surgery. In repeat bypass sur‐ gery CCTA is utilized to identify the location of a previously utilized graft. Clips may often create challenges in assessing bypass grafts because of beam hardening artifact and their potential to obscure the graft lumen or anastomosis point. Below is an example of a 3d surface rendering of patient with prior coronary artery by‐ pass surgery (Figure 6) [40]. The saphenous vein graft (SVG) to the right coronary artery is seen taking off from the aorta and inserting into the RCA. The origins of 2 other SVG are also noted adjacent to the SVG to RCA going to the left coronary sys‐ tem. The maximum intensity projection reveals a significant stenosis in the inser‐ tion site of the SVG to RCA [40].

with non-calcified obstructive disease and thus should not be triaged based on a negative

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**Figure 7.** 30 year old male with history of 15 pack history of smoking, cocaine abuse presents with intermittent sub‐ sternal pressure of 3 days duration. Coronary CT was done. Non-contrast scan showed zero calcium score but CCTA showed high grade stenosis in the LAD and diagonal. The image on left is a view of the mid LAD showing mainly non-

It is extremely important to define the etiology of cardiomyopathies to enable appropri‐ ate management and therapies. CCTA can be of critical importance to rule out ischemic cardiomyopathy in a non-invasive manner. CCTA has immensely robust accuracy at evaluating the proximal vascular bed with accuracy approaching almost 97-100%. This attribute becomes most relevant in the context of ischemic cardiomyopathy which per the standardized definition proposed by Felker et al [46][Patients with 75% stenosis of left main or proximal LAD, patients with 75% stenosis of two or more epicardial vessels] yields a very high diagnostic odds ratio for ischemic cardiomyopathy. Several studies have evaluated the diagnostic accuracy of CCTA in comparison with invasive angiogra‐ phy. We performed a meta analysis of all 6 studies involving 452 patients with cardio‐ myopathy of undetermined cause who underwent CTA. All patients also underwent diagnostic invasive angiography. The pooled summary estimate of sensitivity was 98% and specificity 97% yielding a negative likelihood ratio of 0.06 for ischemic cardiomyop‐ athy. The receiver operator curve analysis showed a robust discriminate diagnostic accu‐ racy of ischemic etiology with an AUC of 0.99( Figure 8). With a pooled sensitivity of 98%, an ischemic etiology of left ventricular systolic dysfunction can be accurately "ruled out" with CTA (>16 slices). A negative study hence essentially excludes the presence of ischemic cardiomyopathy. A positive CTA effectively "rules in" the probability that an underlying cardiomyopathy could be related to significant epicardial coronary stenosis. Hence, CTA can be considered as an invaluable imaging modality for evaluating patients

calcified obstructive plaque. Coronary angiography confirms high grade LAD.

**4.** Role of CCTA in Assessing Etiology of Cardiomyopathy

with left ventricular dysfunction of a suspected ischemic etiology [47].

calcium score alone (see Figure 7 below)

#### **Figure 6.**

#### **3.** Role of CCTA in Emergency Department:

A significant amount of money is wasted on inappropriate chest pain evaluations and ad‐ missions. Given CTA's high NPV, the test would most benefit the intermediate-probability patients in the ED. By using CTA, hospitalization could be avoided in patients presenting to ED with chest pain. Logistic issues such as ED scanner availability and 24 hour expertise in CTA interpretation limit use of CTA in most institutions. Triple rule out protocols have been developed and studied to rule out coronary disease, pulmonary embolism and aortic dissec‐ tion [27, 41, 42]. These are however not used widely due to logistic issues and since often one or more of these 3 etiologies can be ruled out clinically. A recent meta analysis by Sa‐ mad et al [43] synthesized data from 9 studies involving 1349 patients presenting to the emergency room with suspected acute coronary syndrome (ACS). Endpoint was the diag‐ nostic performance of CTA for ACS. The bivariate summary estimate of sensitivity of CTA for ACS diagnosis was 95% (95% CI 88-100) and specificity was 87% (95% CI 83-92), yielding a negative likelihood ratio of 0.06 (95% CI 0-0.14) and positive likelihood ratio of 7.4 (95% CI 4.8-10). Based on this meta analysis of all the clinical studies, coronary CTA with its high sensitivity and a low negative likelihood ratio of 0.06, is effective in ruling out the presence of ACS in low to intermediate risk patients presenting to the ED with acute chest pain. More recently the role of CCTA in ER has been studied in 2 important randomized trials the AC‐ RIN-PA [44] and the ROMICAT-2. Both studies showed that CCTA has an outstanding neg‐ ative predictive value with low subsequent event rates although conventional management including stress testing also achieved comparable results. There was shorter length of stay and quicker discharge directly from ED in CCTA arm although costs were the same between CCTA and conventional testing in ROMICAT-2. Also radiation doses and downstream test‐ ing were higher in CCTA arm in ROMICAT-2 [45]. An important point with regards to use of CCTA in ED is that although a zero calcium score makes obstructive CAD highly unlikely as a cause of chest pain it is now clear that young patients (age < 50, smokers) may present with non-calcified obstructive disease and thus should not be triaged based on a negative calcium score alone (see Figure 7 below)

**Figure 7.** 30 year old male with history of 15 pack history of smoking, cocaine abuse presents with intermittent sub‐ sternal pressure of 3 days duration. Coronary CT was done. Non-contrast scan showed zero calcium score but CCTA showed high grade stenosis in the LAD and diagonal. The image on left is a view of the mid LAD showing mainly noncalcified obstructive plaque. Coronary angiography confirms high grade LAD.

#### **4.** Role of CCTA in Assessing Etiology of Cardiomyopathy

**Figure 6.**

**3.** Role of CCTA in Emergency Department:

A significant amount of money is wasted on inappropriate chest pain evaluations and ad‐ missions. Given CTA's high NPV, the test would most benefit the intermediate-probability patients in the ED. By using CTA, hospitalization could be avoided in patients presenting to ED with chest pain. Logistic issues such as ED scanner availability and 24 hour expertise in CTA interpretation limit use of CTA in most institutions. Triple rule out protocols have been developed and studied to rule out coronary disease, pulmonary embolism and aortic dissec‐ tion [27, 41, 42]. These are however not used widely due to logistic issues and since often one or more of these 3 etiologies can be ruled out clinically. A recent meta analysis by Sa‐ mad et al [43] synthesized data from 9 studies involving 1349 patients presenting to the emergency room with suspected acute coronary syndrome (ACS). Endpoint was the diag‐ nostic performance of CTA for ACS. The bivariate summary estimate of sensitivity of CTA for ACS diagnosis was 95% (95% CI 88-100) and specificity was 87% (95% CI 83-92), yielding a negative likelihood ratio of 0.06 (95% CI 0-0.14) and positive likelihood ratio of 7.4 (95% CI 4.8-10). Based on this meta analysis of all the clinical studies, coronary CTA with its high sensitivity and a low negative likelihood ratio of 0.06, is effective in ruling out the presence of ACS in low to intermediate risk patients presenting to the ED with acute chest pain. More recently the role of CCTA in ER has been studied in 2 important randomized trials the AC‐ RIN-PA [44] and the ROMICAT-2. Both studies showed that CCTA has an outstanding neg‐ ative predictive value with low subsequent event rates although conventional management including stress testing also achieved comparable results. There was shorter length of stay and quicker discharge directly from ED in CCTA arm although costs were the same between CCTA and conventional testing in ROMICAT-2. Also radiation doses and downstream test‐ ing were higher in CCTA arm in ROMICAT-2 [45]. An important point with regards to use of CCTA in ED is that although a zero calcium score makes obstructive CAD highly unlikely as a cause of chest pain it is now clear that young patients (age < 50, smokers) may present

86 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

It is extremely important to define the etiology of cardiomyopathies to enable appropri‐ ate management and therapies. CCTA can be of critical importance to rule out ischemic cardiomyopathy in a non-invasive manner. CCTA has immensely robust accuracy at evaluating the proximal vascular bed with accuracy approaching almost 97-100%. This attribute becomes most relevant in the context of ischemic cardiomyopathy which per the standardized definition proposed by Felker et al [46][Patients with 75% stenosis of left main or proximal LAD, patients with 75% stenosis of two or more epicardial vessels] yields a very high diagnostic odds ratio for ischemic cardiomyopathy. Several studies have evaluated the diagnostic accuracy of CCTA in comparison with invasive angiogra‐ phy. We performed a meta analysis of all 6 studies involving 452 patients with cardio‐ myopathy of undetermined cause who underwent CTA. All patients also underwent diagnostic invasive angiography. The pooled summary estimate of sensitivity was 98% and specificity 97% yielding a negative likelihood ratio of 0.06 for ischemic cardiomyop‐ athy. The receiver operator curve analysis showed a robust discriminate diagnostic accu‐ racy of ischemic etiology with an AUC of 0.99( Figure 8). With a pooled sensitivity of 98%, an ischemic etiology of left ventricular systolic dysfunction can be accurately "ruled out" with CTA (>16 slices). A negative study hence essentially excludes the presence of ischemic cardiomyopathy. A positive CTA effectively "rules in" the probability that an underlying cardiomyopathy could be related to significant epicardial coronary stenosis. Hence, CTA can be considered as an invaluable imaging modality for evaluating patients with left ventricular dysfunction of a suspected ischemic etiology [47].

**7. Prognostic value**

Whereas the diagnostic accuracy of CCTA has been rigorously established, increasing num‐ ber of studies have also evaluated the prognostic value of CCTA. A recent meta analysis in‐ cluded eighteen studies involving 9,592 patients with a median follow-up of 20 months for adverse cardiac events [51]. The authors computed a pooled annualized event MACE rate of 8.8% for obstructive (any vessel with >50% luminal stenosis) disease versus 0.17% per year for normal CCTA (p < 0.05) and 3.2% versus 0.15% for death or MI (p < 0.05) Figure 9. Fur‐ thermore, the pooled negative likelihood ratio for MACE after normal CCTA findings was 0.008 (95% CI: 0.0004 to 0.17, p < 0.001). Patients with a normal CTA can hence be confident‐ ly reassured given a very low risk of death, MI or revascularization fairly comparable to an otherwise healthy population(<1%). Furthermore, the low event rate for normal CTA (0.16%) is comparable to other well established non invasive risk stratification modalities in‐ cluding stress echocardiography (0.45%) and myocardial perfusion stress imaging (0.54%). CTA has hence emerged as a well established clinical tool that carries not only robust diag‐

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nostic accuracy but also has powerful predictive accuracy as well [51].

**8. Physiological significance of stenoses identified by CTA**

That, coronary angiography is merely a "luminogram" and does not provide much insight into the hemodynamic significance of a stenotic lesion, is a fact that has been rigorously es‐ tablished for the past two decades. This well-recognized limitation has been documented re‐

**Figure 9.** Adapted with permission from Hulten et al [51]

**Figure 8. Diagnostic accuracy of CCTA for ischemic cardiomyopathy.** Adapted with permission from Bhatti et al [47].

#### **6. Comparison of MSCT angiography and Invasive angiography**

Since the first report of Moshage et al over 17 years ago [48], numerous studies and meta analyses have been published confirming the superior diagnostic performance of MSCT in comparison with invasive angiography as the reference standard.. The largest meta analysis to date collated data from 89 studies with 7516 patients [49]. Bivariate analysis yielded a mean sensitivity and specificity were 97.2% (95% CI, 96.2% to 98.0%) and 87.4% (CI, 84.5% to 89.8%) for CT. Negative likelihood ratio was 0.03 (0.02-0.04) whereas the positive likelihood ratio was modest at 7.7(6.2-9.5) area under the curve was 0.98 (CI, 0.96 to 0.99) for CT. The resulting sensitivity of 98.1% for scanners with more than 16 detector rows was significantly higher (*P* < 0.050) than that for scanners with a maximum of 16 rows (95.6%). The high nega‐ tive predictive value of CTA best suites it as an effective rule-out test for significant CAD.

Despite the use of newer generation scanners (>64 slice), coronary calcification remains the Achilles heel of CTA. A recent analysis from the CORE 64 study demonstrated that the ro‐ bust AUC of CTA (0.93) significantly decreased to (0.81) in patients with calcium score >600 [50]. Furthermore, the negative predictive value of CTA decreased from 0.93 in patients with Calcium score <100 to 0.75 in patients with calcium score >100. High pretest probability of CAD and high calcium score negatively impacts the diagnostic performance of CTA and must be carefully considered in test selection.

## **7. Prognostic value**

**Figure 8. Diagnostic accuracy of CCTA for ischemic cardiomyopathy.** Adapted with permission from Bhatti et al [47].

Since the first report of Moshage et al over 17 years ago [48], numerous studies and meta analyses have been published confirming the superior diagnostic performance of MSCT in comparison with invasive angiography as the reference standard.. The largest meta analysis to date collated data from 89 studies with 7516 patients [49]. Bivariate analysis yielded a mean sensitivity and specificity were 97.2% (95% CI, 96.2% to 98.0%) and 87.4% (CI, 84.5% to 89.8%) for CT. Negative likelihood ratio was 0.03 (0.02-0.04) whereas the positive likelihood ratio was modest at 7.7(6.2-9.5) area under the curve was 0.98 (CI, 0.96 to 0.99) for CT. The resulting sensitivity of 98.1% for scanners with more than 16 detector rows was significantly higher (*P* < 0.050) than that for scanners with a maximum of 16 rows (95.6%). The high nega‐ tive predictive value of CTA best suites it as an effective rule-out test for significant CAD.

Despite the use of newer generation scanners (>64 slice), coronary calcification remains the Achilles heel of CTA. A recent analysis from the CORE 64 study demonstrated that the ro‐ bust AUC of CTA (0.93) significantly decreased to (0.81) in patients with calcium score >600 [50]. Furthermore, the negative predictive value of CTA decreased from 0.93 in patients with Calcium score <100 to 0.75 in patients with calcium score >100. High pretest probability of CAD and high calcium score negatively impacts the diagnostic performance of CTA and

must be carefully considered in test selection.

**6. Comparison of MSCT angiography and Invasive angiography**

88 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Whereas the diagnostic accuracy of CCTA has been rigorously established, increasing num‐ ber of studies have also evaluated the prognostic value of CCTA. A recent meta analysis in‐ cluded eighteen studies involving 9,592 patients with a median follow-up of 20 months for adverse cardiac events [51]. The authors computed a pooled annualized event MACE rate of 8.8% for obstructive (any vessel with >50% luminal stenosis) disease versus 0.17% per year for normal CCTA (p < 0.05) and 3.2% versus 0.15% for death or MI (p < 0.05) Figure 9. Fur‐ thermore, the pooled negative likelihood ratio for MACE after normal CCTA findings was 0.008 (95% CI: 0.0004 to 0.17, p < 0.001). Patients with a normal CTA can hence be confident‐ ly reassured given a very low risk of death, MI or revascularization fairly comparable to an otherwise healthy population(<1%). Furthermore, the low event rate for normal CTA (0.16%) is comparable to other well established non invasive risk stratification modalities in‐ cluding stress echocardiography (0.45%) and myocardial perfusion stress imaging (0.54%). CTA has hence emerged as a well established clinical tool that carries not only robust diag‐ nostic accuracy but also has powerful predictive accuracy as well [51].

**Figure 9.** Adapted with permission from Hulten et al [51]

## **8. Physiological significance of stenoses identified by CTA**

That, coronary angiography is merely a "luminogram" and does not provide much insight into the hemodynamic significance of a stenotic lesion, is a fact that has been rigorously es‐ tablished for the past two decades. This well-recognized limitation has been documented re‐

tients (159 vessels) in a prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained via Noninvasive Fractional Flow Reserve) study. On a per-vessel basis, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 84.3%, 87.9%, 82.2%, 73.9%, 92.2%, respectively, for FFRCT and were 58.5%, 91.4%, 39.6%, 46.5%, 88.9%, respectively, for CCTA stenosis yielding an AUC of 0.9 for FFR CT and 0.75 for CTA. There was fair correlation between invasive FFR and FFRCT (r = 0.717, p < 0.001) although FFR Ct had slight underestimation (0.022 ± 0.116, p = 0.016). The results of the larger 285 patient DEFACTO trial comparing CT FFR and invasive FFR are awaited later this year and would further consolidate the role of non invasive FFR in the evaluation

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**9. Complimentary role of CTA in guiding complex PCI like Chronic total**

The unprecedented spatial resolution and 3D reconstruction of the epicardial coronary ves‐ sels has led to its role as an indispensable tool in guiding complex coronary interventions including recanalizing chronic total occlusions (CTO); the most challenging subset of com‐ plex coronary lesions. The display of CTA images as a 3D roadmap, side-by-side with live angiography images is instrumental in providing the interventional team access to the oc‐ cluded channel. Furthermore, synchronization of the CTA image orientation with the Carm, allows for selection of the ideal treatment projection angle without additional contrast medium or radiation exposure. Several studies have validated the use of CTA in guiding

Despite the introduction of drug eluting stents, instent restenosis (ISR) from neointimal hy‐ perplasia remains a real issue. For patients with recurrent chest pain following stent implan‐ tation, invasive coronary angiography is often performed to evaluate the presence of ISR. However, the need for a noninvasive alternative approach for ISR detection is more desira‐ ble. The experience with older generation CTA systems (4 and 16 slice) in evaluation of ISR was very disappointing largely related to motion and blooming artifacts. The improved spa‐ tial and temporal resolution with 64,128 and 256 slice scanners seems to have ameliorated those limitations. Carrabba et al [58] performed a meta analysis of nine studies involving 598 participants with 978 stents evaluated for ISR with CTA (64 slice) using invasive coronary angiography as the reference standard. More than 60% of the studied stents were >3 mm in diameter. Approximately 10% of the stents were unassessable. The pooled sensitivity and specificity of CTA was 86% (95% CI 80-91%) and 93%( 95% CI 91-95%) respectively yielding an AUC of 0.94 for per stent analysis. The calculated positive and negative predictive values were 70.4% and 97.2%, respectively. CTA can hence 64-MDCT can hence reliably rule out ISR and further evaluation by means of invasive coronary angiography can be avoided.

**10. Diagnostic accuracy of CTA for in-stent restenosis**

of intermediate coronary lesions see on CTA.

**occlusion (CTOs)**

CTO intervention [57].

peatedly by intravascular ultrasound imaging and stress testing. It has been known that coronary angiography often leads to overestimation of the functional significance of epicar‐ dial coronary stenoses. In this regard, fractional flow reserve (FFR) has emerged as a power‐ ful catheter based tool that provides robust information about the functional severity of the lesion. FFR calculated from coronary pressure measurement, is a reliable, invasive index to indicate if a stenosis is ischemia-related and can be determined in the catheterization labora‐ tory in a simple and rapid way. By taking the ratio of the coronary pressure measured distal to the stenosis to aortic pressure as the normal perfusion pressure (distal coronary pressure/ aortic pressure) and obtaining these measurements when the microvascular resistance was minimal and assumed to be constant (that is, at maximal hyperemia), the percentage of nor‐ mal coronary flow, or a fraction of normal flow (i.e., FFR), can be calculated. FFR has a uni‐ form normal value of 1.0 for every patient and every coronary artery; it is not dependent on changes in heart rate, blood pressure, or contractility; it accounts for collateral flow; and it has a sharp threshold value to indicate inducible ischemia: FFR < 0.75 always indicates indu‐ cible ischemia; FFR > 0.80 excludes ischemia in 90% of the cases [15, 17-20, 23, 46, 52-54]. The grey zone is very limited, which is important for clinical decision making in an individual patient. Coronary pressure measurements can be easily performed by a pressure wire, with almost identical mechanical properties as normal guide wires, and barely prolong the proce‐ dure, even when multiple vessels are interrogated. The ischemic threshold of FFR has been replicated independently with different noninvasive functional tests in numerous studies (including exercise electrocardiography, dobutamine stress echocardiography, and MPI) as well as alongside one another in the same population. An FFR >0.75 identified coronary stenoses in patients with inducible myocardial ischemia with high sensitivity (88%), specific‐ ity (100%), positive predictive value (100%), and overall accuracy (93%). FFR has a high re‐ producibility and low intra-individual variability. Several randomized clinical trials including DEFER, FAME and now FAME II have established the prognostic utility of FFR.Consequently, now, measurement of FFR during invasive coronary angiography is the gold standard for identifying coronary artery lesions that cause ischemia and improves clin‐ ical decision-making for revascularization.

Similar limitations of stenoses especially in the intermediate range (50-70%) are widely seen in CT angiograms. This poses both diagnostic and therapeutic challenges. Meijboom et al [55] evaluated 89 lesions in 79 patients with stable angina. Lesion correlation with invasive angiography was performed and FFR of stenoses was measured. The authors demonstrated very poor correlation between CTA and invasive coronary angiography with hemodynami‐ cally significant stenosis (FFR<0.75); diagnostic accuracy 64% for FFR <0.8 and 49% for FFR< 0.75. CTA overestimated the functional significance of coronary stenoses (poor specificity/ high false positive rate) even after excluding segments with high calcification and coronary motion. Hence patients with intermediate stenoses on CTA require further evaluation by ei‐ ther FFR evaluation of stress testing.

Recently, evaluation of FFR from CCTA data (FFRCT) has been proposed as a noninvasive method for identifying ischemic lesions. This employs the concept of computational fluid dynamics (CFD) Koo et al [56] correlated FFR from CT data with invasive FFR in 103 pa‐ tients (159 vessels) in a prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained via Noninvasive Fractional Flow Reserve) study. On a per-vessel basis, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 84.3%, 87.9%, 82.2%, 73.9%, 92.2%, respectively, for FFRCT and were 58.5%, 91.4%, 39.6%, 46.5%, 88.9%, respectively, for CCTA stenosis yielding an AUC of 0.9 for FFR CT and 0.75 for CTA. There was fair correlation between invasive FFR and FFRCT (r = 0.717, p < 0.001) although FFR Ct had slight underestimation (0.022 ± 0.116, p = 0.016). The results of the larger 285 patient DEFACTO trial comparing CT FFR and invasive FFR are awaited later this year and would further consolidate the role of non invasive FFR in the evaluation of intermediate coronary lesions see on CTA.

peatedly by intravascular ultrasound imaging and stress testing. It has been known that coronary angiography often leads to overestimation of the functional significance of epicar‐ dial coronary stenoses. In this regard, fractional flow reserve (FFR) has emerged as a power‐ ful catheter based tool that provides robust information about the functional severity of the lesion. FFR calculated from coronary pressure measurement, is a reliable, invasive index to indicate if a stenosis is ischemia-related and can be determined in the catheterization labora‐ tory in a simple and rapid way. By taking the ratio of the coronary pressure measured distal to the stenosis to aortic pressure as the normal perfusion pressure (distal coronary pressure/ aortic pressure) and obtaining these measurements when the microvascular resistance was minimal and assumed to be constant (that is, at maximal hyperemia), the percentage of nor‐ mal coronary flow, or a fraction of normal flow (i.e., FFR), can be calculated. FFR has a uni‐ form normal value of 1.0 for every patient and every coronary artery; it is not dependent on changes in heart rate, blood pressure, or contractility; it accounts for collateral flow; and it has a sharp threshold value to indicate inducible ischemia: FFR < 0.75 always indicates indu‐ cible ischemia; FFR > 0.80 excludes ischemia in 90% of the cases [15, 17-20, 23, 46, 52-54]. The grey zone is very limited, which is important for clinical decision making in an individual patient. Coronary pressure measurements can be easily performed by a pressure wire, with almost identical mechanical properties as normal guide wires, and barely prolong the proce‐ dure, even when multiple vessels are interrogated. The ischemic threshold of FFR has been replicated independently with different noninvasive functional tests in numerous studies (including exercise electrocardiography, dobutamine stress echocardiography, and MPI) as well as alongside one another in the same population. An FFR >0.75 identified coronary stenoses in patients with inducible myocardial ischemia with high sensitivity (88%), specific‐ ity (100%), positive predictive value (100%), and overall accuracy (93%). FFR has a high re‐ producibility and low intra-individual variability. Several randomized clinical trials including DEFER, FAME and now FAME II have established the prognostic utility of FFR.Consequently, now, measurement of FFR during invasive coronary angiography is the gold standard for identifying coronary artery lesions that cause ischemia and improves clin‐

90 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Similar limitations of stenoses especially in the intermediate range (50-70%) are widely seen in CT angiograms. This poses both diagnostic and therapeutic challenges. Meijboom et al [55] evaluated 89 lesions in 79 patients with stable angina. Lesion correlation with invasive angiography was performed and FFR of stenoses was measured. The authors demonstrated very poor correlation between CTA and invasive coronary angiography with hemodynami‐ cally significant stenosis (FFR<0.75); diagnostic accuracy 64% for FFR <0.8 and 49% for FFR< 0.75. CTA overestimated the functional significance of coronary stenoses (poor specificity/ high false positive rate) even after excluding segments with high calcification and coronary motion. Hence patients with intermediate stenoses on CTA require further evaluation by ei‐

Recently, evaluation of FFR from CCTA data (FFRCT) has been proposed as a noninvasive method for identifying ischemic lesions. This employs the concept of computational fluid dynamics (CFD) Koo et al [56] correlated FFR from CT data with invasive FFR in 103 pa‐

ical decision-making for revascularization.

ther FFR evaluation of stress testing.

## **9. Complimentary role of CTA in guiding complex PCI like Chronic total occlusion (CTOs)**

The unprecedented spatial resolution and 3D reconstruction of the epicardial coronary ves‐ sels has led to its role as an indispensable tool in guiding complex coronary interventions including recanalizing chronic total occlusions (CTO); the most challenging subset of com‐ plex coronary lesions. The display of CTA images as a 3D roadmap, side-by-side with live angiography images is instrumental in providing the interventional team access to the oc‐ cluded channel. Furthermore, synchronization of the CTA image orientation with the Carm, allows for selection of the ideal treatment projection angle without additional contrast medium or radiation exposure. Several studies have validated the use of CTA in guiding CTO intervention [57].

### **10. Diagnostic accuracy of CTA for in-stent restenosis**

Despite the introduction of drug eluting stents, instent restenosis (ISR) from neointimal hy‐ perplasia remains a real issue. For patients with recurrent chest pain following stent implan‐ tation, invasive coronary angiography is often performed to evaluate the presence of ISR. However, the need for a noninvasive alternative approach for ISR detection is more desira‐ ble. The experience with older generation CTA systems (4 and 16 slice) in evaluation of ISR was very disappointing largely related to motion and blooming artifacts. The improved spa‐ tial and temporal resolution with 64,128 and 256 slice scanners seems to have ameliorated those limitations. Carrabba et al [58] performed a meta analysis of nine studies involving 598 participants with 978 stents evaluated for ISR with CTA (64 slice) using invasive coronary angiography as the reference standard. More than 60% of the studied stents were >3 mm in diameter. Approximately 10% of the stents were unassessable. The pooled sensitivity and specificity of CTA was 86% (95% CI 80-91%) and 93%( 95% CI 91-95%) respectively yielding an AUC of 0.94 for per stent analysis. The calculated positive and negative predictive values were 70.4% and 97.2%, respectively. CTA can hence 64-MDCT can hence reliably rule out ISR and further evaluation by means of invasive coronary angiography can be avoided. Caution is still advised for smaller stents and the fact that almost 10% of the studies were still uninterpretable despite the use of 64 detector scanners.

repetitive exposure to radiation. Furthermore, imaging sequences or views can easily be re‐ peated. Thus, a hybrid anatomic and functional assessment is clinically feasible at present in centers with experience with MRCA. With CCTA, valves and ventricular function assessment comes at the cost of higher radiation exposure as retrospective triggered acquisition is needed. CT perfusion imaging for ischemia and viability is still not well validated compared to cardiac MRI but has been performed for both viability [62, 63] and perfusion [64, 65] and is being tested against SPECT in ongoing clinical trials. Promising new studies with CCTA with lower radia‐ tion doses encompassing a complete anatomical-functional assessment compared to tradition‐ al SPECT imaging has been published recently [66] but this aspect of CCTA is not ready for clinical use. Although MRCA does offer high temporal resolution, good spatial resolution, high soft tissue contrast and the ability to generate any three dimensional image without need for ionizing radiation it is much more challenging to perform as it requires selection of the cor‐ rect pulse sequences and each pulse sequence needs many parallel slices or slab volumes to cover the entire heart. Free breathing MRCA acquisitions can take 5-15 minutes compared to a few seconds with current 64-320 slice CCTA. Spatial resolution of CCTA is superior to MRCA (0.4 to -0.6 mm with CCTA compared to 1.5 mm with MRCA). The disadvantage for MRCA compared to CCTA in terms of speed of acquisition is difficult to overcome although breath hold MRCA may offer some improvement in time required for acquisition compared to free breathing techniques [67]. The temporal resolution of CCTA is limited by the gantry rotation speed and hence cannot be altered. On the contrary free breathing MRCA temporal resolution can be flexibly determined using imaging parameters. The acquisition window position and the length within the RR interval can be individually set [68]. This is an important advantage

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**14. Diagnostic accuracy of CCTA versus MRCA for CAD**

bility and accuracy for MRCA on a practical level across many institutions.

The diagnostic accuracy of CCTA is well established with it outstanding negative predic‐ tive value ( 97.2%) and moderate-to good positive predictive value (87.4%) based on cu‐ mulative data from 89 studies of 7519 patients( 69). This compares much more favorably to MRCA which has a sensitivity of 87.1% and specificity of 70.3 % based on 20 studies of 989 patients [69]. Furthermore, in patients suspected of CAD or with acute disease at presentation, CCTA has an outstanding negative likelihood ratio of 0.03(0.02-0.04) and 0.06(0.02-0.19) respectively [69]. A meta-analysis of CCTA versus MRCA [49] and a re‐ cent study comparing state of art 64 slice CCTA to 32 channel 3T MRCA [70] both con‐ cluded that although both modalities performed well for CAD detection CCTA outperformed MRCA. Furthermore CCTA was completed in 13.9+/= 1.1 sec compared to 17 +/- 4.7 minutes for MRCA [70]. The expert consensus document on "appropriate" use of CT and MRI imaging published in 2006 gave an appropriate indication for CCTA to rule out significant CAD in patients with chest pain and intermediate likelihood of CAD. On the contrary the document gave a recommendation of "inappropriate" for MRCA for the same indication [71]. This reflects the lack of adequate data demonstrating the feasi‐

with MRCA.

## **11. Comparison of coronary computed tomography angiography and magnetic resonance coronary angiography**

This section aims to compare the techniques of coronary computed tomography angiogra‐ phy (CCTA) with magnetic resonance coronary angiography (MRCA) from the standpoint of coronary and cardiac imaging.

## **12. Comparison of technical aspects CCTA to MRCA**

Currently the majority of the institutions utilize 64 slice technology (in-plane spatial resolu‐ tion of 0.4 x 0.4 mm with a slice thickness of 0.6 mm and a 360o gantry rotation in about 330 milliseconds). More recently dual source CCTA technology has pushed the envelope further and has delivered a temporal resolution of 70-83 msec with an in plane resolution of 0.4 mm [59]. Furthermore, 256 and 320 slice CT- scanners are available in limited institutions across the world which can image the entire heart in 1 beat thus obviating many limitations with current 64 slice scanners such as irregular heart rhythm, breath hold issues and opening op‐ tions for perfusion CCCTA imaging.

The tremendous advantages that CCTA holds over MRCA with such high spatial resolution relates to: 1. ability to visualize small diameter vessels including distal coronary branches, 2. increased ability to quantify calcium and reduce blooming artifacts, 3. better visualization of stents, and 4. better plaque morphology assessment. The temporal resolution advances in CCTA has enabled: 1. enhanced ability to freeze cardiac motion, 2. additional reconstruction capabilities within cardiac cycle, and 3. reduced scan time.

The obvious disadvantages of CCTA compared to MRCA are: 1. radiation exposure which depending on the scanner, mode of acquisition and protocol modifications can range from 1 milliseivert to > 15 milliseiverts[60, 61], 2. use of iodinated contrast which could pose issues for patients with underlying renal dysfunction, and 3. need for slow heart rates which re‐ quire use of beta-blockers.

## **13. One stop shop imaging : MRCA versus CCTA**

A very attractive advantage with MRCA is that it can combined with detailed cardiac MRI ex‐ am to provide a "one stop shop" assessment is easily achievable where coronary disease, valves, stress/rest perfusion for ischemia and viability and overall cardiac and adjacent thora‐ cic and extra-thoracic anatomy can be all studied without concern for nephrotoxic contrast or repetitive exposure to radiation. Furthermore, imaging sequences or views can easily be re‐ peated. Thus, a hybrid anatomic and functional assessment is clinically feasible at present in centers with experience with MRCA. With CCTA, valves and ventricular function assessment comes at the cost of higher radiation exposure as retrospective triggered acquisition is needed. CT perfusion imaging for ischemia and viability is still not well validated compared to cardiac MRI but has been performed for both viability [62, 63] and perfusion [64, 65] and is being tested against SPECT in ongoing clinical trials. Promising new studies with CCTA with lower radia‐ tion doses encompassing a complete anatomical-functional assessment compared to tradition‐ al SPECT imaging has been published recently [66] but this aspect of CCTA is not ready for clinical use. Although MRCA does offer high temporal resolution, good spatial resolution, high soft tissue contrast and the ability to generate any three dimensional image without need for ionizing radiation it is much more challenging to perform as it requires selection of the cor‐ rect pulse sequences and each pulse sequence needs many parallel slices or slab volumes to cover the entire heart. Free breathing MRCA acquisitions can take 5-15 minutes compared to a few seconds with current 64-320 slice CCTA. Spatial resolution of CCTA is superior to MRCA (0.4 to -0.6 mm with CCTA compared to 1.5 mm with MRCA). The disadvantage for MRCA compared to CCTA in terms of speed of acquisition is difficult to overcome although breath hold MRCA may offer some improvement in time required for acquisition compared to free breathing techniques [67]. The temporal resolution of CCTA is limited by the gantry rotation speed and hence cannot be altered. On the contrary free breathing MRCA temporal resolution can be flexibly determined using imaging parameters. The acquisition window position and the length within the RR interval can be individually set [68]. This is an important advantage with MRCA.

## **14. Diagnostic accuracy of CCTA versus MRCA for CAD**

Caution is still advised for smaller stents and the fact that almost 10% of the studies were

This section aims to compare the techniques of coronary computed tomography angiogra‐ phy (CCTA) with magnetic resonance coronary angiography (MRCA) from the standpoint

Currently the majority of the institutions utilize 64 slice technology (in-plane spatial resolu‐

milliseconds). More recently dual source CCTA technology has pushed the envelope further and has delivered a temporal resolution of 70-83 msec with an in plane resolution of 0.4 mm [59]. Furthermore, 256 and 320 slice CT- scanners are available in limited institutions across the world which can image the entire heart in 1 beat thus obviating many limitations with current 64 slice scanners such as irregular heart rhythm, breath hold issues and opening op‐

The tremendous advantages that CCTA holds over MRCA with such high spatial resolution relates to: 1. ability to visualize small diameter vessels including distal coronary branches, 2. increased ability to quantify calcium and reduce blooming artifacts, 3. better visualization of stents, and 4. better plaque morphology assessment. The temporal resolution advances in CCTA has enabled: 1. enhanced ability to freeze cardiac motion, 2. additional reconstruction

The obvious disadvantages of CCTA compared to MRCA are: 1. radiation exposure which depending on the scanner, mode of acquisition and protocol modifications can range from 1 milliseivert to > 15 milliseiverts[60, 61], 2. use of iodinated contrast which could pose issues for patients with underlying renal dysfunction, and 3. need for slow heart rates which re‐

A very attractive advantage with MRCA is that it can combined with detailed cardiac MRI ex‐ am to provide a "one stop shop" assessment is easily achievable where coronary disease, valves, stress/rest perfusion for ischemia and viability and overall cardiac and adjacent thora‐ cic and extra-thoracic anatomy can be all studied without concern for nephrotoxic contrast or

gantry rotation in about 330

**11. Comparison of coronary computed tomography angiography and**

92 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

still uninterpretable despite the use of 64 detector scanners.

**12. Comparison of technical aspects CCTA to MRCA**

tion of 0.4 x 0.4 mm with a slice thickness of 0.6 mm and a 360o

capabilities within cardiac cycle, and 3. reduced scan time.

**13. One stop shop imaging : MRCA versus CCTA**

**magnetic resonance coronary angiography**

of coronary and cardiac imaging.

tions for perfusion CCCTA imaging.

quire use of beta-blockers.

The diagnostic accuracy of CCTA is well established with it outstanding negative predic‐ tive value ( 97.2%) and moderate-to good positive predictive value (87.4%) based on cu‐ mulative data from 89 studies of 7519 patients( 69). This compares much more favorably to MRCA which has a sensitivity of 87.1% and specificity of 70.3 % based on 20 studies of 989 patients [69]. Furthermore, in patients suspected of CAD or with acute disease at presentation, CCTA has an outstanding negative likelihood ratio of 0.03(0.02-0.04) and 0.06(0.02-0.19) respectively [69]. A meta-analysis of CCTA versus MRCA [49] and a re‐ cent study comparing state of art 64 slice CCTA to 32 channel 3T MRCA [70] both con‐ cluded that although both modalities performed well for CAD detection CCTA outperformed MRCA. Furthermore CCTA was completed in 13.9+/= 1.1 sec compared to 17 +/- 4.7 minutes for MRCA [70]. The expert consensus document on "appropriate" use of CT and MRI imaging published in 2006 gave an appropriate indication for CCTA to rule out significant CAD in patients with chest pain and intermediate likelihood of CAD. On the contrary the document gave a recommendation of "inappropriate" for MRCA for the same indication [71]. This reflects the lack of adequate data demonstrating the feasi‐ bility and accuracy for MRCA on a practical level across many institutions.

## **15. Assessment of coronary anomalies and aneurysms: CCTA versus MRCA**

not compromised [80]. The flip side of this is the added advantage of detection of cor‐ onary calcium during the non-contrast portion of CCTA which serves both to diagnose atherosclerosis [81] and in its absence make obstructive CAD highly unlikely both in asymptomatic patients and in patient with suspected cardiac etiology of chest pain [82, 83]. Coronary calcium also provides powerful prognostic information and is incremen‐ tal in risk assessment beyond traditional risk scores like Framingham risk scores [84]. Furthermore, identifying substantial calcium may also help in decision making for the physician as the CCTA portion of the test could be cancelled and more definitive test‐ ing towards significance of underlying lesion could be pursued wither with stress test‐ ing or angiography. MRCA lack this important " heads up" diagnostic advantage that CCTA possess as part of its armamentarium due to its inability to image calcium. More recently some investigators have tried to exploit the different capabilities of CCTA and MRCA by combining both technologies in patients with significant calcifica‐ tion. In a small study of 18 patients who underwent 64 slice CCTA, 3D free breathing MRCA and coronary angiography, MRCA had better diagnostic image quality and per‐ formed better in detection of obstructive CAD in coronary segments with focal rather than diffuse calcification and overall performed better than CCTA in detecting signifi‐

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cant CAD in patients with high calcium scores [80].

**17. Imaging bypass grafts and stents: CCTA versus MRCA**

CCTA is an outstanding modality for imaging bypass grafts. In a study by Liu and collea‐ gues [85] 228 patients underwent 64 slice CCTA to evaluate diagnostic accuracy of CCTA for bypass graft disease. The sensitivity, specificity, positive negative predictive value and over‐ all accuracy were reported at an impressive 93.3%, 98.1%, 93.3%, 98.1%, and 97.7 % respec‐ tively. Major disadvantages include higher contrast dose, increased radiation from longer scanning to cover the anatomy of origin and course of grafts and artifacts related to clips from surgery. The anastamotic sites in particular can sometimes be challenging to evaluate. In comparison, in a study by Langerak et al,[86] MRCA showed a sensitivity and specificity of 83 and 100% for graft occlusion,82%, and 88% for graft stenosis >/= 50% and 73% and 80% for graft stenosis >/= 70%. MRCA also suffers from signal void artifacts from metallic im‐ plants, clips, etc. In addition it seems to perform inferior to CCTA in consistently identifying severely diseased yet patent vessels [86] making its widespread applicability for bypass graft evaluation less feasible. Furthermore even though CCTA has limitations with radiation the population with CABG are older and hence the lifetime risk of cancer is less of a con‐ cern. Newer generation 64 slice CCTA has also shown promise in imaging stent lumen al‐ though stents less than 3 mm tend to cause unacceptable degree of lumen visualization and blooming artifacts (highest with tantalum stents and lowest with titanium and nitinol based alloys) and CCTA is not recommended below this size. A recent study on coronary stent pa‐ tency with CCTA showed a promising 89% sensitivity and 95% specificity [87]. MRCA data with stents is limited but the stainless steel composition of stents make imaging challenging as in-stent integrity and persistent assessment can be compromised. The attractive force and

One important indication where MRCA could be very helpful is imaging for anomalous cor‐ onaries in children and young adults where exposure to radiation from CCTA is undesirable [72]. Coronary arteries in MRCA can be imaged without nephrotoxic contrast administra‐ tion. The high T2/T1 signal in steady state free precession imaging (SSFP) acts as a natural contrast agent providing coronary lumen definition [73]. However, SSFP imaging has great‐ er susceptibility to artifacts and newer sequences such as fast low angle shots (FLASH) show better imaging characteristics at 3.0T compared to SSFP [74] also showing a 50% reduction in scan time [75]. CCTA offers outstanding spatial resolution and is the widely preferred tech‐ nique at least in adults to evaluate anomalous coronaries as long as there are no inherent contraindications to its use. ACC/AHA appropriate use guidelines for CCTA /MRI [71] gives CCTA and MRCA an " appropriate" indication score with CCTA receiving a higher score of 9 compared to MRCA which also receives a high score of 8. MRCA may also be used for serial follow-up of coronary aneurysms which can be a sequelae of Kawasaki disease partic‐ ularly in adolescents and young adults who otherwise may need repeated angiography.[76, 77] CCTA again is excellent to delineate these aneurysms but suffers from limitations of re‐ petitive radiation exposure.

## **16. Comparison of Technical Challenges in Imaging for CCTA and MRCA**

#### **16.1. Motion artifact issues : CCTA versus MRCA**

Motion artifacts pose a significant problem with both MRCA and CCTA. In MRCA this can be intrinsic related to cardiac contraction /relaxation or extrinsic attributable to dia‐ phragm and chest wall movement during respiration [35]. Furthermore, MRCA requires expertise to perform and interpret and is currently limited largely to academic centers with a dedicated 1.5 or a 3T cardiac magnet at least in North America. In CCTA motion artifacts are related to patient motion and respiratory based artifact (as CCTA imaging is during breath hold). In contrast 64 slice CCTA is available in most large institutions and practices and the training and interpretation process is much more feasible for physi‐ cians desiring to practice this technology.

#### **16.2. Calcification issues: CCTA versus MRCA**

Calcification of coronary arteries is seen in at least 50-70% of patients with atheroscler‐ otic plaques [78]. Calcium poses a significant limitation for accuracy of CCTA due to blooming/beam hardening artifacts compromising lumen assessment [79]. However it is not a limitation for MRCA for assessing the lumen of the coronary arteries as MRI does not have issues with beam hardening or blooming. Thus lumen visualization is not compromised [80]. The flip side of this is the added advantage of detection of cor‐ onary calcium during the non-contrast portion of CCTA which serves both to diagnose atherosclerosis [81] and in its absence make obstructive CAD highly unlikely both in asymptomatic patients and in patient with suspected cardiac etiology of chest pain [82, 83]. Coronary calcium also provides powerful prognostic information and is incremen‐ tal in risk assessment beyond traditional risk scores like Framingham risk scores [84]. Furthermore, identifying substantial calcium may also help in decision making for the physician as the CCTA portion of the test could be cancelled and more definitive test‐ ing towards significance of underlying lesion could be pursued wither with stress test‐ ing or angiography. MRCA lack this important " heads up" diagnostic advantage that CCTA possess as part of its armamentarium due to its inability to image calcium. More recently some investigators have tried to exploit the different capabilities of CCTA and MRCA by combining both technologies in patients with significant calcifica‐ tion. In a small study of 18 patients who underwent 64 slice CCTA, 3D free breathing MRCA and coronary angiography, MRCA had better diagnostic image quality and per‐ formed better in detection of obstructive CAD in coronary segments with focal rather than diffuse calcification and overall performed better than CCTA in detecting signifi‐ cant CAD in patients with high calcium scores [80].

## **17. Imaging bypass grafts and stents: CCTA versus MRCA**

**15. Assessment of coronary anomalies and aneurysms: CCTA versus**

94 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**16. Comparison of Technical Challenges in Imaging for CCTA and**

Motion artifacts pose a significant problem with both MRCA and CCTA. In MRCA this can be intrinsic related to cardiac contraction /relaxation or extrinsic attributable to dia‐ phragm and chest wall movement during respiration [35]. Furthermore, MRCA requires expertise to perform and interpret and is currently limited largely to academic centers with a dedicated 1.5 or a 3T cardiac magnet at least in North America. In CCTA motion artifacts are related to patient motion and respiratory based artifact (as CCTA imaging is during breath hold). In contrast 64 slice CCTA is available in most large institutions and practices and the training and interpretation process is much more feasible for physi‐

Calcification of coronary arteries is seen in at least 50-70% of patients with atheroscler‐ otic plaques [78]. Calcium poses a significant limitation for accuracy of CCTA due to blooming/beam hardening artifacts compromising lumen assessment [79]. However it is not a limitation for MRCA for assessing the lumen of the coronary arteries as MRI does not have issues with beam hardening or blooming. Thus lumen visualization is

One important indication where MRCA could be very helpful is imaging for anomalous cor‐ onaries in children and young adults where exposure to radiation from CCTA is undesirable [72]. Coronary arteries in MRCA can be imaged without nephrotoxic contrast administra‐ tion. The high T2/T1 signal in steady state free precession imaging (SSFP) acts as a natural contrast agent providing coronary lumen definition [73]. However, SSFP imaging has great‐ er susceptibility to artifacts and newer sequences such as fast low angle shots (FLASH) show better imaging characteristics at 3.0T compared to SSFP [74] also showing a 50% reduction in scan time [75]. CCTA offers outstanding spatial resolution and is the widely preferred tech‐ nique at least in adults to evaluate anomalous coronaries as long as there are no inherent contraindications to its use. ACC/AHA appropriate use guidelines for CCTA /MRI [71] gives CCTA and MRCA an " appropriate" indication score with CCTA receiving a higher score of 9 compared to MRCA which also receives a high score of 8. MRCA may also be used for serial follow-up of coronary aneurysms which can be a sequelae of Kawasaki disease partic‐ ularly in adolescents and young adults who otherwise may need repeated angiography.[76, 77] CCTA again is excellent to delineate these aneurysms but suffers from limitations of re‐

**MRCA**

petitive radiation exposure.

**16.1. Motion artifact issues : CCTA versus MRCA**

cians desiring to practice this technology.

**16.2. Calcification issues: CCTA versus MRCA**

**MRCA**

CCTA is an outstanding modality for imaging bypass grafts. In a study by Liu and collea‐ gues [85] 228 patients underwent 64 slice CCTA to evaluate diagnostic accuracy of CCTA for bypass graft disease. The sensitivity, specificity, positive negative predictive value and over‐ all accuracy were reported at an impressive 93.3%, 98.1%, 93.3%, 98.1%, and 97.7 % respec‐ tively. Major disadvantages include higher contrast dose, increased radiation from longer scanning to cover the anatomy of origin and course of grafts and artifacts related to clips from surgery. The anastamotic sites in particular can sometimes be challenging to evaluate. In comparison, in a study by Langerak et al,[86] MRCA showed a sensitivity and specificity of 83 and 100% for graft occlusion,82%, and 88% for graft stenosis >/= 50% and 73% and 80% for graft stenosis >/= 70%. MRCA also suffers from signal void artifacts from metallic im‐ plants, clips, etc. In addition it seems to perform inferior to CCTA in consistently identifying severely diseased yet patent vessels [86] making its widespread applicability for bypass graft evaluation less feasible. Furthermore even though CCTA has limitations with radiation the population with CABG are older and hence the lifetime risk of cancer is less of a con‐ cern. Newer generation 64 slice CCTA has also shown promise in imaging stent lumen al‐ though stents less than 3 mm tend to cause unacceptable degree of lumen visualization and blooming artifacts (highest with tantalum stents and lowest with titanium and nitinol based alloys) and CCTA is not recommended below this size. A recent study on coronary stent pa‐ tency with CCTA showed a promising 89% sensitivity and 95% specificity [87]. MRCA data with stents is limited but the stainless steel composition of stents make imaging challenging as in-stent integrity and persistent assessment can be compromised. The attractive force and local heart generated with stent imaging at 1.5 T and 3T is not a major issue the local sus‐ ceptibility artifacts can be a big problem [88, 89]. This is less of problem with tantalum com‐ pared to stainless steel stents. In the USA both Cypher and Taxus Liberte stents are approved for imaging with MRI immediately after implantation.

#### **18. Contrast issues: CCTA versus MRCA**

CCTA has to utilize iodinated contrast agents between 80-120 ml for opacification of cor‐ onary vessels. This is an obvious limitation for those with underlying chronic kidney dis‐ ease particularly Stage 3 and above as it is potentially nephrotoxic. MRCA on the other hand utilizes the natural signal differences seen in SSFP imaging to visualize coronaries and does not require gadolinium contrast although it can be utilized. Currently used ga‐ dolinium compounds remain intravascular only for a short period of time thus limiting the benefit of contrast enhancement for MRCA for a short period of time. However some advances in MRI contrast agents have been made with newer agents with more pro‐ longed intravascular time now being available. These agents increase contrast to noise ra‐ tio with MRCA and hold promise to improve diagnostic accuracy although no large scale studies have been performed as yet. It is important o note that gadolinium chelates can cause nephrogenic systemic fibrosis and are usually contraindicated in patients with glomerular filtration rates of < 30 ml/min.

**Figure 10.**

CCTA and MRCA.

**20. Patient acceptance of CCTA versus MRCA**

ment in closed space and noise associated with MR imaging.

**21. Training issues CCTA versus MRCA**

is easier to establish and execute than a MRCA program.

CCTA enjoys a much shorter time to completion of study compared to MRCA (20 versus 60 minutes respectively) which is a major attraction from the patient perspective [97]. For a mo‐ dality to be overall successful in clinical practice it should not only be accurate, demonstrate clinical benefit and cost effective but also preferred by patients [98]. Studies have shown that patients prefer CCTA to MRCA [99]. This is mainly driven by longer imaging times, confine‐

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97

Guidelines exist both from American College of Radiology [100] and the American College of Cardiology [101] for specific training requirements for gaining expertise in CCTA. Un‐ fortunately no such guidelines exist for MRCA and given the complexity involved in image acquisition the degree of expertise needed to independently perform and interpret MRCA is likely to substantially greater with regards to training requirements. CCTA program clearly

Table 5 summarizes various advantages and disadvantages from the authors perspective of

#### **19. Plaque imaging: CCTA versus MRCA**

Plaque imaging is an exciting area of intense research and potential application of CCTA given its capacity to image the vessel wall and provide information beyond luminal narrow‐ ing. It can detect and characterize atherosclerotic plaques as calcified, non-calcified and mixed composition (Figure 10).[90] It is now known that regardless of degree of luminal stenosis even non-obstructive plaques as detected by CCTA carries adverse prognosis [91]. However, inter-observer variability of measurement of plaque dimensions is substantial and routine plaque measurements is not feasible at this time. However CCTA shows promise in identifying certain high risk characteristics such as bulky plaques, spotty calcification and positive remodeling all of which have been shown to be related to acute coronary syn‐ dromes [92]. With MRI, although once felt to be not possible, several investigators have im‐ aged the coronary vessel wall and plaque successfully including subclinical wall thickening [93, 94], although from point of practical applicability this has yet to find a place in the clini‐ cal arena. Because of the lack of radiation exposure in MRCA it is ideally suited for followup imaging for assessing plaque progression [95] or to follow-up intermediate range stenosis where anatomy can be combined with a functional assessment of significance of le‐ sion with stress –rest perfusion sequences [96].

**Figure 10.**

local heart generated with stent imaging at 1.5 T and 3T is not a major issue the local sus‐ ceptibility artifacts can be a big problem [88, 89]. This is less of problem with tantalum com‐ pared to stainless steel stents. In the USA both Cypher and Taxus Liberte stents are

96 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

CCTA has to utilize iodinated contrast agents between 80-120 ml for opacification of cor‐ onary vessels. This is an obvious limitation for those with underlying chronic kidney dis‐ ease particularly Stage 3 and above as it is potentially nephrotoxic. MRCA on the other hand utilizes the natural signal differences seen in SSFP imaging to visualize coronaries and does not require gadolinium contrast although it can be utilized. Currently used ga‐ dolinium compounds remain intravascular only for a short period of time thus limiting the benefit of contrast enhancement for MRCA for a short period of time. However some advances in MRI contrast agents have been made with newer agents with more pro‐ longed intravascular time now being available. These agents increase contrast to noise ra‐ tio with MRCA and hold promise to improve diagnostic accuracy although no large scale studies have been performed as yet. It is important o note that gadolinium chelates can cause nephrogenic systemic fibrosis and are usually contraindicated in patients with

Plaque imaging is an exciting area of intense research and potential application of CCTA given its capacity to image the vessel wall and provide information beyond luminal narrow‐ ing. It can detect and characterize atherosclerotic plaques as calcified, non-calcified and mixed composition (Figure 10).[90] It is now known that regardless of degree of luminal stenosis even non-obstructive plaques as detected by CCTA carries adverse prognosis [91]. However, inter-observer variability of measurement of plaque dimensions is substantial and routine plaque measurements is not feasible at this time. However CCTA shows promise in identifying certain high risk characteristics such as bulky plaques, spotty calcification and positive remodeling all of which have been shown to be related to acute coronary syn‐ dromes [92]. With MRI, although once felt to be not possible, several investigators have im‐ aged the coronary vessel wall and plaque successfully including subclinical wall thickening [93, 94], although from point of practical applicability this has yet to find a place in the clini‐ cal arena. Because of the lack of radiation exposure in MRCA it is ideally suited for followup imaging for assessing plaque progression [95] or to follow-up intermediate range stenosis where anatomy can be combined with a functional assessment of significance of le‐

approved for imaging with MRI immediately after implantation.

**18. Contrast issues: CCTA versus MRCA**

glomerular filtration rates of < 30 ml/min.

**19. Plaque imaging: CCTA versus MRCA**

sion with stress –rest perfusion sequences [96].

## **20. Patient acceptance of CCTA versus MRCA**

CCTA enjoys a much shorter time to completion of study compared to MRCA (20 versus 60 minutes respectively) which is a major attraction from the patient perspective [97]. For a mo‐ dality to be overall successful in clinical practice it should not only be accurate, demonstrate clinical benefit and cost effective but also preferred by patients [98]. Studies have shown that patients prefer CCTA to MRCA [99]. This is mainly driven by longer imaging times, confine‐ ment in closed space and noise associated with MR imaging.

## **21. Training issues CCTA versus MRCA**

Guidelines exist both from American College of Radiology [100] and the American College of Cardiology [101] for specific training requirements for gaining expertise in CCTA. Un‐ fortunately no such guidelines exist for MRCA and given the complexity involved in image acquisition the degree of expertise needed to independently perform and interpret MRCA is likely to substantially greater with regards to training requirements. CCTA program clearly is easier to establish and execute than a MRCA program.

Table 5 summarizes various advantages and disadvantages from the authors perspective of CCTA and MRCA.

**Acknowledgements**

**Author details**

**References**

2005/07/01.

2005/08/30.

We are indebted for the expert manuscript preparation assistance of Mrs Nandita S. Mani,

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and Abdul Hakeem2

Noninvasive Modalities for Coronary Angiography

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99

MLIS, Sladen Library, Henry Ford Hospital, Detroit MI, USA

Karthikeyan Ananthasubramaniam1\*, Sabha Bhatti1

\*Address all correspondence to: kananth1@hfhs.org

2 William Beaumont Hospital Royal Oak MI, USA

2007;15(4):609-37, vii. Epub 2007/11/03.

1 Henry Ford Hospital, Heart and Vascular Institute, Detroit MI, USA

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**Table 6.**

#### **22. Future perspectives**

Noninvasive coronary angiography involving CCTA and MRCA has revolutionized delin‐ eation of coronary anatomy in a safe and fast way. CCTA has advanced much more in this aspect with fast imaging with single breath holds and 1 beat acquisition lasting a few sec‐ onds. The radiation and iodine based contrast are the major disadvantages although cur‐ rently radiation doses below 1 millisievert are achievable with CCTA. MRCA with whole heart 3D imaging and 32 channel coils and 3T magnets have improved coronary imaging significantly but still lags behind and is not available widely. We foresee that CCTA will be‐ come mainstream for coronary imaging in low to intermediate risk populations with chest pains syndromes in the near future with exciting prospects of comprehensive cardiac imag‐ ing of perfusion and viability and plaque imaging.

## **Acknowledgements**

We are indebted for the expert manuscript preparation assistance of Mrs Nandita S. Mani, MLIS, Sladen Library, Henry Ford Hospital, Detroit MI, USA

## **Author details**

Karthikeyan Ananthasubramaniam1\*, Sabha Bhatti1 and Abdul Hakeem2

\*Address all correspondence to: kananth1@hfhs.org

1 Henry Ford Hospital, Heart and Vascular Institute, Detroit MI, USA

2 William Beaumont Hospital Royal Oak MI, USA

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**Table 6.**

**22. Future perspectives**

ing of perfusion and viability and plaque imaging.

Noninvasive coronary angiography involving CCTA and MRCA has revolutionized delin‐ eation of coronary anatomy in a safe and fast way. CCTA has advanced much more in this aspect with fast imaging with single breath holds and 1 beat acquisition lasting a few sec‐ onds. The radiation and iodine based contrast are the major disadvantages although cur‐ rently radiation doses below 1 millisievert are achievable with CCTA. MRCA with whole heart 3D imaging and 32 channel coils and 3T magnets have improved coronary imaging significantly but still lags behind and is not available widely. We foresee that CCTA will be‐ come mainstream for coronary imaging in low to intermediate risk populations with chest pains syndromes in the near future with exciting prospects of comprehensive cardiac imag‐

98 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease


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**Chapter 5**

**Non-Invasive Study of Coronary**

Vincenzo Gianturco and Bruno Dino Bodini

Additional information is available at the end of the chapter

Maurizio Turiel, Luigi Gianturco,

http://dx.doi.org/10.5772/54042

phological and functional damage.

**1. Introduction**

**Circulation by Means of a Transthoracic**

**Dipyridamole Stress Echocardiography**

**with Coronary Flow Reserve Evaluation**

Ultrasound techniques represent easy and useful diagnostic tools able to detect cardiac mor‐

Transthoracic echocardiography is a reliable, cheap and non-invasive technique that allows an accurate evaluation of valvular abnormalities, pericardial diseases and ventricular wall motion defects, while Doppler analysis is useful to study left ventricular diastolic filling, val‐ vularfuctioning and pulmonary pressures. Rexhepaj et al [1] found significant differences in early diastolic flow velocity (E), atrial flow velocity (A) and E/A ratio in rheumatoid arthritis (RA) patients compared to the control group, suggesting that a subclinical impairment of left and right ventricular function is present in RA patients, when left ventricular thickness,

A new clinical application of ultrasound imaging is represented by the transthoracic dipyri‐ damole stress echocardiography with coronary flow reserve (CFR) evaluation. CFR is as‐ sessed in the distal left anterior descending coronary artery (LAD) defined by the ratio between peak diastolic velocity during stress and at baseline(Fig. 1-2). It is a highly sensitive (>90%) diagnostic marker for coronary artery disease (CAD)[2, 3] and, when associated with the evaluation of the regional wall motion analysis, it becomes also highly specific [4]. In lit‐ erature reports, a value of CFR < 2 has been shown to accurately predict the presence of cor‐ onary stenosis. In absence of epicardial coronary stenosis, an abnormal CFR may reflect an

> © 2013 Turiel et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

dimensions and myocardial performance indexes were still normal.


**Chapter 5**

**Non-Invasive Study of Coronary Circulation by Means of a Transthoracic Dipyridamole Stress Echocardiography with Coronary Flow Reserve Evaluation**

Maurizio Turiel, Luigi Gianturco, Vincenzo Gianturco and Bruno Dino Bodini

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54042

**1. Introduction**

tients with known or suspected coronary artery disease. Journal of the American Col‐

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[100] Jacobs JE, Boxt LM, Desjardins B, Fishman EK, Larson PA, Schoepf J, et al. ACR prac‐ tice guideline for the performance and interpretation of cardiac computed tomogra‐ phy (CT). Journal of the American College of Radiology : JACR. 2006;3(9):677-85.

[101] Budoff MJ, Cohen MC, Garcia MJ, Hodgson JM, Hundley WG, Lima JA, et al. ACCF/AHA clinical competence statement on cardiac imaging with computed to‐ mography and magnetic resonance: a report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training. Journal of the American College of Cardiolo‐

netic resonance imaging. Circulation. 2000;102(5):506-10. Epub 2000/08/02.

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lege of Cardiology. 2007;49(1):62-70. Epub 2007/01/09.

108 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

culation. 2000;102(21):2582-7. Epub 2000/11/22.

ing. 2011;2(1):9-24. Epub 2012/02/22.

2009;253(3):734-44. Epub 2009/10/30.

gy. 2005;46(2):383-402. Epub 2005/07/19.

2007;2(2):e246. Epub 2007/03/01.

Epub 2007/04/07.

2006/09/20.

2009;54(1):49-57. Epub 2009/06/27.

Ultrasound techniques represent easy and useful diagnostic tools able to detect cardiac mor‐ phological and functional damage.

Transthoracic echocardiography is a reliable, cheap and non-invasive technique that allows an accurate evaluation of valvular abnormalities, pericardial diseases and ventricular wall motion defects, while Doppler analysis is useful to study left ventricular diastolic filling, val‐ vularfuctioning and pulmonary pressures. Rexhepaj et al [1] found significant differences in early diastolic flow velocity (E), atrial flow velocity (A) and E/A ratio in rheumatoid arthritis (RA) patients compared to the control group, suggesting that a subclinical impairment of left and right ventricular function is present in RA patients, when left ventricular thickness, dimensions and myocardial performance indexes were still normal.

A new clinical application of ultrasound imaging is represented by the transthoracic dipyri‐ damole stress echocardiography with coronary flow reserve (CFR) evaluation. CFR is as‐ sessed in the distal left anterior descending coronary artery (LAD) defined by the ratio between peak diastolic velocity during stress and at baseline(Fig. 1-2). It is a highly sensitive (>90%) diagnostic marker for coronary artery disease (CAD)[2, 3] and, when associated with the evaluation of the regional wall motion analysis, it becomes also highly specific [4]. In lit‐ erature reports, a value of CFR < 2 has been shown to accurately predict the presence of cor‐ onary stenosis. In absence of epicardial coronary stenosis, an abnormal CFR may reflect an

© 2013 Turiel et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

impaired coronary microcirculation in patients with reperfused myocardial infarct, arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholes‐ terolemia, syndrome X, hypertrophic cardiomyopathy and other diseases [5].The assessment of CFR has also a prognostic value, so that a reduced CFR correlates with a negative progno‐ sis [6]. Recently, new evidence underlined that not only the binary (normal-abnormal) re‐ sponse in CFR but the continuous spectrum of CFR value is a strong independent prognostic predictor in patients with known or suspected CAD [7].

nary microcirculation involvement present in early RA and was associated with endothelial

Non-Invasive Study of Coronary Circulation by Means of a Transthoracic Dipyridamole Stress Echocardiography…

http://dx.doi.org/10.5772/54042

111

Tissue Doppler Imaging (TDI) representsa new imaging modality which allows the meas‐ urement of myocardial velocities. Till now, TDI has been considered a reliable tool for the assessment of myocardial deformation, but this method is limited by angle-dependency and only deformation along the ultrasound beam can be derived from velocities, while myocar‐ dium deforms simultaneously in 3 dimensions [10]. Recently, Birdane et al [11] demonstrat‐ ed that RA patients had a significant impairment of TDI biventricular diastolic functional parameters compared to healthy controls depending on age and use of steroids. To over‐ come TDI limitations, speckle tracking analysis has been introduced to evaluate myocardial

strain along the longitudinal, circumferential and radial axis [12].

**Figure 2.** Doppler sampling of LAD: ratio between peak diastolic velocity during stress and at baseline.

Another very useful application of echocardiography in systemic autoimmune diseases is the echo transesophageal approach which is widely recognized as more sensitive than the transthoracic evaluation for the detection of valvular lesions [13] and identification of intra‐

In particular, Turiel et al [14] observed a large prevalence (61%) of valvular thickening or vegetations and/or potential embolic sources by transesophageal echocardiographic ap‐ proach in 56 patients with primary antiphospholipid syndrome followed up for 5 years.

dysfunction.

cardiac masses.

**Figure 1.** Distal left anterior descending (LAD) flow at color-Doppler.

Hirata et al [8] found a significant reduction of CFR in premenopausal women with SLE compared with age- and sex-matched controls. They concluded that microvascular impair‐ ment in SLE could be explained by functional alteration of endothelium which is responsible for the decrease vasodilation in response to pharmacological stress.

Turiel et al. 9 detected a significant impairment of CFR in 25 early RA patients, with disease duration less than 1 year and without any anti-rheumatic therapy. The reduced CFR in ab‐ sence of wall motion abnormalities at rest and during pharmacological stress showed a coro‐ nary microcirculation involvement present in early RA and was associated with endothelial dysfunction.

Tissue Doppler Imaging (TDI) representsa new imaging modality which allows the meas‐ urement of myocardial velocities. Till now, TDI has been considered a reliable tool for the assessment of myocardial deformation, but this method is limited by angle-dependency and only deformation along the ultrasound beam can be derived from velocities, while myocar‐ dium deforms simultaneously in 3 dimensions [10]. Recently, Birdane et al [11] demonstrat‐ ed that RA patients had a significant impairment of TDI biventricular diastolic functional parameters compared to healthy controls depending on age and use of steroids. To over‐ come TDI limitations, speckle tracking analysis has been introduced to evaluate myocardial strain along the longitudinal, circumferential and radial axis [12].

impaired coronary microcirculation in patients with reperfused myocardial infarct, arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholes‐ terolemia, syndrome X, hypertrophic cardiomyopathy and other diseases [5].The assessment of CFR has also a prognostic value, so that a reduced CFR correlates with a negative progno‐ sis [6]. Recently, new evidence underlined that not only the binary (normal-abnormal) re‐ sponse in CFR but the continuous spectrum of CFR value is a strong independent

110 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

prognostic predictor in patients with known or suspected CAD [7].

**Figure 1.** Distal left anterior descending (LAD) flow at color-Doppler.

for the decrease vasodilation in response to pharmacological stress.

Hirata et al [8] found a significant reduction of CFR in premenopausal women with SLE compared with age- and sex-matched controls. They concluded that microvascular impair‐ ment in SLE could be explained by functional alteration of endothelium which is responsible

Turiel et al. 9 detected a significant impairment of CFR in 25 early RA patients, with disease duration less than 1 year and without any anti-rheumatic therapy. The reduced CFR in ab‐ sence of wall motion abnormalities at rest and during pharmacological stress showed a coro‐

**Figure 2.** Doppler sampling of LAD: ratio between peak diastolic velocity during stress and at baseline.

Another very useful application of echocardiography in systemic autoimmune diseases is the echo transesophageal approach which is widely recognized as more sensitive than the transthoracic evaluation for the detection of valvular lesions [13] and identification of intra‐ cardiac masses.

In particular, Turiel et al [14] observed a large prevalence (61%) of valvular thickening or vegetations and/or potential embolic sources by transesophageal echocardiographic ap‐ proach in 56 patients with primary antiphospholipid syndrome followed up for 5 years.

## **2. Utility of coronary flow reserve assessment in systemic autoimmune diseases**

Higher ADMA plasmatic levels are reported in many conditions associated with high CV risk such as hypercholesterolemia, hypertriglyceridemia [31], peripheral artery disease [32], diabetes mellitus type II [33], acute coronary syndrome [34], chronic renal failure [35]. More‐ over, Surdacki et al [36] evidenced in RA patient an association between high ADMA plas‐ matic levels and increased IMT at common carotid artery. Turiel et al. [37]observed an inverse correlation between ADMA and CFR in early stages of RA thus indicating a subclin‐ ical heart involvement already present at the beginning of the development of the disease.

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113

Many clinical trials evidenced potential effects against atherosclerosis of therapies lead with disease modifying anti-rheumatic drugs (DMARDs), going beyond the simple control of in‐ flammatory process and of disease activity (Tab. 1). In particular Hurlimann et al. [38] showed that anti-TNFα can not only reduce disease activity indexes, but also increase endo‐ thelial function in RA. Moreover, Sitia et al. [39] observed that long time treatment with

DMARDs can reverse endothelial dysfunction, in early stages of disease.

**Table 1.** Disease modifying anti-rheumatic drugs (DMARDs) in common use. (From American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid

arthritis. Arthritis Rheum 2002; 46: 328-46, modified).

Patients suffering from systemic autoimmune diseases (SADs), especially RA, present high‐ er risk of acute myocardial infarction and stroke [15], correlated with disease duration [16] with higher frequency of silent myocardial infarction and sudden death compared to gener‐ al population [17]. This increase in cardiovascular (CV) risk seems not depending on tradi‐ tional risk factors, thus suggesting a dominating role of RA-related risk factors [18, 19]. During these last years, attempts of explaining the accelerated atherosclerosis pathogenic pathways in RA were made; Attention particularly focused importance of chronic systemic inflammatory processwith high pro-inflammatory cytokines plasmatic levels. Presence of pro-atherogenic alterations such as dislipidemy, insulin-resistance, trombofilia and oxida‐ tive stress look favoring development of endothelial dysfunction that may be the initial stage of the atherosclerotic process [20, 21]. Arosio et al. [22], showed a reduced vasodilata‐ tion endothelium-dependant, changes in micro circle reactivity and an increased arterial stiffness in RA female patients.

Today non invasive evaluation of carotid median intimal thickness (IMT) is considered an early atherosclerosis clinical marker [23]. Kumeda et al. [24] observed in RA patients an in‐ creased IMT of common carotid and femoral artery, related to disease severity and duration. According to these evidences, Ciftci et al. [25] confirmed increased IMT and presence of re‐ duced coronary flow reserve (CFR) in RA patients, correlating CV risk to disease duration. Moreover, Chung et al. [26], studied extension of coronary calcifications with CT, showing that patient with a long history of RA presents greater prevalence and severity of coronary calcifications compared to patients with early RA, also correlated with smoking and increase eritrosedimentation rate (ESR).

Nowadays, trans-thoracic echocardiographic evaluation of CFR by pharmacological stress (adenosine or dipyridamole)is considered a very useful exam as diagnose marker highly sensible (>90%) for coronary disease [27]. If associated with LV regional kinesis evaluation, acquires high specificity too. CFR value< 2 measured about at middle-distal tract of left ante‐ rior descending artery can accurately predict the presence of coronary significative stenosis. If epicardial vessels are free from significant stenosis a reduced CFR can be evidence of an alteration in coronary microcirculation in patients with reperfused myocardial infarction, high blood pressure with or without LV hypertrophy, diabetes mellitus, hypercholesterole‐ mia, X syndrome, hypertrophic cardiomyopathy and collagen diseases. CFR measure has prognostic value in different pathologic conditions too[28].

Turiel et al. [29] showed a statistically significative variation of CFR among RA patients re‐ lated with disease duration.

Endothelium function can be also studied through measure of asymmetric dymethilargi‐ nine(ADMA) plasmatic levels. Many clinical evidences support a close association between ADMA level and CV involvement in patients autoimmune diseases [30].

Higher ADMA plasmatic levels are reported in many conditions associated with high CV risk such as hypercholesterolemia, hypertriglyceridemia [31], peripheral artery disease [32], diabetes mellitus type II [33], acute coronary syndrome [34], chronic renal failure [35]. More‐ over, Surdacki et al [36] evidenced in RA patient an association between high ADMA plas‐ matic levels and increased IMT at common carotid artery. Turiel et al. [37]observed an inverse correlation between ADMA and CFR in early stages of RA thus indicating a subclin‐ ical heart involvement already present at the beginning of the development of the disease.

**2. Utility of coronary flow reserve assessment in systemic autoimmune**

112 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Patients suffering from systemic autoimmune diseases (SADs), especially RA, present high‐ er risk of acute myocardial infarction and stroke [15], correlated with disease duration [16] with higher frequency of silent myocardial infarction and sudden death compared to gener‐ al population [17]. This increase in cardiovascular (CV) risk seems not depending on tradi‐ tional risk factors, thus suggesting a dominating role of RA-related risk factors [18, 19]. During these last years, attempts of explaining the accelerated atherosclerosis pathogenic pathways in RA were made; Attention particularly focused importance of chronic systemic inflammatory processwith high pro-inflammatory cytokines plasmatic levels. Presence of pro-atherogenic alterations such as dislipidemy, insulin-resistance, trombofilia and oxida‐ tive stress look favoring development of endothelial dysfunction that may be the initial stage of the atherosclerotic process [20, 21]. Arosio et al. [22], showed a reduced vasodilata‐ tion endothelium-dependant, changes in micro circle reactivity and an increased arterial

Today non invasive evaluation of carotid median intimal thickness (IMT) is considered an early atherosclerosis clinical marker [23]. Kumeda et al. [24] observed in RA patients an in‐ creased IMT of common carotid and femoral artery, related to disease severity and duration. According to these evidences, Ciftci et al. [25] confirmed increased IMT and presence of re‐ duced coronary flow reserve (CFR) in RA patients, correlating CV risk to disease duration. Moreover, Chung et al. [26], studied extension of coronary calcifications with CT, showing that patient with a long history of RA presents greater prevalence and severity of coronary calcifications compared to patients with early RA, also correlated with smoking and increase

Nowadays, trans-thoracic echocardiographic evaluation of CFR by pharmacological stress (adenosine or dipyridamole)is considered a very useful exam as diagnose marker highly sensible (>90%) for coronary disease [27]. If associated with LV regional kinesis evaluation, acquires high specificity too. CFR value< 2 measured about at middle-distal tract of left ante‐ rior descending artery can accurately predict the presence of coronary significative stenosis. If epicardial vessels are free from significant stenosis a reduced CFR can be evidence of an alteration in coronary microcirculation in patients with reperfused myocardial infarction, high blood pressure with or without LV hypertrophy, diabetes mellitus, hypercholesterole‐ mia, X syndrome, hypertrophic cardiomyopathy and collagen diseases. CFR measure has

Turiel et al. [29] showed a statistically significative variation of CFR among RA patients re‐

Endothelium function can be also studied through measure of asymmetric dymethilargi‐ nine(ADMA) plasmatic levels. Many clinical evidences support a close association between

**diseases**

stiffness in RA female patients.

eritrosedimentation rate (ESR).

lated with disease duration.

prognostic value in different pathologic conditions too[28].

ADMA level and CV involvement in patients autoimmune diseases [30].

Many clinical trials evidenced potential effects against atherosclerosis of therapies lead with disease modifying anti-rheumatic drugs (DMARDs), going beyond the simple control of in‐ flammatory process and of disease activity (Tab. 1). In particular Hurlimann et al. [38] showed that anti-TNFα can not only reduce disease activity indexes, but also increase endo‐ thelial function in RA. Moreover, Sitia et al. [39] observed that long time treatment with DMARDs can reverse endothelial dysfunction, in early stages of disease.


**Table 1.** Disease modifying anti-rheumatic drugs (DMARDs) in common use. (From American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum 2002; 46: 328-46, modified).

In addition, Mäki-Petäjä et al. [40] in a recent study confirmed the efficacy of associating ezetimibe and simvastatin in reducing the inflammatory process, but also in improving aortic stiffness in RA. Anyway, the possible validation of efficacy of the therapy with statin and/or biological drugs in modifying the evolution of atherosclerosis needs further perspective clinical trials.

thritis without clinically evident cardiovascular disease. Int J Clin Pract 2006; 60:

http://dx.doi.org/10.5772/54042

115

Non-Invasive Study of Coronary Circulation by Means of a Transthoracic Dipyridamole Stress Echocardiography…

[2] Caiati C, Zedda N, Montaldo C, Montisci R, Ruscazio M, Lai G, Cadeddu M, Meloni L, Iliceto S. Contrast-enhanced transthoracic second harmonic echo Doppler with ad‐ enosine: a noninvasive, rapid and effective method for coronary flow reserve assess‐

[3] Hozumi T, Yoshida K, Ogata Y, Akasaka T, Asami Y, Takagi T, Morioka S. Non inva‐ sive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color Doppler echocardiography.

[4] Rigo F, Richieri M, Pasanisi E, Cutaia V, Zanella C, Della Valentina P, Di Pede F, Rav‐ iele A, Picano E. Usefulness of coronary flow reserve over regional wall motion when added to dual-imaging dipyridamole echocardiography. Am J Cardiol 2003; 91:

[5] Dimitrow PP. Coronary flow reserve-measurement and application: focus on trans‐ thoracic Doppler echocardiography. Boston/Dordrecht/London: Kluwer Academic

[6] Rigo F, Gherardi S, Galderisi M, Pratali L, Cortigiani L, Sicari R, Picano E. The prog‐ nostic impact of coronary flow-reserve assessed by Doppler echocardiography in

[7] Cortigiani L, Rigo F, Gherardi S, Bovenzi F, Picano E, Sicari R. Implication of the con‐ tinuous prognostic spectrum of Doppler echocardiographic derived coronary flow

[8] Hirata K, Kadirvelu A, Kinjo M, Sciacca R, Sugioka K, Otsuka R, Choy A, Chow SK, Yoshiyama M, Yoshikawa J, Homma S, Lang CC. Altered coronary vasomotor func‐ tion in young patients with Systemic Lupus Erythematosus. Arthritis and Rheum

[9] Turiel M, Tomasoni L, Sitia S, Cicala S, Gianturco L, Ricci C, Atzeni F, De Gennaro Colonna V, Longhi M, Sarzi-Puttini P. Effects of long-term disease-modifying anti‐ rheumatic drugs on endothelial function in patients with early rheumatoid arthritis.

[10] Dandel M, Hetzer R. Echocardiographic strain and strain rate imaging – Clinical ap‐

[11] Birdane A, Korkmaz C, Ata N, Cavusoglu Y, Kasifoglu T, Dogan SM, Gorenek B, Goktekin O, Unalir A, Timuralp B. Tissue Doppler imaging in the evaluation of the left and right ventricular diastolic functions in Rheumatoid Arthritis. Echocardiogra‐

[12] Sitia S, Tomasoni L, Turiel M. Speckle tracking echocardiography: a new approach to

non-ischemic dilated cardiomyopathy. Eur Heart J 2006;27:1319-1323.

reserve on left anterior descending artery. Am J Cardiol 2010; 105:158-162.

683-688.

269-273.

Publishers. 2002.

2007; 56: 1904-1909.

phy 2007; 24: 485-493.

Cardiovasc Ther. 2010 Oct;28(5):e53-64.

plications. Int J Cardiol 2009; 132: 11-24.

myocardial function. World J Cardiol 2010; 2: 1-5.

ment. J Am Coll Cardiol 1999; 34:122-130.

Circulation 1998; 97: 1557-1562.

## **3. Conclusions**

Subclinical CV involvement related to specific and non-specific risk factors is frequent in systemic autoimmunity diseases. It begins rapidly after the onset of the disease and pro‐ gresses with disease duration. All cardiac structures may be affected, and the cardiac com‐ plications include a variety of clinical manifestations. As CV involvement is associated with an unfavorable prognosis, the early detection of subclinical cardiac involvement in asympto‐ matic SADs patients is essential and then modern techniques nowhere existing and in this chapter illustrated are very very important to reach such goal.

## **Conflict of interest**

None

## **Author details**

Maurizio Turiel1 , Luigi Gianturco1 , Vincenzo Gianturco2 and Bruno Dino Bodini3

\*Address all correspondence to: maurizio.turiel@unimi.it

1 Cardiology Unit, IRCCS Galeazzi Orthopedic Institute, Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

2 Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriat‐ rics Sciences, Sapienza University of Rome, Italy

3 Rehabilitation Unit, IRCCSGaleazzi Orthopedic Institute, Italy

### **References**

[1] NoneRexhepaj N, Bajraktari G, Berisha I, Beqiri A, Shatri F, Hima F, Elezi S, Ndrepe‐ pa G. Left and right ventricular diastolic functions in patients with rheumatoid ar‐ thritis without clinically evident cardiovascular disease. Int J Clin Pract 2006; 60: 683-688.

In addition, Mäki-Petäjä et al. [40] in a recent study confirmed the efficacy of associating ezetimibe and simvastatin in reducing the inflammatory process, but also in improving aortic stiffness in RA. Anyway, the possible validation of efficacy of the therapy with statin and/or biological drugs in modifying the evolution of atherosclerosis needs further

114 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Subclinical CV involvement related to specific and non-specific risk factors is frequent in systemic autoimmunity diseases. It begins rapidly after the onset of the disease and pro‐ gresses with disease duration. All cardiac structures may be affected, and the cardiac com‐ plications include a variety of clinical manifestations. As CV involvement is associated with an unfavorable prognosis, the early detection of subclinical cardiac involvement in asympto‐ matic SADs patients is essential and then modern techniques nowhere existing and in this

, Vincenzo Gianturco2

1 Cardiology Unit, IRCCS Galeazzi Orthopedic Institute, Department of Biomedical Sciences

2 Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriat‐

[1] NoneRexhepaj N, Bajraktari G, Berisha I, Beqiri A, Shatri F, Hima F, Elezi S, Ndrepe‐ pa G. Left and right ventricular diastolic functions in patients with rheumatoid ar‐

and Bruno Dino Bodini3

chapter illustrated are very very important to reach such goal.

, Luigi Gianturco1

for Health, University of Milan, Milan, Italy

rics Sciences, Sapienza University of Rome, Italy

\*Address all correspondence to: maurizio.turiel@unimi.it

3 Rehabilitation Unit, IRCCSGaleazzi Orthopedic Institute, Italy

perspective clinical trials.

**3. Conclusions**

**Conflict of interest**

**Author details**

Maurizio Turiel1

**References**

None


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[26] Chung CP, Oeser A, Raggi P, Gebretsadik T, Shintani AK, Sokka T, Pincus T, Avalos I, Stein CM. Increased coronary-artery atherosclerosis in rheumatoid arthritis. Arthri‐

Non-Invasive Study of Coronary Circulation by Means of a Transthoracic Dipyridamole Stress Echocardiography…

http://dx.doi.org/10.5772/54042

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[27] Kerekes G, Soltész P, Nurmohamed MT, Gonzalez-Gay MA, Turiel M, Végh E, Shoe‐ nfeld Y, McInnes I, Szekanecz Z. Validated methods for assessment of subclinical

[28] Sitia S, Atzeni F, Sarzi-Puttini P, Di Bello V, Tomasoni L, Delfino L, Antonini-Canter‐ in F, Di Salvo G, De Gennaro Colonna V, La Carrubba S, Carerj S, Turiel M. Cardio‐ vascular involvement in systemic autoimmune diseases. Autoimmunity Rev 2009; 8:

[29] Atzeni F, Sarzi-Puttini P, Delfino L, et al. Decreased coronary flow reserve in patients

[30] De Gennaro Colonna V, Pascale V, Bianchi M, Ferrario P, Morelli F, Pascale W, Tom‐ asoni L, Turiel M. Asymmetric dimethylarginine (ADMA): an endogenous inhibitor of nitric oxide sinthase and a novel cardiovascular risk molecole. Medical Science

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[32] Boger RH, Bode-Boger SM, Thiele W, Junker W, Alexander K, Frölich JC. Biochemi‐ cal evidence for impaired nitric oxide synthesis in patients with peripheral arterial

[33] Stuhlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP, Reaven GM, Tsao PS. Relationship between insulin resistance and an endogenous nitric ox‐

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[35] MacAllister RJ, Rambausek MH, Vallance P, Williams D, Hoffmann KH, Ritz E. Con‐ centration of dimethyl-l-arginine in the plasma of patients with end-stage renal fail‐

[36] Surdacki A, Martens-Lobenhoffer J, Wloch A, Marewicz E, Rakowski T, Wieczorek-Surdacka E, Dubiel JS, Pryjma J, Bode-Böger SM. Elevated plasma asymmetric di‐ methyl- L-arginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum 2007; 56: 809-19. [37] Turiel M, Tomasoni L, Delfino L, Bodini B, Bacchiani G, Atzeni F, Sarzi-Puttini P, De Gennaro Colonna V. Clinical implications of assessing coronary flow reserve and

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116 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease


plasma asymmetric dimethylarginine in early rheumatoid arthritis. Eur J Echocar‐ diogr 2007; 8: S35.

**Chapter 6**

**Computed Tomography Imaging of**

G.J. Pelgrim, M. Oudkerk and R. Vliegenthart

Additional information is available at the end of the chapter

In this chapter the possibilities of computed tomography (CT) for imaging of the coronary arteries are examined. Only in the last decades CT has entered the field of cardiac imaging, due to technical developments. First the history of CT in cardiac imaging is described. When did this technique enter clinical practice and what level of temporal and spatial resolution

The goal of the CT technique described in this chapter is to image the coronary arteries. It is important to know how a CT scan for coronary imaging is made. This is discussed in the second part of the chapter. Contraindications to coronary CT angiography (CCTA) are put forward followed by the explanation of scan acquisition techniques. A detailed overview is

One of the main disadvantages of CCTA is the patient exposure to radiation to acquire the imaging data. Therefore, an important goal in CCTA imaging is to reduce the radiation dose while maintaining diagnostic image quality. There are multiple developments in the area of

The diagnostic accuracy of CCTA has been investigated extensively in recent years. In this section the diagnostic accuracy of different CT scanner generations for calcium scoring and CCTA are expanded upon. This includes results for different parameters used in diagnostic

What are the indications for CCTA examinations? This is the question which is answered in the fifth section. While this is a dynamic field, the main indications, supported by different consensus statements, are discussed. Approximately ten indications are described and or‐ dered by relevance. Examples of different indications are shown by patient CCTA images.

and reproduction in any medium, provided the original work is properly cited.

© 2013 Pelgrim et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

provided regarding different CCTA scan protocols and types of acquisitions.

CT radiation reduction, which are discussed in the next section.

accuracy studies, such as sensitivity and specificity.

**the Coronary Arteries**

http://dx.doi.org/10.5772/54044

**1. Introduction**

does it reach nowadays?


**Chapter 6**

## **Computed Tomography Imaging of the Coronary Arteries**

G.J. Pelgrim, M. Oudkerk and R. Vliegenthart

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54044

## **1. Introduction**

plasma asymmetric dimethylarginine in early rheumatoid arthritis. Eur J Echocar‐

[38] Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, Béchir M, Spiek‐ er LE, Neidhart M, Michel BA, Gay RE, Lüscher TF, Gay S, Ruschitzka F. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheu‐

118 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

[39] Sitia S, Tomasoni L, Cicala S, Delfino L, Atzeni F, Sarzi-Puttini P, De Gennaro Colon‐ na V, Turiel M. Effects of long-term disease-modifying antirheumatic drugs on endo‐ thelial function in patients with early rheumatoid arthritis. Eur J Echocardiogr 2008;

[40] Mäki-Petäjä KM, Booth AD, Hall FC, Wallace SM, Brown J, McEniery CM, Wilkinson IB. Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiff‐ ness and improve endothelial function in rheumatoid arthritis. J Am Coll Cardiol

diogr 2007; 8: S35.

9:166.

2007; 50: 852-8.

matoid arthritis. Circulation 2002; 106: 2184-7.

In this chapter the possibilities of computed tomography (CT) for imaging of the coronary arteries are examined. Only in the last decades CT has entered the field of cardiac imaging, due to technical developments. First the history of CT in cardiac imaging is described. When did this technique enter clinical practice and what level of temporal and spatial resolution does it reach nowadays?

The goal of the CT technique described in this chapter is to image the coronary arteries. It is important to know how a CT scan for coronary imaging is made. This is discussed in the second part of the chapter. Contraindications to coronary CT angiography (CCTA) are put forward followed by the explanation of scan acquisition techniques. A detailed overview is provided regarding different CCTA scan protocols and types of acquisitions.

One of the main disadvantages of CCTA is the patient exposure to radiation to acquire the imaging data. Therefore, an important goal in CCTA imaging is to reduce the radiation dose while maintaining diagnostic image quality. There are multiple developments in the area of CT radiation reduction, which are discussed in the next section.

The diagnostic accuracy of CCTA has been investigated extensively in recent years. In this section the diagnostic accuracy of different CT scanner generations for calcium scoring and CCTA are expanded upon. This includes results for different parameters used in diagnostic accuracy studies, such as sensitivity and specificity.

What are the indications for CCTA examinations? This is the question which is answered in the fifth section. While this is a dynamic field, the main indications, supported by different consensus statements, are discussed. Approximately ten indications are described and or‐ dered by relevance. Examples of different indications are shown by patient CCTA images.

© 2013 Pelgrim et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The future of cardiac CT is the last topic discussed. There are ample opportunities for future cardiac CT research such as CT perfusion imaging. These options are briefly mentioned.

in one rotation. Already 4- and 16-row MDCT scanners caused a revolution in cardiac imag‐ ing, however diagnostic accuracy in terms of specificity was generally low. [6-10] Sensitivity and negative predictive value were already good. MDCT proved useful in evaluation of cor‐ onary anomalies and bypass graft patency. Although the 16-row MDCT scanners had im‐ proved spatial resolution, making detection and characterization of coronary plaques and coronary wall changes possible, high heart rates, stents and severely calcified arteries, how‐

Computed Tomography Imaging of the Coronary Arteries

http://dx.doi.org/10.5772/54044

121

In 2004, the next generation of MDCT scanners was introduced, with 32, 40 and 64 sli‐ ces, another step forward in speed of volume coverage. Compared to 16-row MDCT scanners, the gantry rotation time of 64-row MDCT scanners improved from 500 ms to 330 ms. This translates in an improvement in temporal resolution from 250 ms to 165 ms, as only half a rotation is needed to acquire the data required for the image recon‐ struction. The visualization of the coronary arteries was again markedly improved, with a high sensitivity and specificity achieved for evaluation of coronary stenosis. [13-15] Ex‐ aminations in patients with high heart rates were reported to still yield diagnostic im‐ ages, with the use of multisegment reconstruction algorithms, reducing influence of

Dual source computed tomography (DSCT) is one of the latest improvements in CT imaging modalities. The DSCT scanners consist of 2 tube-detector systems mounted in the same gantry, off-set by 90 degrees (perpendicular). Compared with conventional sin‐ gle-source CT scanners, the temporal resolution of this CT scanner is twice as high. This is because the temporal resolution is equal to a quarter of the gantry rotation. The other parameters, such as gantry rotation time, are equal to single-source CT scanners. In DSCT, the temporal resolution is further improved to 83 ms, further reducing the influ‐ ence of motion artifacts on the image quality. Studies have shown an improvement in the assessment of the moving heart at a high heart rate without the need to use medica‐ tion to control the heart rate during the examination. [18-22] Multiple studies have as‐ sessed the difference in image quality and accuracy of DSCT compared to 64-row scanners. [23-25] The higher temporal resolution resulted in better image quality and di‐

Recent expansion of the detector width in MDCT has resulted in CT scanners with 256 and 320 detector rows. These systems allow for coverage of up to 320 slices during one rotation and in one heartbeat. This allows coverage of the whole heart in one gantry rotation. The principle of these CT scanners is the use of a cone beam. The X-ray tube can reach the detec‐ tors at the edges of the gantry readout, possibly displaying the whole heart in one scan. However, the 320-slice coverage comes at a cost as the temporal resolution is lowered to 350

The introduction of CT and different generations of CT scanners over time is described in Table 1. Continuously, new technologies are developed to improve the diagnostic perform‐ ance of the CT technique for imaging the coronary arteries, including the spatial and tempo‐

ms and the edge of the scan range is prone to artifacts. [26-28]

ever, affected the image quality negatively. [11, 12]

motion artifacts. [16, 17]

agnostic accuracy.

ral resolution.

## **2. Computed tomography**

Computed tomography (CT) has been utilized in numerous fields in clinical practice since its invention in the 1970s. The first CT scanner was developed in 1971 by Geoffrey Houns‐ field and installed at the Atkinson-Morley hospital in England. CT uses X-ray radiation to acquire 2D cross-sectional images of the body. X-ray imaging uses the different properties of different tissues to distinguish them in the image data. These images are acquired by a rapid 360 degree circular motion of the X-ray tube. The images are registered by the circular ray of X-ray detectors located in the gantry surrounding the patient. Then, a 2 dimensional recon‐ struction is made using the principle that an internal structure of the body can be made us‐ ing multiple X-ray projections. To reconstruct a CT image, data from approximately 1800 of gantry rotation are required. From the start in 1972, CT has had an important role in diag‐ nostics as non-invasive imaging technique.

In cardiac imaging, however, CT did not gain ground until developments in recent years. Early CT modalities were limited in their ability to display cardiac morphological information due to the interference of cardiac motion and spatial resolution. The diame‐ ter of coronary arteries varies from large, 3 mm, to small, 1.5 mm. Therefore, the spa‐ tial resolution of the angiography technique should be at least 1 mm. [1] Temporal resolution was not sufficient to display the heart due to cardiac motion. Therefore, until recently, invasive coronary angiography (ICA) was the only accurate method for coro‐ nary imaging. [2, 3]

CT for cardiac imaging first entered the field with the development of electron beam computed tomography (EBCT) in the 1980s. EBCT was specifically developed for cardiac imaging, combining very high temporal resolution (50-100ms) with prospective electro‐ cardiographic (ECG) triggering. The high temporal resolution combined with ECG trig‐ gering greatly reduced cardiac motion artifacts. The main clinical application of EBCT was the quantification of coronary calcium deposits in a so-called calcium score. The cal‐ cium score is correlated with degree and severity of coronary artery disease (CAD) and is a strong predictor of coronary events. [4, 5]The application of calcium scoring is ex‐ plained in more detail further in this chapter. Main limitation of EBCT is the spatial res‐ olution of between 1.5 mm and 3 mm in the z-axis. This prevents EBCT to accurately determine the severity of CAD, especially in CCTA setting. After the introduction of multidetector CT (MDCT) scanners in 1990s (see below) and due to limited availability of EBCT scanners, EBCT was used less frequently and eventually replaced by MDCT systems from 2003 onwards.

The developments in CT were rapid, compared to other imaging fields in the last decades. These developments have led to considerably improved temporal and spatial resolution. MDCT scanners use multiple detectors to acquire the data, scanning multiple detector rows in one rotation. Already 4- and 16-row MDCT scanners caused a revolution in cardiac imag‐ ing, however diagnostic accuracy in terms of specificity was generally low. [6-10] Sensitivity and negative predictive value were already good. MDCT proved useful in evaluation of cor‐ onary anomalies and bypass graft patency. Although the 16-row MDCT scanners had im‐ proved spatial resolution, making detection and characterization of coronary plaques and coronary wall changes possible, high heart rates, stents and severely calcified arteries, how‐ ever, affected the image quality negatively. [11, 12]

The future of cardiac CT is the last topic discussed. There are ample opportunities for future cardiac CT research such as CT perfusion imaging. These options are briefly mentioned.

120 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Computed tomography (CT) has been utilized in numerous fields in clinical practice since its invention in the 1970s. The first CT scanner was developed in 1971 by Geoffrey Houns‐ field and installed at the Atkinson-Morley hospital in England. CT uses X-ray radiation to acquire 2D cross-sectional images of the body. X-ray imaging uses the different properties of different tissues to distinguish them in the image data. These images are acquired by a rapid 360 degree circular motion of the X-ray tube. The images are registered by the circular ray of X-ray detectors located in the gantry surrounding the patient. Then, a 2 dimensional recon‐ struction is made using the principle that an internal structure of the body can be made us‐ ing multiple X-ray projections. To reconstruct a CT image, data from approximately 1800 of gantry rotation are required. From the start in 1972, CT has had an important role in diag‐

In cardiac imaging, however, CT did not gain ground until developments in recent years. Early CT modalities were limited in their ability to display cardiac morphological information due to the interference of cardiac motion and spatial resolution. The diame‐ ter of coronary arteries varies from large, 3 mm, to small, 1.5 mm. Therefore, the spa‐ tial resolution of the angiography technique should be at least 1 mm. [1] Temporal resolution was not sufficient to display the heart due to cardiac motion. Therefore, until recently, invasive coronary angiography (ICA) was the only accurate method for coro‐

CT for cardiac imaging first entered the field with the development of electron beam computed tomography (EBCT) in the 1980s. EBCT was specifically developed for cardiac imaging, combining very high temporal resolution (50-100ms) with prospective electro‐ cardiographic (ECG) triggering. The high temporal resolution combined with ECG trig‐ gering greatly reduced cardiac motion artifacts. The main clinical application of EBCT was the quantification of coronary calcium deposits in a so-called calcium score. The cal‐ cium score is correlated with degree and severity of coronary artery disease (CAD) and is a strong predictor of coronary events. [4, 5]The application of calcium scoring is ex‐ plained in more detail further in this chapter. Main limitation of EBCT is the spatial res‐ olution of between 1.5 mm and 3 mm in the z-axis. This prevents EBCT to accurately determine the severity of CAD, especially in CCTA setting. After the introduction of multidetector CT (MDCT) scanners in 1990s (see below) and due to limited availability of EBCT scanners, EBCT was used less frequently and eventually replaced by MDCT

The developments in CT were rapid, compared to other imaging fields in the last decades. These developments have led to considerably improved temporal and spatial resolution. MDCT scanners use multiple detectors to acquire the data, scanning multiple detector rows

**2. Computed tomography**

nostics as non-invasive imaging technique.

nary imaging. [2, 3]

systems from 2003 onwards.

In 2004, the next generation of MDCT scanners was introduced, with 32, 40 and 64 sli‐ ces, another step forward in speed of volume coverage. Compared to 16-row MDCT scanners, the gantry rotation time of 64-row MDCT scanners improved from 500 ms to 330 ms. This translates in an improvement in temporal resolution from 250 ms to 165 ms, as only half a rotation is needed to acquire the data required for the image recon‐ struction. The visualization of the coronary arteries was again markedly improved, with a high sensitivity and specificity achieved for evaluation of coronary stenosis. [13-15] Ex‐ aminations in patients with high heart rates were reported to still yield diagnostic im‐ ages, with the use of multisegment reconstruction algorithms, reducing influence of motion artifacts. [16, 17]

Dual source computed tomography (DSCT) is one of the latest improvements in CT imaging modalities. The DSCT scanners consist of 2 tube-detector systems mounted in the same gantry, off-set by 90 degrees (perpendicular). Compared with conventional sin‐ gle-source CT scanners, the temporal resolution of this CT scanner is twice as high. This is because the temporal resolution is equal to a quarter of the gantry rotation. The other parameters, such as gantry rotation time, are equal to single-source CT scanners. In DSCT, the temporal resolution is further improved to 83 ms, further reducing the influ‐ ence of motion artifacts on the image quality. Studies have shown an improvement in the assessment of the moving heart at a high heart rate without the need to use medica‐ tion to control the heart rate during the examination. [18-22] Multiple studies have as‐ sessed the difference in image quality and accuracy of DSCT compared to 64-row scanners. [23-25] The higher temporal resolution resulted in better image quality and di‐ agnostic accuracy.

Recent expansion of the detector width in MDCT has resulted in CT scanners with 256 and 320 detector rows. These systems allow for coverage of up to 320 slices during one rotation and in one heartbeat. This allows coverage of the whole heart in one gantry rotation. The principle of these CT scanners is the use of a cone beam. The X-ray tube can reach the detec‐ tors at the edges of the gantry readout, possibly displaying the whole heart in one scan. However, the 320-slice coverage comes at a cost as the temporal resolution is lowered to 350 ms and the edge of the scan range is prone to artifacts. [26-28]

The introduction of CT and different generations of CT scanners over time is described in Table 1. Continuously, new technologies are developed to improve the diagnostic perform‐ ance of the CT technique for imaging the coronary arteries, including the spatial and tempo‐ ral resolution.


As stated before, motion artifacts on CCTA are observed more frequently in patients with higher and irregular heart rates. This negatively affects the image quality and reliability of detecting or excluding coronary stenoses. For earlier generation 16- to 64-row MDCT scan‐ ners it has been proven that the highest image quality is achieved in patients with a low heart rate (< 65 beats per minute). [30-32] It was shown that breath hold at end-inspiration reduces the heart rate by (on average) 6 beats per minute, which can be tested prior to per‐ forming the CCTA acquisition. In case of a patient's heart rate higher than 70 per minute it is advised to reduce the heart rate by medication. This can be done by administration of intra‐

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Patients are positioned on the CT table in supine position. The three ECG leads are attached to the patient body to acquire an adequate ECG tracing, which is synchronized with the raw image data. Furthermore, an 18-gauge intravenous-line is inserted to ensure a correct injec‐ tion of the contrast agent. The actual acquisition protocol consists of three steps: a topogram, a determination of the contrast arrival time using a test contrast bolus or acquisition of re‐ petitive images during contrast injection for bolus tracking and the actual CCTA scan.

First, a low-energy topogram is acquired to enable accurate positioning of the scan volume. Af‐ terwards, a non-contrast scan can be performed to obtain a coronary artery calcification (CAC) score. The coronary calcium score is a calculation of the amount of coronary artery calcium. The most commonly used method for coronary calcium quantification is the calcium score accord‐ ing to Agatston. [33] A negative CT scan for coronary calcium shows no calcification in the cor‐ onaries. A positive test means CAD is present, also when a patient is asymptomatic. The amount of calcification, expressed in the calcium score, can help to predict the risk of coronary events. The extent of CAD is graded according to the calcium, shown in table 3. The height of the calcium score is also strongly related to the risk of coronary heart disease. [34-37] At this moment, the strongest indication for coronary calcium scoring is in asymptomatic individuals at intermediate risk based on risk factors, to improve risk stratification. [38] For 64-row MDCT and earlier CT generations, a calcium score above 1000 is generally considered a contraindica‐ tion for performing CCTA. The reason is twofold: patients with a very high calcium score have a considerable probability of having one or more significant stenosis, and severe calcifications

Two techniques are available to correctly start the CCTA acquisition, based on arrival of contrast in the coronary arteries: the bolus tracking and the bolus timing technique. Bolus tracking involves a series of axial low-dose images to track the bolus of contrast material (every 2 seconds), monitoring the contrast enhancement in a region of interest (ROI) in the ascending aorta. The CCTA imaging sequence is initiated when the Hounsfield Unit (HU) in the ROI reaches a certain predefined level, usually 100 HU. The bolus timing technique in‐ volves an extra low-dose scan acquisition of a single slice. Here, a small contrast bolus fol‐ lowed by a saline flush is injected to determine the contrast arrival time. An axial low-dose image is generated every 2 seconds at a predefined ROI in the ascending aorta. The time be‐ tween the start of the contrast injection and the arrival of contrast bolus in ROI is used as the scan delay for the actual CCTA. Both methods have similar results and have proven its use‐

cause blooming artifacts that limit the assessment of luminal narrowing.

venous injection of 5-25 mg metoprolol.

fulness in multiple research studies.

**Table 1.** Development in computed tomography with highlights through the years

## **3. Imaging the coronary arteries by CCTA**

The goal of coronary CT angiography (CCTA) is to image the coronary arteries, detect coro‐ nary artery calcification, and evaluate coronary stenosis or occlusion. Final aim is to aid the cardiologist in determining the best patient treatment and management.

High quality images are the most important prerequisite in the diagnostic assessment of the coronary arteries. Certain factors need to be taken into account to ensure a high-quality CCTA examination in the correct patient. These factors include selecting the right patients for the examination, proper patient preparation, an adequate CT scanner, optimal CT scan protocol, including synchronization of the CT data with the ECG information and proper re‐ construction of image data, and dedicated software for evaluation of the coronary CT im‐ ages. Furthermore, a prerequisite for CCTA is the injection of iodinated contrast material to delineate the lumen of the coronary arteries. Therefore, an absolute contraindication for CCTA is an allergy for iodine. An overview of contraindications for CCTA are listed in table 2. [29] Apart from general contraindications for CT, there are some specific contraindications for CCTA, such as high or irregular heart rates.


**Table 2.** Contraindications for coronary CTA

As stated before, motion artifacts on CCTA are observed more frequently in patients with higher and irregular heart rates. This negatively affects the image quality and reliability of detecting or excluding coronary stenoses. For earlier generation 16- to 64-row MDCT scan‐ ners it has been proven that the highest image quality is achieved in patients with a low heart rate (< 65 beats per minute). [30-32] It was shown that breath hold at end-inspiration reduces the heart rate by (on average) 6 beats per minute, which can be tested prior to per‐ forming the CCTA acquisition. In case of a patient's heart rate higher than 70 per minute it is advised to reduce the heart rate by medication. This can be done by administration of intra‐ venous injection of 5-25 mg metoprolol.

**Computed tomography development**

**Year Technique**

**3. Imaging the coronary arteries by CCTA**

for CCTA, such as high or irregular heart rates.

Heart rate "/> 65 beats/minute refractory to heart-rate lowering agents

Inability to cooperate with scan acquisition and/or breath hold instructions

Creatinine "/> 1.8 ( estimated Glomerular Filtration < 60), measurement of kidney function

Atrial fibrillation (permanent or at time of the study)

Bigeminy, Trigeminy, high degree heart block

Failed steroid preparation for contrast allergy Morbid obesity (body mass index "/> 40)

**Table 2.** Contraindications for coronary CTA

**CCTA Contraindications**

Calcium score "/> 1000

Severe asthma

Pregnancy

1971 **First computed tomography scanner**

122 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

1990s **Multidetector CT scanner** 2004 **32-, 40-, 60-row multidetector CT**

2007 **256- and 320-slice CT**

**Table 1.** Development in computed tomography with highlights through the years

cardiologist in determining the best patient treatment and management.

1980s **Electron beam computed tomography (EBCT)**

2006 **Dual source computed tomography (DSCT)**

The goal of coronary CT angiography (CCTA) is to image the coronary arteries, detect coro‐ nary artery calcification, and evaluate coronary stenosis or occlusion. Final aim is to aid the

High quality images are the most important prerequisite in the diagnostic assessment of the coronary arteries. Certain factors need to be taken into account to ensure a high-quality CCTA examination in the correct patient. These factors include selecting the right patients for the examination, proper patient preparation, an adequate CT scanner, optimal CT scan protocol, including synchronization of the CT data with the ECG information and proper re‐ construction of image data, and dedicated software for evaluation of the coronary CT im‐ ages. Furthermore, a prerequisite for CCTA is the injection of iodinated contrast material to delineate the lumen of the coronary arteries. Therefore, an absolute contraindication for CCTA is an allergy for iodine. An overview of contraindications for CCTA are listed in table 2. [29] Apart from general contraindications for CT, there are some specific contraindications

Patients are positioned on the CT table in supine position. The three ECG leads are attached to the patient body to acquire an adequate ECG tracing, which is synchronized with the raw image data. Furthermore, an 18-gauge intravenous-line is inserted to ensure a correct injec‐ tion of the contrast agent. The actual acquisition protocol consists of three steps: a topogram, a determination of the contrast arrival time using a test contrast bolus or acquisition of re‐ petitive images during contrast injection for bolus tracking and the actual CCTA scan.

First, a low-energy topogram is acquired to enable accurate positioning of the scan volume. Af‐ terwards, a non-contrast scan can be performed to obtain a coronary artery calcification (CAC) score. The coronary calcium score is a calculation of the amount of coronary artery calcium. The most commonly used method for coronary calcium quantification is the calcium score accord‐ ing to Agatston. [33] A negative CT scan for coronary calcium shows no calcification in the cor‐ onaries. A positive test means CAD is present, also when a patient is asymptomatic. The amount of calcification, expressed in the calcium score, can help to predict the risk of coronary events. The extent of CAD is graded according to the calcium, shown in table 3. The height of the calcium score is also strongly related to the risk of coronary heart disease. [34-37] At this moment, the strongest indication for coronary calcium scoring is in asymptomatic individuals at intermediate risk based on risk factors, to improve risk stratification. [38] For 64-row MDCT and earlier CT generations, a calcium score above 1000 is generally considered a contraindica‐ tion for performing CCTA. The reason is twofold: patients with a very high calcium score have a considerable probability of having one or more significant stenosis, and severe calcifications cause blooming artifacts that limit the assessment of luminal narrowing.

Two techniques are available to correctly start the CCTA acquisition, based on arrival of contrast in the coronary arteries: the bolus tracking and the bolus timing technique. Bolus tracking involves a series of axial low-dose images to track the bolus of contrast material (every 2 seconds), monitoring the contrast enhancement in a region of interest (ROI) in the ascending aorta. The CCTA imaging sequence is initiated when the Hounsfield Unit (HU) in the ROI reaches a certain predefined level, usually 100 HU. The bolus timing technique in‐ volves an extra low-dose scan acquisition of a single slice. Here, a small contrast bolus fol‐ lowed by a saline flush is injected to determine the contrast arrival time. An axial low-dose image is generated every 2 seconds at a predefined ROI in the ascending aorta. The time be‐ tween the start of the contrast injection and the arrival of contrast bolus in ROI is used as the scan delay for the actual CCTA. Both methods have similar results and have proven its use‐ fulness in multiple research studies.


developed to reduce the radiation dose and enhance tube current modulation. These recon‐ struction techniques have shown to reduce image noise and improve image quality. [40, 41]

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Prospective ECG-triggering is a technique used in cardiac CT that uses forward-looking pre‐ diction of R wave timing (see Figure 1). This is step-and-shoot non-spiral acquisition with‐ out table motion during imaging. Main advantage of prospective ECG-triggering is the lower radiation dose compared to retrospective ECG-triggering, see below. A disadvantage is the possibility of non-diagnostic coronary artery segments in case of unexpected changes or irregularity in the heart rate, as retrospective manipulation of the CT image data is gener‐

**Figure 1.** Different triggering techniques used to lower radiation dose. In retrospective triggering, the acquisition is constant and afterwards, the best cardiac phase is reconstructed for analysis. In prospective triggering, the acquisition is only performed during small parts of the cardiac phase, reducing radiation dose. In ECG-gated tube current modula‐ tion, the tube current is lowered during phases more likely to have motion artifacts and normal in the area of interest.

ally not possible. [42-44]

**Table 3.** Cardiac calcium score related to the extent of CAD

When the correct volume and scan delay have been selected, the actual CCTA scan can be performed. A volume dataset of the coronary arteries is required, covering the entire heart. The scan is acquired during breath hold. A contrast agent with a high concentration of io‐ dine is used (300mg/ml) to ensure adequate opacification of the coronary arteries. A total amount of 60-80 ml of contrast agent is injected with an injection speed of approximately 4-6 ml/s, which is flushed by a saline bolus of 40-70 ml (4-6 ml/s).

The scanning parameters are different from vendor to vendor and per scanner generation. These parameters are beyond the scope of this chapter and can be obtained from the vendor of the CT scanner.

CCTA scans are usually acquired in spiral mode, with continuous acquisition of data throughout the whole cardiac cycle (see Figure 1). The quality of the reconstructed axial im‐ ages is determined by multiple parameters.

The use of retrospective ECG-triggering enables the reconstruction of CCTA images at dif‐ ferent time points in the R-R interval. The R-R interval is the time between two R-tops in a normal cardiac cycle. In previous studies it has been shown that the optimal visualization window for coronary imaging, nearly free of motion artifacts is mid-diastole, at 60% to 70% of the R-R interval. In patients with higher or irregular heart rates however, better image quality is usually obtained at 25% to 35% of the R-R interval.

Slice thickness is dependent on the parameters of the specific CT scanner. Thinner slices im‐ prove the quality of the 3-dimensional dataset and the quality of the reconstructed images; on the downside it also increases the image noise which could potentially limit the diagnos‐ tic accuracy of the CCTA examination.

The CCTA images are usually reconstructed with a medium smooth reconstruction kernel. The reconstruction kernel, also referred to as ´filter´ or ´algorithm´ by some CT vendors, is one of the most important parameters affecting the image quality. In general, there is a tradeoff between the spatial resolution and noise for each kernel. Smooth kernels generate images with low noise, resulting in lower spatial resolution. A sharp kernel however, gener‐ ates images with high spatial resolution but also have increased noise levels. [39] Recently, iterative reconstruction techniques have been introduced. These techniques reduce image noise by iteratively comparing the acquired image to a modeled projection. This algorithm is

developed to reduce the radiation dose and enhance tube current modulation. These recon‐ struction techniques have shown to reduce image noise and improve image quality. [40, 41]

**Cardiac calcium score Extent of CAD, risk of coronary events in the next 5 year**

11-100 Mild evidence of CAD, low-moderate risk of coronary events 101-400 Moderate evidence of CAD, moderate risk of coronary events

When the correct volume and scan delay have been selected, the actual CCTA scan can be performed. A volume dataset of the coronary arteries is required, covering the entire heart. The scan is acquired during breath hold. A contrast agent with a high concentration of io‐ dine is used (300mg/ml) to ensure adequate opacification of the coronary arteries. A total amount of 60-80 ml of contrast agent is injected with an injection speed of approximately 4-6

The scanning parameters are different from vendor to vendor and per scanner generation. These parameters are beyond the scope of this chapter and can be obtained from the vendor

CCTA scans are usually acquired in spiral mode, with continuous acquisition of data throughout the whole cardiac cycle (see Figure 1). The quality of the reconstructed axial im‐

The use of retrospective ECG-triggering enables the reconstruction of CCTA images at dif‐ ferent time points in the R-R interval. The R-R interval is the time between two R-tops in a normal cardiac cycle. In previous studies it has been shown that the optimal visualization window for coronary imaging, nearly free of motion artifacts is mid-diastole, at 60% to 70% of the R-R interval. In patients with higher or irregular heart rates however, better image

Slice thickness is dependent on the parameters of the specific CT scanner. Thinner slices im‐ prove the quality of the 3-dimensional dataset and the quality of the reconstructed images; on the downside it also increases the image noise which could potentially limit the diagnos‐

The CCTA images are usually reconstructed with a medium smooth reconstruction kernel. The reconstruction kernel, also referred to as ´filter´ or ´algorithm´ by some CT vendors, is one of the most important parameters affecting the image quality. In general, there is a tradeoff between the spatial resolution and noise for each kernel. Smooth kernels generate images with low noise, resulting in lower spatial resolution. A sharp kernel however, gener‐ ates images with high spatial resolution but also have increased noise levels. [39] Recently, iterative reconstruction techniques have been introduced. These techniques reduce image noise by iteratively comparing the acquired image to a modeled projection. This algorithm is

0 No evidence of CAD, very low risk of coronary events 1-10 Minimal evidence of CAD, low risk of coronary events

124 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

"/>400 Severe evidence of CAD, high risk of coronary events

**Table 3.** Cardiac calcium score related to the extent of CAD

ages is determined by multiple parameters.

tic accuracy of the CCTA examination.

of the CT scanner.

ml/s, which is flushed by a saline bolus of 40-70 ml (4-6 ml/s).

quality is usually obtained at 25% to 35% of the R-R interval.

Prospective ECG-triggering is a technique used in cardiac CT that uses forward-looking pre‐ diction of R wave timing (see Figure 1). This is step-and-shoot non-spiral acquisition with‐ out table motion during imaging. Main advantage of prospective ECG-triggering is the lower radiation dose compared to retrospective ECG-triggering, see below. A disadvantage is the possibility of non-diagnostic coronary artery segments in case of unexpected changes or irregularity in the heart rate, as retrospective manipulation of the CT image data is gener‐ ally not possible. [42-44]

**Figure 1.** Different triggering techniques used to lower radiation dose. In retrospective triggering, the acquisition is constant and afterwards, the best cardiac phase is reconstructed for analysis. In prospective triggering, the acquisition is only performed during small parts of the cardiac phase, reducing radiation dose. In ECG-gated tube current modula‐ tion, the tube current is lowered during phases more likely to have motion artifacts and normal in the area of interest.

## **4. CCTA radiation exposure**

The retrospectively ECG-gated CT is associated with relatively high radiation dose because of low pitch and overlapping data. Effective doses that have been published vary between 2 and 30 mSv, a prospective triggering mode has an effective radiation dose of between 1-3 mSv in adults. [42-45]

current is reduced, which is a downside of this technique. The potential dose reduction

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The introduction of the second generation DSCT scanners made high-pitch helical scanning possible. This prospectively ECG triggered technique involves a high speed of the patient table. Due to this high pitch, the heart can be scanned in a fraction of one heartbeat. This eliminates overlapping volume coverage of sequential sections. Early results show dose re‐

Scan range is a term that indicates the z range (length) of the body which is scanned. There‐ fore, the larger the scan range is set, the higher the radiation exposure will be. The scan range should be limited to the range that is ultimately necessary to clarify the diagnostic questionnaire. A scan of the coronaries should not include the aortic root unless this is spe‐ cifically asked by the referring physician. This will limit unnecessary radiation exposure.

Some factors of minor importance are slice thickness, acquisition time, overlap and pitch. Thinner slices will increase radiation dose because of the larger overlap and lower pitch, which increases acquisition time. The thinner slices need equal amounts of data to have same contrast-to-noise ratio compared to thicker slices. Because of this effect, the table speed needs to be slower with more overlap. This results in higher radiation exposure. With wider detector ranges and dynamic scanning, these factors become less important. A summary of

The options to reduce radiation dose are numerous and radiation dose is gradually declin‐ ing. As stated before, radiation dose of CTA acquisition over time ranges from 2 to 30 mSv. [45] In more recent scanners with optimal, up-to-date scanning protocols, the radiation dose

ductions of up to 80% and CCTA examinations with <1 mSv radiation dose. [25]

of ECG-gated tube current modulation is 13%-46%. [25].

important dose reduction parameters in CCTA is given in table 4.

Triggering (Retrospective, prospective or ECG-gated tube current modulation)

**Radiation dose reduction**

High pitch helical scanning Image reconstruction

Tube current Tube voltage

Scan range Slice thickness

Acquisition time

Pitch Overlap

Scanner type (Multidetector, DSCT, etc.)

**Table 4.** Factors in radiation dose reduction

will generally be around 3 to 4 mSv with a maximum of up to 7 mSv. [24, 25]

Radiation is a potential threat, which can cause harm to the human body. Therefore, mini‐ mizing radiation exposure to patients is of critical importance for physicians. The Interna‐ tional Commission on Radiological Protection (ICRP) estimated that chance of acquiring fatal radiogenic cancer in the adult population is approximately 0.005%/mSv. Furthermore, it is assumed that there is no safe amount of radiation; any radiation amount is potentially harmful. Thus, effort should be taken to keep radiation doses as low as possible while main‐ taining diagnostic scan relevance. This radiological principle is also expressed as 'As Low As Reasonably Achievable' or ALARA. Multiple factors influence the radiation exposure, in‐ cluding scanner type, tube current, tube voltage, ECG triggering, high pitch helical scan‐ ning, scan range, slice thickness, acquisition time, overlap and pitch. Those factors influencing the radiation exposure should all be taken into account, minimizing the radia‐ tion to the lowest level possible.

Tube current can be modified according to the patient body mass index (BMI). Higher tube current increases the amount of photons per exposure time, reducing the image noise, but at the same time increasing the radiation dose. Patients with higher BMI need higher tube current to reduce the noise level, generated by the higher amount of tissue penetrated. The tube current should only be increased to a level necessary for acquiring adequate diagnostic images.

Increasing tube voltage will lead to higher energy X-ray beams with higher tissue pene‐ tration, and substantially increased radiation dose. Generally, 100 to 120 KeV tube vol‐ tages are sufficient for cardiac imaging. Only in really large patients, 140 KeV could be used. Reducing tube voltage will reduce radiation dose in proportion to the square of changes in tube voltage. [46, 47]

ECG synchronization is of particular importance for the amount of radiation exposure. As aforementioned, in retrospective ECG triggering data are acquired throughout the whole cardiac cycle and only the data with the least motion are used for reconstruction. In prospective ECG triggering, the tube is only activated during a predefined cardiac phase with presumably the greatest likelihood of minimal cardiac motion. Because there is no radiation exposure during the remainder of the cardiac cycle, this results in a dose reduction potential of 31%-86%. [25] In case of retrospective ECG triggering, ECG-based tube current modulation is an effective form of dose reduction (see Figure 1). This mod‐ ulation utilizes the concept that coronary motion is least during end-systole and end-dia‐ stole. Therefore, the tube current is reduced by up to 96% during periods with presumably more cardiac motion and ramped up during diastole, when motion is at its lowest (for heart rates up to 65 bpm). [46] The image quality of phases with lower tube current is reduced, which is a downside of this technique. The potential dose reduction of ECG-gated tube current modulation is 13%-46%. [25].

The introduction of the second generation DSCT scanners made high-pitch helical scanning possible. This prospectively ECG triggered technique involves a high speed of the patient table. Due to this high pitch, the heart can be scanned in a fraction of one heartbeat. This eliminates overlapping volume coverage of sequential sections. Early results show dose re‐ ductions of up to 80% and CCTA examinations with <1 mSv radiation dose. [25]

Scan range is a term that indicates the z range (length) of the body which is scanned. There‐ fore, the larger the scan range is set, the higher the radiation exposure will be. The scan range should be limited to the range that is ultimately necessary to clarify the diagnostic questionnaire. A scan of the coronaries should not include the aortic root unless this is spe‐ cifically asked by the referring physician. This will limit unnecessary radiation exposure.

Some factors of minor importance are slice thickness, acquisition time, overlap and pitch. Thinner slices will increase radiation dose because of the larger overlap and lower pitch, which increases acquisition time. The thinner slices need equal amounts of data to have same contrast-to-noise ratio compared to thicker slices. Because of this effect, the table speed needs to be slower with more overlap. This results in higher radiation exposure. With wider detector ranges and dynamic scanning, these factors become less important. A summary of important dose reduction parameters in CCTA is given in table 4.

The options to reduce radiation dose are numerous and radiation dose is gradually declin‐ ing. As stated before, radiation dose of CTA acquisition over time ranges from 2 to 30 mSv. [45] In more recent scanners with optimal, up-to-date scanning protocols, the radiation dose will generally be around 3 to 4 mSv with a maximum of up to 7 mSv. [24, 25]


**Table 4.** Factors in radiation dose reduction

**4. CCTA radiation exposure**

tion to the lowest level possible.

adequate diagnostic images.

changes in tube voltage. [46, 47]

mSv in adults. [42-45]

The retrospectively ECG-gated CT is associated with relatively high radiation dose because of low pitch and overlapping data. Effective doses that have been published vary between 2 and 30 mSv, a prospective triggering mode has an effective radiation dose of between 1-3

126 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Radiation is a potential threat, which can cause harm to the human body. Therefore, mini‐ mizing radiation exposure to patients is of critical importance for physicians. The Interna‐ tional Commission on Radiological Protection (ICRP) estimated that chance of acquiring fatal radiogenic cancer in the adult population is approximately 0.005%/mSv. Furthermore, it is assumed that there is no safe amount of radiation; any radiation amount is potentially harmful. Thus, effort should be taken to keep radiation doses as low as possible while main‐ taining diagnostic scan relevance. This radiological principle is also expressed as 'As Low As Reasonably Achievable' or ALARA. Multiple factors influence the radiation exposure, in‐ cluding scanner type, tube current, tube voltage, ECG triggering, high pitch helical scan‐ ning, scan range, slice thickness, acquisition time, overlap and pitch. Those factors influencing the radiation exposure should all be taken into account, minimizing the radia‐

Tube current can be modified according to the patient body mass index (BMI). Higher tube current increases the amount of photons per exposure time, reducing the image noise, but at the same time increasing the radiation dose. Patients with higher BMI need higher tube current to reduce the noise level, generated by the higher amount of tissue penetrated. The tube current should only be increased to a level necessary for acquiring

Increasing tube voltage will lead to higher energy X-ray beams with higher tissue pene‐ tration, and substantially increased radiation dose. Generally, 100 to 120 KeV tube vol‐ tages are sufficient for cardiac imaging. Only in really large patients, 140 KeV could be used. Reducing tube voltage will reduce radiation dose in proportion to the square of

ECG synchronization is of particular importance for the amount of radiation exposure. As aforementioned, in retrospective ECG triggering data are acquired throughout the whole cardiac cycle and only the data with the least motion are used for reconstruction. In prospective ECG triggering, the tube is only activated during a predefined cardiac phase with presumably the greatest likelihood of minimal cardiac motion. Because there is no radiation exposure during the remainder of the cardiac cycle, this results in a dose reduction potential of 31%-86%. [25] In case of retrospective ECG triggering, ECG-based tube current modulation is an effective form of dose reduction (see Figure 1). This mod‐ ulation utilizes the concept that coronary motion is least during end-systole and end-dia‐ stole. Therefore, the tube current is reduced by up to 96% during periods with presumably more cardiac motion and ramped up during diastole, when motion is at its lowest (for heart rates up to 65 bpm). [46] The image quality of phases with lower tube

### **5. Diagnostic and prognostic accuracy**

Scientific consensus documents have been published that address the appropriate use, di‐ agnostic performance, prognostic value and interpretation of CCTA. [29, 48] Coronary ar‐ tery calcium (CAC) is one of the parameters that can be assessed as part of a coronary CT acquisition protocol. As indicated, this involves a separate, non-contrast-enhanced CT scan prior to CCTA. The diagnostic and prognostic value of CAC was assessed in a sys‐ tematic review by Sarwar et al. in 2009. [49] Only 146 of 25.903 asymptomatic individu‐ als without CAC (0.56%) experienced a cardiovascular event during mean follow-up of 51 months. In 7 studies assessing the prognostic value of CAC in a symptomatic popula‐ tion, 1.8% of the patients without CAC had a cardiovascular event during mean followup of 42 months. Furthermore, the combined 18 studies indicated that the presence of CAC had a sensitivity and negative predictive value of 98% and 93%, respectively, for the detection of significant CAD on invasive coronary angiography. Prospective, popula‐ tion-based studies have shown that the calcium score is a very strong predictor of coro‐ nary events in asymptomatic individuals, with relative risks up to 10.

was shown to have a high diagnostic accuracy in detecting coronary stenosis, both at >50% and >70%. Even more importantly, the 99% NPV establishes CCTA as an alternative for ICA

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Miller et al. (2008) also examined the accuracy of 64-row multidetector CT compared to con‐ ventional ICA. [55] In 291 patients with calcium score below 600, coronary segments with a diameter of >1.5 mm were analyzed by CCTA and ICA. 56% of the patients had obstructive CAD. Patient-based diagnostic accuracy of CCTA for ruling out stenosis >50% according to ICA revealed an area under the curve (AUC) of 0.93, with sensitivity, specificity, PPV, NPV of 85%, 90%, 91% and 83% respectively. The PPV and NPV in this study indicated that

Baumuller et al. compared CCTA with DSCT and 64-row MDCT in the diagnosis of signifi‐ cant coronary stenosis in 200 patients. [24] Of these patients, 100 underwent DSCT and 100 underwent MDCT. On a segment basis, sensitivity and specificity for DSCT were 96.4% and 97.4% respectively. For 64-row MDCT the sensitivity and specificity were 92.4% and 95.3% respectively. The NPV for DSCT and 64-row MDCT was 99.5% and 98.8% respectively. DSCT showed significantly improved accuracy and specificity for the diagnosis of signifi‐ cant stenosis on a segment basis, but shows comparable diagnostic accuracy compared to

In a study by Leber et al., DSCT was performed in 88 patients. [20] Results showed an over‐ all sensitivity and specificity on a segment base of 95% and 90% respectively. DSCT accu‐ rately ruled out coronary stenosis in patients with intermediate pretest likelihood for CAD, independent of the heart rate. Higher heart rates did not show significant decrease in diag‐

A non-comprehensive overview of studies regarding the diagnostic accuracy of CT (64-row and DSCT) for significant stenosis versus ICA is shown in table 5. It can be concluded from most studies that CCTA has a good sensitivity, specificity and excellent NPV. Thus, CCTA can be used to rule out or detect the presence of CAD in selected symptomatic populations

Another important aspect of CCTA is the possibility to predict coronary events in symp‐ tomatic patients. This may have consequences for clinical management. Hulten et al. per‐ formed a systematic review and meta-analysis on the prognostic value of CCTA. In 18 studies 9.592 patients were evaluated with a median follow-up time of 20 months. [63] Major adverse cardiac events (MACE) occurred at an absolute rate of 0.6% (myocardial infarction (MI) or death) in patients with negative scan results. Occurrence of MACE in the positive scan group was 8.2%, with MI or death in 3.7%. Adverse cardiovascular events among patients with a normal CCTA are very rare and comparable to the base‐ line risks among healthy patients. The negative likelihood ratio of CCTA with normal findings is comparable to reported values for stress myocardial perfusion scans and

to rule out significant CAD.

CCTA cannot replace ICA at that time.

64-row MDCT on a per patient-analysis.

nostic accuracy.

suspected of CAD.

stress echocardiography.

A systematic review and meta-analysis by Den Dekker et al. assessed the sensitivity and specificity of CCTA with 16-MDCT and newer CT scanner generations for significant stenosis at different degrees of coronary calcification. [50] 51 studies reported on the im‐ pact of calcium scoring on diagnostic performance of CCTA and were included the re‐ view. 27 out of 51 were suitable for the meta-analysis. Calcium scores were categorized as 0-100, 101-400, 401-1000, and >1000. On a patient-basis, sensitivity of CCTA for signifi‐ cant stenosis was 95.8%, 95.6%, 97.6% and 99.0%, respectively. Specificity of CCTA was 91.2%, 88.2%, 50.6% and 84.0%, respectively, for 64-row MDCT and newer scanners. The 16-row MDCT generation performed significantly worse than the more recently intro‐ duced scanners. Specificity was lower in the group with a calcium score of 401-1000, mainly because of low numbers of patients. These results suggest that even in severely calcified coronary arteries, the sensitivity and specificity of CCTA for significant stenosis is high, in case of 64-row MDCT or newer scanners. A cut-off for calcium scoring for CCTA in newer CT systems no longer seems necessary.

A systematic review and meta-analysis from 2007 by Abdulla et al. evaluated the diag‐ nostic accuracy of 64-multidetector CT compared with conventional invasive coronary angiography (ICA) for coronary stenosis. [51] Mean sensitivity and specificity of CCTA to detect and exclude significant stenosis on a patient basis were 98% and 91% respec‐ tively. Single center studies have shown that the negative predictive value (NPV) of CCTA for 64-row MDCT scanners is high (>95%) and are clinically useful to rule out sig‐ nificant CAD. [15, 52, 53]

The diagnostic accuracy of ECG-gated 64-row MDCT in individuals without known CAD was assessed in a prospective multicenter trial named ACCURACY. [54] A total of 230 sub‐ jects underwent both CCTA and ICA. On a patient-based level the sensitivity, specificity, PPV and NPV to detect >50% stenosis were 95%, 83%, 64% and 99% respectively. The test characteristics for >70% stenosis were 94%, 83%, 48% and 99%, respectively. 64-row MDCT was shown to have a high diagnostic accuracy in detecting coronary stenosis, both at >50% and >70%. Even more importantly, the 99% NPV establishes CCTA as an alternative for ICA to rule out significant CAD.

**5. Diagnostic and prognostic accuracy**

Scientific consensus documents have been published that address the appropriate use, di‐ agnostic performance, prognostic value and interpretation of CCTA. [29, 48] Coronary ar‐ tery calcium (CAC) is one of the parameters that can be assessed as part of a coronary CT acquisition protocol. As indicated, this involves a separate, non-contrast-enhanced CT scan prior to CCTA. The diagnostic and prognostic value of CAC was assessed in a sys‐ tematic review by Sarwar et al. in 2009. [49] Only 146 of 25.903 asymptomatic individu‐ als without CAC (0.56%) experienced a cardiovascular event during mean follow-up of 51 months. In 7 studies assessing the prognostic value of CAC in a symptomatic popula‐ tion, 1.8% of the patients without CAC had a cardiovascular event during mean followup of 42 months. Furthermore, the combined 18 studies indicated that the presence of CAC had a sensitivity and negative predictive value of 98% and 93%, respectively, for the detection of significant CAD on invasive coronary angiography. Prospective, popula‐ tion-based studies have shown that the calcium score is a very strong predictor of coro‐

128 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

A systematic review and meta-analysis by Den Dekker et al. assessed the sensitivity and specificity of CCTA with 16-MDCT and newer CT scanner generations for significant stenosis at different degrees of coronary calcification. [50] 51 studies reported on the im‐ pact of calcium scoring on diagnostic performance of CCTA and were included the re‐ view. 27 out of 51 were suitable for the meta-analysis. Calcium scores were categorized as 0-100, 101-400, 401-1000, and >1000. On a patient-basis, sensitivity of CCTA for signifi‐ cant stenosis was 95.8%, 95.6%, 97.6% and 99.0%, respectively. Specificity of CCTA was 91.2%, 88.2%, 50.6% and 84.0%, respectively, for 64-row MDCT and newer scanners. The 16-row MDCT generation performed significantly worse than the more recently intro‐ duced scanners. Specificity was lower in the group with a calcium score of 401-1000, mainly because of low numbers of patients. These results suggest that even in severely calcified coronary arteries, the sensitivity and specificity of CCTA for significant stenosis is high, in case of 64-row MDCT or newer scanners. A cut-off for calcium scoring for

A systematic review and meta-analysis from 2007 by Abdulla et al. evaluated the diag‐ nostic accuracy of 64-multidetector CT compared with conventional invasive coronary angiography (ICA) for coronary stenosis. [51] Mean sensitivity and specificity of CCTA to detect and exclude significant stenosis on a patient basis were 98% and 91% respec‐ tively. Single center studies have shown that the negative predictive value (NPV) of CCTA for 64-row MDCT scanners is high (>95%) and are clinically useful to rule out sig‐

The diagnostic accuracy of ECG-gated 64-row MDCT in individuals without known CAD was assessed in a prospective multicenter trial named ACCURACY. [54] A total of 230 sub‐ jects underwent both CCTA and ICA. On a patient-based level the sensitivity, specificity, PPV and NPV to detect >50% stenosis were 95%, 83%, 64% and 99% respectively. The test characteristics for >70% stenosis were 94%, 83%, 48% and 99%, respectively. 64-row MDCT

nary events in asymptomatic individuals, with relative risks up to 10.

CCTA in newer CT systems no longer seems necessary.

nificant CAD. [15, 52, 53]

Miller et al. (2008) also examined the accuracy of 64-row multidetector CT compared to con‐ ventional ICA. [55] In 291 patients with calcium score below 600, coronary segments with a diameter of >1.5 mm were analyzed by CCTA and ICA. 56% of the patients had obstructive CAD. Patient-based diagnostic accuracy of CCTA for ruling out stenosis >50% according to ICA revealed an area under the curve (AUC) of 0.93, with sensitivity, specificity, PPV, NPV of 85%, 90%, 91% and 83% respectively. The PPV and NPV in this study indicated that CCTA cannot replace ICA at that time.

Baumuller et al. compared CCTA with DSCT and 64-row MDCT in the diagnosis of signifi‐ cant coronary stenosis in 200 patients. [24] Of these patients, 100 underwent DSCT and 100 underwent MDCT. On a segment basis, sensitivity and specificity for DSCT were 96.4% and 97.4% respectively. For 64-row MDCT the sensitivity and specificity were 92.4% and 95.3% respectively. The NPV for DSCT and 64-row MDCT was 99.5% and 98.8% respectively. DSCT showed significantly improved accuracy and specificity for the diagnosis of signifi‐ cant stenosis on a segment basis, but shows comparable diagnostic accuracy compared to 64-row MDCT on a per patient-analysis.

In a study by Leber et al., DSCT was performed in 88 patients. [20] Results showed an over‐ all sensitivity and specificity on a segment base of 95% and 90% respectively. DSCT accu‐ rately ruled out coronary stenosis in patients with intermediate pretest likelihood for CAD, independent of the heart rate. Higher heart rates did not show significant decrease in diag‐ nostic accuracy.

A non-comprehensive overview of studies regarding the diagnostic accuracy of CT (64-row and DSCT) for significant stenosis versus ICA is shown in table 5. It can be concluded from most studies that CCTA has a good sensitivity, specificity and excellent NPV. Thus, CCTA can be used to rule out or detect the presence of CAD in selected symptomatic populations suspected of CAD.

Another important aspect of CCTA is the possibility to predict coronary events in symp‐ tomatic patients. This may have consequences for clinical management. Hulten et al. per‐ formed a systematic review and meta-analysis on the prognostic value of CCTA. In 18 studies 9.592 patients were evaluated with a median follow-up time of 20 months. [63] Major adverse cardiac events (MACE) occurred at an absolute rate of 0.6% (myocardial infarction (MI) or death) in patients with negative scan results. Occurrence of MACE in the positive scan group was 8.2%, with MI or death in 3.7%. Adverse cardiovascular events among patients with a normal CCTA are very rare and comparable to the base‐ line risks among healthy patients. The negative likelihood ratio of CCTA with normal findings is comparable to reported values for stress myocardial perfusion scans and stress echocardiography.


**Figure 2.** CCTA of a 61 year old women. A) 3D volume rendered reconstruction of the heart and the coronaries. The coronary arteries can be seen in the 3D reconstruction. B) Reconstruction of the right coronary artery (RCA) without CAD. C) Reconstruction of the left anterior descending artery of the same patient, also without stenosis. D) Circumflex

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**Figure 3.** Overview of transverse CCTA images of a patient with an occlusion of the left main artery. In figs. A to C the

arrow indicates the origin of the total occlusion. In image D the CX artery (retrograde filled) is pointed out.

(CX) reconstruction, not showing any disease.

**Table 5.** Accuracy of DSCT and 64-row CT in the detection of coronary stenosis on a segment level in comparison to ICA.

## **6. Indications**

Even though CCTA has only become a viable potential alternative for ICA for selected pa‐ tients since the development of 64-MDCT, already a number of indications are supported by scientific societies, and the number of indications is rapidly increasing. In 2008, a report of a writing group deployed by the Working Group Nuclear Cardiology and Cardiac CT of the European Society of Cardiology (ESC) and the European Council of Nuclear Cardiology (ECNC) was written with the indications, applications, limitations and training require‐ ments for CCTA analysis. [64] In 2010, the American College of Cardiology Foundation (ACCF) along with key- and subspecialty societies conducted an appropriate use review of common clinical scenarios where CCTA is frequently considered and applied. [48] For po‐ tential clinical applications, the advantages and disadvantages of CCTA must be weighed against ICA. The following section lists the potential clinical indications for the use of CTA. This list starts with the strongest indication and reports to less frequent and less strong indi‐ cations, taking different opinions of aforementioned societies into account.

The strongest indication for CCTA is to rule out significant luminal stenosis in stable patients with suspected CAD, at low-intermediate pretest likelihood of disease. As stated above, litera‐ ture convincingly demonstrates that CCTA has a high negative predictive value and allows to reliably rule out CAD. [48, 64-66] Here, the aim is to avoid ICA when CT shows the absence of clinically relevant CAD. Based on clinical and statistical considerations, CCTA will be most useful in patients with an intermediate likelihood of CAD. The false-positive rate may be too high, for patients with a very low pretest likelihood. In patients with high pretest likelihood, it is not likely that a negative CT result excludes significant CAD.

**Author Sensitivity (%) Specificity (%) PPV (%) NPV (%) Number of patients**

**Table 5.** Accuracy of DSCT and 64-row CT in the detection of coronary stenosis on a segment level in comparison to ICA.

Even though CCTA has only become a viable potential alternative for ICA for selected pa‐ tients since the development of 64-MDCT, already a number of indications are supported by scientific societies, and the number of indications is rapidly increasing. In 2008, a report of a writing group deployed by the Working Group Nuclear Cardiology and Cardiac CT of the European Society of Cardiology (ESC) and the European Council of Nuclear Cardiology (ECNC) was written with the indications, applications, limitations and training require‐ ments for CCTA analysis. [64] In 2010, the American College of Cardiology Foundation (ACCF) along with key- and subspecialty societies conducted an appropriate use review of common clinical scenarios where CCTA is frequently considered and applied. [48] For po‐ tential clinical applications, the advantages and disadvantages of CCTA must be weighed against ICA. The following section lists the potential clinical indications for the use of CTA. This list starts with the strongest indication and reports to less frequent and less strong indi‐

The strongest indication for CCTA is to rule out significant luminal stenosis in stable patients with suspected CAD, at low-intermediate pretest likelihood of disease. As stated above, litera‐ ture convincingly demonstrates that CCTA has a high negative predictive value and allows to reliably rule out CAD. [48, 64-66] Here, the aim is to avoid ICA when CT shows the absence of clinically relevant CAD. Based on clinical and statistical considerations, CCTA will be most useful in patients with an intermediate likelihood of CAD. The false-positive rate may be too high, for patients with a very low pretest likelihood. In patients with high pretest likelihood, it

cations, taking different opinions of aforementioned societies into account.

is not likely that a negative CT result excludes significant CAD.

**6. Indications**

Meijboom et al.[56] 99 64 86 97 360 Miller et al.[55] 85 90 91 83 291 Budoff et al.[54] 95 83 64 99 230 Baumuller et al.[24] 96.4 97.4 83.2 99.5 200 Tsiflikas et al.[57] 94 79 88 90 170 Sun et al.[58] 84.3 98.6 92.2 96.9 103 Ropers et al.[59] 98 81 79 99 100 Brodoefel et al.[19] 100 81.5 93.6 100 100 Weustink et al.[60] 99 87 96 95 100 Leber et al.[20] 95 90 74 99 88 Oncel et al.[53] 100 100 100 99 80 Raff et al.[15] 95 90 93 98 70 Ehara et al.[61] 98 86 98 86 69 Mollet et al.[52] 99 95 76 99 51 Achenbach et al.[62] 100 82 72 100 50 Johnson et al.[22] 100 89 89 100 35

130 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Figure 2.** CCTA of a 61 year old women. A) 3D volume rendered reconstruction of the heart and the coronaries. The coronary arteries can be seen in the 3D reconstruction. B) Reconstruction of the right coronary artery (RCA) without CAD. C) Reconstruction of the left anterior descending artery of the same patient, also without stenosis. D) Circumflex (CX) reconstruction, not showing any disease.

**Figure 3.** Overview of transverse CCTA images of a patient with an occlusion of the left main artery. In figs. A to C the arrow indicates the origin of the total occlusion. In image D the CX artery (retrograde filled) is pointed out.

Another application of CCTA is to rule out CAD in acute chest pain. This concerns pa‐ tients presenting to the emergency room with acute chest pain, without direct evidence of myocardial infarction based on e.g. electrocardiogram or myocardial enzymes. In these patients, further testing is often necessary in order to rule out significant CAD, or prolonged observation in the emergency room. Coronary CTA has been found useful in these patients to rapidly assess the coronary arteries for the presence of luminal steno‐ sis. Recent studies have shown the efficiency of applying CCTA in the emergency room. [67, 68]

CCTA can determine the complex course of anomalous coronary arteries. CCTA is the technique of choice for patient workup in known anomalous coronary vessels or vessels suspected to be anomalous because of the ease of data acquisition and the high resolu‐ tion of the data set. CT has been qualified as an appropriate technique for evaluation of coronary anomalies. [48, 69-71] An example of CCTA analysis of coronary anomalies is shown in figure 4.

> **Figure 5.** Evaluation after bypass-surgery, same patient as in figure 4. A) The distal left internal mammary artery (LI‐ MA) is anastomosed with the proximal LAD at the location of the former anomalous left coronary artery. B) The graft

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Significant coronary artery disease, mainly left main disease, needs to be ruled out before non-coronary cardiac surgery. Cardiothoracic surgeons often request coronary angiography to rule out CAD in patients scheduled for cardiac surgery, for instance valve replacement. For this purpose, stress testing is not reliable enough, as ischemia could possibly be masked by the underlying pathology. CCTA may be a useful technique to analyze the coronary ar‐ teries, without having to perform an ICA. Meijboom et al. addressed the use of CCTA in the detection of CAD prior to aortic valve replacement. [72] The overall sensitivity and specifici‐ ty of CCTA for detecting CAD was, respectively 100% and 82%. So, it can be assumed that patients scheduled for cardiac surgery can be evaluated by CCTA for the detection of CAD,

It has been determined that CCTA has a high accuracy for the detection of bypass graft stenosis and occlusion. [73-77] Bypass grafts are arteries or veins from elsewhere in the pa‐ tient's body, grafted to the coronary arteries to bypass coronary stenosis and improve blood supply to the myocardium, shown in figure 5. Especially venous grafts have a larger diame‐ ter and are less prone to motion, which is an advantage for image quality. Coronary artery calcifications and dimensions of native coronary arteries complicate assessment of native coronary arteries in patients with bypass grafts. Recent studies showed that the sensitivity and specificity is lower in bypass graft patients. [75] Therefore, in clinical cases in which on‐ ly bypass graft evaluation is required, CCTA use may be beneficial. If the coronary arteries

Recent statements agree on the value of coronary calcium scoring in asymptomatic individ‐ uals at intermediate risk of cardiovascular disease. In these patients, the calcium score has

shown to improve risk stratification compared to cardiovascular risk factors. [36, 37]

without subgroups such as arrhythmias and unstable patients.

also require assessment, value of CCTA will be limited.

and distal LAD show good contrast filling.

**Figure 4.** Patient with a coronary anomaly. A) The anomalous left coronary artery arises from the proximal RCA, through the septum into the LAD. B) Maximum intensity projection of the anomalous left coronary artery.

Another application of CCTA is to rule out CAD in acute chest pain. This concerns pa‐ tients presenting to the emergency room with acute chest pain, without direct evidence of myocardial infarction based on e.g. electrocardiogram or myocardial enzymes. In these patients, further testing is often necessary in order to rule out significant CAD, or prolonged observation in the emergency room. Coronary CTA has been found useful in these patients to rapidly assess the coronary arteries for the presence of luminal steno‐ sis. Recent studies have shown the efficiency of applying CCTA in the emergency

132 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

CCTA can determine the complex course of anomalous coronary arteries. CCTA is the technique of choice for patient workup in known anomalous coronary vessels or vessels suspected to be anomalous because of the ease of data acquisition and the high resolu‐ tion of the data set. CT has been qualified as an appropriate technique for evaluation of coronary anomalies. [48, 69-71] An example of CCTA analysis of coronary anomalies is

**Figure 4.** Patient with a coronary anomaly. A) The anomalous left coronary artery arises from the proximal RCA,

through the septum into the LAD. B) Maximum intensity projection of the anomalous left coronary artery.

room. [67, 68]

shown in figure 4.

**Figure 5.** Evaluation after bypass-surgery, same patient as in figure 4. A) The distal left internal mammary artery (LI‐ MA) is anastomosed with the proximal LAD at the location of the former anomalous left coronary artery. B) The graft and distal LAD show good contrast filling.

Significant coronary artery disease, mainly left main disease, needs to be ruled out before non-coronary cardiac surgery. Cardiothoracic surgeons often request coronary angiography to rule out CAD in patients scheduled for cardiac surgery, for instance valve replacement. For this purpose, stress testing is not reliable enough, as ischemia could possibly be masked by the underlying pathology. CCTA may be a useful technique to analyze the coronary ar‐ teries, without having to perform an ICA. Meijboom et al. addressed the use of CCTA in the detection of CAD prior to aortic valve replacement. [72] The overall sensitivity and specifici‐ ty of CCTA for detecting CAD was, respectively 100% and 82%. So, it can be assumed that patients scheduled for cardiac surgery can be evaluated by CCTA for the detection of CAD, without subgroups such as arrhythmias and unstable patients.

It has been determined that CCTA has a high accuracy for the detection of bypass graft stenosis and occlusion. [73-77] Bypass grafts are arteries or veins from elsewhere in the pa‐ tient's body, grafted to the coronary arteries to bypass coronary stenosis and improve blood supply to the myocardium, shown in figure 5. Especially venous grafts have a larger diame‐ ter and are less prone to motion, which is an advantage for image quality. Coronary artery calcifications and dimensions of native coronary arteries complicate assessment of native coronary arteries in patients with bypass grafts. Recent studies showed that the sensitivity and specificity is lower in bypass graft patients. [75] Therefore, in clinical cases in which on‐ ly bypass graft evaluation is required, CCTA use may be beneficial. If the coronary arteries also require assessment, value of CCTA will be limited.

Recent statements agree on the value of coronary calcium scoring in asymptomatic individ‐ uals at intermediate risk of cardiovascular disease. In these patients, the calcium score has shown to improve risk stratification compared to cardiovascular risk factors. [36, 37]

Multiple less frequent and less strongly supported applications for CCTA imaging are known. For instance, CTA can be used as an alternative when cardiac catheterization is im‐ possible or carries too much risk. Percutaneous coronary intervention (PCI) planning could also be an indication for CCTA. CT can more reliably identify parameters influencing PCI outcome such as length and extent of the stenosis than ICA. [78] Assessment of coronary stent lumen is also a possibility with CCTA. The ability to assess the stents depends on many factors including stent type and diameter.

contrast in the myocardium can be derived based on images at different KeV energy levels,

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**Figure 6.** Dynamic CT perfusion analysis in a pig heart. The heart is divided into 6 segments (5 white lines and 1 blue line). Mean attenuation over time is monitored. B) Upslope of contrast enhancement in the 6 different segments in HU (not corrected for baseline -1024). Segments S2 and S3 have significantly lower upslope, corresponding with an ap‐

Recent advances in modern CT technique have established CCTA as an accepted modality for coronary angiography in specific patients groups. One of the most important uses of CCTA is to exclude significant CAD in symptomatic patients at low-intermediate probabili‐ ty of significant stenosis. To yield most benefit from CCTA, patient selection remains impor‐ tant. Appropriate use will largely depend on patient characteristics, for instance pre-test likelihood of CAD. The advances in CT scanner technology have reduced the concerns about radiation dose, an important prior disadvantage. Exciting new imaging techniques in cardiac CTA could evolve in a comprehensive test for the assessment of CAD, making anal‐

an indication of blood distribution in the myocardium.

ysis of both anatomy and function possible in one modality.

\*Address all correspondence to: g.j.pelgrim@umcg.nl

Medical Center Groningen, Groningen, Netherlands

and R. Vliegenthart1,2

1 Department of Radiology, University of Groningen, University Medical Center Groningen,

2 Center for Medical Imaging – North East Netherlands, University of Groningen, University

plied stenosis in the CX artery.

**8. Conclusion**

**Author details**

G.J. Pelgrim1,2\*, M. Oudkerk2

Groningen, Netherlands


**Table 6.** Table Indications for CCTA analysis

## **7. Potential new application**

It is important to realize that the presence of a significant stenosis on CCTA does not equate with hemodynamically significant CAD. Not all stenoses result in reduced myocardial per‐ fusion in stress, and not all patients with a positive ischemia test have coronary stenosis. Thus, whereas angiographic evaluation of coronary artery pathology (morphological infor‐ mation) is needed on the one hand, assessment of inducible ischemia (functional informa‐ tion) due to coronary narrowing is necessary on the other hand. The number of different examinations that a patient has to undergo may be considerably reduced by combining mor‐ phological and functional data acquisition in one technique. CT, PET/CT and SPECT/CT have the potential of providing both functional and morphological information. [79] CT per‐ fusion imaging is still early in development. It has different imaging options such as dynam‐ ic perfusion CT and (static) dual energy CT. Dynamic perfusion CT acquires multiple images of the contrast buildup in the myocardium, which can be monitored. Myocardial segments perfused by a stenotic artery will have a slower and lower contrast upslope result‐ ing in a hypodense area in the myocardium. In dual-energy imaging, the amount of iodine contrast in the myocardium can be derived based on images at different KeV energy levels, an indication of blood distribution in the myocardium.

**Figure 6.** Dynamic CT perfusion analysis in a pig heart. The heart is divided into 6 segments (5 white lines and 1 blue line). Mean attenuation over time is monitored. B) Upslope of contrast enhancement in the 6 different segments in HU (not corrected for baseline -1024). Segments S2 and S3 have significantly lower upslope, corresponding with an ap‐ plied stenosis in the CX artery.

## **8. Conclusion**

Multiple less frequent and less strongly supported applications for CCTA imaging are known. For instance, CTA can be used as an alternative when cardiac catheterization is im‐ possible or carries too much risk. Percutaneous coronary intervention (PCI) planning could also be an indication for CCTA. CT can more reliably identify parameters influencing PCI outcome such as length and extent of the stenosis than ICA. [78] Assessment of coronary stent lumen is also a possibility with CCTA. The ability to assess the stents depends on

134 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

It is important to realize that the presence of a significant stenosis on CCTA does not equate with hemodynamically significant CAD. Not all stenoses result in reduced myocardial per‐ fusion in stress, and not all patients with a positive ischemia test have coronary stenosis. Thus, whereas angiographic evaluation of coronary artery pathology (morphological infor‐ mation) is needed on the one hand, assessment of inducible ischemia (functional informa‐ tion) due to coronary narrowing is necessary on the other hand. The number of different examinations that a patient has to undergo may be considerably reduced by combining mor‐ phological and functional data acquisition in one technique. CT, PET/CT and SPECT/CT have the potential of providing both functional and morphological information. [79] CT per‐ fusion imaging is still early in development. It has different imaging options such as dynam‐ ic perfusion CT and (static) dual energy CT. Dynamic perfusion CT acquires multiple images of the contrast buildup in the myocardium, which can be monitored. Myocardial segments perfused by a stenotic artery will have a slower and lower contrast upslope result‐ ing in a hypodense area in the myocardium. In dual-energy imaging, the amount of iodine

many factors including stent type and diameter.

Detection of CAD in symptomatic patients with suspected CAD Detection of CAD in asymptomatic individuals without known CAD Detection of CAD in a newly diagnosed heart failure without known CAD

Clarify unclear findings in other noninvasive imaging techniques

Evaluation of anomalies of coronary arterial and thoracic arteriovenous vessels

Rule out CAD before non-coronary cardiac surgery

Evaluation of complex adult congenital heart disease Evaluation of ventricular morphology and systolic function

Assessment post CABG (Graft evaluation) Assessment post PCI (Stent evaluation)

**Table 6.** Table Indications for CCTA analysis

**7. Potential new application**

**CCTA Indications**

Recent advances in modern CT technique have established CCTA as an accepted modality for coronary angiography in specific patients groups. One of the most important uses of CCTA is to exclude significant CAD in symptomatic patients at low-intermediate probabili‐ ty of significant stenosis. To yield most benefit from CCTA, patient selection remains impor‐ tant. Appropriate use will largely depend on patient characteristics, for instance pre-test likelihood of CAD. The advances in CT scanner technology have reduced the concerns about radiation dose, an important prior disadvantage. Exciting new imaging techniques in cardiac CTA could evolve in a comprehensive test for the assessment of CAD, making anal‐ ysis of both anatomy and function possible in one modality.

## **Author details**

G.J. Pelgrim1,2\*, M. Oudkerk2 and R. Vliegenthart1,2

\*Address all correspondence to: g.j.pelgrim@umcg.nl

1 Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

2 Center for Medical Imaging – North East Netherlands, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

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**Chapter 7**

**Clinical and Research Applications**

**in Coronary Artery Disease**

Takao Hasegawa and Kenei Shimada

http://dx.doi.org/10.5772/54078

**1. Introduction**

tion of ACS.

Additional information is available at the end of the chapter

ing technique for both clinical and research purposes.

protection, optimal stent landing zone.

**of Optical Coherence Tomography Imaging**

Optical coherence tomography (OCT) is an optical analog of intravascular ultrasound (IVUS) that allows microscopic visualization of coronary plaque types and intracoronary tis‐ sue. The high-resolution images of OCT produce an intense interest in adopting this imag‐

In clinical aspects, OCT imaging for undergoing percutaneous coronary intervention (PCI) is feasible and provides superior resolution of arterial pathology than IVUS. During PCI, OCT can assess pre-procedural coronary plaque morphology and acute effects of coronary inter‐ vention (dissection, tissue prolapse, thrombi, and incomplete stent apposition (ISA)). More‐ over, OCT provides more useful information to consider PCI strategy, such as distal

In research aspects, OCT provides characterization of coronary plaque to assess factors asso‐ ciated with acute coronary syndrome (ACS) and vessel healing process after stent implanta‐ tion. Recent studies have shown that OCT is useful for the assessment of coronary atherosclerotic plaques (plaque rupture, erosion, thin-cap fibroatheroma (TCFA), and intra‐ coronary thrombi) in patients with ACS. In addition, OCT can detect the proliferation of va‐ sa vasorum and the distribution of macrophages surrounding vulnerable plaques. OCT provides cardiologists with the tool they need to better understand the pathological condi‐

According to vessel healing after stent implantation, OCT can provide stent strut coverage, ISA, and restenotic tissue characteristics at follow up. Previous OCT studies have shown that delayed neointimal coverage after drug-eluting stent (DES) implantation vs. bare metal

and reproduction in any medium, provided the original work is properly cited.

© 2013 Hasegawa and Shimada; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,


## **Clinical and Research Applications of Optical Coherence Tomography Imaging in Coronary Artery Disease**

Takao Hasegawa and Kenei Shimada

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54078

## **1. Introduction**

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142 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Clinic; 79: 1017-23.

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can heart journal; 150: 775-81.

100-11.

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Optical coherence tomography (OCT) is an optical analog of intravascular ultrasound (IVUS) that allows microscopic visualization of coronary plaque types and intracoronary tis‐ sue. The high-resolution images of OCT produce an intense interest in adopting this imag‐ ing technique for both clinical and research purposes.

In clinical aspects, OCT imaging for undergoing percutaneous coronary intervention (PCI) is feasible and provides superior resolution of arterial pathology than IVUS. During PCI, OCT can assess pre-procedural coronary plaque morphology and acute effects of coronary inter‐ vention (dissection, tissue prolapse, thrombi, and incomplete stent apposition (ISA)). More‐ over, OCT provides more useful information to consider PCI strategy, such as distal protection, optimal stent landing zone.

In research aspects, OCT provides characterization of coronary plaque to assess factors asso‐ ciated with acute coronary syndrome (ACS) and vessel healing process after stent implanta‐ tion. Recent studies have shown that OCT is useful for the assessment of coronary atherosclerotic plaques (plaque rupture, erosion, thin-cap fibroatheroma (TCFA), and intra‐ coronary thrombi) in patients with ACS. In addition, OCT can detect the proliferation of va‐ sa vasorum and the distribution of macrophages surrounding vulnerable plaques. OCT provides cardiologists with the tool they need to better understand the pathological condi‐ tion of ACS.

According to vessel healing after stent implantation, OCT can provide stent strut coverage, ISA, and restenotic tissue characteristics at follow up. Previous OCT studies have shown that delayed neointimal coverage after drug-eluting stent (DES) implantation vs. bare metal

© 2013 Hasegawa and Shimada; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

stent (BMS) implantation. Pathological studies have indicated that the proportion of delayed neointimal coverage represents the best morphometric predictor of late stent thrombosis. Recent OCT studies demonstrate that restenotic tissue characteristics is completely different between BMS and DES. Therefore, OCT can play an important role to assess the safety pro‐ file of novel DES systems.

FD-OCT imaging methods, utilize a light source with variable wavelength that is tuned to continuously oscillate between 1250 and 1350 nm, a so-called wavelength swept laser, in‐ stead of the broadband light source used in TD-OCT. As a result, FD-OCT system can ena‐ ble faster image acquisition and greater scan depths compared with TD-OCT system. Intravascular OCT examination has been frustrated by requiring blood removal. However, FD-OCT system can enable faster image acquisition and greater scan depths compared with TD-OCT system. As a result, only intermittent injection of transparent fluid through guiding catheter for a few seconds enables to obtain entire coronary images [6, 7]. FD-OCT system has been developed (Dragonfly imaging catheter and C7- XR OCT system; LightLab Imag‐ ing, Inc., St Jude Medical,St Paul, Minnesota, USA). Differences between TD- (M3) and FD-OCT (C7-XR) systems are shown in Table 1 [8]. This advance may provide dramatic improvements in understanding coronary atherosclerosis and response to intravascular in‐

Clinical and Research Applications of Optical Coherence Tomography Imaging in Coronary Artery Disease

http://dx.doi.org/10.5772/54078

145

In clinical aspects, OCT imaging for undergoing PCI is feasible and provides superior reso‐ lution of arterial pathology than intravascular ultrasound. During PCI, OCT can assess pre-

Regarding to plaque characterization, OCT can differentiate three types of coronary plaques, such as fibrous, calcified, and lipid-rich. Fibrous plaque is characterized by a homogenous high signal region with low attenuation, calcified plaque by a well-delineated, low-signal re‐ gion with sharp borders, and lipid-rich plaques as a low-signal region with diffuse borders [9]. Importantly, a histology-controlled OCT study showed >90% sensitivity and specificity for detecting lipid-rich plaque in comparisons with pathological specimens. [9, 10]. More‐ over, OCT can recognize vulnerable plaques, such as plaque rupture, erosion, intracoronary

Assessment of plaque characteristics before PCI is useful to choose optimal interventional strategy. Tanaka et al. showed that TCFA was often observed at target lesions of the patients with no reflow after PCI compared with good reflow (50% versus 16%, *P =* 0*.*005). The fre‐ quency of the no reflow phenomenon increased according to the lipid arc assessed by OCT [11]. When OCT detects lipid-rich plaque and TCFA especially in patients with ACS, we

Another aspect, plaque type at the stent edges has an impact on the occurrence of edge dis‐ sections. Gonzalo et al. showed that presence of edge dissection was significantly more fre‐ quent when the plaque type at the edge was fibrocalcific (43.8%) or lipid rich (37.5%) than when the plaque was fibrous (10%) [12]. This study demonstrated that complex plaque type at the stent edge might influence on the presence of edge dissections from OCT observation. The OCT guide stenting might be a useful assistance to achieve optimal landing zone.

After PCI, OCT can assess acute effects of coronary intervention (dissection, tissue prolapse, and ISA). Dissection, tissue prolapse, and ISA were observed more often with OCT than

should consider to use distal protection devices to prevent no-reflow phenomenon.

terventions such as angioplasty and stenting.

procedural coronary plaque morphology.

thrombus, TCFA.

**3. Clinical applications of OCT imaging**

Finally, we introduce usefulness of 3-dimensional reconstruction of the OCT images and 1-μm resolution OCT.

## **2. Differences between IVUS and OCT**

OCT is an optical analog of IVUS, used to examine the coronary arteries. There is a pressing need for improved characterization of coronary pathology to better recognize the factors as‐ sociated with coronary vessel disease and to guide the selection of better interventional strategies. The resolution and contrast of OCT is attractive for these applications and suita‐ ble catheters to access the coronary arteries in detail. There are several differences between IVUS and OCT, as shown in Table 1 [1]. The resolution of OCT (10-20 μm) is 10-fold higher than that of IVUS (100-150 μm), but the penetration depth is lower with OCT (1-2 mm) than with IVUS (4-8 mm) [2]. According to other important difference between IVUS and OCT, the removal of blood is not need for IVUS examination but OCT examination. To examine coronary arteries, blood must first be removed during an OCT examination because of the strong attenuation of light by blood [3].

OCT imaging uses an interferometry technique based on time-delay measurements of the light reflected or backscattered from the tissues [4]. We can use two processing modes used for intracoronary OCT imaging, the first generation time-domain OCT (TD-OCT) imaging systems and the more recently available second generation frequency-domain OCT (FD-OCT) imaging systems [5, 6].

The first-generation OCT (ImageWire and M2/3 OCT system; LightLab Imaging, Inc., West‐ ford, Massachusetts) incorporated both an OCT imaging wire and an over-the-wire occlu‐ sion balloon. To deliver the image wire and remove blood from the target lesion, an overthe-wire occlusion balloon catheter was used. The OCT imaging procedure started with advancing a 0.014-inch coronary guide wire distal to the target lesion. The occlusion catheter is passed along the guide wire through the lesion. After the guide wire and OCT image wire were exchanged, the occlusion balloon is pulled back proximal to the lesion. Then, ringer's solution was continuously flushed at 0.5–0.6 ml/s through the occlusion catheter lumen us‐ ing a power injector, and the balloon was inflated to 0.3–0.5 atm by an inflation device to block blood flow. When an OCT image well appeared, a motorized pullback was initiated from the imaging system console. The first-generation OCT was not user-friendly and had several disadvantages of complex procedure, such as balloon occlusion and relatively short length of image acquisition due to the limited frame rate. To improve these disadvantage, a new generation of OCT systems, termed FD-OCT imaging methods, has been developed.

FD-OCT imaging methods, utilize a light source with variable wavelength that is tuned to continuously oscillate between 1250 and 1350 nm, a so-called wavelength swept laser, in‐ stead of the broadband light source used in TD-OCT. As a result, FD-OCT system can ena‐ ble faster image acquisition and greater scan depths compared with TD-OCT system. Intravascular OCT examination has been frustrated by requiring blood removal. However, FD-OCT system can enable faster image acquisition and greater scan depths compared with TD-OCT system. As a result, only intermittent injection of transparent fluid through guiding catheter for a few seconds enables to obtain entire coronary images [6, 7]. FD-OCT system has been developed (Dragonfly imaging catheter and C7- XR OCT system; LightLab Imag‐ ing, Inc., St Jude Medical,St Paul, Minnesota, USA). Differences between TD- (M3) and FD-OCT (C7-XR) systems are shown in Table 1 [8]. This advance may provide dramatic improvements in understanding coronary atherosclerosis and response to intravascular in‐ terventions such as angioplasty and stenting.

## **3. Clinical applications of OCT imaging**

stent (BMS) implantation. Pathological studies have indicated that the proportion of delayed neointimal coverage represents the best morphometric predictor of late stent thrombosis. Recent OCT studies demonstrate that restenotic tissue characteristics is completely different between BMS and DES. Therefore, OCT can play an important role to assess the safety pro‐

144 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Finally, we introduce usefulness of 3-dimensional reconstruction of the OCT images and 1-μm

OCT is an optical analog of IVUS, used to examine the coronary arteries. There is a pressing need for improved characterization of coronary pathology to better recognize the factors as‐ sociated with coronary vessel disease and to guide the selection of better interventional strategies. The resolution and contrast of OCT is attractive for these applications and suita‐ ble catheters to access the coronary arteries in detail. There are several differences between IVUS and OCT, as shown in Table 1 [1]. The resolution of OCT (10-20 μm) is 10-fold higher than that of IVUS (100-150 μm), but the penetration depth is lower with OCT (1-2 mm) than with IVUS (4-8 mm) [2]. According to other important difference between IVUS and OCT, the removal of blood is not need for IVUS examination but OCT examination. To examine coronary arteries, blood must first be removed during an OCT examination because of the

OCT imaging uses an interferometry technique based on time-delay measurements of the light reflected or backscattered from the tissues [4]. We can use two processing modes used for intracoronary OCT imaging, the first generation time-domain OCT (TD-OCT) imaging systems and the more recently available second generation frequency-domain OCT (FD-

The first-generation OCT (ImageWire and M2/3 OCT system; LightLab Imaging, Inc., West‐ ford, Massachusetts) incorporated both an OCT imaging wire and an over-the-wire occlu‐ sion balloon. To deliver the image wire and remove blood from the target lesion, an overthe-wire occlusion balloon catheter was used. The OCT imaging procedure started with advancing a 0.014-inch coronary guide wire distal to the target lesion. The occlusion catheter is passed along the guide wire through the lesion. After the guide wire and OCT image wire were exchanged, the occlusion balloon is pulled back proximal to the lesion. Then, ringer's solution was continuously flushed at 0.5–0.6 ml/s through the occlusion catheter lumen us‐ ing a power injector, and the balloon was inflated to 0.3–0.5 atm by an inflation device to block blood flow. When an OCT image well appeared, a motorized pullback was initiated from the imaging system console. The first-generation OCT was not user-friendly and had several disadvantages of complex procedure, such as balloon occlusion and relatively short length of image acquisition due to the limited frame rate. To improve these disadvantage, a new generation of OCT systems, termed FD-OCT imaging methods, has been developed.

file of novel DES systems.

**2. Differences between IVUS and OCT**

strong attenuation of light by blood [3].

OCT) imaging systems [5, 6].

resolution OCT.

In clinical aspects, OCT imaging for undergoing PCI is feasible and provides superior reso‐ lution of arterial pathology than intravascular ultrasound. During PCI, OCT can assess preprocedural coronary plaque morphology.

Regarding to plaque characterization, OCT can differentiate three types of coronary plaques, such as fibrous, calcified, and lipid-rich. Fibrous plaque is characterized by a homogenous high signal region with low attenuation, calcified plaque by a well-delineated, low-signal re‐ gion with sharp borders, and lipid-rich plaques as a low-signal region with diffuse borders [9]. Importantly, a histology-controlled OCT study showed >90% sensitivity and specificity for detecting lipid-rich plaque in comparisons with pathological specimens. [9, 10]. More‐ over, OCT can recognize vulnerable plaques, such as plaque rupture, erosion, intracoronary thrombus, TCFA.

Assessment of plaque characteristics before PCI is useful to choose optimal interventional strategy. Tanaka et al. showed that TCFA was often observed at target lesions of the patients with no reflow after PCI compared with good reflow (50% versus 16%, *P =* 0*.*005). The fre‐ quency of the no reflow phenomenon increased according to the lipid arc assessed by OCT [11]. When OCT detects lipid-rich plaque and TCFA especially in patients with ACS, we should consider to use distal protection devices to prevent no-reflow phenomenon.

Another aspect, plaque type at the stent edges has an impact on the occurrence of edge dis‐ sections. Gonzalo et al. showed that presence of edge dissection was significantly more fre‐ quent when the plaque type at the edge was fibrocalcific (43.8%) or lipid rich (37.5%) than when the plaque was fibrous (10%) [12]. This study demonstrated that complex plaque type at the stent edge might influence on the presence of edge dissections from OCT observation. The OCT guide stenting might be a useful assistance to achieve optimal landing zone.

After PCI, OCT can assess acute effects of coronary intervention (dissection, tissue prolapse, and ISA). Dissection, tissue prolapse, and ISA were observed more often with OCT than with IVUS [13, 14]. Coronary dissection is frequently observed at the distal stent edge be‐ cause of the oversized stent diameter or complex types of plaque at the stent edge by OCT. When there is no limited coronary flow by angiography and adequate area of the true lumen by OCT, no additional procedure might be necessary for the treatment of coronary dissec‐ tion [15].

[20]. Macrophages detected by OCT were observed as a 'bright spot', with a high signal var‐ iance from the surrounding tissue. Tearney et al. [21] and MacNeill et al. [16] descried OCT is capable to evaluate cap macrophage content accurately. High degree of positive correla‐ tion was observed between OCT and histological measurements of macrophage density in fibrous cap (*r <* 0*.*84, *P <* 0*.*0001). OCT provided to detect a cap macrophage density > 10%

Clinical and Research Applications of Optical Coherence Tomography Imaging in Coronary Artery Disease

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147

According to vessel healing after stent implantation, OCT can provide stent strut cover‐ age, ISA, and restenotic tissue characteristics at follow up. Previous OCT studies have shown that delayed neointimal coverage after DES implantation vs. BMS implantation [22]. Pathological studies have indicated that the proportion of delayed neointimal cover‐ age represents the best morphometric predictor of late stent thrombosis [23, 24]. Recent OCT studies demonstrate that restenotic tissue characteristics is completely different be‐ tween BMS and DES [21, 25]. Therefore, OCT can play an important role to assess the

Recently, a second-generation OCT technology, termed FD-OCT, has been developed that solves the TD-OCT limitations by imaging at much higher frame rates with slightly deeper penetration depth and greater scan area. In combination with a short, non-occlusive flush and rapid spiral pullback, the higher frame rates generated by FD-OCT enable imaging of the 3-dimensional reconstruction of longer segments of coronary arteries. The 3-dimensional OCT can express all of the coronary microanatomy and pathology previously visualized by OCT, including lipid pools, calcium, macrophages, thin fibrous caps, cholesterol crystals, thrombus, stent, and stents with neointimal hyperplasia [26]. The 3-dimensional OCT may be useful as a research tool for assessing human coronary pathophysiology and as a clinical

Progress in understanding, diagnosis, and treatment of coronary artery disease has been hindered because of inability to observe cells and extracellular components associated with human coronary atherosclerosis *in situ*. A μOCT system with a very broad bandwidth light source and common-path spectral-domain OCT technology provides 1-μm axial resolution ranging in tissue [27]. The μOCT is possible to visualize many key cellular and subcellular features relevant to atherogenesis, plaque rupture, thrombosis, and neointimal healing after stenting *in situ*. The μOCT technology has the potential to make a significant impact in car‐

The high resolution of OCT provides histology-grade definition of the microstructures of coronary atherosclerosis in vivo. Introduction of this attractive imaging method contributes

with 100% sensitivity and specificity [19].

safety profile of novel DES systems.

diovascular pathology.

**6. Conclusion**

**5. Future directions of OCT imaging**

tool for guiding the management of coronary artery disease.

There are 2 types of tissue prolapse, plaque prolapse or thrombus prolapse. OCT can distin‐ guish between plaque prolapse and thrombus prolapse. Plaque prolapse is characterized by smooth surface with no signal attenuation, and thrombus protrusion by irregular surface with significant signal attenuation. Minor tissue prolapse identified by IVUS was not found to be associated with angiographic in-stent restenosis [16]. However, the relationship tissue prolapse identified by OCT and angiographic in-stent restenosis has not been elucidated.

ISA by OCT was identified as clear separation between at least one stent strut and the vessel wall. To check the stent apposition to the vessel wall, the distance between surface of stent strut and adjacent inatima border should be measured because of differences of stent and polymer thickness [8]. Small ISA, which is detected by only OCT but not by IVUS, could dis‐ appear by neointimal growth during follow-up period [15].

## **4. Research applications of OCT imaging**

In research aspects, OCT can provide characterization of coronary plaque to assess factors associated with ACS and vessel healing process after stent implantation.

The first OCT study to assess in vivo culprit lesion morphology in patients with ACS showed that higher frequency of TCFA in ACS compared with stable angina pectoris (72% in acute myocardial infarction (AMI), 50% in unstable angina pectoris, and 20% in stable an‐ gina pectoris; *P =* 0*.*012) [2]. Kubo et al. showed superiorities of TD-OCT for the detection of plaque rupture (73% vs. 40% vs. 43%, *P =* 0*.*021), erosion (23% vs. 0% vs. 3%, *P =* 0*.*003), and thrombus (100% vs. 33% vs. 100%, *P <* 0*.*001) compared with IVUS and coronary angioscopy in patients with AMI [17]. The frequency of vulnerable plaque (plaque rupture, erosion, and thrombus) by detected OCT was similar to that of the pathological reports. As described above, OCT is more useful to assess atherosclerotic plaque instability compared to other in‐ tracoronary imaging devices.

OCT has been proposed as a high resolution imaging modality that can identify vasa vaso‐ rum as microchannels with tiny black holes (50-100 μm). The proliferation of vasa vasorum has been identified recently as a common feature of vulnerable plaque [18]. Kitabata et al. demonstrated increase of microvessels counts in TCFA [19]. An observational study of OCT revealed that the presence of microvessels in the plaques was also associated with positive remodeling and elevated high-sensitive C-reactive protein levels [19]. The OCT evaluation of microvessels counts might be helpful for assessing plaque vulnerability.

Moreover, the other unique aspect of OCT is the detection of macrophages. Degradation of the fibrous cap matrix by macrophages is associated with atherosclerotic plaque instability [20]. Macrophages detected by OCT were observed as a 'bright spot', with a high signal var‐ iance from the surrounding tissue. Tearney et al. [21] and MacNeill et al. [16] descried OCT is capable to evaluate cap macrophage content accurately. High degree of positive correla‐ tion was observed between OCT and histological measurements of macrophage density in fibrous cap (*r <* 0*.*84, *P <* 0*.*0001). OCT provided to detect a cap macrophage density > 10% with 100% sensitivity and specificity [19].

According to vessel healing after stent implantation, OCT can provide stent strut cover‐ age, ISA, and restenotic tissue characteristics at follow up. Previous OCT studies have shown that delayed neointimal coverage after DES implantation vs. BMS implantation [22]. Pathological studies have indicated that the proportion of delayed neointimal cover‐ age represents the best morphometric predictor of late stent thrombosis [23, 24]. Recent OCT studies demonstrate that restenotic tissue characteristics is completely different be‐ tween BMS and DES [21, 25]. Therefore, OCT can play an important role to assess the safety profile of novel DES systems.

## **5. Future directions of OCT imaging**

Recently, a second-generation OCT technology, termed FD-OCT, has been developed that solves the TD-OCT limitations by imaging at much higher frame rates with slightly deeper penetration depth and greater scan area. In combination with a short, non-occlusive flush and rapid spiral pullback, the higher frame rates generated by FD-OCT enable imaging of the 3-dimensional reconstruction of longer segments of coronary arteries. The 3-dimensional OCT can express all of the coronary microanatomy and pathology previously visualized by OCT, including lipid pools, calcium, macrophages, thin fibrous caps, cholesterol crystals, thrombus, stent, and stents with neointimal hyperplasia [26]. The 3-dimensional OCT may be useful as a research tool for assessing human coronary pathophysiology and as a clinical tool for guiding the management of coronary artery disease.

Progress in understanding, diagnosis, and treatment of coronary artery disease has been hindered because of inability to observe cells and extracellular components associated with human coronary atherosclerosis *in situ*. A μOCT system with a very broad bandwidth light source and common-path spectral-domain OCT technology provides 1-μm axial resolution ranging in tissue [27]. The μOCT is possible to visualize many key cellular and subcellular features relevant to atherogenesis, plaque rupture, thrombosis, and neointimal healing after stenting *in situ*. The μOCT technology has the potential to make a significant impact in car‐ diovascular pathology.

## **6. Conclusion**

with IVUS [13, 14]. Coronary dissection is frequently observed at the distal stent edge be‐ cause of the oversized stent diameter or complex types of plaque at the stent edge by OCT. When there is no limited coronary flow by angiography and adequate area of the true lumen by OCT, no additional procedure might be necessary for the treatment of coronary dissec‐

146 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

There are 2 types of tissue prolapse, plaque prolapse or thrombus prolapse. OCT can distin‐ guish between plaque prolapse and thrombus prolapse. Plaque prolapse is characterized by smooth surface with no signal attenuation, and thrombus protrusion by irregular surface with significant signal attenuation. Minor tissue prolapse identified by IVUS was not found to be associated with angiographic in-stent restenosis [16]. However, the relationship tissue prolapse identified by OCT and angiographic in-stent restenosis has not been elucidated.

ISA by OCT was identified as clear separation between at least one stent strut and the vessel wall. To check the stent apposition to the vessel wall, the distance between surface of stent strut and adjacent inatima border should be measured because of differences of stent and polymer thickness [8]. Small ISA, which is detected by only OCT but not by IVUS, could dis‐

In research aspects, OCT can provide characterization of coronary plaque to assess factors

The first OCT study to assess in vivo culprit lesion morphology in patients with ACS showed that higher frequency of TCFA in ACS compared with stable angina pectoris (72% in acute myocardial infarction (AMI), 50% in unstable angina pectoris, and 20% in stable an‐ gina pectoris; *P =* 0*.*012) [2]. Kubo et al. showed superiorities of TD-OCT for the detection of plaque rupture (73% vs. 40% vs. 43%, *P =* 0*.*021), erosion (23% vs. 0% vs. 3%, *P =* 0*.*003), and thrombus (100% vs. 33% vs. 100%, *P <* 0*.*001) compared with IVUS and coronary angioscopy in patients with AMI [17]. The frequency of vulnerable plaque (plaque rupture, erosion, and thrombus) by detected OCT was similar to that of the pathological reports. As described above, OCT is more useful to assess atherosclerotic plaque instability compared to other in‐

OCT has been proposed as a high resolution imaging modality that can identify vasa vaso‐ rum as microchannels with tiny black holes (50-100 μm). The proliferation of vasa vasorum has been identified recently as a common feature of vulnerable plaque [18]. Kitabata et al. demonstrated increase of microvessels counts in TCFA [19]. An observational study of OCT revealed that the presence of microvessels in the plaques was also associated with positive remodeling and elevated high-sensitive C-reactive protein levels [19]. The OCT evaluation

Moreover, the other unique aspect of OCT is the detection of macrophages. Degradation of the fibrous cap matrix by macrophages is associated with atherosclerotic plaque instability

appear by neointimal growth during follow-up period [15].

associated with ACS and vessel healing process after stent implantation.

of microvessels counts might be helpful for assessing plaque vulnerability.

**4. Research applications of OCT imaging**

tracoronary imaging devices.

tion [15].

The high resolution of OCT provides histology-grade definition of the microstructures of coronary atherosclerosis in vivo. Introduction of this attractive imaging method contributes significant progression in both clinical and research aspects. Clinically, OCT can provide more useful information to consider PCI strategy for getting the optimal interventional re‐ sults. On the other hand, OCT is a useful imaging device for understanding, diagnosis, and treatment of coronary artery disease. In the future direction of OCT systems, 3-dimensional OCT and μOCT may be upcoming in the field of coronary artery disease. These novel OCT technologies will play an important role for investigation of coronary artery disease.

**References**

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http://dx.doi.org/10.5772/54078

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IVUS, intravascular ultrasound; OCT, optical coherence tomography; TD, time-domain; FD, frequency-domain; fps, frames per second.

Modified from Terashima M et al, korean j intern med 2012;27:1-12.

#### **Table 1.** Differences among IVUS, TD-OCT, and FD-OCT


IVUS, intravascular ultrasound; OCT, optical coherence tomography; ISA, incomplete stent apposition.

**Table 2.** Acute effects of coronary intervention between IVUS and OCT

## **Author details**

Takao Hasegawa and Kenei Shimada

\*Address all correspondence to: shimadak@med.osaka-cu.ac.jp

Department of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan

## **References**

significant progression in both clinical and research aspects. Clinically, OCT can provide more useful information to consider PCI strategy for getting the optimal interventional re‐ sults. On the other hand, OCT is a useful imaging device for understanding, diagnosis, and treatment of coronary artery disease. In the future direction of OCT systems, 3-dimensional OCT and μOCT may be upcoming in the field of coronary artery disease. These novel OCT

**IVUS TD-OCT (M3) FD-OCT (C7)**

**IVUS OCT**

technologies will play an important role for investigation of coronary artery disease.

148 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Axial resolution, μm 100-150 15-20 12-15 Lateral resolution, μm 150-300 39 19 Frame rate, fps 30 20 100 Pullback speed, mm/s 0.5-2.0 0.5-2.0 10-25 Scan diameter, mm 8-10 6.8 10 Penetration depth, mm 4-8 1-2 1-2 Balloon occlusion Unnecessary Necessary Unnecessary

IVUS, intravascular ultrasound; OCT, optical coherence tomography; TD, time-domain; FD, frequency-domain; fps,

Department of Internal Medicine and Cardiology, Osaka City University Graduate School of

Dissection ○ ◎ Tissue prolapse △ ◎ ISA ○ ◎ Stent expansion ◎ ○ Lesion coverage ○ ○ IVUS, intravascular ultrasound; OCT, optical coherence tomography; ISA, incomplete stent apposition.

frames per second.

**Author details**

Takao Hasegawa and Kenei Shimada

Medicine, Abeno-ku, Osaka, Japan

Modified from Terashima M et al, korean j intern med 2012;27:1-12.

**Table 2.** Acute effects of coronary intervention between IVUS and OCT

\*Address all correspondence to: shimadak@med.osaka-cu.ac.jp

**Table 1.** Differences among IVUS, TD-OCT, and FD-OCT


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**Chapter 8**

**Multidector CT Imaging of Coronary**

Additional information is available at the end of the chapter

Bong Gun Song

**1. Introduction**

http://dx.doi.org/10.5772/54085

**Artery Stent and Coronary Artery Bypass Graft**

Coronary artery stenting has become the most important nonsurgical treatment for coronary artery disease. However, in-stent restenosis occurs at a relatively high rate and this problem has led to the routine use of invasive angiography for assessing stent patency. Although cor‐ onary angiography is the clinical gold standard and it is a very effective diagnostic tool for detecting such in-stent restenosis, it's clearly an invasive procedure with its associated mor‐ bidity and mortality risks. Therefore, a noninvasive technique for detecting in-stent resteno‐ sis would be of great interest and use for following up patients after coronary angioplasty. Multidetector-row CT (MDCT) is being increasingly used for noninvasive coronary artery imaging as it has high diagnostic accuracy for detecting coronary artery stenosis in native, non-stented, coronary arteries. The recently introduced 64-slice CT offers more improved spatial and temporal resolution than does 4 and 16-slice CT and this results in superior visu‐ alization of the stent lumen and in-stent restenosis. However, although 64-slice MDCT al‐ lows for improved stent visualization, a relevant part (up to 47%) of the stent lumen is still not assessable (Mahnken et al., 2006). The metal of the stents can cause blooming artifacts that prevent the accurate interpretation of a lumen's patency. To improve a stent's visualiza‐ tion, numerous methods have been attempted such as dedicated post-processing or the use of dual-source CT. However, because of its presently limited sensitivity and high radiation exposure, MDCT should not be used as the first-line test to screen for in-stent restenosis in asymptomatic patients. Given its high specificity and negative predictive value, MDCT

might be valuable for confirming stent occlusion in symptomatic patients.

Coronary artery bypass graft (CABG) surgery is the standard care in the treatment of ad‐ vanced coronary artery disease. Notwithstanding the clear benefits of bypass grafting, recur‐ rent chest pain after myocardial revascularization surgery is a common postoperative

and reproduction in any medium, provided the original work is properly cited.

© 2013 Song; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

## **Multidector CT Imaging of Coronary Artery Stent and Coronary Artery Bypass Graft**

Bong Gun Song

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54085

## **1. Introduction**

Coronary artery stenting has become the most important nonsurgical treatment for coronary artery disease. However, in-stent restenosis occurs at a relatively high rate and this problem has led to the routine use of invasive angiography for assessing stent patency. Although cor‐ onary angiography is the clinical gold standard and it is a very effective diagnostic tool for detecting such in-stent restenosis, it's clearly an invasive procedure with its associated mor‐ bidity and mortality risks. Therefore, a noninvasive technique for detecting in-stent resteno‐ sis would be of great interest and use for following up patients after coronary angioplasty. Multidetector-row CT (MDCT) is being increasingly used for noninvasive coronary artery imaging as it has high diagnostic accuracy for detecting coronary artery stenosis in native, non-stented, coronary arteries. The recently introduced 64-slice CT offers more improved spatial and temporal resolution than does 4 and 16-slice CT and this results in superior visu‐ alization of the stent lumen and in-stent restenosis. However, although 64-slice MDCT al‐ lows for improved stent visualization, a relevant part (up to 47%) of the stent lumen is still not assessable (Mahnken et al., 2006). The metal of the stents can cause blooming artifacts that prevent the accurate interpretation of a lumen's patency. To improve a stent's visualiza‐ tion, numerous methods have been attempted such as dedicated post-processing or the use of dual-source CT. However, because of its presently limited sensitivity and high radiation exposure, MDCT should not be used as the first-line test to screen for in-stent restenosis in asymptomatic patients. Given its high specificity and negative predictive value, MDCT might be valuable for confirming stent occlusion in symptomatic patients.

Coronary artery bypass graft (CABG) surgery is the standard care in the treatment of ad‐ vanced coronary artery disease. Notwithstanding the clear benefits of bypass grafting, recur‐ rent chest pain after myocardial revascularization surgery is a common postoperative

© 2013 Song; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

presentation and the long-term clinical outcome after myocardial revascularization surgery is largely dependent on graft patency and the progression of coronary artery disease. There‐ fore, assessment of the status of the grafts and graft disease after CABG surgery is an impor‐ tant issue in cardiology. Although conventional coronary angiography is still standard method for assessment of the status of naïve and recipient vessels after CABG surgery, it is an invasive and costly procedure that is not risk-free. Recently, MDCT with retrospective electrocardiographic (ECG) gating has gained rapid acceptance as a diagnostic cardiac imag‐ ing modality, allowing assessment of coronary bypass graft patency with high spatial reso‐ lution. Initial assessment of bypass grafts was done with single-slice scanners and electronbeam CT. Subsequently, the addition of electrocardiographic (ECG) gating and the improved capabilities available with 4- or 16-slice MDCT scanners for rapid scanning of the area of interest led to promising results in the imaging of bypass grafts (Marano et al., 2005; Ueyama et al., 1999). Recently, the introduction of 64-slice MDCT permitted improved tem‐ poral resolution (94 to 200 msec) and spatial resolution (upto submillimeter) and reduction of both cardiac and respiratory motion, leading to improved assessment of graft stenosis and occlusion (Frazier et al., 2005; Lee et al., 2010). Moreover, 3-dimensional (3D) image processing and advanced volumetric visualization techniques now allow radiologists and cardiologists to evaluate coronary grafts in multiple planes using various projections. With the capability of acquiring 3D data volumes along with its tomographic nature, it shares many of the advantages of intravascular ultrasound and thus has the potential to enhance the practice of percutaneous coronary intervention (PCI) in the catheterization laboratory by providing data which was difficult to obtain by invasive coronary angiography (Song et al., 2010; Dikkers et al., 2007; Vembar et al., 2003). MDCT scanners characterized by submillime‐ ter spatial resolution and a temporal resolution of 94 to 200 ms are now available and are increasingly used for cardiac imaging with promising results.

tion), beta-blockers can be administered before CT acquisition (Frazier et al., 2005; Marano et al., 2005). Oral or intravenous beta-adrenergic blocking medications, specifically metoprolol (Lopressor; Novartis Pharmaceuticals Corp., East Hanover, NJ), are administered prior to scanning to prevent heart rate variabilityand tachycardia. Retrospective ECG-gated CTA is essential for optimal image acquisition and reconstruction of evenly spaced phases of the cardiac cycle. The images are acquired in a limited field of view with axial images centered on the heart. Using 60% to 80% of the R-R interval, with 0.6-0.75 mm thick images recon‐ structed in 0.4-0.5 mm increments, axial source images, three-dimensional (3D) volume-ren‐

Multidector CT Imaging of Coronary Artery Stent and Coronary Artery Bypass Graft

http://dx.doi.org/10.5772/54085

155

There are a variety of protocols for image acquisition in the evaluation of patients after CABG surgery. In many respects, the protocol is similar to that for coronary CT angiogra‐ phy (CTA). One important difference is that the scan should be extended superiorly to in‐ clude the origins of the internal mammary arteries. Scanning is performed with the patient in the supine position, during breath-hold. After placement of the leads for ECG recording on the chest wall and a check of the heart rate, a noncontrast CT scan image is acquired through the entire thorax in order to define the volume of the subsequent CT angiography and to detect associated or unsuspected findings. Hence, MDCT angiography is performed during ECG recording, from the subclavian arteries to the cardiac base; in patients with ve‐ nous grafts, a smaller scanning volume starting from the lower third of the ascending aorta is usually sufficient. On the contrary, when a right gastroepiploic artery (RGEA) has been used, the scanning volume should include the upper abdomen. Since the left internal mam‐ mary artery (LIMA) is the most frequently used graft to the anterior cardiac wall, a right arm venous access is preferable in order to avoid streak artifacts from the left subclavian vein that may hamper a complete evaluation of LIMA course and takeoff. Both 3D volumerendering and MPR images are used to assess the bypass grafts, proximal and/or distal graft anastomoses, and the cardiac anatomy. In particular, curved multiplanar images with cen‐ terlines through the bypass grafts and native coronary arteries are obtained. To correctly as‐ sess graft patency and/or the presence of significant stenosis and occlusion, a thorough knowledge of CABG anatomy and its configuration on CTA is important for radiologists and cardiologists. There are 2 types of bypass grafts, arterial and venous. Venous grafts are generally larger in caliber than arterial grafts, and for this reason, jointly to the absence of surgical clips along their course, venous grafts are usually better assessable by noninvasive imaging techniques. In order of frequency of use, graft arteries include the internal mamma‐ ry arteries (IMAs), radial arteries (RAs), right gastroepiploic artery (RGEA), and inferior epi‐ gastric artery. Although arterial grafts have better long-term outcomes, venous grafts, specifically saphenous vein grafts (SVGs), are more readily available. CTA following CABG surgery is done by first assessing the morphology and size of the ascending aorta and the origin of the in situ vessel such as the IMA. Then, graft patency is assessed for homogene‐ ous, contrast-enhanced graft lumen and for regular shape and border of the graft wall. The graft is usually divided into 3 different segments: the origin or proximal anastomosis of the graft, the body of the graft, and the single (or sequential) distal anastomosis. During the CTA evaluation of bypass grafts, the proximal anastomosis is usually better visualized than

dered images, and multiplanar reformatted (MPR) images are generated.

#### **2. Imaging acquisition**

#### **2.1. Image protocol**

Cardiac CTA technique requires rapid injection of nonionic, iodinated, low-osmolar intrave‐ nous contrast. A bolus of 100 to 120 mL nonionic contrast material (high iodine concentra‐ tion is recommended) is administered intravenously using an automatic injector at a flow rate of 3 to 4 mL/s. A region of interest was placed in the descending aorta by using a preset threshold of 150 HU; a 10-second delay followed before scanning was begun to ensure fill‐ ing of the distal vessels with contrast material. Axial images are reconstructed in the mid-tolate diastolic phase, using a fraction (percentage; relative delay) of the R-R interval of the cardiac cycle. Images are acquired with a heart rate < 70 beats per minute, if possible, and with breath-holding during mid-inspiration to prevent substantial inflow of unopacified blood into the right atrium, which may result in heterogeneity of contrast. Low heart rates (< 65 beats/min for 16-slice MDCT or < 70 beats/min for 64-slice MDCT) are recommended to obtain high-quality CT scans, and in the absence of contraindications (heart failure, systolic BP < 100 mm Hg, atrioventricular blockade greater than grade I, and referred adverse reac‐ tion), beta-blockers can be administered before CT acquisition (Frazier et al., 2005; Marano et al., 2005). Oral or intravenous beta-adrenergic blocking medications, specifically metoprolol (Lopressor; Novartis Pharmaceuticals Corp., East Hanover, NJ), are administered prior to scanning to prevent heart rate variabilityand tachycardia. Retrospective ECG-gated CTA is essential for optimal image acquisition and reconstruction of evenly spaced phases of the cardiac cycle. The images are acquired in a limited field of view with axial images centered on the heart. Using 60% to 80% of the R-R interval, with 0.6-0.75 mm thick images recon‐ structed in 0.4-0.5 mm increments, axial source images, three-dimensional (3D) volume-ren‐ dered images, and multiplanar reformatted (MPR) images are generated.

presentation and the long-term clinical outcome after myocardial revascularization surgery is largely dependent on graft patency and the progression of coronary artery disease. There‐ fore, assessment of the status of the grafts and graft disease after CABG surgery is an impor‐ tant issue in cardiology. Although conventional coronary angiography is still standard method for assessment of the status of naïve and recipient vessels after CABG surgery, it is an invasive and costly procedure that is not risk-free. Recently, MDCT with retrospective electrocardiographic (ECG) gating has gained rapid acceptance as a diagnostic cardiac imag‐ ing modality, allowing assessment of coronary bypass graft patency with high spatial reso‐ lution. Initial assessment of bypass grafts was done with single-slice scanners and electronbeam CT. Subsequently, the addition of electrocardiographic (ECG) gating and the improved capabilities available with 4- or 16-slice MDCT scanners for rapid scanning of the area of interest led to promising results in the imaging of bypass grafts (Marano et al., 2005; Ueyama et al., 1999). Recently, the introduction of 64-slice MDCT permitted improved tem‐ poral resolution (94 to 200 msec) and spatial resolution (upto submillimeter) and reduction of both cardiac and respiratory motion, leading to improved assessment of graft stenosis and occlusion (Frazier et al., 2005; Lee et al., 2010). Moreover, 3-dimensional (3D) image processing and advanced volumetric visualization techniques now allow radiologists and cardiologists to evaluate coronary grafts in multiple planes using various projections. With the capability of acquiring 3D data volumes along with its tomographic nature, it shares many of the advantages of intravascular ultrasound and thus has the potential to enhance the practice of percutaneous coronary intervention (PCI) in the catheterization laboratory by providing data which was difficult to obtain by invasive coronary angiography (Song et al., 2010; Dikkers et al., 2007; Vembar et al., 2003). MDCT scanners characterized by submillime‐ ter spatial resolution and a temporal resolution of 94 to 200 ms are now available and are

154 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Cardiac CTA technique requires rapid injection of nonionic, iodinated, low-osmolar intrave‐ nous contrast. A bolus of 100 to 120 mL nonionic contrast material (high iodine concentra‐ tion is recommended) is administered intravenously using an automatic injector at a flow rate of 3 to 4 mL/s. A region of interest was placed in the descending aorta by using a preset threshold of 150 HU; a 10-second delay followed before scanning was begun to ensure fill‐ ing of the distal vessels with contrast material. Axial images are reconstructed in the mid-tolate diastolic phase, using a fraction (percentage; relative delay) of the R-R interval of the cardiac cycle. Images are acquired with a heart rate < 70 beats per minute, if possible, and with breath-holding during mid-inspiration to prevent substantial inflow of unopacified blood into the right atrium, which may result in heterogeneity of contrast. Low heart rates (< 65 beats/min for 16-slice MDCT or < 70 beats/min for 64-slice MDCT) are recommended to obtain high-quality CT scans, and in the absence of contraindications (heart failure, systolic BP < 100 mm Hg, atrioventricular blockade greater than grade I, and referred adverse reac‐

increasingly used for cardiac imaging with promising results.

**2. Imaging acquisition**

**2.1. Image protocol**

There are a variety of protocols for image acquisition in the evaluation of patients after CABG surgery. In many respects, the protocol is similar to that for coronary CT angiogra‐ phy (CTA). One important difference is that the scan should be extended superiorly to in‐ clude the origins of the internal mammary arteries. Scanning is performed with the patient in the supine position, during breath-hold. After placement of the leads for ECG recording on the chest wall and a check of the heart rate, a noncontrast CT scan image is acquired through the entire thorax in order to define the volume of the subsequent CT angiography and to detect associated or unsuspected findings. Hence, MDCT angiography is performed during ECG recording, from the subclavian arteries to the cardiac base; in patients with ve‐ nous grafts, a smaller scanning volume starting from the lower third of the ascending aorta is usually sufficient. On the contrary, when a right gastroepiploic artery (RGEA) has been used, the scanning volume should include the upper abdomen. Since the left internal mam‐ mary artery (LIMA) is the most frequently used graft to the anterior cardiac wall, a right arm venous access is preferable in order to avoid streak artifacts from the left subclavian vein that may hamper a complete evaluation of LIMA course and takeoff. Both 3D volumerendering and MPR images are used to assess the bypass grafts, proximal and/or distal graft anastomoses, and the cardiac anatomy. In particular, curved multiplanar images with cen‐ terlines through the bypass grafts and native coronary arteries are obtained. To correctly as‐ sess graft patency and/or the presence of significant stenosis and occlusion, a thorough knowledge of CABG anatomy and its configuration on CTA is important for radiologists and cardiologists. There are 2 types of bypass grafts, arterial and venous. Venous grafts are generally larger in caliber than arterial grafts, and for this reason, jointly to the absence of surgical clips along their course, venous grafts are usually better assessable by noninvasive imaging techniques. In order of frequency of use, graft arteries include the internal mamma‐ ry arteries (IMAs), radial arteries (RAs), right gastroepiploic artery (RGEA), and inferior epi‐ gastric artery. Although arterial grafts have better long-term outcomes, venous grafts, specifically saphenous vein grafts (SVGs), are more readily available. CTA following CABG surgery is done by first assessing the morphology and size of the ascending aorta and the origin of the in situ vessel such as the IMA. Then, graft patency is assessed for homogene‐ ous, contrast-enhanced graft lumen and for regular shape and border of the graft wall. The graft is usually divided into 3 different segments: the origin or proximal anastomosis of the graft, the body of the graft, and the single (or sequential) distal anastomosis. During the CTA evaluation of bypass grafts, the proximal anastomosis is usually better visualized than the distal anastomosis. In cases in which the distal anastomosis is not well evaluated, the by‐ pass graft is usually considered patent as long as contrast is evident within the graft lumen.

plane spatial resolution of 230 μm and the ability to reconstruct images with the use of a

Multidector CT Imaging of Coronary Artery Stent and Coronary Artery Bypass Graft

http://dx.doi.org/10.5772/54085

157

**Scheme 1.** High definition (HD) versus non-HD CT imagings. HD images show more clearly visualization of the stent

Coronary artery stenting is currently the standard practice in nonsurgical myocardial revascu‐ larization. However, coronary in-stent restenosis attributable to intimal hyperplasia remains problematic, with an incidence rate of 20% to 30%. The evaluation of stent patency is a major is‐ sue in the follow-up after stent placement. It would be desirable to obviate the use of invasive and costly angiography in the evaluation of stent patency. Initial studies using 4-detector coro‐ nary CTA for the evaluation of stent patency showed difficulties in imaging small and high-at‐ tenuating structures such as coronary stents (Table 1). With 16-detector coronary CTA, coronary artery stent patency has been assessed on the basis of contrast enhancement measurements or pixel count methods. However, stent diameter (≤ 3 mm), strut thickness, and stent material are still a cause of poor lumen visualization. In a study by Gilard et al, 232 stents were evaluated in vivo with 16-detector CT. Lumen interpretability depended on stent diameter: for stents with di‐ ameter > 3mm, 81% of lumens were interpretable, compared with 51% for stents with diameter ≤ 3 mm (Gilard et al., 2006). Restenosis detection depended on stent diameter: for stents with di‐ ameter > 3 mm, sensitivity and specificity of MDCT were 86% and 100%, respectively. For small stents with diameter ≤ 3 mm, corresponding values were 54% and 100% (Lefebvre et al., 2007; Pu‐ gliese et al., 2006). As stated by Kitagawa et al, the importance of metal artifacts and partial vol‐ ume effect of stents is related to the stent material, the stent diameter and thickness, and the strut

**3. Coronary artery stent imaging with MDCT**

and in-stent area.

novel applied ASIR algorithm, has been developed (Min et al., 2009).

#### **2.2. Image noise**

The advantages of MDCT are the relatively rapid imaging time and high spatial resolu‐ tion attributable to the multi-row detector system. Numerous studies dealing with MDCT coronary bypass angiography have reported cardiac and respiratory motion arti‐ facts as the most significant limitations in the reliable assessment of graft patency and stenosis of recipient vessels. It is well known that heart rate greatly influences image quality and stenosis detection. The introduction of 64-slice MDCT scanners, with faster gantry rotation times and shorter breath-hold times, improved diagnostic image quality by reducing cardiac and respiratory motion artifacts. However, optimum performance was observed primarily in patients with heart rates below 70 beats per minute. Even with improved spatial and temporal resolution with 64-slice technology, routine adminis‐ tration of β-blockers is still required. If graft segment image quality is suboptimal due to motion artifacts, a potential remedy is to obtain additional image reconstructions in smaller increments throughout the cardiac cycle. The other limitations of MDCT are the presence of calcification and metal clip artifacts, which make assessment of graft patency difficult, and accurate evaluation of the degree of stenosis impossible. Nevertheless, the thinner slices of 64-slice MDCT give increased temporal resolution, and 3-dimentional re‐ constructions show consistent detail in every plane. Moreover, bypass grafts are charac‐ terized by minor calcification compared to naive vessels, allowing more accurate analysis in most cases. Coronary calcifications and metal clip artifacts still remain a challenging issue with 64-slice cardiac CT despite improvements with the use of sharper image fil‐ ters, e.g. the B46 Kernel (Siemens Medical Solutions) (Seifarth et al., 2005). The another important limitation is the high radiation dose required for 64-slice MDCT, although electrocardiogram-dependent dose modulation can reduce this by 30%–50%. The minimi‐ zation of radiation exposure as well as optimization of the diagnostic accuracy in calci‐ fied vessels remain the chief goals for future MDCT advances.

#### **2.3. Strategies for reduction of radiation dose and image noise**

Current limitations of coronary CTA include image noise and radiation dose. As a result, a number of techniques and strategies have become available on newer CT platforms to ena‐ ble dose reduction in coronary CT. These include sequential or prospective ECG triggering, reduced tube voltage scanning, and high-pitch helical scanning. Recently, iterative recon‐ struction (Adaptive Statistical Iterative Reconstruction [ASIR], GE Healthcare) has been in‐ troduced as a new reconstruction algorithm (Rajiah et al., 2012; Leipsic et al., 2007; Min et al., 2009). In comparison with filtered back projection (FBP), ASIR reduces image noise (increase contrast-to-noise ratio [CNR]) by iteratively comparing the acquired image to a modeled projection. This reconstruction algorithm is used to help deal with one of the primary issues of dose and tube current reduction for coronary CTA with FBP: increased image noise with decreased tube current. Recently, a high-definition CT (HDCT) scanner, with improved inplane spatial resolution of 230 μm and the ability to reconstruct images with the use of a novel applied ASIR algorithm, has been developed (Min et al., 2009).

**Scheme 1.** High definition (HD) versus non-HD CT imagings. HD images show more clearly visualization of the stent and in-stent area.

## **3. Coronary artery stent imaging with MDCT**

the distal anastomosis. In cases in which the distal anastomosis is not well evaluated, the by‐ pass graft is usually considered patent as long as contrast is evident within the graft lumen.

156 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The advantages of MDCT are the relatively rapid imaging time and high spatial resolu‐ tion attributable to the multi-row detector system. Numerous studies dealing with MDCT coronary bypass angiography have reported cardiac and respiratory motion arti‐ facts as the most significant limitations in the reliable assessment of graft patency and stenosis of recipient vessels. It is well known that heart rate greatly influences image quality and stenosis detection. The introduction of 64-slice MDCT scanners, with faster gantry rotation times and shorter breath-hold times, improved diagnostic image quality by reducing cardiac and respiratory motion artifacts. However, optimum performance was observed primarily in patients with heart rates below 70 beats per minute. Even with improved spatial and temporal resolution with 64-slice technology, routine adminis‐ tration of β-blockers is still required. If graft segment image quality is suboptimal due to motion artifacts, a potential remedy is to obtain additional image reconstructions in smaller increments throughout the cardiac cycle. The other limitations of MDCT are the presence of calcification and metal clip artifacts, which make assessment of graft patency difficult, and accurate evaluation of the degree of stenosis impossible. Nevertheless, the thinner slices of 64-slice MDCT give increased temporal resolution, and 3-dimentional re‐ constructions show consistent detail in every plane. Moreover, bypass grafts are charac‐ terized by minor calcification compared to naive vessels, allowing more accurate analysis in most cases. Coronary calcifications and metal clip artifacts still remain a challenging issue with 64-slice cardiac CT despite improvements with the use of sharper image fil‐ ters, e.g. the B46 Kernel (Siemens Medical Solutions) (Seifarth et al., 2005). The another important limitation is the high radiation dose required for 64-slice MDCT, although electrocardiogram-dependent dose modulation can reduce this by 30%–50%. The minimi‐ zation of radiation exposure as well as optimization of the diagnostic accuracy in calci‐

fied vessels remain the chief goals for future MDCT advances.

**2.3. Strategies for reduction of radiation dose and image noise**

Current limitations of coronary CTA include image noise and radiation dose. As a result, a number of techniques and strategies have become available on newer CT platforms to ena‐ ble dose reduction in coronary CT. These include sequential or prospective ECG triggering, reduced tube voltage scanning, and high-pitch helical scanning. Recently, iterative recon‐ struction (Adaptive Statistical Iterative Reconstruction [ASIR], GE Healthcare) has been in‐ troduced as a new reconstruction algorithm (Rajiah et al., 2012; Leipsic et al., 2007; Min et al., 2009). In comparison with filtered back projection (FBP), ASIR reduces image noise (increase contrast-to-noise ratio [CNR]) by iteratively comparing the acquired image to a modeled projection. This reconstruction algorithm is used to help deal with one of the primary issues of dose and tube current reduction for coronary CTA with FBP: increased image noise with decreased tube current. Recently, a high-definition CT (HDCT) scanner, with improved in-

**2.2. Image noise**

Coronary artery stenting is currently the standard practice in nonsurgical myocardial revascu‐ larization. However, coronary in-stent restenosis attributable to intimal hyperplasia remains problematic, with an incidence rate of 20% to 30%. The evaluation of stent patency is a major is‐ sue in the follow-up after stent placement. It would be desirable to obviate the use of invasive and costly angiography in the evaluation of stent patency. Initial studies using 4-detector coro‐ nary CTA for the evaluation of stent patency showed difficulties in imaging small and high-at‐ tenuating structures such as coronary stents (Table 1). With 16-detector coronary CTA, coronary artery stent patency has been assessed on the basis of contrast enhancement measurements or pixel count methods. However, stent diameter (≤ 3 mm), strut thickness, and stent material are still a cause of poor lumen visualization. In a study by Gilard et al, 232 stents were evaluated in vivo with 16-detector CT. Lumen interpretability depended on stent diameter: for stents with di‐ ameter > 3mm, 81% of lumens were interpretable, compared with 51% for stents with diameter ≤ 3 mm (Gilard et al., 2006). Restenosis detection depended on stent diameter: for stents with di‐ ameter > 3 mm, sensitivity and specificity of MDCT were 86% and 100%, respectively. For small stents with diameter ≤ 3 mm, corresponding values were 54% and 100% (Lefebvre et al., 2007; Pu‐ gliese et al., 2006). As stated by Kitagawa et al, the importance of metal artifacts and partial vol‐ ume effect of stents is related to the stent material, the stent diameter and thickness, and the strut design (Kitagawa et al., 2006). In vitro studies comparing 16-slice CT with 4-slice CT showed im‐ provement in lumen visibility, with the same medium smooth body kernel (B30f) for reconstruc‐ tion (Maintz et al., 2003). The use of a dedicated high spatial resolution reconstruction kernel (sharp kernel or "B46f"), compared with a standard reconstruction kernel (medium-smooth kernel or "B30f"), resulted in a further improvement of the visible stent lumen diameter because, with the B46f-kernel, the stent boundary was depicted more sharply than on the B30f-kernel im‐ ages. Further, a larger window width to suppress the high attenuation of the stent strut seemed to contribute better delineation and more accurate measurement of the in-stent lumen. In a phantom study, Seifarth et al. showed that the use of 64-slice CT results in superior visualization of the stent lumen and in-stent stenosis, compared with 16-slice CT (Seifarth et al., 2006). In addi‐ tion to evaluating the in vitro and in vivo performance of 64-slice CT for stent analysis, further developments could focus on the design of stents to reduce artifacts.

**3.2. Partial volume averaging and interpolation**

the stent lumen (Lefebvre et al., 2007; Pugliese et al., 2006).

thrombus formation, thereby reducing the incidence of stent thrombosis.

**3.3. Stent type**

Another obstacle to coronary stent imaging is related to partial volume averaging and in‐ terpolation. Inherent in all digital tomographic imaging techniques, partial volume aver‐ aging yields a CT number that represents average attenuation of the materials within a voxel. At stent imaging in vessels with a large diameter, such as the aorta or iliac arter‐ ies, partial volume averaging effects are present but are limited to the proximity of the vessel wall. In coronary arteries with smaller diameters, the artifacts are of the same magnitude, but a reliable assessment of the lumen is much more problematic. The small‐ er the stent, the more detrimental the effect of partial volume averaging on the assessa‐ bility of the in-stent lumen. The thinner detector width on 64-section CT scanners partly solves this problem by reducing the voxel size and thereby the general assessability of

Multidector CT Imaging of Coronary Artery Stent and Coronary Artery Bypass Graft

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159

The visibility of lumens of different stents varies and this largely depends upon the stent type and the diameter. The blooming effect is more disturbing for smaller coronary stents with thicker struts. Uninterpretable images tend to be obtained for stents with thicker struts and/or a smaller diameter. When the lumen diameter is less than 3mm, the lumen visibility is worse. Regarding the type of stent, the most severe artifacts are found with tantalum, gold or gold-coated stents, or with covered stent grafts as compared with stainless steel stents. Maintz et al. recently evaluated 68 different stents in vitro with using 64-slice MDCT and they created a catalogue of the CT appearance of most of the currently available coronary stents (Maintz et al., 2009). They confirmed that the high variability for stent lumen visibility depended on the stent type, and this was previously reported on with using 4-slice and 16 slice CT. They also concluded that while in vivo studies will be required to verify their re‐ sults, it can be assumed that a reliable evaluation of lumens of stents in the more advantageous stent types, such as the Radius, Teneo, Symbiot or Flex standard stents, will be possible with using 64-slice MDCT. First-generation drug-eluting stents, which released sirolimus or paclitaxel, were shown to be superior to bare-metal stents and to balloon angio‐ plasty in reducing the magnitude of neointimal proliferation, the incidence of clinical reste‐ nosis, and the need for reintervention. Unfortunately, late stent thrombosis (thrombosis that occurs 30 days or more after implantation of the stent) is more likely to occur with drugeluting stents than with bare-metal stents. The gradual release of the antiproliferative agent effectively inhibits endothelialization of the stent struts, thereby allowing them to continue to serve as a nidus for platelet aggregation and thrombus formation. Second or third-genera‐ tion drug-eluting stents are designed to provide better stent deployment, safety, and effica‐ cy. They differ from the first-generation stents with respect to the antiproliferative agent, the polymer layer (which acts as a reservoir for controlled drug delivery), and the stent frame. Improvements in stent structure may result in better stent apposition to the vessel wall, im‐ proved endothelialization (a thin stent strut elicits less neointimal proliferation and requires less endothelialization to cover the struts completely), and reduced platelet aggregation and


**Table 1.** Results of studies of the use of MDCT to evaluate coronary stent patency.

#### **3.1. Beam hardening and blooming effect**

Metallic struts cause a severe CT artifact known as blooming effect. Blooming effect results from beam hardening and causes the stent struts to appear thicker than they are and, often, to overlap the vessel lumen. As a result the in-stent luminal diameter is underestimated. The en‐ ergy spectrum of the x-ray beam increases as it passes through a hyperattenuating structure be‐ cause lower-energy photons are absorbed more rapidly than are higher-energy photons, resulting in the beam being more intense when it reaches the detectors. Calcified spots of vessel wall near or at the outer surface of an implanted stent also contribute to beam hardening, which further erodes the assessability of the stent lumen. Depending on the metal type and the design of the stent, the magnitude of this artifact varies. As a rule, the depiction of stents with the slim‐ mest profile is least affected by blooming artifacts (Lefebvre et al., 2007; Pugliese et al., 2006).

#### **3.2. Partial volume averaging and interpolation**

Another obstacle to coronary stent imaging is related to partial volume averaging and in‐ terpolation. Inherent in all digital tomographic imaging techniques, partial volume aver‐ aging yields a CT number that represents average attenuation of the materials within a voxel. At stent imaging in vessels with a large diameter, such as the aorta or iliac arter‐ ies, partial volume averaging effects are present but are limited to the proximity of the vessel wall. In coronary arteries with smaller diameters, the artifacts are of the same magnitude, but a reliable assessment of the lumen is much more problematic. The small‐ er the stent, the more detrimental the effect of partial volume averaging on the assessa‐ bility of the in-stent lumen. The thinner detector width on 64-section CT scanners partly solves this problem by reducing the voxel size and thereby the general assessability of the stent lumen (Lefebvre et al., 2007; Pugliese et al., 2006).

#### **3.3. Stent type**

design (Kitagawa et al., 2006). In vitro studies comparing 16-slice CT with 4-slice CT showed im‐ provement in lumen visibility, with the same medium smooth body kernel (B30f) for reconstruc‐ tion (Maintz et al., 2003). The use of a dedicated high spatial resolution reconstruction kernel (sharp kernel or "B46f"), compared with a standard reconstruction kernel (medium-smooth kernel or "B30f"), resulted in a further improvement of the visible stent lumen diameter because, with the B46f-kernel, the stent boundary was depicted more sharply than on the B30f-kernel im‐ ages. Further, a larger window width to suppress the high attenuation of the stent strut seemed to contribute better delineation and more accurate measurement of the in-stent lumen. In a phantom study, Seifarth et al. showed that the use of 64-slice CT results in superior visualization of the stent lumen and in-stent stenosis, compared with 16-slice CT (Seifarth et al., 2006). In addi‐ tion to evaluating the in vitro and in vivo performance of 64-slice CT for stent analysis, further

158 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

developments could focus on the design of stents to reduce artifacts.

**Patients**

Pump, et al., 2000 Electron beam 202 321 - Distal

Gilard, et al., 2006 16-MDCT 143 232 2.5-4.5 visualize

**Table 1.** Results of studies of the use of MDCT to evaluate coronary stent patency.

**3.1. Beam hardening and blooming effect**

**Number of Stents**

Electron beam 117 152 2.5- 3.0 Distal

4-MDCT 29 47 3.0-5.0 Distal

4-MDCT 48 72 2.5-4.5 Distal

16-MDCT 22 68 2.25-5.0 Distal

Metallic struts cause a severe CT artifact known as blooming effect. Blooming effect results from beam hardening and causes the stent struts to appear thicker than they are and, often, to overlap the vessel lumen. As a result the in-stent luminal diameter is underestimated. The en‐ ergy spectrum of the x-ray beam increases as it passes through a hyperattenuating structure be‐ cause lower-energy photons are absorbed more rapidly than are higher-energy photons, resulting in the beam being more intense when it reaches the detectors. Calcified spots of vessel wall near or at the outer surface of an implanted stent also contribute to beam hardening, which further erodes the assessability of the stent lumen. Depending on the metal type and the design of the stent, the magnitude of this artifact varies. As a rule, the depiction of stents with the slim‐ mest profile is least affected by blooming artifacts (Lefebvre et al., 2007; Pugliese et al., 2006).

**Stent Caliber (mm)**

**Criteria for patency**

runoff

runoff

runoff

runoff

runoff

lumen

**Sensitivity (%) Specificity (%)**

78 98

72 60

100 100

100 100

78 100

100 92

**Authors CT technique Number of**

Knollman, et al.,

Maintz, et al., 2003

Ligabue, et al.,

Schuijf, et al., 2004

2004

2004

The visibility of lumens of different stents varies and this largely depends upon the stent type and the diameter. The blooming effect is more disturbing for smaller coronary stents with thicker struts. Uninterpretable images tend to be obtained for stents with thicker struts and/or a smaller diameter. When the lumen diameter is less than 3mm, the lumen visibility is worse. Regarding the type of stent, the most severe artifacts are found with tantalum, gold or gold-coated stents, or with covered stent grafts as compared with stainless steel stents. Maintz et al. recently evaluated 68 different stents in vitro with using 64-slice MDCT and they created a catalogue of the CT appearance of most of the currently available coronary stents (Maintz et al., 2009). They confirmed that the high variability for stent lumen visibility depended on the stent type, and this was previously reported on with using 4-slice and 16 slice CT. They also concluded that while in vivo studies will be required to verify their re‐ sults, it can be assumed that a reliable evaluation of lumens of stents in the more advantageous stent types, such as the Radius, Teneo, Symbiot or Flex standard stents, will be possible with using 64-slice MDCT. First-generation drug-eluting stents, which released sirolimus or paclitaxel, were shown to be superior to bare-metal stents and to balloon angio‐ plasty in reducing the magnitude of neointimal proliferation, the incidence of clinical reste‐ nosis, and the need for reintervention. Unfortunately, late stent thrombosis (thrombosis that occurs 30 days or more after implantation of the stent) is more likely to occur with drugeluting stents than with bare-metal stents. The gradual release of the antiproliferative agent effectively inhibits endothelialization of the stent struts, thereby allowing them to continue to serve as a nidus for platelet aggregation and thrombus formation. Second or third-genera‐ tion drug-eluting stents are designed to provide better stent deployment, safety, and effica‐ cy. They differ from the first-generation stents with respect to the antiproliferative agent, the polymer layer (which acts as a reservoir for controlled drug delivery), and the stent frame. Improvements in stent structure may result in better stent apposition to the vessel wall, im‐ proved endothelialization (a thin stent strut elicits less neointimal proliferation and requires less endothelialization to cover the struts completely), and reduced platelet aggregation and thrombus formation, thereby reducing the incidence of stent thrombosis.

**Scheme 2.** Detail render of drug-eluting stents. Diverse drug-eluting stents are currently available, differing in the type of metal used, stent design, and drug coating.

**Scheme 4.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Taxus, first-generation

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**Scheme 5.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Xience, second-genera‐

Paclitaxel-eluting stent.

tion Everolimus-eluting stent.

**Scheme 3.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Cypher, first-generation Sirolimus-eluting stent.

**Scheme 4.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Taxus, first-generation Paclitaxel-eluting stent.

**Scheme 2.** Detail render of drug-eluting stents. Diverse drug-eluting stents are currently available, differing in the

160 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Scheme 3.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Cypher, first-generation

type of metal used, stent design, and drug coating.

Sirolimus-eluting stent.

**Scheme 5.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Xience, second-genera‐ tion Everolimus-eluting stent.

**Stent trade name Metal platform Coating drug used** Cypher Stainless steel Sirolimus (Rapamune)

Prominent contrast enhancement in the lumen is a prerequisite for robust coronary CT an‐ giography. It is achieved not only by optimizing the contrast material injection parameters (example, using a high-concentration contrast agent and a fast injection rate) but also by ac‐ curately synchronizing CT data acquisition with the passage of the contrast agent by means of bolus tracking or a test bolus. Edge-enhancing convolution filters, which may be used for better delineation of stents, have the drawback of producing noisier data sets. If such convo‐ lution filter is used, the assessability of in-stent lumen particularly benefits from the pres‐ ence of high degree of intraluminal contrast enhancement, which somewhat compensates for the kernel-related noise. A high degree of intraluminal enhancement is recommended es‐ pecially for the investigation of stent patency in vessels that have a small diameter and thus

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Residual cardiac motion is of the utmost importance as a cause of vessel non-assessabil‐ ity at MDCT. Residual cardiac motion also plays a role in exacerbating metal-related ar‐ tifacts such as beam hardening or partial volume averaging effects. The use of high gantry rotation speeds, multisegmental reconstruction techniques, and beta-blockers to lower the heart rate consistently improves the interpretability of MDCT. ECG-based ed‐ iting techniques allow improvement of image quality for patients with mild irregulari‐ ties in sinus rhythm, such as premature beats, and for those with bundle-branch block

As mentioned earlier, the direct visualization of the in-stent lumen is important for assessing patency, because collateral vessels may be feeding vessel segment distal to the occluded stent in a retrograde direction. An accurate intraluminal evaluation can best be performed by means of multiplanar reformation of the CT data volume. The stent may be considered to be occluded if the lumen inside the device appears darker than the contrast-enhanced vessel lumen proximal to the stent. Unless severe artifacts affect the CT data set, stent evaluation may proceed beyond a judgment of patency or occlusion. Nonocclusive in-stent neointimal hyperplasia is characterized by the presence of a darker rim between the stent and the con‐ trast-enhanced vessel lumen and is secondary to the healing response to procedurerelated

Endeavor Cobalt-chromium Zotarolimus Taxus Stainless steel Paclitaxel (Taxol) Xience, Promus Cobalt-chromium Everolimus (Afinitor)

**Table 2.** Types of Drug-Eluting Stents Available for Clinical Use

contain less blood (Lefebvre et al., 2007; Pugliese et al., 2006).

**3.4. Optimization of contrast enhancement**

**3.5. Residual cardiac motion**

**3.6. In-stent lumen evaluation**

(Lefebvre et al., 2007; Pugliese et al., 2006).

**Scheme 6.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Endeavor, second-gen‐ eration Zotarolimus-eluting stent.

**Scheme 7.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Promus, third-genera‐ tion Everolimus-eluting stent.


**Table 2.** Types of Drug-Eluting Stents Available for Clinical Use

#### **3.4. Optimization of contrast enhancement**

Prominent contrast enhancement in the lumen is a prerequisite for robust coronary CT an‐ giography. It is achieved not only by optimizing the contrast material injection parameters (example, using a high-concentration contrast agent and a fast injection rate) but also by ac‐ curately synchronizing CT data acquisition with the passage of the contrast agent by means of bolus tracking or a test bolus. Edge-enhancing convolution filters, which may be used for better delineation of stents, have the drawback of producing noisier data sets. If such convo‐ lution filter is used, the assessability of in-stent lumen particularly benefits from the pres‐ ence of high degree of intraluminal contrast enhancement, which somewhat compensates for the kernel-related noise. A high degree of intraluminal enhancement is recommended es‐ pecially for the investigation of stent patency in vessels that have a small diameter and thus contain less blood (Lefebvre et al., 2007; Pugliese et al., 2006).

#### **3.5. Residual cardiac motion**

**Scheme 6.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Endeavor, second-gen‐

162 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Scheme 7.** Type of metal used, stent design, and images of fluoroscopy and 64-slice MDCT of Promus, third-genera‐

eration Zotarolimus-eluting stent.

tion Everolimus-eluting stent.

Residual cardiac motion is of the utmost importance as a cause of vessel non-assessabil‐ ity at MDCT. Residual cardiac motion also plays a role in exacerbating metal-related ar‐ tifacts such as beam hardening or partial volume averaging effects. The use of high gantry rotation speeds, multisegmental reconstruction techniques, and beta-blockers to lower the heart rate consistently improves the interpretability of MDCT. ECG-based ed‐ iting techniques allow improvement of image quality for patients with mild irregulari‐ ties in sinus rhythm, such as premature beats, and for those with bundle-branch block (Lefebvre et al., 2007; Pugliese et al., 2006).

#### **3.6. In-stent lumen evaluation**

As mentioned earlier, the direct visualization of the in-stent lumen is important for assessing patency, because collateral vessels may be feeding vessel segment distal to the occluded stent in a retrograde direction. An accurate intraluminal evaluation can best be performed by means of multiplanar reformation of the CT data volume. The stent may be considered to be occluded if the lumen inside the device appears darker than the contrast-enhanced vessel lumen proximal to the stent. Unless severe artifacts affect the CT data set, stent evaluation may proceed beyond a judgment of patency or occlusion. Nonocclusive in-stent neointimal hyperplasia is characterized by the presence of a darker rim between the stent and the con‐ trast-enhanced vessel lumen and is secondary to the healing response to procedurerelated vessel injury. If neointimal hyperplasia exceeds a luminal diameter reduction of 50%, the process is consistent with hemodynamically significant in-stent restenosis. Instent restenosis typically occurs as a localized nonenhancing lesion, often (but not invariably) associated with complex lesion anatomy and discontinuity in lesion coverage. Restenosis may occur ei‐ ther within or adjacent to the stent (within 5 mm of the stent extremities). Edge restenosis might occur because of a decrease in local drug availability, incomplete lesion coverage due to a gap between two stents, procedure-related trauma, or damage to the polymer coating of a stent from calcifications or an overlapping stent.

#### **3.7. Coronary stent fracture**

Stent fracture (SF) is an important and potentially serious complication of drug-eluting stents (DES), resulting in thrombosis and in-stent restenosis. Recent reports suggest that the preva‐ lence of fracture ranges between 1.9% and 2.6% (Dimitrios et al., 2011; Lim et al., 2008). SF is probably related to mechanical fatigue of the metallic stent strut, which may be aggravated by highly pulsatile structures such as myocardial bridge, use of long stents or DES unsupported by neointimal tissue. SF may also result from a manufacturing defect. Various factors that have been implicated for a stent fracture include vessel tortuosity, the presence of a right coronary artery lesion, overlapping stents, and the use of a DES such as a sirolimus-eluting stent. In gen‐ eral stent fractures have been reported to be more common when placed in the right coronary artery (RCA) probably due to its curved course, than in the left anterior descending (LAD) or circumflex (LCX) coronary arteries. The type of stent also influences its risk for fracture. The Cypher stent is more prone to fracture as compared to Taxus and Endeavor stents. Overlap‐ ping stents are more likely to fracture rather than isolated stents. The presence of stent fracture was classified as grade I to V: I = involving a single-strut fracture; II = 2 or more strut fractures without deformation; III = 2 or more strut fractures with deformation; IV = multiple strut frac‐ tures with acquired transection but without gap; and V = multiple strut fractures with acquired transection with gap in the stent body (Nakazawa et al., 2009).

**Scheme 9.** Images of fluoroscopy and 64-slice MDCT of stent fracture type I. A single strut fracture is seen in the mid

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**Scheme 10.** Images of fluoroscopy and 64-slice MDCT of stent fracture type II. Two strut fractures are seen in the prox‐

portion of the stent in RCA.

imal and distal portion of the stent in LCX.

**Scheme 8.** Classification of stent fracture.

vessel injury. If neointimal hyperplasia exceeds a luminal diameter reduction of 50%, the process is consistent with hemodynamically significant in-stent restenosis. Instent restenosis typically occurs as a localized nonenhancing lesion, often (but not invariably) associated with complex lesion anatomy and discontinuity in lesion coverage. Restenosis may occur ei‐ ther within or adjacent to the stent (within 5 mm of the stent extremities). Edge restenosis might occur because of a decrease in local drug availability, incomplete lesion coverage due to a gap between two stents, procedure-related trauma, or damage to the polymer coating of

164 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Stent fracture (SF) is an important and potentially serious complication of drug-eluting stents (DES), resulting in thrombosis and in-stent restenosis. Recent reports suggest that the preva‐ lence of fracture ranges between 1.9% and 2.6% (Dimitrios et al., 2011; Lim et al., 2008). SF is probably related to mechanical fatigue of the metallic stent strut, which may be aggravated by highly pulsatile structures such as myocardial bridge, use of long stents or DES unsupported by neointimal tissue. SF may also result from a manufacturing defect. Various factors that have been implicated for a stent fracture include vessel tortuosity, the presence of a right coronary artery lesion, overlapping stents, and the use of a DES such as a sirolimus-eluting stent. In gen‐ eral stent fractures have been reported to be more common when placed in the right coronary artery (RCA) probably due to its curved course, than in the left anterior descending (LAD) or circumflex (LCX) coronary arteries. The type of stent also influences its risk for fracture. The Cypher stent is more prone to fracture as compared to Taxus and Endeavor stents. Overlap‐ ping stents are more likely to fracture rather than isolated stents. The presence of stent fracture was classified as grade I to V: I = involving a single-strut fracture; II = 2 or more strut fractures without deformation; III = 2 or more strut fractures with deformation; IV = multiple strut frac‐ tures with acquired transection but without gap; and V = multiple strut fractures with acquired

a stent from calcifications or an overlapping stent.

transection with gap in the stent body (Nakazawa et al., 2009).

**3.7. Coronary stent fracture**

**Scheme 8.** Classification of stent fracture.

**Scheme 9.** Images of fluoroscopy and 64-slice MDCT of stent fracture type I. A single strut fracture is seen in the mid portion of the stent in RCA.

**Scheme 10.** Images of fluoroscopy and 64-slice MDCT of stent fracture type II. Two strut fractures are seen in the prox‐ imal and distal portion of the stent in LCX.

**Scheme 11.** Images of fluoroscopy and 64-slice MDCT of stent fracture type III. Transverse fracture with deformation is seen in the proximal portion of the stent in middle RCA. The stent in proximal RCA is intact in coronary angiography suggesting pseudo-lesion due to step artifact in MDCT.

> **Scheme 13.** Images of fluoroscopy and 64-slice MDCT of restenosis due to stent fracture. (Left) Thrombus with steno‐ sis is seen in the proximal edge of the LAD stent. (Right) Transverse fracture with stent displacement and moderate

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**Scheme 14.** Images of fluoroscopy and 64-slice MDCT of pseudoaneurysm due to stent fracture. Type I fracture with

stenosis is seen in the RCA stent.

pseudoaneurysm formation is seen in the LAD stent.

**Scheme 12.** Images of fluoroscopy and 64-slice MDCT of stent fracture type IV. Multiple strut fractures with acquired transection without gap are seen in the proximal and mid portion of the stent in RCA. The distal portion of the stent is intact in coronary angiography suggesting pseudo-lesion due to step artifact in MDCT.

**Scheme 13.** Images of fluoroscopy and 64-slice MDCT of restenosis due to stent fracture. (Left) Thrombus with steno‐ sis is seen in the proximal edge of the LAD stent. (Right) Transverse fracture with stent displacement and moderate stenosis is seen in the RCA stent.

**Scheme 11.** Images of fluoroscopy and 64-slice MDCT of stent fracture type III. Transverse fracture with deformation is seen in the proximal portion of the stent in middle RCA. The stent in proximal RCA is intact in coronary angiography

166 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Scheme 12.** Images of fluoroscopy and 64-slice MDCT of stent fracture type IV. Multiple strut fractures with acquired transection without gap are seen in the proximal and mid portion of the stent in RCA. The distal portion of the stent is

intact in coronary angiography suggesting pseudo-lesion due to step artifact in MDCT.

suggesting pseudo-lesion due to step artifact in MDCT.

**Scheme 14.** Images of fluoroscopy and 64-slice MDCT of pseudoaneurysm due to stent fracture. Type I fracture with pseudoaneurysm formation is seen in the LAD stent.

SF has been evaluated mainly by using conventional coronary angiography or fluoroscopy and in selected cases by intravascular ultrasound (IVUS). Recently, MDCT has been found to be more sensitive than conventional coronary angiography in the detection of SF, due to its nearly isotropic multi-planar imaging capabilities, that can depict stents in their long and short axes (Lim et al., 2008; Pang et al., 2009). MDCT imaging on 64-slice scanners provide most of the relevant details required to assess stents on follow-up. In a retrospective evalua‐ tion, 64-slice MDCT angiography of 371 patients with 545 stents identified 24 SFs, of which 6 were not detected on conventional angiograms at the initial readings (Lim et al., 2008). An *in vitro* comparison of 64-slice MDCT, conventional cine-angiography, and IVUS revealed that MDCT had high accuracy for the evaluation of coronary SF (Pang et al., 2009). The impor‐ tant features that must be evaluated in all post-stent follow-up include not only the evalua‐ tion of in-stent thrombosis, but also features such as stent migration, fracture, buckling, and rarely coronary perforation and aneurysms or pseudoaneurysms (Dimitrios et al., 2011).

al., 1985; Campeau et al., 1983). Saphenousveins are fairly simple to access and harvest from the lower extremities, and they are more versatile and widely available than arteri‐ al grafts. In addition, during the intra- and perioperative period, saphenous veins are re‐ sistant to spasm versus their arterial counterparts. However, the use of SVG is limited by distortion from varicose and sclerotic disease as well as a higher occurrence of intimal hyperplasia and atherosclerotic changes after exposure to systemic blood pressure, result‐ ing in lower patency rates. Graft occlusion can also occur due to vascular damage dur‐ ing harvesting of the saphenous vein. In a large study, the SVG patency was 88% perioperatively, 81% at 1 year, 75% at 5 years, and 50% at greater than or equal to 15 years (Fitzgibbon et al., 1996). The graft attrition rate between 1 and 6 years after CABG surgery is 1% to 2% per year, and between 6 and 10 years is 4% per year. The great sa‐ phenous vein is the vein routinely used for CABG surgery. The proximal anastomosis of the venous graft with the ascending aorta is usually performed cranial to the origin of coronary arteries and as distal as the proximal portion of the aortic arch. The SVG can be sutured directly to the anterior portion of the ascending aorta or attached with an anastomotic device, allowing faster, sutureless attachment. The device, called the Symme‐ try Bypass System aortic connector (St Jude Medical, St Paul, Minn), alters the common appearance of the bypass graft by requiring the aortic connector to be anastomosed per‐ pendicularly to the aorta (Mack et al., 2003; Poston et al., 2004). Recent reports have documented the development of significant stenosis and occlusion in 13.7%-15.5% of vein grafts attached with the aortic connector (Carrel et al., 2003; Wiklund et al., 2002). In or‐ der to support the course of the aortovenous anastomosis, the left-sided SVG is connect‐ ed to the left side of the aorta, stabilizing the graft on top of the main pulmonary artery. A right-sided SVG is attached either to the lower aspect or right side of the ascending aorta, allowing the graft to traverse the right arterio-ventricular groove. SVGs tend to ap‐

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**Figure 1.** Saphenous vein grafts. Three-dimensional volume-rendered images show the typical appearance of right (arrow) and left (arrowhead) saphenous vein grafts (SVGs) sutured to the anterior aorta. The left SVG is attached to

pear as large contrast-filled vessels (Fig.1).

## **4. Coronary artery bypass graft imaging with MDCT**

#### **4.1. Coronary bypass graft lumen assessment: Graft patency and stenoses**

Coronary bypass graft CT can be performed with 2 different objectives, each with a sep‐ arate clinical context and goal: the evaluation of graft patency, and the evaluation of graft and anastomotic stenoses. Within the first postoperative month, the main cause of graft failure is thrombosis.75 Graft closure from thrombosis at 1 month is a known com‐ plication in 10% to 15% of cases. Coronary bypass graft patency assessment has been shown to be excellent with ECG-gated 4-detector CT, with mean sensibility and specifici‐ ty for occlusion of 97% and 98%, respectively, in comparison with catheter angiography (Nieman K et al., 2003; Marano R et al., 2004). With 16-detector CT, accuracy is also ex‐ cellent, with mean sensitivity of 100 % and mean specificity of 99% for detecting bypass graft occlusion, in comparison with catheter angiography (Chiurlia E et al., 2005; Ander‐ son K et al., 2006). Recent studies using 64-slice MDCT have reported sensitivity and specificity values of 95% to 100% and 93% to 100%, respectively, for graft occlusion and high-grade stenosis with > 50% luminal narrowing. Since naïve coronary arteries and cor‐ onary grafts are small vessels, 2 to 4 mm in diameter, and are characterized by both complex anatomy and continuous movements, high spatial and temporal resolutions are mandatory to visualize these vessels at MDCT. Vascular clips in the proximity of grafts and their anastomoses, as well as artifacts owing to residual cardiac motion, can be a cause of significant artifacts for the evaluation of graft stenoses.

#### **4.2. Type of arterial or vein graft**

#### *4.2.1. Saphenous vein Graft (SVG)*

The SVG was first successfully used in a CABG operation by Sabiston in 1962. Both the benefits and limitations of SVG have been well documented in the literature (Bourassa et al., 1985; Campeau et al., 1983). Saphenousveins are fairly simple to access and harvest from the lower extremities, and they are more versatile and widely available than arteri‐ al grafts. In addition, during the intra- and perioperative period, saphenous veins are re‐ sistant to spasm versus their arterial counterparts. However, the use of SVG is limited by distortion from varicose and sclerotic disease as well as a higher occurrence of intimal hyperplasia and atherosclerotic changes after exposure to systemic blood pressure, result‐ ing in lower patency rates. Graft occlusion can also occur due to vascular damage dur‐ ing harvesting of the saphenous vein. In a large study, the SVG patency was 88% perioperatively, 81% at 1 year, 75% at 5 years, and 50% at greater than or equal to 15 years (Fitzgibbon et al., 1996). The graft attrition rate between 1 and 6 years after CABG surgery is 1% to 2% per year, and between 6 and 10 years is 4% per year. The great sa‐ phenous vein is the vein routinely used for CABG surgery. The proximal anastomosis of the venous graft with the ascending aorta is usually performed cranial to the origin of coronary arteries and as distal as the proximal portion of the aortic arch. The SVG can be sutured directly to the anterior portion of the ascending aorta or attached with an anastomotic device, allowing faster, sutureless attachment. The device, called the Symme‐ try Bypass System aortic connector (St Jude Medical, St Paul, Minn), alters the common appearance of the bypass graft by requiring the aortic connector to be anastomosed per‐ pendicularly to the aorta (Mack et al., 2003; Poston et al., 2004). Recent reports have documented the development of significant stenosis and occlusion in 13.7%-15.5% of vein grafts attached with the aortic connector (Carrel et al., 2003; Wiklund et al., 2002). In or‐ der to support the course of the aortovenous anastomosis, the left-sided SVG is connect‐ ed to the left side of the aorta, stabilizing the graft on top of the main pulmonary artery. A right-sided SVG is attached either to the lower aspect or right side of the ascending aorta, allowing the graft to traverse the right arterio-ventricular groove. SVGs tend to ap‐ pear as large contrast-filled vessels (Fig.1).

SF has been evaluated mainly by using conventional coronary angiography or fluoroscopy and in selected cases by intravascular ultrasound (IVUS). Recently, MDCT has been found to be more sensitive than conventional coronary angiography in the detection of SF, due to its nearly isotropic multi-planar imaging capabilities, that can depict stents in their long and short axes (Lim et al., 2008; Pang et al., 2009). MDCT imaging on 64-slice scanners provide most of the relevant details required to assess stents on follow-up. In a retrospective evalua‐ tion, 64-slice MDCT angiography of 371 patients with 545 stents identified 24 SFs, of which 6 were not detected on conventional angiograms at the initial readings (Lim et al., 2008). An *in vitro* comparison of 64-slice MDCT, conventional cine-angiography, and IVUS revealed that MDCT had high accuracy for the evaluation of coronary SF (Pang et al., 2009). The impor‐ tant features that must be evaluated in all post-stent follow-up include not only the evalua‐ tion of in-stent thrombosis, but also features such as stent migration, fracture, buckling, and rarely coronary perforation and aneurysms or pseudoaneurysms (Dimitrios et al., 2011).

168 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**4. Coronary artery bypass graft imaging with MDCT**

cause of significant artifacts for the evaluation of graft stenoses.

**4.2. Type of arterial or vein graft**

*4.2.1. Saphenous vein Graft (SVG)*

**4.1. Coronary bypass graft lumen assessment: Graft patency and stenoses**

Coronary bypass graft CT can be performed with 2 different objectives, each with a sep‐ arate clinical context and goal: the evaluation of graft patency, and the evaluation of graft and anastomotic stenoses. Within the first postoperative month, the main cause of graft failure is thrombosis.75 Graft closure from thrombosis at 1 month is a known com‐ plication in 10% to 15% of cases. Coronary bypass graft patency assessment has been shown to be excellent with ECG-gated 4-detector CT, with mean sensibility and specifici‐ ty for occlusion of 97% and 98%, respectively, in comparison with catheter angiography (Nieman K et al., 2003; Marano R et al., 2004). With 16-detector CT, accuracy is also ex‐ cellent, with mean sensitivity of 100 % and mean specificity of 99% for detecting bypass graft occlusion, in comparison with catheter angiography (Chiurlia E et al., 2005; Ander‐ son K et al., 2006). Recent studies using 64-slice MDCT have reported sensitivity and specificity values of 95% to 100% and 93% to 100%, respectively, for graft occlusion and high-grade stenosis with > 50% luminal narrowing. Since naïve coronary arteries and cor‐ onary grafts are small vessels, 2 to 4 mm in diameter, and are characterized by both complex anatomy and continuous movements, high spatial and temporal resolutions are mandatory to visualize these vessels at MDCT. Vascular clips in the proximity of grafts and their anastomoses, as well as artifacts owing to residual cardiac motion, can be a

The SVG was first successfully used in a CABG operation by Sabiston in 1962. Both the benefits and limitations of SVG have been well documented in the literature (Bourassa et

**Figure 1.** Saphenous vein grafts. Three-dimensional volume-rendered images show the typical appearance of right (arrow) and left (arrowhead) saphenous vein grafts (SVGs) sutured to the anterior aorta. The left SVG is attached to

the mid-portion of left anterior descending (LAD) artery and the right SVG is attached to the distal-portion of right coronary artery (RCA).

SVG may present a horizontal or slightly oblique course on axial images, especially when the distal anastomosis is placed on the LCx or a diagonal branch to supply the left cardiac wall. In these cases, the graft can be recognized in the fatty tissue of mediastinum, posterior to the sternum and anterior to the RVOT. On occasion, the distal SVG is anastomosed se‐ quentially to greater than or equal to 2 coronary vessels or in the same vessel, using side-toside and end-to-side anastomoses. The naive vessel distal to the anastamotic site should be assessed and is recognized by its position and smaller caliber compared with the SVG (Fig. 3, 4). Typically, venous grafts are larger than arterial grafts and are not accompanied by sur‐ gical clips along their course. Sometimes a circumferential clip can be identified at the site of

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**Figure 4.** Saphenous vein graft. Three-dimensional volume-rendered images show the left saphenous vein graft

The internal mammary artery (IMA) is characterized by unique resistance to atherosclerosis and extremely high long-term patency rates compared with the saphenous vein. The IMA has a nonfenestrated internal elastic laminawithout vaso vasorum inside the vessel wall, which tends to protect against cellular migration and intimal hyperplasia. Moreover, the medial layer of IMA is thin and poor of muscle cells with poor vasoreactivity. In addition, the endothelium produces vasodilator(nitric oxide) and platelet inhibitor (prostacyclin). Gly‐ cosaminoglycan and lipid compositions of IMA result in being less atherogenetic in compar‐ ison with venous grafts. Therefore, use of the IMA decreases all postoperative cardiac events and mortality, and is associated with a long-term patency rate well >90% at 10 years (Loop

(SVG), which is attached to the mid-portion of left anterior descending (LAD) artery.

*4.2.2. Internal Mammary Artery (IMA)*

et al., 1986; Motwani & Topol, 1998).

proximal anastomosis with the ascending aorta (Fig.1).

An SVG to the right side is attached to the distal right coronary artery (RCA), posterior descending artery (PDA), or distal LAD artery. The distal anastomosis may lie on the phrenic wall of the heart. An SVG to the left side is attached distally to the LAD artery, diagonal artery, left circumflex (LCx) artery, or the obtuse marginal (OM) arteries, by tra‐ versing anteriorly and superiorly to the right ventricular outflow tractor main pulmona‐ ry artery (Fig. 2, 3, 4).

**Figure 2.** Saphenous vein grafts. Three-dimensional volume-rendered images show the typical appearance of right (arrow) and left (arrowhead) saphenous vein grafts (SVGs) sutured to the anterior aorta. The right SVG is attached to the mid-portion of left anterior descending (LAD) artery and the left SVG is attached to the obtuse marginal (OM) artery.

**Figure 3.** Saphenous vein graft. Three-dimensional volume-rendered images show the left saphenous vein graft (SVG) with its anastomosis with the left circumflex (LCx) artery.

SVG may present a horizontal or slightly oblique course on axial images, especially when the distal anastomosis is placed on the LCx or a diagonal branch to supply the left cardiac wall. In these cases, the graft can be recognized in the fatty tissue of mediastinum, posterior to the sternum and anterior to the RVOT. On occasion, the distal SVG is anastomosed se‐ quentially to greater than or equal to 2 coronary vessels or in the same vessel, using side-toside and end-to-side anastomoses. The naive vessel distal to the anastamotic site should be assessed and is recognized by its position and smaller caliber compared with the SVG (Fig. 3, 4). Typically, venous grafts are larger than arterial grafts and are not accompanied by sur‐ gical clips along their course. Sometimes a circumferential clip can be identified at the site of proximal anastomosis with the ascending aorta (Fig.1).

**Figure 4.** Saphenous vein graft. Three-dimensional volume-rendered images show the left saphenous vein graft (SVG), which is attached to the mid-portion of left anterior descending (LAD) artery.

#### *4.2.2. Internal Mammary Artery (IMA)*

the mid-portion of left anterior descending (LAD) artery and the right SVG is attached to the distal-portion of right

170 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

An SVG to the right side is attached to the distal right coronary artery (RCA), posterior descending artery (PDA), or distal LAD artery. The distal anastomosis may lie on the phrenic wall of the heart. An SVG to the left side is attached distally to the LAD artery, diagonal artery, left circumflex (LCx) artery, or the obtuse marginal (OM) arteries, by tra‐ versing anteriorly and superiorly to the right ventricular outflow tractor main pulmona‐

**Figure 2.** Saphenous vein grafts. Three-dimensional volume-rendered images show the typical appearance of right (arrow) and left (arrowhead) saphenous vein grafts (SVGs) sutured to the anterior aorta. The right SVG is attached to the mid-portion of left anterior descending (LAD) artery and the left SVG is attached to the obtuse marginal

**Figure 3.** Saphenous vein graft. Three-dimensional volume-rendered images show the left saphenous vein graft (SVG)

with its anastomosis with the left circumflex (LCx) artery.

coronary artery (RCA).

ry artery (Fig. 2, 3, 4).

(OM) artery.

The internal mammary artery (IMA) is characterized by unique resistance to atherosclerosis and extremely high long-term patency rates compared with the saphenous vein. The IMA has a nonfenestrated internal elastic laminawithout vaso vasorum inside the vessel wall, which tends to protect against cellular migration and intimal hyperplasia. Moreover, the medial layer of IMA is thin and poor of muscle cells with poor vasoreactivity. In addition, the endothelium produces vasodilator(nitric oxide) and platelet inhibitor (prostacyclin). Gly‐ cosaminoglycan and lipid compositions of IMA result in being less atherogenetic in compar‐ ison with venous grafts. Therefore, use of the IMA decreases all postoperative cardiac events and mortality, and is associated with a long-term patency rate well >90% at 10 years (Loop et al., 1986; Motwani & Topol, 1998).

#### *4.2.3. Left IMA*

The Left IMA (LIMA) is the vessel of choice for the surgical revascularization of the left an‐ terior descending (LAD) artery for its biological and anatomical characteristiscs, being the conduit more proximal to the LAD artery and the easiest to harvest both in median sternoto‐ my and mini-thoracotomy. Due to anatomical proximity to the LAD artery and favorable patency rates, the left IMA (LIMA) is most commonly used as an in situ graft to revascular‐ ize the LAD or diagonal artery, supplying the anterior or anterolateral cardiac wall. The LI‐ MA extends from its origin at the subclavian artery and courses through the anterior mediastinum along the right ventricular outflow tract after being separated surgically from its original position in the left parasternalRegion (Fig. 5).

**Figure 6.** Left internal mammary artery (IMA) graft. Three-dimensional volume-rendered images show the left IMA graft from its origin at the left subclavian artery to its anastomosis with the left anterior descending (LAD) artery. There is also a right saphenous vein graft (SVG) sutured to the anterior aorta with its anastomosis with the posterior descending artery (PDA). The left saphenous vein grafts (SVG) are attached to diagonal artery and the obtuse margin‐

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The right IMA (RIMA) is used less frequently than the LIMA. The RIMA may be used in a variety of ways. As an in situ graft, The RIMA remains attached to the right subclavian ar‐ tery proximally and anastomoses with the target coronary artery distally. However, it is more commonly used as "free" graft from the ascending aorta to the RCA or from the LIMA to the left circumflex artery (LCx) or obtuse marginal (OM) branches. In cases in which both in situ IMAs are necessary for revascularization of the left heart, either the RIMA is connect‐ ed to the LCx artery or OM branches by extension through the transverse sinus of the peri‐ cardium and the LIMA is attached to the LAD artery or the RIMA is attached to the LAD artery and the LIMA is anastomosed to the LCx artery or other side branches (OM or diag‐ nonal branches). Otherwise, the RIMA can be removed from the right subclavian artery and used as a composite or free graft. As a segment of a composite graft to perform an arterial "T" or "Y" graft, the RIMA is anastomosed proximally to LIMA, allowing total arterial revas‐ cularization instead of using a venous graft with LIMA. As a free graft, a RIMA is anasto‐ mosed to the anterior ascending aorta and used in the same way as an SVG. The CTA appearance of the RIMA is similar to that of the LIMA. As already described for LIMA grafts, surgical clips are used to occlude collaterals. Studies have shown that total arterial myocardial revascularzation has the advantages of decreased recurrent angina and superior patency rates at 1 year when compared with those of conventional coronary artery bypass

surgery in which a LIMA graft is coupled with an SVG (Muneretto et al., 2003).

The first use of the radial artery (RA) as arterial conduit for coronary revascularization has been de-scribed by Carpentier et al in 1971 (Carpentier et al., 1973). As a muscular

al (OM) artery.

*4.2.4. Right IMA*

*4.2.5. Radial Artery (RA)*

**Figure 5.** Left internal mammary artery (IMA) graft. Three-dimensional volume-rendered images show the left IMA graft from its origin at the left subclavian artery to its anastomosis with the left anterior descending (LAD) artery. There is also a left saphenous vein graft (SVG), which is attached to the obtuse marginal (OM) artery. Note the smaller diameter of the arterial graft compared with that of the venous graft.

Infrequently, sequential distal anastomoses, with side-to-side and end-to-side anastomoses to the diagonal and LAD arteries, respectively, or involving separate sections of the LAD ar‐ tery, are performed. On axial images, the LIMA is no longer visible in its usual site, on the left side of the sternum, but courses as a small vessel in the anterior mediastinum along the right ventricle outflow tract (RVOT). Although in most cases LIMA grafts show a single dis‐ tal anastomosis to the left anterior descending artery (LAD) or a diagonal branch, multiple sequential anastomoses to both the LAD and diagonal branches are sometimes performed. Surgical clips are routinely used to occlude collaterals and to avoid arterial bleeding and can be seen either adjacent to the graft or at the original site of the LIMA. As with other grafts, on CTA, the distal anastamosis is typically most difficult to visualize. Surgical clips are used routinely to occlude branch vessels of the IMA, and metallic artifact may limit assessment in some instances (Fig. 6).

**Figure 6.** Left internal mammary artery (IMA) graft. Three-dimensional volume-rendered images show the left IMA graft from its origin at the left subclavian artery to its anastomosis with the left anterior descending (LAD) artery. There is also a right saphenous vein graft (SVG) sutured to the anterior aorta with its anastomosis with the posterior descending artery (PDA). The left saphenous vein grafts (SVG) are attached to diagonal artery and the obtuse margin‐ al (OM) artery.

#### *4.2.4. Right IMA*

*4.2.3. Left IMA*

The Left IMA (LIMA) is the vessel of choice for the surgical revascularization of the left an‐ terior descending (LAD) artery for its biological and anatomical characteristiscs, being the conduit more proximal to the LAD artery and the easiest to harvest both in median sternoto‐ my and mini-thoracotomy. Due to anatomical proximity to the LAD artery and favorable patency rates, the left IMA (LIMA) is most commonly used as an in situ graft to revascular‐ ize the LAD or diagonal artery, supplying the anterior or anterolateral cardiac wall. The LI‐ MA extends from its origin at the subclavian artery and courses through the anterior mediastinum along the right ventricular outflow tract after being separated surgically from

172 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Figure 5.** Left internal mammary artery (IMA) graft. Three-dimensional volume-rendered images show the left IMA graft from its origin at the left subclavian artery to its anastomosis with the left anterior descending (LAD) artery. There is also a left saphenous vein graft (SVG), which is attached to the obtuse marginal (OM) artery. Note the smaller

Infrequently, sequential distal anastomoses, with side-to-side and end-to-side anastomoses to the diagonal and LAD arteries, respectively, or involving separate sections of the LAD ar‐ tery, are performed. On axial images, the LIMA is no longer visible in its usual site, on the left side of the sternum, but courses as a small vessel in the anterior mediastinum along the right ventricle outflow tract (RVOT). Although in most cases LIMA grafts show a single dis‐ tal anastomosis to the left anterior descending artery (LAD) or a diagonal branch, multiple sequential anastomoses to both the LAD and diagonal branches are sometimes performed. Surgical clips are routinely used to occlude collaterals and to avoid arterial bleeding and can be seen either adjacent to the graft or at the original site of the LIMA. As with other grafts, on CTA, the distal anastamosis is typically most difficult to visualize. Surgical clips are used routinely to occlude branch vessels of the IMA, and metallic artifact may limit assessment in

its original position in the left parasternalRegion (Fig. 5).

diameter of the arterial graft compared with that of the venous graft.

some instances (Fig. 6).

The right IMA (RIMA) is used less frequently than the LIMA. The RIMA may be used in a variety of ways. As an in situ graft, The RIMA remains attached to the right subclavian ar‐ tery proximally and anastomoses with the target coronary artery distally. However, it is more commonly used as "free" graft from the ascending aorta to the RCA or from the LIMA to the left circumflex artery (LCx) or obtuse marginal (OM) branches. In cases in which both in situ IMAs are necessary for revascularization of the left heart, either the RIMA is connect‐ ed to the LCx artery or OM branches by extension through the transverse sinus of the peri‐ cardium and the LIMA is attached to the LAD artery or the RIMA is attached to the LAD artery and the LIMA is anastomosed to the LCx artery or other side branches (OM or diag‐ nonal branches). Otherwise, the RIMA can be removed from the right subclavian artery and used as a composite or free graft. As a segment of a composite graft to perform an arterial "T" or "Y" graft, the RIMA is anastomosed proximally to LIMA, allowing total arterial revas‐ cularization instead of using a venous graft with LIMA. As a free graft, a RIMA is anasto‐ mosed to the anterior ascending aorta and used in the same way as an SVG. The CTA appearance of the RIMA is similar to that of the LIMA. As already described for LIMA grafts, surgical clips are used to occlude collaterals. Studies have shown that total arterial myocardial revascularzation has the advantages of decreased recurrent angina and superior patency rates at 1 year when compared with those of conventional coronary artery bypass surgery in which a LIMA graft is coupled with an SVG (Muneretto et al., 2003).

#### *4.2.5. Radial Artery (RA)*

The first use of the radial artery (RA) as arterial conduit for coronary revascularization has been de-scribed by Carpentier et al in 1971 (Carpentier et al., 1973). As a muscular artery from the forearm, the RA has a prominent medial layer and elevated vasoreactivi‐ ty, which results in a lower patency rate than that of IMA grafts (Possati et al., 2003). The RA is usually harvested from the nondominant arm and is used as a third arterial graft, either as a free or composite graft or to avoid using a venous graft in case of un‐ availability of IMA grafts. The RA is often grafted to supply the left cardiac wall (LCx, OM). On CTA, the caliber of the RA is similar to the IMA, but it typically is visualized coursing from the ascending aorta to the naïve coronary artery (Fig. 7). In the early post‐ operative period, the RA may be reduced in caliber and may be difficult to identify be‐ cause of vasospasm. In addition, because the RA is a muscular artery, the number of surgical clips used to close collaterals along the graft is usually higher than with IMA. This may represent a limit for noninvasive assessment of RA grafts with MDCT because of artifacts from surgical clips limiting a full CTA evaluation of an RA graft.

characteristics of RGEA are similar to IMA, but unclear benefits for third or fourth arterial grafts, the increment of surgery time, and the involvement of an additional body cavity are the main drawbacks limiting the widespread use of this conduit. Occasionally, the RGEA is used to supply the inferior cardiac wall and is anastomosed as an in situ graft to the posteri‐ or descending artery (PDA). In these cases, the mobilized artery is seen coursing anterior to the liver and through the diaphragm to reach the site of anastomosis. Small clips can be identified at the original site of the RGEA, near the small curvature of stomach. These in‐ stances require that the surgical history be conveyed to the radiologist so the CTA protocol can be modified to include the upper abdomen, because the gastroepiploic artery is freed to course anteriorly to the liver and through the diaphragm to reach the target vessel. The infe‐ rior epigastric artery (IEA) is an arterial branch of the abdominal wall, arising from the ex‐ ternal iliac artery and coursing inside the abdominal rectus muscle. Similar to the radial artery (RA), the IEA has a predominant muscular structure, while the limited length of the vessel with an adequate caliber is a constraint to using this vessel only as a lateral branch of

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Bypass graft failures are classified either as early or late following CABG surgery. Dur‐ ing the early phase, usually within 1 month after CABG surgery, the most common cause of graft failure is thrombosis from platelet dysfunction at the site of focal endo‐ thelial damage during surgical harvesting and anastomosis. Graft closure from thrombo‐ sis at 1 month is a recognized complication in 10-15% of cases (Fitzgibbon et al., 1996). Perioperative venous graft failure after off-pump CABG procedures is chiefly deter‐ mined by the two factors of graft endothelial damage and patient hypercoagulability. Early bypass graft failure can also be due to a malpositioned graft (Ricci et al., 2000). If the graft is too long, it may twist or kink. Technical factors associated with use of an aortic connector may predispose venous grafts to kinking (Traverse et al., 2003). Latephase venous graft failure is due primarily to progressive changes related to systemic blood pressure exposure. One month after surgery, the venous graft starts to undergo neointimal hyperplasia. Although this process does not produce significant stenosis, it is the foundation for later development of graft atheroma. Beyond 1 year, atherosclerosis is the dominant process, resulting in graft stenosis and occlusion. On the other hand, arterial grafts, specifically IMA graft, are resistant to atheroma development. Late IMA graft failure is more commonly due to progression of atherosclerotic disease in the na‐ tive coronary artery distal to the graft anastomosis. CTA can delineate multiple findings associated with graft stenosis and occlusion. Calcifiedand noncalcified atherosclerotic plaque is readily identified, and the calculation of the extent of graft narrowing is straightforward. Occlusion can be determined by non-visualization of a vessel which is known to have been used for surgical grafting. In many instances, the most proximal part of an occluded aortocoronary graft fills with contrast, creating a small out-pouch‐ ing from the ascending aorta, allowing a diagnosis. Acute or chronic graft occlusion can

a multiple arterial graft.

**4.3. Complication**

*4.3.1. Graft failure*

**Figure 7.** Radial artery (RA) graft. (A) Three-dimensional volume-rendered image shows radial artery graft sutured to the anterior aorta with its anastomosis with diagonal artery. There are also left internal mammary artery (LIMA) graft from its origin at the left subclavian artery to its anastomosis with the left anterior descending (LAD) artery and right saphenous vein graft (SVG), which is attached to the distal right coronary artery (RCA). Note the diameter of the RA is similar to the IMA, but it typically is visualized coursing from the ascending aorta to the diagonal artery. (B) Curved multiplanar reformation image shows patent RA graft within the anterior mediastinum. The full extent of the graft is seen from the ascending aorta to diagonal artery.

#### *4.2.6. Right gastroepiploic artery (RGEA) and inferior epigastric artery (IEA)*

The use of right gastroepiploic and inferior epigastric arteries in CABG procedures has been limited because of the need to extend the median sternotomy to expose the abdominal cavi‐ ty (Buche et al., 1992; Manapat et al., 1994; Pym et al., 1987). Although the use of these arter‐ ies increases surgical time and technical difficulty of the surgery, these arteries can be used as a free graft to perform total arterial revascularization. The use of the RGEA was first de‐ scribed by Pym et al in June 1984 (Pym et al., 1987). Although it has been originally used in reoperation, in the absence of other suitable conduits, RGEA is now used as secondary, terti‐ ary, or quaternary arterial conduit to provide all-arterial revascularization. The biological characteristics of RGEA are similar to IMA, but unclear benefits for third or fourth arterial grafts, the increment of surgery time, and the involvement of an additional body cavity are the main drawbacks limiting the widespread use of this conduit. Occasionally, the RGEA is used to supply the inferior cardiac wall and is anastomosed as an in situ graft to the posteri‐ or descending artery (PDA). In these cases, the mobilized artery is seen coursing anterior to the liver and through the diaphragm to reach the site of anastomosis. Small clips can be identified at the original site of the RGEA, near the small curvature of stomach. These in‐ stances require that the surgical history be conveyed to the radiologist so the CTA protocol can be modified to include the upper abdomen, because the gastroepiploic artery is freed to course anteriorly to the liver and through the diaphragm to reach the target vessel. The infe‐ rior epigastric artery (IEA) is an arterial branch of the abdominal wall, arising from the ex‐ ternal iliac artery and coursing inside the abdominal rectus muscle. Similar to the radial artery (RA), the IEA has a predominant muscular structure, while the limited length of the vessel with an adequate caliber is a constraint to using this vessel only as a lateral branch of a multiple arterial graft.

#### **4.3. Complication**

artery from the forearm, the RA has a prominent medial layer and elevated vasoreactivi‐ ty, which results in a lower patency rate than that of IMA grafts (Possati et al., 2003). The RA is usually harvested from the nondominant arm and is used as a third arterial graft, either as a free or composite graft or to avoid using a venous graft in case of un‐ availability of IMA grafts. The RA is often grafted to supply the left cardiac wall (LCx, OM). On CTA, the caliber of the RA is similar to the IMA, but it typically is visualized coursing from the ascending aorta to the naïve coronary artery (Fig. 7). In the early post‐ operative period, the RA may be reduced in caliber and may be difficult to identify be‐ cause of vasospasm. In addition, because the RA is a muscular artery, the number of surgical clips used to close collaterals along the graft is usually higher than with IMA. This may represent a limit for noninvasive assessment of RA grafts with MDCT because

174 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

of artifacts from surgical clips limiting a full CTA evaluation of an RA graft.

**Figure 7.** Radial artery (RA) graft. (A) Three-dimensional volume-rendered image shows radial artery graft sutured to the anterior aorta with its anastomosis with diagonal artery. There are also left internal mammary artery (LIMA) graft from its origin at the left subclavian artery to its anastomosis with the left anterior descending (LAD) artery and right saphenous vein graft (SVG), which is attached to the distal right coronary artery (RCA). Note the diameter of the RA is similar to the IMA, but it typically is visualized coursing from the ascending aorta to the diagonal artery. (B) Curved multiplanar reformation image shows patent RA graft within the anterior mediastinum. The full extent of the graft is

The use of right gastroepiploic and inferior epigastric arteries in CABG procedures has been limited because of the need to extend the median sternotomy to expose the abdominal cavi‐ ty (Buche et al., 1992; Manapat et al., 1994; Pym et al., 1987). Although the use of these arter‐ ies increases surgical time and technical difficulty of the surgery, these arteries can be used as a free graft to perform total arterial revascularization. The use of the RGEA was first de‐ scribed by Pym et al in June 1984 (Pym et al., 1987). Although it has been originally used in reoperation, in the absence of other suitable conduits, RGEA is now used as secondary, terti‐ ary, or quaternary arterial conduit to provide all-arterial revascularization. The biological

*4.2.6. Right gastroepiploic artery (RGEA) and inferior epigastric artery (IEA)*

seen from the ascending aorta to diagonal artery.

#### *4.3.1. Graft failure*

Bypass graft failures are classified either as early or late following CABG surgery. Dur‐ ing the early phase, usually within 1 month after CABG surgery, the most common cause of graft failure is thrombosis from platelet dysfunction at the site of focal endo‐ thelial damage during surgical harvesting and anastomosis. Graft closure from thrombo‐ sis at 1 month is a recognized complication in 10-15% of cases (Fitzgibbon et al., 1996). Perioperative venous graft failure after off-pump CABG procedures is chiefly deter‐ mined by the two factors of graft endothelial damage and patient hypercoagulability. Early bypass graft failure can also be due to a malpositioned graft (Ricci et al., 2000). If the graft is too long, it may twist or kink. Technical factors associated with use of an aortic connector may predispose venous grafts to kinking (Traverse et al., 2003). Latephase venous graft failure is due primarily to progressive changes related to systemic blood pressure exposure. One month after surgery, the venous graft starts to undergo neointimal hyperplasia. Although this process does not produce significant stenosis, it is the foundation for later development of graft atheroma. Beyond 1 year, atherosclerosis is the dominant process, resulting in graft stenosis and occlusion. On the other hand, arterial grafts, specifically IMA graft, are resistant to atheroma development. Late IMA graft failure is more commonly due to progression of atherosclerotic disease in the na‐ tive coronary artery distal to the graft anastomosis. CTA can delineate multiple findings associated with graft stenosis and occlusion. Calcifiedand noncalcified atherosclerotic plaque is readily identified, and the calculation of the extent of graft narrowing is straightforward. Occlusion can be determined by non-visualization of a vessel which is known to have been used for surgical grafting. In many instances, the most proximal part of an occluded aortocoronary graft fills with contrast, creating a small out-pouch‐ ing from the ascending aorta, allowing a diagnosis. Acute or chronic graft occlusion can sometimes be differentiated by the diameter of the bypass graft. In chronic occlusion, the diameter is usually reduced from scarring, as compared with acute occlusion in which the diameter is usually enlarged.

*4.3.5. Sternal infection*

*4.3.6. Pulmonary embolism*

*4.3.7. Incidental findings*

these cases identified clinically (Shammas, 2000).

The sternal infection is an important complication of the CABG surgery, with a prevalence of 1% to 20% (Roy, 1998). Three different compartments may be affected: the presternal (cel‐ lulitis, sinus tracts, and abscess), sternal (osteomyelitis, and dehiscence), or retrosternal (me‐ diastinitis, hematoma, and abscess) compartments (Li & Fishman, 2003). Risk factors include diabetes mellitus, obesity, current cigarette smoking, and steroid therapy. Surgical risk fac‐ tors include complexity of surgery, type of bone saw used, type of sternal closure, length of surgical time, blood transfusions, and early reexploration to control hemorrhage. The CTA is important in revealing the extent and depth of infection, which, in turn, will help guide treatment planning. Usually, the preservation of mediastinalfat planes in CTA excludes sur‐ gical intervention. On the other hand, obliteration of mediastinalfat planes and diffuse soft tissue infiltration without or with gas collection, or low-density fluid collections within the mediastinum, are concerning for sternal infection. Recently published studies reported a 1-

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Clinical diagnosis of deep vein thrombosis and pulmonary embolism may be especially challenging because postoperative atelectasis, pleural effusion, or fluid overload may all contribute to the development of chest pain and dyspnea after CABG surgery. A recent re‐ port regarding pulmonary embolism in the post-CABG surgery population showed an over‐ all prevalence of 23% for deep vein thrombosis by 1 week after surgery, with less than 2% of

Although the intent of CTA after CABG surgery is to assess bypass graft patency and surgi‐ cal complications, incidental findings are also frequently detected. In a recent study, 13.1% of patients in the immediate postoperative period had unsuspected noncardiac findings, in‐ cluding pulmonary embolism, pulmonary nodules, pneumonia, mucous plugging, and pneumothorax. (Mueller et al., 2007) Therefore, radiologists need to be aware of clinically

Despite image-degrading effects caused by the metallic scaffold of the stent, recent experi‐ ence with the current generation of 64-section scanners suggests improved assessability of the in-stent lumen with the capability to appreciate more subtle degrees of in-stent neointi‐ mal hyperplasia. Knowledge of the different types of artifacts and how they can be compen‐ sated for with dedicated postprocessing and appropriate image views and window settings is a prerequisite for reliable depiction of the in-stent lumen and leads to a more robust appli‐ cation of CT findings. In future, the development of biodegradable stents may create opti‐ mal conditions for noninvasive post-implantation follow-up with MDCT. In recent years, MDCT with retrospective ECG gating has gained rapid acceptance as a diagnostic cardiac imaging modality, allowing assessment of coronary bypass graft patency with high spatial resolution. This tool could play an important role in patients with recurrence of chest pain

significant findings with possible life-threatening consequences. 5. Conclusions

year mortality rate of approximately 22% (Loop et al., 1986; Sarr et al., 1984).

#### *4.3.2. Graft vasospasm*

Radial artery (RA) grafts are susceptible to vasospasm because the RA is a muscular artery with elevated vasoreactivity. The appearance is similar to fixed graft stenosis, although the luminal narrowing is more extensive in length. Nevertheless, the administration of intrao‐ perative alpha-adrenergic antagonist solution or posteroperative calcium channel blockers can overcome many cases of graft vasospasm postoperatively (Locker et al., 2002; Myers & Fremes, 2003).

#### *4.3.3. Graft aneurysm*

There are 2 types of bypass graft aneurysms: true aneurysms and pseudoaneurysms (Dubois & Vandervoort, 2001; Mohara et al., 1998). True aneuryms are usually found 5 to 7 years af‐ ter CABG surgery and are related to atherosclerotic disease. On the other hand, pseudoa‐ neuryms more commonly occur within 6 months after surgery, although they may also arise several years later. Pseudoaneurysms arise at either proximal or distal anastomotic sites. Pseudoaneurysm cases that are found earlier may be related to infection or tension at the anastomotic site, resulting in suture rupture. In late-onset pseudoaneurysms, similar to true aneurysms, atherosclerotic changes likely played a role. Currently, there is no clear guide‐ line for surgery. Nevertheless, size >2 cm has been a cause for concern (Memon et al., 2003). Graft aneurysms may lead to various complications, including compression and mass effect on adjacent structures, thrombosis and embolization of the bypass graft leading to an acute coronary event, formation of fistula to the right atrium and ventricle, sudden rupture lead‐ ing to hemothorax, hemopericardium, or death.

#### *4.3.4. Pericardialand pleuraleffusions*

Approximately 22%-85% of patients have postoperative pericardial effusions after CABG surgery (Meurin et al., 2004; Pepi et al., 1994). Although pericardial effusions are common, only 0.8%-6% of patients progress to cardiac temponade (Katara et al., 2003). Risk factors in‐ clude postoperative coagulation abnormality or use of anticoagulation agents that are often related to the use of cardiopulmonary bypass. Nearly all significant pericardial effusions are diagnosed within 5 days postoperatively, peak in 10 days, and resolve within a month (Ku‐ vin et al., 2002). Postoperative pleural effusions are even more numerous after surgery, a prevalence of 89% within 7 days after surgery (Hurlbut et al., 1990; Vargas et al., 1994). These pleural effusions are usually unilateral, small, left-sided, and without clinical signifi‐ cance. Only 1%-4% of CABG surgery patients proceed to develop clinically significant effu‐ sions that require thoracentesis (Peng et al., 1992).

#### *4.3.5. Sternal infection*

sometimes be differentiated by the diameter of the bypass graft. In chronic occlusion, the diameter is usually reduced from scarring, as compared with acute occlusion in

176 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Radial artery (RA) grafts are susceptible to vasospasm because the RA is a muscular artery with elevated vasoreactivity. The appearance is similar to fixed graft stenosis, although the luminal narrowing is more extensive in length. Nevertheless, the administration of intrao‐ perative alpha-adrenergic antagonist solution or posteroperative calcium channel blockers can overcome many cases of graft vasospasm postoperatively (Locker et al., 2002; Myers &

There are 2 types of bypass graft aneurysms: true aneurysms and pseudoaneurysms (Dubois & Vandervoort, 2001; Mohara et al., 1998). True aneuryms are usually found 5 to 7 years af‐ ter CABG surgery and are related to atherosclerotic disease. On the other hand, pseudoa‐ neuryms more commonly occur within 6 months after surgery, although they may also arise several years later. Pseudoaneurysms arise at either proximal or distal anastomotic sites. Pseudoaneurysm cases that are found earlier may be related to infection or tension at the anastomotic site, resulting in suture rupture. In late-onset pseudoaneurysms, similar to true aneurysms, atherosclerotic changes likely played a role. Currently, there is no clear guide‐ line for surgery. Nevertheless, size >2 cm has been a cause for concern (Memon et al., 2003). Graft aneurysms may lead to various complications, including compression and mass effect on adjacent structures, thrombosis and embolization of the bypass graft leading to an acute coronary event, formation of fistula to the right atrium and ventricle, sudden rupture lead‐

Approximately 22%-85% of patients have postoperative pericardial effusions after CABG surgery (Meurin et al., 2004; Pepi et al., 1994). Although pericardial effusions are common, only 0.8%-6% of patients progress to cardiac temponade (Katara et al., 2003). Risk factors in‐ clude postoperative coagulation abnormality or use of anticoagulation agents that are often related to the use of cardiopulmonary bypass. Nearly all significant pericardial effusions are diagnosed within 5 days postoperatively, peak in 10 days, and resolve within a month (Ku‐ vin et al., 2002). Postoperative pleural effusions are even more numerous after surgery, a prevalence of 89% within 7 days after surgery (Hurlbut et al., 1990; Vargas et al., 1994). These pleural effusions are usually unilateral, small, left-sided, and without clinical signifi‐ cance. Only 1%-4% of CABG surgery patients proceed to develop clinically significant effu‐

which the diameter is usually enlarged.

ing to hemothorax, hemopericardium, or death.

sions that require thoracentesis (Peng et al., 1992).

*4.3.4. Pericardialand pleuraleffusions*

*4.3.2. Graft vasospasm*

Fremes, 2003).

*4.3.3. Graft aneurysm*

The sternal infection is an important complication of the CABG surgery, with a prevalence of 1% to 20% (Roy, 1998). Three different compartments may be affected: the presternal (cel‐ lulitis, sinus tracts, and abscess), sternal (osteomyelitis, and dehiscence), or retrosternal (me‐ diastinitis, hematoma, and abscess) compartments (Li & Fishman, 2003). Risk factors include diabetes mellitus, obesity, current cigarette smoking, and steroid therapy. Surgical risk fac‐ tors include complexity of surgery, type of bone saw used, type of sternal closure, length of surgical time, blood transfusions, and early reexploration to control hemorrhage. The CTA is important in revealing the extent and depth of infection, which, in turn, will help guide treatment planning. Usually, the preservation of mediastinalfat planes in CTA excludes sur‐ gical intervention. On the other hand, obliteration of mediastinalfat planes and diffuse soft tissue infiltration without or with gas collection, or low-density fluid collections within the mediastinum, are concerning for sternal infection. Recently published studies reported a 1 year mortality rate of approximately 22% (Loop et al., 1986; Sarr et al., 1984).

#### *4.3.6. Pulmonary embolism*

Clinical diagnosis of deep vein thrombosis and pulmonary embolism may be especially challenging because postoperative atelectasis, pleural effusion, or fluid overload may all contribute to the development of chest pain and dyspnea after CABG surgery. A recent re‐ port regarding pulmonary embolism in the post-CABG surgery population showed an over‐ all prevalence of 23% for deep vein thrombosis by 1 week after surgery, with less than 2% of these cases identified clinically (Shammas, 2000).

#### *4.3.7. Incidental findings*

Although the intent of CTA after CABG surgery is to assess bypass graft patency and surgi‐ cal complications, incidental findings are also frequently detected. In a recent study, 13.1% of patients in the immediate postoperative period had unsuspected noncardiac findings, in‐ cluding pulmonary embolism, pulmonary nodules, pneumonia, mucous plugging, and pneumothorax. (Mueller et al., 2007) Therefore, radiologists need to be aware of clinically significant findings with possible life-threatening consequences. 5. Conclusions

Despite image-degrading effects caused by the metallic scaffold of the stent, recent experi‐ ence with the current generation of 64-section scanners suggests improved assessability of the in-stent lumen with the capability to appreciate more subtle degrees of in-stent neointi‐ mal hyperplasia. Knowledge of the different types of artifacts and how they can be compen‐ sated for with dedicated postprocessing and appropriate image views and window settings is a prerequisite for reliable depiction of the in-stent lumen and leads to a more robust appli‐ cation of CT findings. In future, the development of biodegradable stents may create opti‐ mal conditions for noninvasive post-implantation follow-up with MDCT. In recent years, MDCT with retrospective ECG gating has gained rapid acceptance as a diagnostic cardiac imaging modality, allowing assessment of coronary bypass graft patency with high spatial resolution. This tool could play an important role in patients with recurrence of chest pain or with unclear stress test results after myocardial revascularization surgery. Therefore, it is crucial that cardiologists and radiologists understand CABG anatomy with knowledge of the type and number of bypass grafts used during myocardial revascularization surgery.

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#### Bong Gun Song

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0003-4975

0938-7994

0160-9289

1816-5370

1906-1911, ISSN 1552-6259

ISSN 1522-1946

(Sep 2004), pp. 1224-1229, ISSN 0735-1097


**Chapter 9**

**A Noninvasive Alternative to Coronary Angiography:**

**[Background]** Segmental left ventricular (LV) wall systolic dysfunction has been considered a significant sign of coronary artery disease (CAD) for many years. However, it is well known that many heart diseases besides CAD cause abnormal LV wall motion. Therefore, it is essential to verify that segmental LV wall systolic dysfunction is due to myocardial ische‐ mia. Although coronary angiography is typically used to determine the clinical significance of CAD, it is also possible to visualize areas of ischemic myocardium noninvasively by echo‐ cardiography using microbubble contrast agents. Perfluorobutane microbubbles, consisting of a hydrogenated egg-phosphatidylserine shell encapsulating perfluorobutane gas, offers the advantage of resistance to destruction by ultrasound, thus enabling repeated scans per

**[Methods]** We used phase-inversion harmonic ultrasonography to assess the ability of per‐ fluorobutane microbubbles to detect ischemic myocardial areas due to coronary artery stenosis in 66 patients who had undergone coronary angiography (CAG). Abnormal LV wall motion was detected by longitudinal strain before CAG. Pre and post-injection images

**[Results]** The injection of perfluorobutane microbubbles caused a significant change in in‐ tensity in the left ventricular wall in the AP and SAX views in segments perfused by normal coronary arteries (p<0.0001), but not in segments perfused by arteries with significant (≥ 75%) stenosis. Receiver operating characteristic curve analysis showed that an intensity dif‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Kakihara; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

were evaluated from late-diastolic points along the time-intensity curve.

**Myocardial Contrast Echocardiography Following**

**Strain Map as a Gate Way to Myocardial Contrast**

**Echocardiography Map**

Additional information is available at the end of the chapter

Ri-ichiro Kakihara

**1. Introduction**

injection.

http://dx.doi.org/10.5772/45953

## **A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map as a Gate Way to Myocardial Contrast Echocardiography Map**

## Ri-ichiro Kakihara

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/45953

## **1. Introduction**

**[Background]** Segmental left ventricular (LV) wall systolic dysfunction has been considered a significant sign of coronary artery disease (CAD) for many years. However, it is well known that many heart diseases besides CAD cause abnormal LV wall motion. Therefore, it is essential to verify that segmental LV wall systolic dysfunction is due to myocardial ische‐ mia. Although coronary angiography is typically used to determine the clinical significance of CAD, it is also possible to visualize areas of ischemic myocardium noninvasively by echo‐ cardiography using microbubble contrast agents. Perfluorobutane microbubbles, consisting of a hydrogenated egg-phosphatidylserine shell encapsulating perfluorobutane gas, offers the advantage of resistance to destruction by ultrasound, thus enabling repeated scans per injection.

**[Methods]** We used phase-inversion harmonic ultrasonography to assess the ability of per‐ fluorobutane microbubbles to detect ischemic myocardial areas due to coronary artery stenosis in 66 patients who had undergone coronary angiography (CAG). Abnormal LV wall motion was detected by longitudinal strain before CAG. Pre and post-injection images were evaluated from late-diastolic points along the time-intensity curve.

**[Results]** The injection of perfluorobutane microbubbles caused a significant change in in‐ tensity in the left ventricular wall in the AP and SAX views in segments perfused by normal coronary arteries (p<0.0001), but not in segments perfused by arteries with significant (≥ 75%) stenosis. Receiver operating characteristic curve analysis showed that an intensity dif‐

© 2013 Kakihara; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ference ≤ 6.3 dB in the AP view could detect ≥ 75% stenosis with a sensitivity of 98%, specif‐ icity of 94% and accuracy of 97%. An intensity difference ≤ 5.1 dB in the SAX view could detect ≥ 75% stenosis with a sensitivity of 97%, specificity of 96% and accuracy of 97%.

Because of these findings and our own clinical experience, we have persisted in our studies on perfluorobutane microbubbles for coronary artery disease. However, at the present time, this contrast agent has only been approved for hepatic diseases in Japan [11]. Here, we re‐ port our experience with the use of perfluorobutane microbubbles to perform MCE in 66 pa‐ tients who had undergone coronary angiography. Our data showed that perfluorobutane microbubbles markedly and stably enhance visualization of ischemic myocardial areas due to significant coronary artery stenosis and provided superior images compared with Levov‐

A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map…

http://dx.doi.org/10.5772/45953

189

Sixty-six patients with a history of coronary angiography (CAG) within the last three months were enrolled in this study, and informed consent was obtained. The study was ap‐ proved by the clinic's ethics committee. All procedures were performed in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experi‐ ments involving humans. The following aspects of the consent form were explained to the patients: 1) the advantages, benefits, risks and possible side effects of the procedure to them specifically as well as to patients with coronary artery disease in general, 2) the cost of the procedure according to the regulations of the National Health Service, 3) the approximate time of the procedure, and 4) the clinic staff and specialists that would be present during the procedure. In addition, the approval of the ethics committee required that the procedure be performed by a special team that included the following personnel: Dr. R. Kakihara since he was in charge of the study, the nurses and echocardiographers who had experience with MCE, at least one specialist in the use of SonazoidTM from Daiichi Sankyo Co. Ltd, and a me‐ chanical engineer and a technical specialist to operate the Vivid 7 Ultrasound System. All 24 patients enrolled had ≥ 75% significant coronary artery stenosis (significant stenosis). Among them, single vessel disease was present in 11 patients, double vessel disease in 9 and triple vessel disease in 4. No subject had a history of previous myocardial infarction. The fol‐ lowing patient data were obtained: age, 69.9±11.4 y/o; body weight, 60.5±12.1 kg; body sur‐ face area, 1.61±4.3 m²; blood pressure, 128.6±15.3/ 67.7±9.9 mmHg; heart rate, 65.3±9.0 beats/ min; LVEF (by angiography), 60.5±4.3%; LDL-cholesterol, 125.6±38.1 mg/dl; and triglyceride, 193.1±134.1 mg/dl. Six patients were treated for diabetes mellitus by oral medication and

Phase-inversion harmonic ultrasonography was performed using the Vivid 7 Dimension digital ultrasound system, Version 7.0.3 (General Electric Healthcare, Inc., U.S.A.), and a 1.5/4.0 MHz active-matrix array (AMA) probe. The images were analyzed offline using EchoPAC PC Version 108.1.4. Phase inversion harmonic sonography is two phase-inverted but otherwise identical sonographic pulses are transmitted. Summing the returning echoes

istTM, but with the caveat that imaging parameters require careful optimization.

**3. Materials and Methods**

their average HbA1c was 6.3±1.5%.

**3.2. Instrumentation**

**3.1. Patients**

**[Conclusions]** These data indicate that when optimal signal intensity difference parameters have been accurately defined, perfluorobutane microbubbles can be used safely for highly sensitive, specific and accurate visualization of ischemic myocardial areas due to coronary artery stenosis.

### **2. Background**

The ability to prevent, diagnosis and treat cardiac disease has improved over the last two decades due to the remarkable and seemingly exponential advances in imaging technology [1,2,3,4 ]. Ironically, the surprising increases in computing power and software design now at the physician's disposal have been greatly enhanced by the advent of a relatively uncom‐ plicated and a readily-synthesized molecule, the microbubble. Perfluorobutane microbub‐ bles consist of a macromolecular shell encapsulating a high molecular weight gas [5] and are typically 1 to 10 μ in diameter. Their small size allows them to be introduced safely into the circulatory system where they enhance ultrasonic wave scattering by blood, thereby provid‐ ing higher contrast to ultrasound images of the left ventricular myocardial wall. Ultrascan‐ ners operating at frequencies < 15 MHz oscillate the microbubbles, which results in increased echo contrast. The vibrating microbubbles also emit harmonic signals that can preferentially enhance the signal-to-noise ratio. In addition to their diagnostic advantages, microbubbles also avoid the use of radiation and are generally more economical to use. Mi‐ crobubble ultrasound technology has been used to image other organs besides the heart (liv‐ er, pancreas, breast and kidney, in particular), and can be used to target drug-delivery vehicles to different organs [6]. Basic biomedical researchers are also benefitting from micro‐ bubble reagents for delivering macromolecules, such as plasmid DNAs, into cells [7].

Two microbubble contrast agents for cardiac echocardiography, OPTISON™ and Defini‐ ty™, are approved for use in the United States, SonoVue™ is approved in Europe and Chi‐ na, and Levovist in Japan. But OPTISON™ and Definity™ are used for opacification of the left ventricular cavity and endocardial border definition only. Levovist is used for myocar‐ dial contrast echocardiography (MCE). Safety problems occurred initially with each agent, but continuing clinical studies overwhelmingly indicated their efficacy and safety [8,9]. More recently, contrast-enhanced ultrasound (CEUS) has been found safe for pediatric use in subjects as young as two years old [10]. Furthermore, at the recent *16th European Symposi‐ um on Ultrasound Contrast Imaging in Rotterdam*, Porter (USA) presented highly compelling evidence that CEUS improved the prediction of patient outcomes when compared with nu‐ clear imaging or non-contrast ultrasound. He also pointed out that contrast imaging avoids subjecting patients to the ionizing radiation inherent in nuclear techniques and suggested that there was significant underutilization of CEUS.

Because of these findings and our own clinical experience, we have persisted in our studies on perfluorobutane microbubbles for coronary artery disease. However, at the present time, this contrast agent has only been approved for hepatic diseases in Japan [11]. Here, we re‐ port our experience with the use of perfluorobutane microbubbles to perform MCE in 66 pa‐ tients who had undergone coronary angiography. Our data showed that perfluorobutane microbubbles markedly and stably enhance visualization of ischemic myocardial areas due to significant coronary artery stenosis and provided superior images compared with Levov‐ istTM, but with the caveat that imaging parameters require careful optimization.

## **3. Materials and Methods**

#### **3.1. Patients**

ference ≤ 6.3 dB in the AP view could detect ≥ 75% stenosis with a sensitivity of 98%, specif‐ icity of 94% and accuracy of 97%. An intensity difference ≤ 5.1 dB in the SAX view could detect ≥ 75% stenosis with a sensitivity of 97%, specificity of 96% and accuracy of 97%.

188 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**[Conclusions]** These data indicate that when optimal signal intensity difference parameters have been accurately defined, perfluorobutane microbubbles can be used safely for highly sensitive, specific and accurate visualization of ischemic myocardial areas due to coronary

The ability to prevent, diagnosis and treat cardiac disease has improved over the last two decades due to the remarkable and seemingly exponential advances in imaging technology [1,2,3,4 ]. Ironically, the surprising increases in computing power and software design now at the physician's disposal have been greatly enhanced by the advent of a relatively uncom‐ plicated and a readily-synthesized molecule, the microbubble. Perfluorobutane microbub‐ bles consist of a macromolecular shell encapsulating a high molecular weight gas [5] and are typically 1 to 10 μ in diameter. Their small size allows them to be introduced safely into the circulatory system where they enhance ultrasonic wave scattering by blood, thereby provid‐ ing higher contrast to ultrasound images of the left ventricular myocardial wall. Ultrascan‐ ners operating at frequencies < 15 MHz oscillate the microbubbles, which results in increased echo contrast. The vibrating microbubbles also emit harmonic signals that can preferentially enhance the signal-to-noise ratio. In addition to their diagnostic advantages, microbubbles also avoid the use of radiation and are generally more economical to use. Mi‐ crobubble ultrasound technology has been used to image other organs besides the heart (liv‐ er, pancreas, breast and kidney, in particular), and can be used to target drug-delivery vehicles to different organs [6]. Basic biomedical researchers are also benefitting from micro‐

bubble reagents for delivering macromolecules, such as plasmid DNAs, into cells [7].

that there was significant underutilization of CEUS.

Two microbubble contrast agents for cardiac echocardiography, OPTISON™ and Defini‐ ty™, are approved for use in the United States, SonoVue™ is approved in Europe and Chi‐ na, and Levovist in Japan. But OPTISON™ and Definity™ are used for opacification of the left ventricular cavity and endocardial border definition only. Levovist is used for myocar‐ dial contrast echocardiography (MCE). Safety problems occurred initially with each agent, but continuing clinical studies overwhelmingly indicated their efficacy and safety [8,9]. More recently, contrast-enhanced ultrasound (CEUS) has been found safe for pediatric use in subjects as young as two years old [10]. Furthermore, at the recent *16th European Symposi‐ um on Ultrasound Contrast Imaging in Rotterdam*, Porter (USA) presented highly compelling evidence that CEUS improved the prediction of patient outcomes when compared with nu‐ clear imaging or non-contrast ultrasound. He also pointed out that contrast imaging avoids subjecting patients to the ionizing radiation inherent in nuclear techniques and suggested

artery stenosis.

**2. Background**

Sixty-six patients with a history of coronary angiography (CAG) within the last three months were enrolled in this study, and informed consent was obtained. The study was ap‐ proved by the clinic's ethics committee. All procedures were performed in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experi‐ ments involving humans. The following aspects of the consent form were explained to the patients: 1) the advantages, benefits, risks and possible side effects of the procedure to them specifically as well as to patients with coronary artery disease in general, 2) the cost of the procedure according to the regulations of the National Health Service, 3) the approximate time of the procedure, and 4) the clinic staff and specialists that would be present during the procedure. In addition, the approval of the ethics committee required that the procedure be performed by a special team that included the following personnel: Dr. R. Kakihara since he was in charge of the study, the nurses and echocardiographers who had experience with MCE, at least one specialist in the use of SonazoidTM from Daiichi Sankyo Co. Ltd, and a me‐ chanical engineer and a technical specialist to operate the Vivid 7 Ultrasound System. All 24 patients enrolled had ≥ 75% significant coronary artery stenosis (significant stenosis). Among them, single vessel disease was present in 11 patients, double vessel disease in 9 and triple vessel disease in 4. No subject had a history of previous myocardial infarction. The fol‐ lowing patient data were obtained: age, 69.9±11.4 y/o; body weight, 60.5±12.1 kg; body sur‐ face area, 1.61±4.3 m²; blood pressure, 128.6±15.3/ 67.7±9.9 mmHg; heart rate, 65.3±9.0 beats/ min; LVEF (by angiography), 60.5±4.3%; LDL-cholesterol, 125.6±38.1 mg/dl; and triglyceride, 193.1±134.1 mg/dl. Six patients were treated for diabetes mellitus by oral medication and their average HbA1c was 6.3±1.5%.

#### **3.2. Instrumentation**

Phase-inversion harmonic ultrasonography was performed using the Vivid 7 Dimension digital ultrasound system, Version 7.0.3 (General Electric Healthcare, Inc., U.S.A.), and a 1.5/4.0 MHz active-matrix array (AMA) probe. The images were analyzed offline using EchoPAC PC Version 108.1.4. Phase inversion harmonic sonography is two phase-inverted but otherwise identical sonographic pulses are transmitted. Summing the returning echoes in a buffer cancels most of the fundamental and odd harmonic echoes and effectively ampli‐ fies the second harmonic. [12]

these settings. The images were acquired from the time-intensity curve in late diastole just before the P wave. Intensity differences before and after SonazoidTM injection were meas‐ ured at the same site. The intensity data were automatically shown on the upper right part of the screen. We examined 3 AP views (APLAX: mid-anterior septum & mid-posterior seg‐ ment; AP2ch: mid-anterior and mid-inferior segment; AP4ch: mid lateral and mid-septal segments) and mid-papillary muscle level SAX views (mid-anterior, mid-lateral, mid-poste‐ rior, mid-inferior, mid-septal a mid-anterior septal segments). The segments in the 3 AP views that were perfused by coronary arteries with significant stenosis were designated as Group A and the segments in the SAX views were designated as Group B. The segments in the AP views that were perfused by normal or coronary arteries without significant stenosis were designated as Group C and the segments in the SAX views were designated as Group D. We compared the intensities of all four groups before and after Sonazoidinjection using a

A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map…

http://dx.doi.org/10.5772/45953

191

**Figure 2.** Process of making the Sonazoid reconstituted product. The "Chemoprotect spike" is inserted in the vial to keep the pressure in the vial unchanged. Then, 2.5 ml of saline is drawn into the syringe. Then the needle is removed and the syringe is connected to the luer part of the "Chemoprotect spike".Then, 2.5 ml of saline is squeezed into the vial through the "Chemoprotect spike". The solution is shaken for one minute with the syringe attached. The reconsti‐ tuted Sonazoid is gathered once in the syringe, and then returned into the vial. To avoid decompression or pressuriza‐

tion in the syringe and vial, these procedures should be performed slowly.

paired t-test.

#### **3.3. The first step**

A longitudinal peak systolic strain map (LPSSM) has high diagnostic reliability to detect segmental left ventricular wall abnormalities. [13,14] Thus, an LPSSM was created on any patient with coronary artery disease (CAD) risk factors. When the LPSSM showed abnormal left ventricular segmental wall systolic function, myocardial contrast echocardiography (MCE) was done using Sonazoid™ to confirm whether the dysfunction was due to myocar‐ dial ischemia.

#### **3.4. The second step**

**Materials:** Sonazoid™ was obtained from Daiichi Sankyo Co. Ltd. (Tokyo, Japan).

**Figure 1.** Magnified reconstituted Sonazoid solution. A macromolecular shell is encapsulated by a high molecular weight gas. The microbubbles are very weak and are destroyed easily by usual physical pressure and MI (mechanical index). Sonazoid reconstituted in saline for injection of 2.5mL: Volume concentration: 6.9μL MB/mL Particle size: 2.3~2.9μm (median diameter) Involving gas: Perflubutane (C4F10) Membrane element: Hydrogenated egg phospha‐ tidyl serine (sodium) pH: 5.7~7.0 Osmotic pressure ratio: 0.9~1.1

Any remaining Sonazoid should be stored at room temperature and used within 2 hours.

Because SonazoidTM microbubbles are susceptible to destruction by physical pressure, 2.5 ml were injected over at least 20 sec, not less than the systemic circulation time under the stress of low dose ATP (0.15 mg/kg/min of Adenosine 5- Triphosphate Disodium) Figure 1, Figure 2, Figure 3, Figure 4.

**Measurements:** The echocardiographer was blinded to the results of CAG in the patients en‐ rolled. Three apex approach (AP) views and one parasternal short axis (SAX) view were re‐ corded per injection. The instrument settings were as follows: mechanical index (MI), 0.4-0.6 for the AP and 0.22 for the SAX views; frame rate, 21.2; and frequency, 1.5/3.0 MHz. These were selected based on the recommendations of the specialist from Daiichi Sankyo Co. Ltd who had experience with liver imaging. The MI was very low so as not to destroy the micro‐ bubbles but high enough to vibrate them. This vibration energy is necessary to create ultra‐ sonic cardiac images. The images taken were clear and of sufficient quality to be analyzed at these settings. The images were acquired from the time-intensity curve in late diastole just before the P wave. Intensity differences before and after SonazoidTM injection were meas‐ ured at the same site. The intensity data were automatically shown on the upper right part of the screen. We examined 3 AP views (APLAX: mid-anterior septum & mid-posterior seg‐ ment; AP2ch: mid-anterior and mid-inferior segment; AP4ch: mid lateral and mid-septal segments) and mid-papillary muscle level SAX views (mid-anterior, mid-lateral, mid-poste‐ rior, mid-inferior, mid-septal a mid-anterior septal segments). The segments in the 3 AP views that were perfused by coronary arteries with significant stenosis were designated as Group A and the segments in the SAX views were designated as Group B. The segments in the AP views that were perfused by normal or coronary arteries without significant stenosis were designated as Group C and the segments in the SAX views were designated as Group D. We compared the intensities of all four groups before and after Sonazoidinjection using a paired t-test.

in a buffer cancels most of the fundamental and odd harmonic echoes and effectively ampli‐

190 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

A longitudinal peak systolic strain map (LPSSM) has high diagnostic reliability to detect segmental left ventricular wall abnormalities. [13,14] Thus, an LPSSM was created on any patient with coronary artery disease (CAD) risk factors. When the LPSSM showed abnormal left ventricular segmental wall systolic function, myocardial contrast echocardiography (MCE) was done using Sonazoid™ to confirm whether the dysfunction was due to myocar‐

**Materials:** Sonazoid™ was obtained from Daiichi Sankyo Co. Ltd. (Tokyo, Japan).

**Figure 1.** Magnified reconstituted Sonazoid solution. A macromolecular shell is encapsulated by a high molecular weight gas. The microbubbles are very weak and are destroyed easily by usual physical pressure and MI (mechanical index). Sonazoid reconstituted in saline for injection of 2.5mL: Volume concentration: 6.9μL MB/mL Particle size: 2.3~2.9μm (median diameter) Involving gas: Perflubutane (C4F10) Membrane element: Hydrogenated egg phospha‐

Any remaining Sonazoid should be stored at room temperature and used within 2 hours.

Because SonazoidTM microbubbles are susceptible to destruction by physical pressure, 2.5 ml were injected over at least 20 sec, not less than the systemic circulation time under the stress of low dose ATP (0.15 mg/kg/min of Adenosine 5- Triphosphate Disodium) Figure 1, Figure

**Measurements:** The echocardiographer was blinded to the results of CAG in the patients en‐ rolled. Three apex approach (AP) views and one parasternal short axis (SAX) view were re‐ corded per injection. The instrument settings were as follows: mechanical index (MI), 0.4-0.6 for the AP and 0.22 for the SAX views; frame rate, 21.2; and frequency, 1.5/3.0 MHz. These were selected based on the recommendations of the specialist from Daiichi Sankyo Co. Ltd who had experience with liver imaging. The MI was very low so as not to destroy the micro‐ bubbles but high enough to vibrate them. This vibration energy is necessary to create ultra‐ sonic cardiac images. The images taken were clear and of sufficient quality to be analyzed at

tidyl serine (sodium) pH: 5.7~7.0 Osmotic pressure ratio: 0.9~1.1

fies the second harmonic. [12]

**3.3. The first step**

dial ischemia.

**3.4. The second step**

2, Figure 3, Figure 4.

**Figure 2.** Process of making the Sonazoid reconstituted product. The "Chemoprotect spike" is inserted in the vial to keep the pressure in the vial unchanged. Then, 2.5 ml of saline is drawn into the syringe. Then the needle is removed and the syringe is connected to the luer part of the "Chemoprotect spike".Then, 2.5 ml of saline is squeezed into the vial through the "Chemoprotect spike". The solution is shaken for one minute with the syringe attached. The reconsti‐ tuted Sonazoid is gathered once in the syringe, and then returned into the vial. To avoid decompression or pressuriza‐ tion in the syringe and vial, these procedures should be performed slowly.

**Figure 5.** Longitudinal peak systolic strain map. This shows abnormal LV wall motion area, does not show ischemic

A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map…

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193

**Figure 6.** The picture of coronary arteries is superimposed on the strain map. By this method the relation between

**Figure 7.** Sonazoid myocardial contrast echocardiography, APLAX views. The patient #7 (see Figure 3 for CAG images) was examined before and after Sonazoid injection. The instrument was set to MI = 0.4. APLAX views before (A) and after (B) Sonazoid. Intensity curves (C). Yellow, LV cavity; red, posterior wall (LCX area); and blue, interventricular sep‐

area. Therefore coronary artery disease is not diagnosis by this map.

coronary arteries and the area of abnormal LV wall motion is confirmed.

tum (LAD #6 area)

**Figure 3.** Chemoprotect Spike. This reconstituted Sonazoid production adjustment device consists of a main body, a luer portion, filter housing, spike part, built in liquid filter for drug solution filtration, and an air filter for ventilation. a : Cap, b : Luer portion, c : Spike (Main body), d : Protective cap, e : Protective cap, f : Filter housing, Fluid filter, Air filter

**Figure 4.** Method and route of injection of reconstituted Sonazoid. Sonazoid (2.5 ml) was injected slowly over 20 sec‐ onds. After finishing the injection of Sonazoid, saline (approximately 10 ml) was injected to flush the delivery route

A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map… http://dx.doi.org/10.5772/45953 193

**Figure 5.** Longitudinal peak systolic strain map. This shows abnormal LV wall motion area, does not show ischemic area. Therefore coronary artery disease is not diagnosis by this map.

**Figure 3.** Chemoprotect Spike. This reconstituted Sonazoid production adjustment device consists of a main body, a luer portion, filter housing, spike part, built in liquid filter for drug solution filtration, and an air filter for ventilation. a : Cap, b : Luer portion, c : Spike (Main body), d : Protective cap, e : Protective cap, f : Filter housing, Fluid filter, Air filter

192 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Figure 4.** Method and route of injection of reconstituted Sonazoid. Sonazoid (2.5 ml) was injected slowly over 20 sec‐ onds. After finishing the injection of Sonazoid, saline (approximately 10 ml) was injected to flush the delivery route

**Figure 6.** The picture of coronary arteries is superimposed on the strain map. By this method the relation between coronary arteries and the area of abnormal LV wall motion is confirmed.

**Figure 7.** Sonazoid myocardial contrast echocardiography, APLAX views. The patient #7 (see Figure 3 for CAG images) was examined before and after Sonazoid injection. The instrument was set to MI = 0.4. APLAX views before (A) and after (B) Sonazoid. Intensity curves (C). Yellow, LV cavity; red, posterior wall (LCX area); and blue, interventricular sep‐ tum (LAD #6 area)

**Figure 8.** Sonazoid myocardial contrast echocardiography, AP 2-chamber views. The instrument was set to MI = 0.4. AP 2-chamber views before (A) and after (B) Sonazoid injection. Time-intensity curves (C). Yellow, LV cavity; red, inferi‐ or wall (RCA area); and blue, anterior wall (LAD area).

**Figure 10.** Sonazoid myocardial contrast echocardiography, SAX- pm views. The instrument was set to MI = 0.22. SAXpm views before (A) and after (B, C) Sonzaoid injection. Time-intensity curves (D). Yellow, LV cavity; blue, anterior

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195

None of the patients experienced adverse affects of this procedure. Each of the 66 pa‐ tients enrolled in the study had undergone CAG and was diagnosed with significant cor‐ onary artery stenosis. Patients were divided into four groups as described above, and myocardial segments perfused by the stenotic and normal vasculatures were examined by ultrasonography before and after Sonazoid administration. The data for one patient (#7) are presented in Figures 5 through Figure 10. Ultrasound images taken before and after Sonazoid administration are shown in 6 Figures, which represent the strain maps and APLAX, AP2ch, AP4ch and SAX-papillary muscle (pm) views, respectively. Figure 5 and Figure 6 show the longitudinal peak systolic strain map and Figure 6 which is superim‐ posed coronary arteries on the map strongly implys this patient experienced no adverse affect and had LAD single vessel disease. Figure 11 shows an angiogram of the left and right coronary arteries. In the left panel, the angiogram (left coronary artery) clearly re‐ veals left anterior descending coronary artery stenosis obstructing 75% of the vessel's nor‐ mal diameter. Stenotic regions are indicated by the arrows.In contrast, no involvement of

The data from 100 myocardial segments (16 patients) perfused by normal coronary arteries and from 283 myocardial segments (50 patients) perfused by stenotic coronary arteries in 66 patients with coronary artery disease were grouped into A, B, C and D as designated above and are summarized in Tables 1 and Table 2. Specifically, the intensity difference between A-pre-injection (A-pre) and A–post-injection (A-post) was 1.3 ± 3.5 dB; the intensity differ‐ ence between B-pre and B-post was 0.9 ± 3.3 dB. The intensity differences in groups A and B were not significant. For C-pre and C-post, the intensities were -33.4 ± 5.1 dB and -22.3 ± 6.8

wall; red, lateral wall (both are LAD #7 area); orange, posterior wall; green, inferior wall.

the right coronary artery could be discerned.

**Figure 9.** Sonazoid myocardial contrast echocardiography, AP-4 chamber views. The instrument was set to MI = 0.4. AP 4 chamber views before (A) and after (B) Sonazoid injection. Time-intensity curves (C). Yellow, LV cavity; red, inter‐ ventricular septum (LAD #6 area); blue, lateral wall and apex (LAD #7 area).

A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map… http://dx.doi.org/10.5772/45953 195

**Figure 10.** Sonazoid myocardial contrast echocardiography, SAX- pm views. The instrument was set to MI = 0.22. SAXpm views before (A) and after (B, C) Sonzaoid injection. Time-intensity curves (D). Yellow, LV cavity; blue, anterior wall; red, lateral wall (both are LAD #7 area); orange, posterior wall; green, inferior wall.

**Figure 8.** Sonazoid myocardial contrast echocardiography, AP 2-chamber views. The instrument was set to MI = 0.4. AP 2-chamber views before (A) and after (B) Sonazoid injection. Time-intensity curves (C). Yellow, LV cavity; red, inferi‐

194 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Figure 9.** Sonazoid myocardial contrast echocardiography, AP-4 chamber views. The instrument was set to MI = 0.4. AP 4 chamber views before (A) and after (B) Sonazoid injection. Time-intensity curves (C). Yellow, LV cavity; red, inter‐

ventricular septum (LAD #6 area); blue, lateral wall and apex (LAD #7 area).

or wall (RCA area); and blue, anterior wall (LAD area).

None of the patients experienced adverse affects of this procedure. Each of the 66 pa‐ tients enrolled in the study had undergone CAG and was diagnosed with significant cor‐ onary artery stenosis. Patients were divided into four groups as described above, and myocardial segments perfused by the stenotic and normal vasculatures were examined by ultrasonography before and after Sonazoid administration. The data for one patient (#7) are presented in Figures 5 through Figure 10. Ultrasound images taken before and after Sonazoid administration are shown in 6 Figures, which represent the strain maps and APLAX, AP2ch, AP4ch and SAX-papillary muscle (pm) views, respectively. Figure 5 and Figure 6 show the longitudinal peak systolic strain map and Figure 6 which is superim‐ posed coronary arteries on the map strongly implys this patient experienced no adverse affect and had LAD single vessel disease. Figure 11 shows an angiogram of the left and right coronary arteries. In the left panel, the angiogram (left coronary artery) clearly re‐ veals left anterior descending coronary artery stenosis obstructing 75% of the vessel's nor‐ mal diameter. Stenotic regions are indicated by the arrows.In contrast, no involvement of the right coronary artery could be discerned.

The data from 100 myocardial segments (16 patients) perfused by normal coronary arteries and from 283 myocardial segments (50 patients) perfused by stenotic coronary arteries in 66 patients with coronary artery disease were grouped into A, B, C and D as designated above and are summarized in Tables 1 and Table 2. Specifically, the intensity difference between A-pre-injection (A-pre) and A–post-injection (A-post) was 1.3 ± 3.5 dB; the intensity differ‐ ence between B-pre and B-post was 0.9 ± 3.3 dB. The intensity differences in groups A and B were not significant. For C-pre and C-post, the intensities were -33.4 ± 5.1 dB and -22.3 ± 6.8

**View Sensitivity Specificity Accuracy**

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197

AP (Δ ≤ 6.3 dB) 0.98 0.94 0.97 SAXpm (Δ ≤ 5.1 dB) 0.97 0.96 0.97

**Table 2.** Sonazoid's detection parameters for coronary artery stenosis. The optimal dB cut-off vales were selected that gave the highest sensitivity and specificity. By ROC, intensity differences ≤ 6.3 dB in AP views detects ≥ 75% stenosis with a sensitivity: 0.98, specificity: 0.94, accuracy: 0.97. In the SAX view an intensity difference ≤ 5.1 dB detects ≥ 75%

The intraobserver reproducibility was determined by imaging the same patients after a fourweek interval and then calculating Cohen's kappa (κ= 0.76, p < 0.001). To obtain the fourweek interval and then calculating Cohen's kappa (κ= 0.76, p < 0.001). To obtain the interobserver reproducibility, the same images were evaluated by another echocardiogra‐ pher who was employed at a different medical institute and had no knowledge of the proto‐ col. The interobserver reproducibility was excellent (κ= 0.98, p < 0.001). These two results indicate that the reproducibly of Sonazoid MCE is sufficient for the use of this agent in the

Remarkable progress has been made over the last decade in medical imaging of the heart and other organs. However, there is still an enormous worldwide mortality and morbidi‐ ty from coronary artery disease. A major hurdle in overcoming this situation is the inabil‐ ity to make a definite diagnosis of coronary artery stenosis or to screen coronary artery disease easily and inexpensively. Although myocardial ischemia it thought to start from 75% stenosis, patients usually have no symptoms with normal daily activities. When the stenosis is ≥ 90%, patients may become symptomatic with normal daily activities. Present‐ ly, CAG is only one diagnostic method, but it is invasive and expensive. Routine preven‐ tative cardiac imaging that would be safe (no ionizing radiation or allergenic contrast dyes), highly sensitive, specific and economical would obviously help mitigate this ongo‐

Echocardiography is one of the areas in which the most exciting advances have been made, and it is especially attractive because it is becoming progressively more miniaturized and can be used in a typical office setting rather than a dedicated imaging center. Current mo‐ dalities include real-time three-dimensional echocardiography, speckle tracking, contrast

Here, we show that Sonazoid can be successfully used in a local clinical setting and this con‐ trast agent allows the accurate detection of coronary artery stenosis ≥ 75%. This may be ac‐ counted for by Sonazoid's resistance to acoustic pressure and its long half-life compared to other microbubble-based contrast agents [15]. Our patients did not experience adverse ef‐ fects during or after the procedure. This is likely due to Sonazoid's intrinsic nontoxicity, but

echocardiography, intracardiac echocardiography and hand-held echocardiography.

stenosis with a sensitivity: 0.97, specificity: 0.96, accuracy: 0.97.

clinical setting.

**4. Discussion**

ing public health burden.

**Figure 11.** Coronary artery angiography. Left: left coronary artery. Left anterior descending artery had 75% stenosis at #7. Right: Right coronary artery was normal.

dB, respectively; and D-pre and D-post were -36.2 ± 4.8 dB and -22.6 ± 10.7 dB, respectively. The intensity differences in groups C (14.1 ± 5.8 dB) and D (11.5 ± 4.3 dB) were both signifi‐ cant (p < 0.001). By ROC (receiver operating characteristic curve) analysis, intensity differen‐ ces ≤ 6.3 dB in the AP views could detect ≥ 75% stenosis with a sensitivity of 98%, specificity of 94% and accuracy of 97%. An intensity difference ≤ 5.1 dB in the SAX view could detect ≥ 75% stenosis with a sensitivity of 97%, specificity of 96% and accuracy of 97%. These data indicate the sensitivity, specificity and diagnostic accuracy of MCE using Sonazoid to detect ≥ 75% stenosis.


**Table 1.** Intensity differences before and after Sonazoid administration. A-pre-injection (A-pre) and –post-injection (Apost): 1.3 ± 3.5 dB. B-pre and B-post: 0.9 ± 3.3 dB. The intensity differences for each pair were not significantly different. C-pre and C-post: -33.4 ± 5.1 dB and -22.3 ± 6.8 dB; D-pre and D-post: -36.2 ± 4.8 dB and -22.6 ± 10.7 dB. The differences between C (14.1 ± 5.8 dB) and D (11.5 ± 4.3 dB) were judged significant (P < 0.001)

A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map… http://dx.doi.org/10.5772/45953 197


**Table 2.** Sonazoid's detection parameters for coronary artery stenosis. The optimal dB cut-off vales were selected that gave the highest sensitivity and specificity. By ROC, intensity differences ≤ 6.3 dB in AP views detects ≥ 75% stenosis with a sensitivity: 0.98, specificity: 0.94, accuracy: 0.97. In the SAX view an intensity difference ≤ 5.1 dB detects ≥ 75% stenosis with a sensitivity: 0.97, specificity: 0.96, accuracy: 0.97.

The intraobserver reproducibility was determined by imaging the same patients after a fourweek interval and then calculating Cohen's kappa (κ= 0.76, p < 0.001). To obtain the fourweek interval and then calculating Cohen's kappa (κ= 0.76, p < 0.001). To obtain the interobserver reproducibility, the same images were evaluated by another echocardiogra‐ pher who was employed at a different medical institute and had no knowledge of the proto‐ col. The interobserver reproducibility was excellent (κ= 0.98, p < 0.001). These two results indicate that the reproducibly of Sonazoid MCE is sufficient for the use of this agent in the clinical setting.

## **4. Discussion**

dB, respectively; and D-pre and D-post were -36.2 ± 4.8 dB and -22.6 ± 10.7 dB, respectively. The intensity differences in groups C (14.1 ± 5.8 dB) and D (11.5 ± 4.3 dB) were both signifi‐ cant (p < 0.001). By ROC (receiver operating characteristic curve) analysis, intensity differen‐ ces ≤ 6.3 dB in the AP views could detect ≥ 75% stenosis with a sensitivity of 98%, specificity of 94% and accuracy of 97%. An intensity difference ≤ 5.1 dB in the SAX view could detect ≥ 75% stenosis with a sensitivity of 97%, specificity of 96% and accuracy of 97%. These data indicate the sensitivity, specificity and diagnostic accuracy of MCE using Sonazoid to detect

**Figure 11.** Coronary artery angiography. Left: left coronary artery. Left anterior descending artery had 75% stenosis at

196 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Stenotic Groups** Group/View Intensity difference A/AP 1.3 ± 3.5 dB (N.S.) B/SAX 0.9 ± 3.3 dB (N.S) **Normal Groups** Group/View Intensity difference C/AP 14.1 ± 5.8 dB (*P* < .001) D/SAX 11.5 ± 4.3 dB (*P* < .001)

**Table 1.** Intensity differences before and after Sonazoid administration. A-pre-injection (A-pre) and –post-injection (Apost): 1.3 ± 3.5 dB. B-pre and B-post: 0.9 ± 3.3 dB. The intensity differences for each pair were not significantly different. C-pre and C-post: -33.4 ± 5.1 dB and -22.3 ± 6.8 dB; D-pre and D-post: -36.2 ± 4.8 dB and -22.6 ± 10.7 dB. The

differences between C (14.1 ± 5.8 dB) and D (11.5 ± 4.3 dB) were judged significant (P < 0.001)

≥ 75% stenosis.

#7. Right: Right coronary artery was normal.

Remarkable progress has been made over the last decade in medical imaging of the heart and other organs. However, there is still an enormous worldwide mortality and morbidi‐ ty from coronary artery disease. A major hurdle in overcoming this situation is the inabil‐ ity to make a definite diagnosis of coronary artery stenosis or to screen coronary artery disease easily and inexpensively. Although myocardial ischemia it thought to start from 75% stenosis, patients usually have no symptoms with normal daily activities. When the stenosis is ≥ 90%, patients may become symptomatic with normal daily activities. Present‐ ly, CAG is only one diagnostic method, but it is invasive and expensive. Routine preven‐ tative cardiac imaging that would be safe (no ionizing radiation or allergenic contrast dyes), highly sensitive, specific and economical would obviously help mitigate this ongo‐ ing public health burden.

Echocardiography is one of the areas in which the most exciting advances have been made, and it is especially attractive because it is becoming progressively more miniaturized and can be used in a typical office setting rather than a dedicated imaging center. Current mo‐ dalities include real-time three-dimensional echocardiography, speckle tracking, contrast echocardiography, intracardiac echocardiography and hand-held echocardiography.

Here, we show that Sonazoid can be successfully used in a local clinical setting and this con‐ trast agent allows the accurate detection of coronary artery stenosis ≥ 75%. This may be ac‐ counted for by Sonazoid's resistance to acoustic pressure and its long half-life compared to other microbubble-based contrast agents [15]. Our patients did not experience adverse ef‐ fects during or after the procedure. This is likely due to Sonazoid's intrinsic nontoxicity, but also by the rapid metabolism of microbubbles via the respiratory system. We compared our results with those of other studies [16, 17] and found similar accuracy for the detection of significant (≥ 75%) coronary artery stenosis. Thus, our data argue for continued investiga‐ tions into its suitability for MCE and ultimate approval for this purpose, especially in view of the limited number of microbubble-based contrast agents now available to cardiologists. In future studies, it will be of great interest to determine whether Sonazoid is capable of de‐ tecting less significant degrees of stenosis.

### **5. Limitations**

The limitations of this method are the same as the limitations of echocardiography. It is diffi‐ cult to obtain good B-mode images in patients with a thick subcutaneous fatty layer or em‐ physematous lung. The reliability of MCE to detect ischemia is clearly dependent on the quality of the B-mode images. Another limitation is the process of making SonazoidTM since the solution is somewhat complex compared with LevovistTM. In addition, the detection of ischemic myocardial areas requires the ability to make and read time-intensity graphs. However, we learned to overcome these limitations after four or five subjects.

**Figure 12.** The image of myocardial contrast echocardiography map (MCE Map: left) and the time-intensity curve of

A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map…

http://dx.doi.org/10.5772/45953

199

The extent of the ischemic myocardial area surely play a more leading and important role as an index more than the severity of coronary artery stenosis to decide the indication of coro‐

The authors heartedly express our thanks to Mr. Yoshio Oonishi (Daiichi Sankyo Co. Ltd, Tokyo, Japan) who kindly provided us with Figures 1, 2, 3 and 4, and also to Mr Kenichiro Morinaga and Mr. Eiji Aoki (SEIKOTEC Co.,Ltd.) who helped me by drawing coronary ar‐ teries on strain maps (http://seikotec.com/). In addition I deeply appreciate Mr. Hisashi Kou‐

[1] Chelliah RK, Senior R. Contrast echocardiography: an update. Curr Cardiol Rep.

the MCE of the patient by MCE MAP.

nary artery intervention.

**Acknowledgements**

**Author details**

Ri-ichiro Kakihara

**References**

2009; 11(3) 216-224.

myou's personal advice to edit this thesis.

Address all correspondence to: ri-ichiro.k@adagio.ocn.ne.jp

Department of Cardiology, Private Kakihara Clinic, Toyohashi, Japan

#### **6. Conclusions**

This study showed that SonazoidTM has good clinical utility and better diagnostic accuracy to detect significant coronary artery stenosis than other contrast agents. This is because the concentration of SonazoidTM in circulating blood is more stable, and the agent has a longer half-life than other contrast agents.

Comparisons between myocardial regions of affected and normal arteries in these patients before and after SonazoidTM administration under low-dose ATP stress showed that MCE could detect ≥75% stenosis with a sensitivity of 97%, specificity of 96% and accuracy of 97%. An important factor in achieving these results was the optimization of the MI settings. We believe that these data, taken together with patients not experiencing adverse effects during or after the procedure, provide a compelling argument for extending these studies, with the ultimate goal of providing cardiologists a powerful new tool for routine echocardiography.

The ability of this MCE method to identify various degrees of coronary artery stenosis needs to be confirmed in larger, randomized trials. Although conventional echocardiography can‐ not detect the extent of myocardial tissue ischemia due to coronary artery stenosis, it can de‐ tect LV wall systolic dysfunction due to myocardial ischemia by strain mapping. By applying these two methods, we could develop a new and more accurate diagnostic meth‐ od. The creation of an MCE map along with a strain map might be used to directly diagnose the severity of coronary artery stenosis and extent of the ischemic myocardial area.

A Noninvasive Alternative to Coronary Angiography: Myocardial Contrast Echocardiography Following Strain Map… http://dx.doi.org/10.5772/45953 199

**Figure 12.** The image of myocardial contrast echocardiography map (MCE Map: left) and the time-intensity curve of the MCE of the patient by MCE MAP.

The extent of the ischemic myocardial area surely play a more leading and important role as an index more than the severity of coronary artery stenosis to decide the indication of coro‐ nary artery intervention.

## **Acknowledgements**

also by the rapid metabolism of microbubbles via the respiratory system. We compared our results with those of other studies [16, 17] and found similar accuracy for the detection of significant (≥ 75%) coronary artery stenosis. Thus, our data argue for continued investiga‐ tions into its suitability for MCE and ultimate approval for this purpose, especially in view of the limited number of microbubble-based contrast agents now available to cardiologists. In future studies, it will be of great interest to determine whether Sonazoid is capable of de‐

198 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The limitations of this method are the same as the limitations of echocardiography. It is diffi‐ cult to obtain good B-mode images in patients with a thick subcutaneous fatty layer or em‐ physematous lung. The reliability of MCE to detect ischemia is clearly dependent on the quality of the B-mode images. Another limitation is the process of making SonazoidTM since the solution is somewhat complex compared with LevovistTM. In addition, the detection of ischemic myocardial areas requires the ability to make and read time-intensity graphs.

This study showed that SonazoidTM has good clinical utility and better diagnostic accuracy to detect significant coronary artery stenosis than other contrast agents. This is because the concentration of SonazoidTM in circulating blood is more stable, and the agent has a longer

Comparisons between myocardial regions of affected and normal arteries in these patients before and after SonazoidTM administration under low-dose ATP stress showed that MCE could detect ≥75% stenosis with a sensitivity of 97%, specificity of 96% and accuracy of 97%. An important factor in achieving these results was the optimization of the MI settings. We believe that these data, taken together with patients not experiencing adverse effects during or after the procedure, provide a compelling argument for extending these studies, with the ultimate goal of providing cardiologists a powerful new tool for routine echocardiography.

The ability of this MCE method to identify various degrees of coronary artery stenosis needs to be confirmed in larger, randomized trials. Although conventional echocardiography can‐ not detect the extent of myocardial tissue ischemia due to coronary artery stenosis, it can de‐ tect LV wall systolic dysfunction due to myocardial ischemia by strain mapping. By applying these two methods, we could develop a new and more accurate diagnostic meth‐ od. The creation of an MCE map along with a strain map might be used to directly diagnose

the severity of coronary artery stenosis and extent of the ischemic myocardial area.

However, we learned to overcome these limitations after four or five subjects.

tecting less significant degrees of stenosis.

**5. Limitations**

**6. Conclusions**

half-life than other contrast agents.

The authors heartedly express our thanks to Mr. Yoshio Oonishi (Daiichi Sankyo Co. Ltd, Tokyo, Japan) who kindly provided us with Figures 1, 2, 3 and 4, and also to Mr Kenichiro Morinaga and Mr. Eiji Aoki (SEIKOTEC Co.,Ltd.) who helped me by drawing coronary ar‐ teries on strain maps (http://seikotec.com/). In addition I deeply appreciate Mr. Hisashi Kou‐ myou's personal advice to edit this thesis.

## **Author details**

Ri-ichiro Kakihara

Address all correspondence to: ri-ichiro.k@adagio.ocn.ne.jp

Department of Cardiology, Private Kakihara Clinic, Toyohashi, Japan

## **References**

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[17] Binder T, Assayag P, Baer F, Flachskampf F, Kamp O, Nienaber C, Nihoyannopoulos P, Piérard L, Steg G, Vanoverschelde JL, Van der Wouw P, Meland N, Marelli C, Lindvall K. NC100100, a new echo contrast agent for the assessment of myocardial perfusion--safety and comparison with technetium-99m sestamibi single-photon emission computed tomography in a randomized multicenter study. Clin Cardiol.

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[2] Platts D, West C, Boga T, Hamilton-Craig C, Burstow D. Direct visualization of septal perforator coronary arterial blood flow during perflutren microsphere contrast echo‐

[3] Cheng AS, Pegg TJ, Karamitsos TD, Searle N, Jerosch-Herold M, Choudhury RP, Banning AP, Neubauer S, Robson MD, Selvanayagam JB. Cardiovascular magnetic resonance perfusion imaging at 3-tesla for the detection of coronary artery disease: a

[4] Schwarz F, Ruzsics B, Schoepf UJ, Bastarrika G, Chiaramida SA, Abro JA, Brothers RL, Vogt S, Schmidt B, Costello P, Zwerner PL. Dual-energy CT of the heart--princi‐

[5] Schutt EG, Klein DH, Mattrey RM, Riess JG. Injectable microbubbles as contrast agents for diagnostic ultrasound imaging: the key role of perfluorochemicals. Angew

[6] Klibanov AL. Microbubble contrast agents: targeted ultrasound imaging and ultra‐ sound-assisted drug-delivery applications. Invest Radiol. 2006;41(3) 354-362.

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**Chapter 10**

**Nuclear Cardiology — In the Era**

**of the Interventional Cardiology**

Branislav Baskot, Igor Ivanov, Dragan Kovacevic,

Slobodan Obradovic, Nenad Ratkovic and

Additional information is available at the end of the chapter

number of manuscript to be published in the field [1, 2, 3]

The strength and breadth of nuclear cardiology lie in its great potential for future creative growth. This growth involves the development of new biologically derived radiopharmaceut‐ icals, avdanced imaging techologies, and a broad/based set of research and clinical aplications involving diagnosis, functional categorization, prognosis, evaluation of therapeutic interven‐ tions, and the ability to deal with many of the major investigative issues in contemporary cardiology such as myocardial hibernation, stunning, and viability. The past decade has been caracteriyed by major advances in nuclear cardiology that have greatly enhanced the clinical utility of the various radionuclide techniques used for the assessment of regional myocardial perfusion and regional and global left ventricular function under resting and stress condotions. Despite the emergence of alternative noninvasive techniques for the diagnosis of coronary aretry disease (CAD) and the assessment of prognosis of viability, such as ergo- stress tests, stress echocardiography, the use and application of nuclear cardiology techniques have continued to increase. The establishment of the American Society of Nuclear Cardiology (ASNC) and its educational programs has led to a greater diffusion on nuclear cardiology technology in the community hospital setings and has promoted the emergence and dissem‐ ination of imaging and procedural guidelines for nuclear cardiology methods. The establish‐ ment of the Journal of Nuclear Cardiology, the official journal of ASNC, allowed a greater

In the few past decade, significant advances have been made in the ability to image the heart with radionuclide tracers under stress and resting conditions in patientse with suspected or

and reproduction in any medium, provided the original work is properly cited.

© 2013 Baskot et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

Miodrag Zivkovic

**1. Introduction**

http://dx.doi.org/10.5772/55484

**Chapter 10**

## **Nuclear Cardiology — In the Era of the Interventional Cardiology**

Branislav Baskot, Igor Ivanov, Dragan Kovacevic, Slobodan Obradovic, Nenad Ratkovic and Miodrag Zivkovic

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55484

## **1. Introduction**

The strength and breadth of nuclear cardiology lie in its great potential for future creative growth. This growth involves the development of new biologically derived radiopharmaceut‐ icals, avdanced imaging techologies, and a broad/based set of research and clinical aplications involving diagnosis, functional categorization, prognosis, evaluation of therapeutic interven‐ tions, and the ability to deal with many of the major investigative issues in contemporary cardiology such as myocardial hibernation, stunning, and viability. The past decade has been caracteriyed by major advances in nuclear cardiology that have greatly enhanced the clinical utility of the various radionuclide techniques used for the assessment of regional myocardial perfusion and regional and global left ventricular function under resting and stress condotions. Despite the emergence of alternative noninvasive techniques for the diagnosis of coronary aretry disease (CAD) and the assessment of prognosis of viability, such as ergo- stress tests, stress echocardiography, the use and application of nuclear cardiology techniques have continued to increase. The establishment of the American Society of Nuclear Cardiology (ASNC) and its educational programs has led to a greater diffusion on nuclear cardiology technology in the community hospital setings and has promoted the emergence and dissem‐ ination of imaging and procedural guidelines for nuclear cardiology methods. The establish‐ ment of the Journal of Nuclear Cardiology, the official journal of ASNC, allowed a greater number of manuscript to be published in the field [1, 2, 3]

In the few past decade, significant advances have been made in the ability to image the heart with radionuclide tracers under stress and resting conditions in patientse with suspected or

© 2013 Baskot et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

known coronary aretry disease (CAD) for the detection of ischemia, determination of prog‐ nosis, assessment of myocardial viability, preoperative risk assessment for patients undergo‐ ing noncardiac surgery, mand evaluation of the efficacy of revasculariyation in patients undergoing coronary artery bypass surgery or an interventional procedure [1, 2, 3].

important noninvasive means of evaluating patients with suspected CAD, with over than 10

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205

The first step in evaluating patients for CAD involves the assessment of the presence of traditional risk factors. Modifiable risks include hypercholesterolemia, hypertension, diabetes mellitus, obesity, tobacco use, and physical inactivity. Nonmodifiable risk factor includes a family history of CAD in first-degree relatives under the age of 60, advanced age, and gender? Once risk factors associated with CAD are evaluated, a patient's risk for having CAD should be assessed. This is often performed by taking symptoms such as a chest pain, age, and gender into account. Symptoms suggestive of CAD, in addition to other risk factors, drive decisions

A cornerstone of the diagnosis of CAD has been exercise tolerance testing (ETT). The ETT is the safe and easily performed, usually in an office setting. But generally, ETT electrocardiog‐

Thus, the major limitation of the ETT is its diagnostic accuracy for the detection of significant CAD. In patients able to exercise, the diagnostic accuracy of stress myocardial perfusion imaging (MPI) is significantly higher than the ETT alone and provides greater risk stratification

raphy (ECG) has a sensitivity of 50 to 70%, and a specificity of 60 to 80%.

millions studies performed in USA annually [1, 2, 16, 17, 18].

**Risk factor assessment**

for further testing [2, 12, 17, 18].

for predicting the future cardiac events.

(Nuclear cardiology –practical applications)

DIP-ECHO dipyridamole echocardiography DOB-ECHO dobutamine echocardiography

**Figure 1.** Diagnostic accuracy of various tests of CAD

DIP- MIBI dipyridamole myocardial perfusion imaging with Tc-99m MIBI DOB-MIBI dobutamine myocardial perfusion imaging with Tc-99m MIBI

ETT exercise treadmill test

For many years, planar imaging and SPECT with 201Tl (201 Talium) constituted the only scintigrafic techniques available for detecting CAD and assessing prognosis in patients undergoing stress perfusion imaging. The major limitation of 201Tl scintigraphy is the high false/positive rate observed in many laboratories, wich is attributed predominantly to image attenuation aretfact and variants of normal that are interpreted as defects consequent to a significant coronary artery stenoses. Although quantification of 201Tl images improves specificity, the false/positive rate remains problematic, particulary in the women and in obese patients. Breast attenuation artifact in women are sometimes difficult to distiguish from perfusion abnormalities secondary to inducible ischemia or myocardial scar.

In recent years, new 99mTc (technetium) labeled perfusion agents have been introduced into clinical practice to enhance the specificity of Single Photon Emission Cumputed Tomography (SPECT) and to provide additional information regarding and global left ventricular systolic function via ECG gating of images [3, 4, 8]. It was immadiately apparent that the quality of images obtained with these 99mTc-labeled radionuclides was superior to that images obtained with 201Tl because of the more favorable psysical characteristic of 99mTc imaging with gamma camera. Perhaps most importantly, 99mTc imaging allows easy gated acqusition, permiting simulateous evaluation of regional systolic thickening, global left ventricular function (LVEF), and myocardial perfusion. One the most significant avdances in myocardial perfusion imaging in the past decade is the development of quantitative SPECT perfusion imaging. Radionuclide imaging is an intrinsically digital technique that is ideally suited for quantification. A number of validated software packages are commercially available for quantification of SPECT myocardial perfusion and function (Auto Quant; Emory Toolbox; 4D/MSPECT; and Wackers Liu CQ), and are carried by the major vendors of nuclear medicine imaging equipment. The basic principles of SPECTR quantification are similar for each of these software packages. Each commercially available package also includes software for computation of LVEF and left ventricular volumes from ECG-gated SPECT images [7, 9, 10, 11].

## **2. Indications for nuclear cardiology procedures**

#### **2.1. Suspected coronary artery disease**

CAD is still the single greatest cause of death of men and women in the world, despite a declining total death rate. Using USA data over 459.000 deaths were due to CAD -1 of every deaths. There are aproximatelly 2.2 million hospital discharges with CAD as the diagnosis annually.

The reduction of the morbidity and mortality due to CAD is thus primary importance to physicians and patients. Stress myocardial perfusion imaging (MPI) has emerged as an important noninvasive means of evaluating patients with suspected CAD, with over than 10 millions studies performed in USA annually [1, 2, 16, 17, 18].

#### **Risk factor assessment**

known coronary aretry disease (CAD) for the detection of ischemia, determination of prog‐ nosis, assessment of myocardial viability, preoperative risk assessment for patients undergo‐ ing noncardiac surgery, mand evaluation of the efficacy of revasculariyation in patients

For many years, planar imaging and SPECT with 201Tl (201 Talium) constituted the only scintigrafic techniques available for detecting CAD and assessing prognosis in patients undergoing stress perfusion imaging. The major limitation of 201Tl scintigraphy is the high false/positive rate observed in many laboratories, wich is attributed predominantly to image attenuation aretfact and variants of normal that are interpreted as defects consequent to a significant coronary artery stenoses. Although quantification of 201Tl images improves specificity, the false/positive rate remains problematic, particulary in the women and in obese patients. Breast attenuation artifact in women are sometimes difficult to distiguish from

In recent years, new 99mTc (technetium) labeled perfusion agents have been introduced into clinical practice to enhance the specificity of Single Photon Emission Cumputed Tomography (SPECT) and to provide additional information regarding and global left ventricular systolic function via ECG gating of images [3, 4, 8]. It was immadiately apparent that the quality of images obtained with these 99mTc-labeled radionuclides was superior to that images obtained with 201Tl because of the more favorable psysical characteristic of 99mTc imaging with gamma camera. Perhaps most importantly, 99mTc imaging allows easy gated acqusition, permiting simulateous evaluation of regional systolic thickening, global left ventricular function (LVEF), and myocardial perfusion. One the most significant avdances in myocardial perfusion imaging in the past decade is the development of quantitative SPECT perfusion imaging. Radionuclide imaging is an intrinsically digital technique that is ideally suited for quantification. A number of validated software packages are commercially available for quantification of SPECT myocardial perfusion and function (Auto Quant; Emory Toolbox; 4D/MSPECT; and Wackers Liu CQ), and are carried by the major vendors of nuclear medicine imaging equipment. The basic principles of SPECTR quantification are similar for each of these software packages. Each commercially available package also includes software for computation of LVEF and left

CAD is still the single greatest cause of death of men and women in the world, despite a declining total death rate. Using USA data over 459.000 deaths were due to CAD -1 of every deaths. There are aproximatelly 2.2 million hospital discharges with CAD as the diagnosis

The reduction of the morbidity and mortality due to CAD is thus primary importance to physicians and patients. Stress myocardial perfusion imaging (MPI) has emerged as an

undergoing coronary artery bypass surgery or an interventional procedure [1, 2, 3].

204 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

perfusion abnormalities secondary to inducible ischemia or myocardial scar.

ventricular volumes from ECG-gated SPECT images [7, 9, 10, 11].

**2. Indications for nuclear cardiology procedures**

**2.1. Suspected coronary artery disease**

annually.

The first step in evaluating patients for CAD involves the assessment of the presence of traditional risk factors. Modifiable risks include hypercholesterolemia, hypertension, diabetes mellitus, obesity, tobacco use, and physical inactivity. Nonmodifiable risk factor includes a family history of CAD in first-degree relatives under the age of 60, advanced age, and gender? Once risk factors associated with CAD are evaluated, a patient's risk for having CAD should be assessed. This is often performed by taking symptoms such as a chest pain, age, and gender into account. Symptoms suggestive of CAD, in addition to other risk factors, drive decisions for further testing [2, 12, 17, 18].

A cornerstone of the diagnosis of CAD has been exercise tolerance testing (ETT). The ETT is the safe and easily performed, usually in an office setting. But generally, ETT electrocardiog‐ raphy (ECG) has a sensitivity of 50 to 70%, and a specificity of 60 to 80%.

Thus, the major limitation of the ETT is its diagnostic accuracy for the detection of significant CAD. In patients able to exercise, the diagnostic accuracy of stress myocardial perfusion imaging (MPI) is significantly higher than the ETT alone and provides greater risk stratification for predicting the future cardiac events.

(Nuclear cardiology –practical applications)

ETT exercise treadmill test

DIP-ECHO dipyridamole echocardiography

DOB-ECHO dobutamine echocardiography

DIP- MIBI dipyridamole myocardial perfusion imaging with Tc-99m MIBI

DOB-MIBI dobutamine myocardial perfusion imaging with Tc-99m MIBI

**Figure 1.** Diagnostic accuracy of various tests of CAD

Because of limitation to performed exercise test (patients with medical illness, debilitation, musculoskeletal problems, and the older who can't reach a predicted maximum heart rate) MPI with pharmacologic stress using vasodilators (dipyridamole, and adenosine) or dobuta‐ mine can be implemented in such patients. In this moment, it has been estimated that 48% to 50% of all stress MPI is performed with pharmacologic agent. Briefly, dipyridamole and adenosine are potent coronary vasodilators that markedly increase coronary blood flow. This increased flow is less pronounced in arteries that are stenotic (flow restricted) due to athero‐ sclerosis. This causes heterogeneous myocardial perfusion, which can be observed using that follows coronary blood flow as an alternative to vasodilator stress. Dobutamine works by increasing myocardial oxygen demand (through increased heart rate, systolic blood pressure, and myocardial contractility) [5, 6, 7, 8, 9]. As in exercise MPI scintigraphic images obtained at rest compared to those obtained during peak pharmacologic stress to distinguish myocardial ischemia from scar tissue (infarct area).

anatomy is known, and despite some limitations in the setting of multivessel disease, MPI remains the test of choise for indentifying the lesion responsible for the ischemic symptoms, or so colled culprit lesion. That is extremly useful for futher management decisions with respect to percutaneous interventions. In compare, the absence of reversible ischemia in patients with

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The current definition of culprit lesion that is zone of ischemia under the coronary stenoses is not quite wright, because that is not definy two pathophysiologic aspects of ischemia; severity and extent. The primary objective of those study was to determinate and localizes culprit lesion by newly introduce parameters SRS (*summary reversible score*) and ISRS (*index of summary reversible score*), under the angiographically detected coronary narrowing ≥75% for the least

In the past two decades, a great body of literature has established the use of nuclear imaging for risk stratification in patients with known or suspected coronary artery disease (CAD). Risk stratification is of crucial importance for the practice of contemporary medicine. Extending the paradigm of noninvasive cardiac testing beyond the detection of disease is especially important, may risk assessment permits patients who are identified as being at a high risk for subsequent cardiac events should receive aggressive management, possi‐ bly including cardiac catheterization for potential revascularization procedures that may improve their outcome. CAD is disease with a wide spectrum of severity and extent with outcome, such as nonfatal myocardial infarction (MI) or cardiac death being related to the severity of disease. Clinical trials have shown that patients with severe CAD as left main coronary artery disease, especially those with left ventricular dysfunction, can benefit from coronary artery bypass graft surgery (CABG) with significant reduction in their mortality rate. Whereas patients with single-vessel or with two-vessel disease (without proximal left anterior descending artery involvement) would have improved symptoms of angina following CABG and percutaneous transluminal coronary angioplasty with or without stent

Coronary angiography, considered the "gold standard" for the diagnosis of CAD, often does not provide information about the physiologic significance of atherosclerotic lesions, espe‐ cially in borderline lesions. More importantly, it does not provide a clear marker of risk of adverse events, especially in patients with moderate disease severity. Andreas Gruentzig said; "*When coronary angiography founded coronary artery disease, I would like to have diagnostic procedure*

The presence of normal scintigraphic MPI study at a high level of stress ( ≥ 85 % of maximum predicted heart rate) or proper pharmacologic stress carries a very benign prognosis, with mortality rate less than 0.5% per year. This finding has been reproduced in many studies. Iskander and Iskandiran, pooling the results of SPECT imaging from more than 12000 patients in 14 studies, demonstrated that the events rate (death/MI) for patients with normal MPI finding is 0.6%, whereas abnormal study carries 7.4% per year event rate,

known CAD is an excellent prognostic marker and predicts a low annual event rate.

one coronary artery [2, 6, 9, 11, 15].

implantation, without any effect on their mortality rate.

*who will give me functional significance that lesion."* [2, 10, 12, 18].

a 12-fold increase [2, 3, 14, 18]..

The diagnostic accuracy of Tc-99m imaging with pharmacologic stress test for angiographi‐ cally significant CAD has been evaluated in numerous study.

(Nuclear cardiology –practical applications)

**Figure 2.** Diagnostic accuracy of stress myocardial perfusion imaging.

#### **2.2. Evaluating and determination CULPRIT lesion, in indication for interventional cardiology**

One of the most powerfull uses of MPI is the evaluation of the risk for future events in patients with suspected or known CAD. Over the years, MPI has evolved as an essential tool in the evaluation and assessment of patient prior to coronary revascularization. It has a dual role. Prior to coronary angiography, MPI is extremly useful in documeting ischemia and determin‐ ing the functional impact of single or multiple lesions indentified subsequently. After coronary anatomy is known, and despite some limitations in the setting of multivessel disease, MPI remains the test of choise for indentifying the lesion responsible for the ischemic symptoms, or so colled culprit lesion. That is extremly useful for futher management decisions with respect to percutaneous interventions. In compare, the absence of reversible ischemia in patients with known CAD is an excellent prognostic marker and predicts a low annual event rate.

Because of limitation to performed exercise test (patients with medical illness, debilitation, musculoskeletal problems, and the older who can't reach a predicted maximum heart rate) MPI with pharmacologic stress using vasodilators (dipyridamole, and adenosine) or dobuta‐ mine can be implemented in such patients. In this moment, it has been estimated that 48% to 50% of all stress MPI is performed with pharmacologic agent. Briefly, dipyridamole and adenosine are potent coronary vasodilators that markedly increase coronary blood flow. This increased flow is less pronounced in arteries that are stenotic (flow restricted) due to athero‐ sclerosis. This causes heterogeneous myocardial perfusion, which can be observed using that follows coronary blood flow as an alternative to vasodilator stress. Dobutamine works by increasing myocardial oxygen demand (through increased heart rate, systolic blood pressure, and myocardial contractility) [5, 6, 7, 8, 9]. As in exercise MPI scintigraphic images obtained at rest compared to those obtained during peak pharmacologic stress to distinguish myocardial

206 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The diagnostic accuracy of Tc-99m imaging with pharmacologic stress test for angiographi‐

ischemia from scar tissue (infarct area).

(Nuclear cardiology –practical applications)

**cardiology**

**Figure 2.** Diagnostic accuracy of stress myocardial perfusion imaging.

**2.2. Evaluating and determination CULPRIT lesion, in indication for interventional**

One of the most powerfull uses of MPI is the evaluation of the risk for future events in patients with suspected or known CAD. Over the years, MPI has evolved as an essential tool in the evaluation and assessment of patient prior to coronary revascularization. It has a dual role. Prior to coronary angiography, MPI is extremly useful in documeting ischemia and determin‐ ing the functional impact of single or multiple lesions indentified subsequently. After coronary

cally significant CAD has been evaluated in numerous study.

The current definition of culprit lesion that is zone of ischemia under the coronary stenoses is not quite wright, because that is not definy two pathophysiologic aspects of ischemia; severity and extent. The primary objective of those study was to determinate and localizes culprit lesion by newly introduce parameters SRS (*summary reversible score*) and ISRS (*index of summary reversible score*), under the angiographically detected coronary narrowing ≥75% for the least one coronary artery [2, 6, 9, 11, 15].

In the past two decades, a great body of literature has established the use of nuclear imaging for risk stratification in patients with known or suspected coronary artery disease (CAD). Risk stratification is of crucial importance for the practice of contemporary medicine. Extending the paradigm of noninvasive cardiac testing beyond the detection of disease is especially important, may risk assessment permits patients who are identified as being at a high risk for subsequent cardiac events should receive aggressive management, possi‐ bly including cardiac catheterization for potential revascularization procedures that may improve their outcome. CAD is disease with a wide spectrum of severity and extent with outcome, such as nonfatal myocardial infarction (MI) or cardiac death being related to the severity of disease. Clinical trials have shown that patients with severe CAD as left main coronary artery disease, especially those with left ventricular dysfunction, can benefit from coronary artery bypass graft surgery (CABG) with significant reduction in their mortality rate. Whereas patients with single-vessel or with two-vessel disease (without proximal left anterior descending artery involvement) would have improved symptoms of angina following CABG and percutaneous transluminal coronary angioplasty with or without stent implantation, without any effect on their mortality rate.

Coronary angiography, considered the "gold standard" for the diagnosis of CAD, often does not provide information about the physiologic significance of atherosclerotic lesions, espe‐ cially in borderline lesions. More importantly, it does not provide a clear marker of risk of adverse events, especially in patients with moderate disease severity. Andreas Gruentzig said; "*When coronary angiography founded coronary artery disease, I would like to have diagnostic procedure who will give me functional significance that lesion."* [2, 10, 12, 18].

The presence of normal scintigraphic MPI study at a high level of stress ( ≥ 85 % of maximum predicted heart rate) or proper pharmacologic stress carries a very benign prognosis, with mortality rate less than 0.5% per year. This finding has been reproduced in many studies. Iskander and Iskandiran, pooling the results of SPECT imaging from more than 12000 patients in 14 studies, demonstrated that the events rate (death/MI) for patients with normal MPI finding is 0.6%, whereas abnormal study carries 7.4% per year event rate, a 12-fold increase [2, 3, 14, 18]..

The current definition of culprit lesion; that is zone of ischemia under the coronary stenoses (what degree? That is not definition. Some autors ofer degree of stenoses ≤ 70 %, some ≤ 75%, even < 80-85% ) is not quite wright, because that is not definy two pathophysiologic aspects of ischemia; severity and extent. Iskander and Iskadrian have also shown that defects reversibility is an important predictor of type of cardiac events, whereas reversible perfusion defects are associated with nonfatal MI. This is very important finding, since a reversible defect on MPI imaging is the only available diagnostic tool that can independently predict the risk of nonfatal MI. Therefore, stress perfusion studies should be reported documenting defect severity (mild, moderate, severe), size (small, moderate, large) and reversibility to provide essential risk stratification.[2, 3, 16].

The aim of the study Baskot at all. [2] was to determine and localize culprit lesion by MPI in cases of angiographically detected coronary narrowing ≥ 75% of at least one coronary artery.

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In the study four hundred and thirty-seven [437] patients were studied. In all of them angio‐ graphically detected significant coronary narrowing (≥ 75% luminal stenosis) before PCI. All the patients were submitted to MPI 99mTc-MIBI, with pharmacologic dipyridamole stress protocol with concomitant low level bicycle exercise 50 W (DipyEX). We measured relative uptake 99mTc-MIBI for each myocardial segment using short-axis tomogram study. A 5-point scoring system was used to assess the difference between uptake degree in stress and rest studies for the same segment, and we created two indices: Sum reversible score (SRS), Index of sum reversibility score (ISRS). In the results a total 1311 vascular territories (7429 segments) were analyzed before elective percutaneous coronary intervention (ePCI). Overall sensitivity, specificity and accuracy using SRS were 89.7%, 86, 7%, and 88, 2%, with a positive predictive value of 92, 7%. Overall sensitivity, specificity and accuracy using ISRS were 92.8%, 89.1%, and 92.3%, and the positive predictive value was 93.7%. Conclusion this work that is DipyEX MPI with two indices created SRS and ISRS significantly improves sensitivity, specificity and accuracy in the determination and localization of culprit lesion in patients undergoing elective PCI. In this work author defined culprit lesion using two physiological aspects; severity of ischemia and extension zone of ischemia. With quantification of these two parameters of culprit lesion, the author determined patients who underwent ePCI with stent implantation,

and who had the best therapy effects with PCI therapy.

Figure showed culprit lesion in the inferolateral segments in the AdenoEx (up line slices) MPI study

**Case 1.**

The size and severity of the perfusion abnormality provide powerful prognostic information and has been shown to directly relate to outcome. MPI perfusion imaging and determination of culprit lesion is more predicitble of cardiac events than coronary angiography. As MPI imaging may identify those patients at high risk for subsequent cardiac events, perfusion imaging may be used to help guide further testing and revascularization procedures, and this obviously has important cost-effectiveness ramifications.

The primary objective of this study was to determinate and localizes culprit lesion by newly introduce parameters SRS (*summary reversible score*) and ISRS (*index of summary reversible score*), under the angiographically detected coronary narrowing ≥75% for the least one coronary artery [2].

The rapid rates of technical advances and improved operator expertise have enabled this technique to gain more widespread application. Despite the large number of PTCA-s per‐ formed yearly, preprocedure documentation of myocardial ischemia is uncommon, occurring in only 29% of patients.

Myocardial perfusion imaging provides information on the extent and location of myocardial ischemia. The assessment of jeopardized myocardium may be performed and provides a measure of the relative value of PTCA in terms of the amount of jeopardized myocardium. The location of the stenosis may dictate the area at risk: extent and severity of perfusion defects were significantly smaller in patients with proximal compared with distal coronary artery occlusions.

Before revascularization is performed, myocardial perfusion imaging may assist in manage‐ ment decisions by demonstrating the presence of myocardial ischemia, viability and delineat‐ ing the severity and extent of coronary artery disease. The significance of equivocal lesions may be determined and culprit vessel may be successfully defined by SPECT imaging before angioplasty [2, 3, 10, 18].

The coronary angiography provides information on the anatomical state of the coronary tree and, specifically, on the large epicardial arteries, while perfusion SPECT facilitates the evaluation of the grade of ischemia that a particular stenosis produces. MPI SPECT is of considerable use in the procedural indications of partial revascularization in patients with chronic coronary artery disease (CAD). In these cases the purpose is to detect the coronary stenosis that provokes the ischemia and is termed the "culprit lesion".

The aim of the study Baskot at all. [2] was to determine and localize culprit lesion by MPI in cases of angiographically detected coronary narrowing ≥ 75% of at least one coronary artery.

In the study four hundred and thirty-seven [437] patients were studied. In all of them angio‐ graphically detected significant coronary narrowing (≥ 75% luminal stenosis) before PCI. All the patients were submitted to MPI 99mTc-MIBI, with pharmacologic dipyridamole stress protocol with concomitant low level bicycle exercise 50 W (DipyEX). We measured relative uptake 99mTc-MIBI for each myocardial segment using short-axis tomogram study. A 5-point scoring system was used to assess the difference between uptake degree in stress and rest studies for the same segment, and we created two indices: Sum reversible score (SRS), Index of sum reversibility score (ISRS). In the results a total 1311 vascular territories (7429 segments) were analyzed before elective percutaneous coronary intervention (ePCI). Overall sensitivity, specificity and accuracy using SRS were 89.7%, 86, 7%, and 88, 2%, with a positive predictive value of 92, 7%. Overall sensitivity, specificity and accuracy using ISRS were 92.8%, 89.1%, and 92.3%, and the positive predictive value was 93.7%. Conclusion this work that is DipyEX MPI with two indices created SRS and ISRS significantly improves sensitivity, specificity and accuracy in the determination and localization of culprit lesion in patients undergoing elective PCI. In this work author defined culprit lesion using two physiological aspects; severity of ischemia and extension zone of ischemia. With quantification of these two parameters of culprit lesion, the author determined patients who underwent ePCI with stent implantation, and who had the best therapy effects with PCI therapy.

**Case 1.**

The current definition of culprit lesion; that is zone of ischemia under the coronary stenoses (what degree? That is not definition. Some autors ofer degree of stenoses ≤ 70 %, some ≤ 75%, even < 80-85% ) is not quite wright, because that is not definy two pathophysiologic aspects of ischemia; severity and extent. Iskander and Iskadrian have also shown that defects reversibility is an important predictor of type of cardiac events, whereas reversible perfusion defects are associated with nonfatal MI. This is very important finding, since a reversible defect on MPI imaging is the only available diagnostic tool that can independently predict the risk of nonfatal MI. Therefore, stress perfusion studies should be reported documenting defect severity (mild, moderate, severe), size (small, moderate, large) and reversibility to provide essential risk

208 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The size and severity of the perfusion abnormality provide powerful prognostic information and has been shown to directly relate to outcome. MPI perfusion imaging and determination of culprit lesion is more predicitble of cardiac events than coronary angiography. As MPI imaging may identify those patients at high risk for subsequent cardiac events, perfusion imaging may be used to help guide further testing and revascularization procedures, and this

The primary objective of this study was to determinate and localizes culprit lesion by newly introduce parameters SRS (*summary reversible score*) and ISRS (*index of summary reversible score*), under the angiographically detected coronary narrowing ≥75% for the least one coronary

The rapid rates of technical advances and improved operator expertise have enabled this technique to gain more widespread application. Despite the large number of PTCA-s per‐ formed yearly, preprocedure documentation of myocardial ischemia is uncommon, occurring

Myocardial perfusion imaging provides information on the extent and location of myocardial ischemia. The assessment of jeopardized myocardium may be performed and provides a measure of the relative value of PTCA in terms of the amount of jeopardized myocardium. The location of the stenosis may dictate the area at risk: extent and severity of perfusion defects were significantly smaller in patients with proximal compared with distal coronary artery

Before revascularization is performed, myocardial perfusion imaging may assist in manage‐ ment decisions by demonstrating the presence of myocardial ischemia, viability and delineat‐ ing the severity and extent of coronary artery disease. The significance of equivocal lesions may be determined and culprit vessel may be successfully defined by SPECT imaging before

The coronary angiography provides information on the anatomical state of the coronary tree and, specifically, on the large epicardial arteries, while perfusion SPECT facilitates the evaluation of the grade of ischemia that a particular stenosis produces. MPI SPECT is of considerable use in the procedural indications of partial revascularization in patients with chronic coronary artery disease (CAD). In these cases the purpose is to detect the coronary

stenosis that provokes the ischemia and is termed the "culprit lesion".

obviously has important cost-effectiveness ramifications.

stratification.[2, 3, 16].

artery [2].

occlusions.

in only 29% of patients.

angioplasty [2, 3, 10, 18].

Figure showed culprit lesion in the inferolateral segments in the AdenoEx (up line slices) MPI study

**•** ACx stenoses 90%, OM with tubular stenosis 50 -70%

Culprit lesion

Coronarography finding

**•** RCA dominant, occluded ostial, venous graft occluded okludiran.

**•** After four month MPI control when we founded in stent stenosis.

**•** Performed PCI with stent implantation (Tsunami gold 3.5 x 15) on LM and ACX

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Nearly after elective PCI intervention we performed MPI with normal finding of perfusion

#### **Case 2.**


Culprit lesion

Nearly after elective PCI intervention we performed MPI with normal finding of perfusion

**•** Patient male 61 year old. St post IM with revascularization 1996 triple ACB (LIMA – LAD;

**•** Coronarography finding ;LM 90%, LAD occluded, LIMA graft wide open. Venous graft on

**•** In April 2010 performed SPECT MPI, finding sugested invasive intervention.

210 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Case 2.**

venous graft on the D1 and

the D1 occluded.

Coronarography finding

Control MPI after four month after PCI

Control Coronarography - fidning in stent stenonis

We finding zone of reversible ischemia in the same area, suggest restenosis

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In the same act PCI with stent implantation

Final effect PCI

Control MPI after four month after PCI

In the same act PCI with stent implantation

212 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Final effect PCI

We finding zone of reversible ischemia in the same area, suggest restenosis

Control Coronarography - fidning in stent stenonis

zation. Finally, patients with a severely abnormal scan treated medically had an annual cardiac death rate of 4.6% versus 1.3% for such patients who were revascularized. In the second study, these investigators showed that medically treated patients who had greater than 20% of the total myocardium rendered ischemic had higher annual cardiac death rate (6.7%) compared with 2.0% for patients with this degree of extensive ischemia who underwent revasculariza‐ tion. For patients with 10% or less of the total myocardium rendered ischemic, there was no

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Exercise myocardial perfusion imaging is a valuable adjunct for separating high to low risk patients who present symptoms consistent with stable CAD, or in patients who have known disease and in whom further prognostication is warranted. Multiple high-risk nuclear imaging variables can be identified, and the greater the extent of exercise/induced ischemia, the greater the risk of cardiac events. Adjunctive variables, such as transient ischemic cavity dilatation and functional assessment with evaluation of regional wall thickening or wall motion and left ventricular ejection fraction greatly assist in the risk stratification process [1, 3, 16, 18].

Nuclear cardiology is uniquely placed to address all the major determinants of prognosis in CAD can be assessed by measurements of stress-induced perfusion or function. These measurements include the amount of infarcted myocardium, the amount of jeopardized myocardium (supplied by vessels with hemodynamically significant stenosis), and the degree of jeopardy (tightness of the individual coronary stenosis). Recent evidence in large patient cohorts has revealed that factor estimating the extent of left ventricular dysfunction (left ventricular ejection fraction, extent of infarcted myocardium, transient ischemic dilatation of the left ventricle and increasing lung uptake) are excellent predictors of cardiac mortality. However, measurements of inducible ischemia are the best predictors of the development of acute coronary syndromes. Several reports have shown that nuclear testing yields incremental prognostic value over clinical information with respect to cardiac death, or the combination of cardiac death and nonfatal myocardial infarction as isolated endpoints. Now it is possible to tailor therapeutic decision making for an individual patient based upon combination of clinical factors and nuclear scan results. Patients with severe perfusion abnormalities on their stress image may have a five- to ten-fold higher likelihood of cardiac death versus patient with a normal myocardial perfusion SPECT. If the defects perfusion determined as a culprit lesion,

invasive therapy (PCI) is an optimized outcome for that patient [2, 12, 13, 15].

with known CAD after PCI [2, 15, 16, 18].

The explosion of PTCA and stent placement in patients with single or multi-vessel disease has created a necessity for early detection of restenosis. A number of clinical studies have docu‐ mented the usefulness of stress MPI for identifying restenosis in patients after PCI. One point of controversy is the optimal time to performing SPECT imaging after coronary intervention. Although current consensus in to obtain an exercise MPI study 4 to 6 weeks post intervention, whenever indicated, the proper timing for use of MPI remains to be determined. Based on existing knowledge about the timing interval of subacute thrombosis (< 4 weeks) and in-stent restenosis (3-6 month), we purpose the algorithm as a guide for the management of patients

difference in outcome between medical therapy and revascularization.

Re PCI with stent implantation

Final effect

Conversely, patients with high-risk scans may benefit from an early invasive strategy with a view toward revascularization depending on coronary anatomical finding. A substantial number of patients undergoing SPECT perfusion imaging will have mild ischemia without a multi-vessel disease scan pattern. If patients with mild ischemia have good exercise tolerance, they should be considered as candidates for intense medical therapy with follow-up exercise SPECT imaging possibly at 1 year. Unpublished data from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluations (COURAGE) trial seem to indicate that many ischemic defects may markedly improve with aggressive lowering of abnormal lipids an the other pharmacological interventions. Hachamovitch and colleagues reported patients with the mildly abnormal scan had a 0.8% annual cardiac death rate compared with 0.9% for those who underwent revascularization. The death rate in medically treated patients who had moderately abnormal scans was 2.3% versus 1.1% for such patients undergoing revasculari‐ zation. Finally, patients with a severely abnormal scan treated medically had an annual cardiac death rate of 4.6% versus 1.3% for such patients who were revascularized. In the second study, these investigators showed that medically treated patients who had greater than 20% of the total myocardium rendered ischemic had higher annual cardiac death rate (6.7%) compared with 2.0% for patients with this degree of extensive ischemia who underwent revasculariza‐ tion. For patients with 10% or less of the total myocardium rendered ischemic, there was no difference in outcome between medical therapy and revascularization.

Exercise myocardial perfusion imaging is a valuable adjunct for separating high to low risk patients who present symptoms consistent with stable CAD, or in patients who have known disease and in whom further prognostication is warranted. Multiple high-risk nuclear imaging variables can be identified, and the greater the extent of exercise/induced ischemia, the greater the risk of cardiac events. Adjunctive variables, such as transient ischemic cavity dilatation and functional assessment with evaluation of regional wall thickening or wall motion and left ventricular ejection fraction greatly assist in the risk stratification process [1, 3, 16, 18].

Re PCI with stent implantation

Final effect

Conversely, patients with high-risk scans may benefit from an early invasive strategy with a view toward revascularization depending on coronary anatomical finding. A substantial number of patients undergoing SPECT perfusion imaging will have mild ischemia without a multi-vessel disease scan pattern. If patients with mild ischemia have good exercise tolerance, they should be considered as candidates for intense medical therapy with follow-up exercise SPECT imaging possibly at 1 year. Unpublished data from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluations (COURAGE) trial seem to indicate that many ischemic defects may markedly improve with aggressive lowering of abnormal lipids an the other pharmacological interventions. Hachamovitch and colleagues reported patients with the mildly abnormal scan had a 0.8% annual cardiac death rate compared with 0.9% for those who underwent revascularization. The death rate in medically treated patients who had moderately abnormal scans was 2.3% versus 1.1% for such patients undergoing revasculari‐

214 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Nuclear cardiology is uniquely placed to address all the major determinants of prognosis in CAD can be assessed by measurements of stress-induced perfusion or function. These measurements include the amount of infarcted myocardium, the amount of jeopardized myocardium (supplied by vessels with hemodynamically significant stenosis), and the degree of jeopardy (tightness of the individual coronary stenosis). Recent evidence in large patient cohorts has revealed that factor estimating the extent of left ventricular dysfunction (left ventricular ejection fraction, extent of infarcted myocardium, transient ischemic dilatation of the left ventricle and increasing lung uptake) are excellent predictors of cardiac mortality. However, measurements of inducible ischemia are the best predictors of the development of acute coronary syndromes. Several reports have shown that nuclear testing yields incremental prognostic value over clinical information with respect to cardiac death, or the combination of cardiac death and nonfatal myocardial infarction as isolated endpoints. Now it is possible to tailor therapeutic decision making for an individual patient based upon combination of clinical factors and nuclear scan results. Patients with severe perfusion abnormalities on their stress image may have a five- to ten-fold higher likelihood of cardiac death versus patient with a normal myocardial perfusion SPECT. If the defects perfusion determined as a culprit lesion, invasive therapy (PCI) is an optimized outcome for that patient [2, 12, 13, 15].

The explosion of PTCA and stent placement in patients with single or multi-vessel disease has created a necessity for early detection of restenosis. A number of clinical studies have docu‐ mented the usefulness of stress MPI for identifying restenosis in patients after PCI. One point of controversy is the optimal time to performing SPECT imaging after coronary intervention. Although current consensus in to obtain an exercise MPI study 4 to 6 weeks post intervention, whenever indicated, the proper timing for use of MPI remains to be determined. Based on existing knowledge about the timing interval of subacute thrombosis (< 4 weeks) and in-stent restenosis (3-6 month), we purpose the algorithm as a guide for the management of patients with known CAD after PCI [2, 15, 16, 18].

The prognostic efficacy of MPI is well established. Subsequent data have demonstrated in various patient subsets that nuclear tests add significant and incremental predictive value to less expensive clinical and exercise testing data. Angiographic data obtained from more expensive cardiac catheterization procedures add little or no significant incremental prognos‐

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217

The introduction of new drugs and interventional devices to treat CAD, coupled with the arrival of manage care, has led to era of cost-containment within the practice of cardiology. Stress MPI is increasingly seen as a gatekeeper for more costly diagnosis and interventional procedures. Steingart et al evaluated 378 patients with a full range of pretest probabilities for CAD, and demonstrated that the results of MPI significantly reduced referring physicians'

Under managed care health systems that operate under cost-containment and capitation, MPI will continue to impact significantly on the decision to perform cardiac catheteriza‐ tion and to refer patients for coronary revascurization. Recommendations for invasive and interventional procedures are often coupled with an appropriate understanding of the prognostic value of MPI. Patients with the normal stress radionuclide study do not generally require referral for additional procedures, even when the likelihood of underly‐ ing CAD is high, as based on clinical and stress ECG data. The need for cardiac catheter‐ ization and coronary revascularization rates should be based on the degree of abnormality as detected by MPI. Thus, there is an increasing role of MPI to play an important gatekeeper function in the current era of managed care and emphasis on cost-contain‐

Stress MPI has became a central guide in decision making with regard to CAD patients. Stress MPI is commonly used either before consideration of coronary revascularization or after its performance, to optimize decision making for CAD patients. Stress MPI is also used after myocardial revascularization procedures, to evaluate therapeutic efficacy; following the stabilization of acute ischemic syndromes; to determine subsequent risk; and before the performance of elective non-cardiac surgery, to identify the high-risk subsets of CAD patients

After all, MPI has became an important instrument in defining cardiac risk and in identifying patients who are most likely to benefit from additional invasive diagnostic testing and potential coronary revascularization. MPI demonstrated significant incremental prognostic

**3. Heart failure — New approach of therapy and diagnostic evaluation of**

Heart failure (HF) is becoming the main clinical challenge in cardiology in the twenty - first century and is associated with high morbidity and mortality. Heart failure is the third most

likelihood of recommending cardiac catheterization, on average by 49%.

who will require coronary revascularization prior to elective surgery.

tic value when added to the results of MPI.

ment [2, 3, 8, 12, 18].

**therapy effect1**

1 Zivkovic Miodrag, Baskot Branislav

**Figure 3.** Recommendation for the diagnostic treatment after PCI.

Asymptomatic patients may be considered for stress MPI 4 to 6 weeks post intervention in order to assess the functional results of PCI and established a new baseline. Subsets of patients that benefit from this approach include those at high risk post PCI (patients with decreased LV function, proximal left anterior descending artery disease, previous sudden death, diabetes mellitus, hazardous occupations, and suboptimal PCI results). Stress MPI is also recommended in patients who develop atypical symptoms after PCI and there is necessity to assess whether these symptoms represent ischemia. Patient with symptoms typical of ischemia < 6 months post intervention should proceed with coronary angiography as a first step, unless contrain‐ dicated. If angina occurs later (> 6 months post PCI), stress/pharmacologic MPI can be used to assess degree and area of ischemia, since progression of native coronary disease rather than in-stent restenosis is more likely.

**Incremental prognostic value of MPI;** Because nuclear test are expensive the cost-effective‐ ness of these tests should demonstrate incremental prognostic information that cannot be derived from less expensive modalities such as clinical patient history and risks factors, standard ECG, and exercise ECG.

The combination clinical and exercise MPI variables provided greater prognostic information than the combination of clinical and angiographic data. Iskandrian et al showed that in medically treated patients with CAD, exercise SPECT imaging provided independent and incremental prognostic information even when catheterization data are available. The extent of perfusion abnormality was the single best predictor of prognosis. MPI added incremental prognostic information and risk-stratified patient even after clinical and exercise information were known. The incremental prognostic information about prognosis and need for coronary angiography provided by MPI has additionally been demonstrated for specific patients subsets: women, patient following coronary angioplasty or CABG, after MI, and with unstable angina. Hachamovitch et al demonstrated the use of MPI to yield incremental prognostic information toward the identification of cardiac death. Patient with a mildly abnormal scan after exercise stress are at low risk for cardiac death, but intermediate risk for nonfatal MI. A noninvasive strategy of optimizing medical therapy in this patient subgroup may result in significant cost saving when compared with invasive management strategy [1, 2, 3, 12, 18].

The prognostic efficacy of MPI is well established. Subsequent data have demonstrated in various patient subsets that nuclear tests add significant and incremental predictive value to less expensive clinical and exercise testing data. Angiographic data obtained from more expensive cardiac catheterization procedures add little or no significant incremental prognos‐ tic value when added to the results of MPI.

The introduction of new drugs and interventional devices to treat CAD, coupled with the arrival of manage care, has led to era of cost-containment within the practice of cardiology. Stress MPI is increasingly seen as a gatekeeper for more costly diagnosis and interventional procedures. Steingart et al evaluated 378 patients with a full range of pretest probabilities for CAD, and demonstrated that the results of MPI significantly reduced referring physicians' likelihood of recommending cardiac catheterization, on average by 49%.

Under managed care health systems that operate under cost-containment and capitation, MPI will continue to impact significantly on the decision to perform cardiac catheteriza‐ tion and to refer patients for coronary revascurization. Recommendations for invasive and interventional procedures are often coupled with an appropriate understanding of the prognostic value of MPI. Patients with the normal stress radionuclide study do not generally require referral for additional procedures, even when the likelihood of underly‐ ing CAD is high, as based on clinical and stress ECG data. The need for cardiac catheter‐ ization and coronary revascularization rates should be based on the degree of abnormality as detected by MPI. Thus, there is an increasing role of MPI to play an important gatekeeper function in the current era of managed care and emphasis on cost-contain‐ ment [2, 3, 8, 12, 18].

Stress MPI has became a central guide in decision making with regard to CAD patients. Stress MPI is commonly used either before consideration of coronary revascularization or after its performance, to optimize decision making for CAD patients. Stress MPI is also used after myocardial revascularization procedures, to evaluate therapeutic efficacy; following the stabilization of acute ischemic syndromes; to determine subsequent risk; and before the performance of elective non-cardiac surgery, to identify the high-risk subsets of CAD patients who will require coronary revascularization prior to elective surgery.

After all, MPI has became an important instrument in defining cardiac risk and in identifying patients who are most likely to benefit from additional invasive diagnostic testing and potential coronary revascularization. MPI demonstrated significant incremental prognostic

## **3. Heart failure — New approach of therapy and diagnostic evaluation of therapy effect1**

Heart failure (HF) is becoming the main clinical challenge in cardiology in the twenty - first century and is associated with high morbidity and mortality. Heart failure is the third most

**No symptoms post PCI Typical Symptoms post PCI Atypical** 

216 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**PTCA- Stent (PCI)**

less than 6 month more than 6 month

**Coronary angiography MPI to guide treatment**

Asymptomatic patients may be considered for stress MPI 4 to 6 weeks post intervention in order to assess the functional results of PCI and established a new baseline. Subsets of patients that benefit from this approach include those at high risk post PCI (patients with decreased LV function, proximal left anterior descending artery disease, previous sudden death, diabetes mellitus, hazardous occupations, and suboptimal PCI results). Stress MPI is also recommended in patients who develop atypical symptoms after PCI and there is necessity to assess whether these symptoms represent ischemia. Patient with symptoms typical of ischemia < 6 months post intervention should proceed with coronary angiography as a first step, unless contrain‐ dicated. If angina occurs later (> 6 months post PCI), stress/pharmacologic MPI can be used to assess degree and area of ischemia, since progression of native coronary disease rather than

**Incremental prognostic value of MPI;** Because nuclear test are expensive the cost-effective‐ ness of these tests should demonstrate incremental prognostic information that cannot be derived from less expensive modalities such as clinical patient history and risks factors,

The combination clinical and exercise MPI variables provided greater prognostic information than the combination of clinical and angiographic data. Iskandrian et al showed that in medically treated patients with CAD, exercise SPECT imaging provided independent and incremental prognostic information even when catheterization data are available. The extent of perfusion abnormality was the single best predictor of prognosis. MPI added incremental prognostic information and risk-stratified patient even after clinical and exercise information were known. The incremental prognostic information about prognosis and need for coronary angiography provided by MPI has additionally been demonstrated for specific patients subsets: women, patient following coronary angioplasty or CABG, after MI, and with unstable angina. Hachamovitch et al demonstrated the use of MPI to yield incremental prognostic information toward the identification of cardiac death. Patient with a mildly abnormal scan after exercise stress are at low risk for cardiac death, but intermediate risk for nonfatal MI. A noninvasive strategy of optimizing medical therapy in this patient subgroup may result in significant cost saving when compared with invasive management strategy [1, 2, 3, 12, 18].

stress MPI

Stress MPI 4-6 weeks

in-stent restenosis is more likely.

standard ECG, and exercise ECG.

**Figure 3.** Recommendation for the diagnostic treatment after PCI.

<sup>1</sup> Zivkovic Miodrag, Baskot Branislav

prevalent cardiovascular disease in the United States. An estimated 5 million people in the USA have heart failure, and the prevalence of the condition increase to 10 million by 2040, according to prediction. The prevalence of heart failure increase with age from less than 1% in the 20 – 30-year-old age group to over 20% in people age 80 years and older. The diagnostic and therapeutic costs involved are estimated to have exceeded \$34 billion in only one year. Despite advances in therapies, the long-term prognosis from patients with heart failure remain poor; 80% of men and 70% of women greater than 65 years of age with heart failure die within 8 years [1, 2, 19, 20, 21].

techniques as nuclear imaging that defect perfusion abnormalities should have a high sensitivity for detection of ischemia, because these abnormalities occur early in the cascade

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219

In the heart failure patients, the combination between the coronary anatomy and the presence of ischemia in the territories of the stenotic vessels determines the need for revascularization.

Another nuclear study performed in the evaluating of therapy effects in HF, is radionu‐ clide angiography (RNV). That is the most reproducible, accurate, and simple method for noninvasively assessing left ventricular ejection fraction (LVEF). RNV are now most often used for serial assessment of LVEF in patients who undergo chemotherapy, assessment of global regional wall motion in patients with recent or old myocardial infarction, and in patients with congestive heart failure. In the patients with heart failure, evaluation of left ventricular systolic function is essential to plan management and determine prognosis. At the present time most RNV are acquired by multiple – view planar image technique. In this moment SPECT RNV is not routinely performed in most nuclear cardiology laborato‐ ries. The greatest attraction of SPECT RNV is the ability to evaluate cardiac chambers and regional wall motion without overlap of other structures. LVEF may be calculated based on count changes from either a conventional planar image (*best septal*) or from SPECT RNV. *In the pilot study Zivkovic, Baskot at all*. We introduced new therapy, hyperbaric oxygenation (HBO) and erythropoietin (EPO) in the treatment of heart failure. The aim of this study is to show positive therapeutic effects of synergistic applications of HBO as a strong generator of regenerator activities in human tissues, and recombinant EPO as a general growth factor, in

HBO is medical procedure of breathing the 100% oxygen under pressures higher than atmospheric pressure is and it carries out into hyperbaric chambers. Contemporary, HBO changes the rheological blood characteristic, recovers the function of blood vessels endothelium and it has good antiaggregation effects. The oxygen's pharmacokinetic and neo-angiogenesis effects and its effect on oxygen-dependent reactions inside the mitochon‐ dria's and homeopathy effect on the other organs are the reasons to use HBO in the treatment of HF. Nuclear imaging by SPECT imaging in the evaluation between ischemic and non-ischemic HF we performed, and followed with quantification per segments before and after therapy in the evaluation positive therapeutic effect. We also performed RNV like gold standard in the evaluation global and regional LVEF before and after the therapy. In the pilot study with 18 patients, we had recovery perfusion in all patients with nonischemic HF. Before therapy we finding with RNV average measured LVEF was 23.4%. After treatment LVEF measured average 34, 3%. The results was increase by 10, 9% (from

Conclusion of this pilot study was that diagnostic information finding by nuclear cardiology (perfusion and function) suggested significantly positive therapy effects HBO and Erythro‐

poietin in the therapy of heart failure ischemic and non-ischemic origin.

In the absence of ischemia, the presence of viability needs to evaluation.

the treatment HF ischemic and non-ischemic origin [19, 20, 21].

5% to 20% measured individually).

[19, 20, 21].

#### **3.1. What we need for good and quality therapy**

The underllying etiology of HF needs to be determined; most patients have CAD (approxi‐ mately 70% - 80%). Nuclear imaging can help in the differentiation between patients with ischemic and non-ischemic HF. In patients with ischemic cardiomiopathy, the precise coronary anatomy is also needed to determinate if revascularization needs to be considered. At present, invasive angiography is performed to obtain the coronary anatomy, but multi-slice CT (MSCT) may also provide this information. The presence of ischemia and viability needs to be deter‐ mined to decide further if revascularization is indicated.

Nuclear imaging is considered the first choice technique for assessment of ischemia and viability; booth single-photon emission CT (SPECT), and positron emission tomography (PET) can provide this information.

Nuclear imaging can provide some indirect evidence in the differentiation between ischemic and non-ischemic HF. With stress,-rest SPECT study, reversible defects indicate ischemia and fixed defects of perfusion indicates scar tissue; booth this findings are markers of coronary artery disease. Moreover, lot of studies with nuclear perfusion imaging demon‐ strated that patients with ischemic HF had extensive and diffuse perfusion defects, whereas tracer uptake (myocardial perfusion) was mostly homogeneous (ischemic) in patients with non-ischemic HF.

Similarly, PET studies also demonstrated that patients with non-ischemic HF had more homogeneous tracer uptake, whereas patients with ischemic HF had areas of severely reduced uptake (reflecting scar formation). Accordingly, nuclear imaging can help in the differentiation between ischemic and non-ischemic cardiomyopathy, but for the diagnosis of underlying coronary artery disease, visualization of the coronary artery is needed. Invasive angiography is the technique of choice, but recently MSCT has been introduced for noninvasive angiography. With 64-slice MSCT and dual-source slice MSCT, we obtained more consistent image quality with improve visualization of the coronary artery tree. In the presence of a flow-limiting stenosis, resting myocardial is preserved, but once an increased myocardial oxygen demand occurs, a perfusion demand-supply mismatch follows, resulting in myocardial ischemia. Then, a sequence of events is initiated, which is referred to as the "ischemic cascade". Perfusion abnormalities occur at an early stage, whereas diastolic and systolic left ventricular dysfunction occur later. Accordingly, such techniques as nuclear imaging that defect perfusion abnormalities should have a high sensitivity for detection of ischemia, because these abnormalities occur early in the cascade [19, 20, 21].

prevalent cardiovascular disease in the United States. An estimated 5 million people in the USA have heart failure, and the prevalence of the condition increase to 10 million by 2040, according to prediction. The prevalence of heart failure increase with age from less than 1% in the 20 – 30-year-old age group to over 20% in people age 80 years and older. The diagnostic and therapeutic costs involved are estimated to have exceeded \$34 billion in only one year. Despite advances in therapies, the long-term prognosis from patients with heart failure remain poor; 80% of men and 70% of women greater than 65 years of age with heart failure die within

218 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The underllying etiology of HF needs to be determined; most patients have CAD (approxi‐ mately 70% - 80%). Nuclear imaging can help in the differentiation between patients with ischemic and non-ischemic HF. In patients with ischemic cardiomiopathy, the precise coronary anatomy is also needed to determinate if revascularization needs to be considered. At present, invasive angiography is performed to obtain the coronary anatomy, but multi-slice CT (MSCT) may also provide this information. The presence of ischemia and viability needs to be deter‐

Nuclear imaging is considered the first choice technique for assessment of ischemia and viability; booth single-photon emission CT (SPECT), and positron emission tomography (PET)

Nuclear imaging can provide some indirect evidence in the differentiation between ischemic and non-ischemic HF. With stress,-rest SPECT study, reversible defects indicate ischemia and fixed defects of perfusion indicates scar tissue; booth this findings are markers of coronary artery disease. Moreover, lot of studies with nuclear perfusion imaging demon‐ strated that patients with ischemic HF had extensive and diffuse perfusion defects, whereas tracer uptake (myocardial perfusion) was mostly homogeneous (ischemic) in patients with

Similarly, PET studies also demonstrated that patients with non-ischemic HF had more homogeneous tracer uptake, whereas patients with ischemic HF had areas of severely reduced uptake (reflecting scar formation). Accordingly, nuclear imaging can help in the differentiation between ischemic and non-ischemic cardiomyopathy, but for the diagnosis of underlying coronary artery disease, visualization of the coronary artery is needed. Invasive angiography is the technique of choice, but recently MSCT has been introduced for noninvasive angiography. With 64-slice MSCT and dual-source slice MSCT, we obtained more consistent image quality with improve visualization of the coronary artery tree. In the presence of a flow-limiting stenosis, resting myocardial is preserved, but once an increased myocardial oxygen demand occurs, a perfusion demand-supply mismatch follows, resulting in myocardial ischemia. Then, a sequence of events is initiated, which is referred to as the "ischemic cascade". Perfusion abnormalities occur at an early stage, whereas diastolic and systolic left ventricular dysfunction occur later. Accordingly, such

8 years [1, 2, 19, 20, 21].

can provide this information.

non-ischemic HF.

**3.1. What we need for good and quality therapy**

mined to decide further if revascularization is indicated.

In the heart failure patients, the combination between the coronary anatomy and the presence of ischemia in the territories of the stenotic vessels determines the need for revascularization. In the absence of ischemia, the presence of viability needs to evaluation.

Another nuclear study performed in the evaluating of therapy effects in HF, is radionu‐ clide angiography (RNV). That is the most reproducible, accurate, and simple method for noninvasively assessing left ventricular ejection fraction (LVEF). RNV are now most often used for serial assessment of LVEF in patients who undergo chemotherapy, assessment of global regional wall motion in patients with recent or old myocardial infarction, and in patients with congestive heart failure. In the patients with heart failure, evaluation of left ventricular systolic function is essential to plan management and determine prognosis. At the present time most RNV are acquired by multiple – view planar image technique. In this moment SPECT RNV is not routinely performed in most nuclear cardiology laborato‐ ries. The greatest attraction of SPECT RNV is the ability to evaluate cardiac chambers and regional wall motion without overlap of other structures. LVEF may be calculated based on count changes from either a conventional planar image (*best septal*) or from SPECT RNV.

*In the pilot study Zivkovic, Baskot at all*. We introduced new therapy, hyperbaric oxygenation (HBO) and erythropoietin (EPO) in the treatment of heart failure. The aim of this study is to show positive therapeutic effects of synergistic applications of HBO as a strong generator of regenerator activities in human tissues, and recombinant EPO as a general growth factor, in the treatment HF ischemic and non-ischemic origin [19, 20, 21].

HBO is medical procedure of breathing the 100% oxygen under pressures higher than atmospheric pressure is and it carries out into hyperbaric chambers. Contemporary, HBO changes the rheological blood characteristic, recovers the function of blood vessels endothelium and it has good antiaggregation effects. The oxygen's pharmacokinetic and neo-angiogenesis effects and its effect on oxygen-dependent reactions inside the mitochon‐ dria's and homeopathy effect on the other organs are the reasons to use HBO in the treatment of HF. Nuclear imaging by SPECT imaging in the evaluation between ischemic and non-ischemic HF we performed, and followed with quantification per segments before and after therapy in the evaluation positive therapeutic effect. We also performed RNV like gold standard in the evaluation global and regional LVEF before and after the therapy. In the pilot study with 18 patients, we had recovery perfusion in all patients with nonischemic HF. Before therapy we finding with RNV average measured LVEF was 23.4%. After treatment LVEF measured average 34, 3%. The results was increase by 10, 9% (from 5% to 20% measured individually).

Conclusion of this pilot study was that diagnostic information finding by nuclear cardiology (perfusion and function) suggested significantly positive therapy effects HBO and Erythro‐ poietin in the therapy of heart failure ischemic and non-ischemic origin.

#### **Case report 1. Patient female with multi vessel disease by coronarography**

SPECT with DipyEX (dipyridamole = concomitant low level exercise 50W) performed and evaluated before and after HBO + EPO therapy

quantification of perfusion by Stierner - segments quantification 07.13.2009

> radionuclide ventriculography (RNV) performed 10.12.2009 after therapy

radionuclide ventriculography (RNV) performed 07.17. 2009 before therapy

radionuclide ventriculography (RNV)

radionuclide ventriculography (RNV)

performed 10.12.2009 after therapy

regional ejection fraction

performed 07.17. 2009 before therapy

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regional ejection fraction

quantification of perfusion by Stierner - segments quantification 10/10/2009

Radonuclide ventriculography for evaluating global ejection fraction Performed before and after HBO = EPO therapy

radionuclide ventriculography (RNV) performed 10.12.2009 after therapy

**Case report 1. Patient female with multi vessel disease by coronarography**

220 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

SPECT with DipyEX (dipyridamole = concomitant low level exercise 50W) performed and evaluated before and after

quantification of perfusion by Stierner - segments quantification 10/10/2009

Radonuclide ventriculography for evaluating global ejection fraction Performed before and after HBO = EPO therapy

quantification of perfusion by Stierner - segments quantification 07.13.2009

HBO + EPO therapy

radionuclide ventriculography (RNV) regional ejection fraction

performed 10.12.2009 after therapy

Provisional chapter 25

223

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Nuclear Cardiology — In the Era of the Interventional Cardiology

#### **Case report 2. Male with non-ischemic heart failure**

SPECT scan performed before HBO = EPO therapy

SPECT MPI performed 13.01.2011 Scan pattern - dilatative myocardiopathy non-ischemic type

482

483 Slika 16

**Summary**

484 **Summary** 

485 The field of cardiovascular imaging is changing. In one hand, myocardial perfusion imaging 486 is a well/established clinical technique for the diagnostic and prognostic workup of coronary 487 artery disease. It has been the mainstay of nuclear cardiology for decades. On the other 488 hand, several alternative imaging methodologies for noninvasive functional assessment of

The field of cardiovascular imaging is changing. In one hand, myocardial perfusion imaging is a well/established clinical technique for the diagnostic and prognostic workup of coronary artery disease. It has been the mainstay of nuclear cardiology for decades. On the other hand, several alternative imaging methodologies for noninvasive functional assessment of ischemic heart disease have emerged, and noninvasive coronary angiography is becoming a clinical reality. Nuclear imaging technology has progressed significantly toward higher sensitivity and resolution, and novel, highly specific radiotracers have been introduced. These develop‐ ments are indicator of steady evolution of nuclear cardiology beyond the assessment of myocardial perfusion and toward characterization of biologic events on the tissue level. It is

**RNV** with global and regional ejection fraction performed 03.23. 2011 – after therapy

**RNV** with global and regional ejection fraction performed 01.17. 2011 – before therapy

Radionuclide venticulography performed before and after HBO = EPO therapy when we seen the greatest increase of LVEF with improve wall motion and regional kinetics

Provisional chapter 25

**RNV** with global and regional ejection fraction performed 01.17. 2011 – before therapy

**RNV** with global and regional ejection fraction performed 03.23. 2011 – after therapy

#### 484 **Summary Summary**

483 Slika 16

482

**Case report 2. Male with non-ischemic heart failure**

222 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

SPECT scan performed before HBO = EPO therapy

SPECT MPI performed 13.01.2011

Radionuclide venticulography performed before and after HBO = EPO therapy when we seen

non-ischemic type

the greatest increase of LVEF with improve wall motion and regional kinetics

Scan pattern - dilatative myocardiopathy

485 The field of cardiovascular imaging is changing. In one hand, myocardial perfusion imaging 486 is a well/established clinical technique for the diagnostic and prognostic workup of coronary 487 artery disease. It has been the mainstay of nuclear cardiology for decades. On the other 488 hand, several alternative imaging methodologies for noninvasive functional assessment of The field of cardiovascular imaging is changing. In one hand, myocardial perfusion imaging is a well/established clinical technique for the diagnostic and prognostic workup of coronary artery disease. It has been the mainstay of nuclear cardiology for decades. On the other hand, several alternative imaging methodologies for noninvasive functional assessment of ischemic heart disease have emerged, and noninvasive coronary angiography is becoming a clinical reality. Nuclear imaging technology has progressed significantly toward higher sensitivity and resolution, and novel, highly specific radiotracers have been introduced. These develop‐ ments are indicator of steady evolution of nuclear cardiology beyond the assessment of myocardial perfusion and toward characterization of biologic events on the tissue level. It is hoped that radiotracers techniques, with their unique translational potential and their superior detection sensitivity, will take a leading role in personalized cardiovascular medicine, in which therapeutic and/or preventive strategies are based on individual disease biology. The value of more specific imaging targets, which are increasingly entering clinical practice. This includes imaging of heart failure, absolute quantification of myocardial blood flow, imaging of myocardial metabolism, and imaging of the cardiac autonomic nervous system.

[4] Masud H. Khandaker, Tod D. Miller, Panithaya Chateronthaitawee, J. Wells Askew, David O. Hodge, Raymond J. Gibbons: Stress single photon emission computed to‐ mography for detection of coronary artery disease and risk stratification of asympto‐ matic patients at moderate risk. Journal of Nuclear Cardiology Vol 16, No 4;516-23

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[5] Shaw LJ, Hendel R., Borges-Neto S. Lauer MS: Prognostic value of normal exercise and adenosine (99m) Tc-tetrofosmine SPECT imaging; results from the multicenter

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[7] Michael I. Miyamoto, Sharon L. Vernicoto, Haresh Majmundar, Gregory S. Thomas: Pharmacological stress myocardial perfusion imaging: A practical approach. Journal

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[12] Gary V. Heller, Robert C. Hendel.: Nuclear Cardiology Practical Applications. McGraw-Hill medical Publishing divison. The McGraw-Hill Companies, Inc. Copy‐

[13] Udelson JE., Beshansky JR., Ballin DS.: Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: a randomized control‐

[14] Baskot B., Jankovic Z., Obradovic S., Rusovic S., Orozovic V., Gligic B., Jung R., Iva‐ novic V., Pavlovic M., Ratkovic N.,: Diagnostic significance of myocardial perfusion scintigraphy in identification and localization of culprit lesions in patients undergo‐

registry of 4,728 patients. J Nucl Med 44: 134, 2003

gy. Vojnosanit Pregl. 2009 Mar;66(3):193-8. Serbian.

of Nuclear Cardiology 2007; vol 14 No 2, 250-55

ology vol 17; No 2;216-24 March/April 2010

American Heart Association. Circulation 2002; 105:539–42.

No 4;483-85 July/August 2009

right 2004; 193-243

led trial. JAMA 2002; 288:2693-2700

ing elective PTCA. VSP vol 65; No 2 (158-62) ; 2008

July/August 2009

The goal of this chapter is to provide the reader with a comprehensive overview of the most recent development in nuclear cardiology, in the era of interventional cardiology. It is hoped that the reader, after going through this article, will share the enthusiasm of the author for this discipline, which holds the potential to be a key component in the new paradigm of early detection coronary artery disease for indication for interventional cardiology, as well as assessment new therapeutic effect (HBO + EPO) of heart failure.

## **Author details**

Branislav Baskot1 , Igor Ivanov2 , Dragan Kovacevic2 , Slobodan Obradovic3 , Nenad Ratkovic3 and Miodrag Zivkovic4

1 Private "Clinic Dr Baskot", Belgrade, Serbia

2 Institute for Cardiovascular Disease Sremska Kamenica, Serbia

3 Clinic for Urgent Medicine, Medical Military Academy, Belgrade, Serbia

4 HBO Medical Center, Medical Practice for Hyperbaric Oxygenation Therapy, Belgrade, Serbia

## **References**


[4] Masud H. Khandaker, Tod D. Miller, Panithaya Chateronthaitawee, J. Wells Askew, David O. Hodge, Raymond J. Gibbons: Stress single photon emission computed to‐ mography for detection of coronary artery disease and risk stratification of asympto‐ matic patients at moderate risk. Journal of Nuclear Cardiology Vol 16, No 4;516-23 July/August 2009

hoped that radiotracers techniques, with their unique translational potential and their superior detection sensitivity, will take a leading role in personalized cardiovascular medicine, in which therapeutic and/or preventive strategies are based on individual disease biology. The value of more specific imaging targets, which are increasingly entering clinical practice. This includes imaging of heart failure, absolute quantification of myocardial blood flow, imaging of

The goal of this chapter is to provide the reader with a comprehensive overview of the most recent development in nuclear cardiology, in the era of interventional cardiology. It is hoped that the reader, after going through this article, will share the enthusiasm of the author for this discipline, which holds the potential to be a key component in the new paradigm of early detection coronary artery disease for indication for interventional cardiology, as well as

myocardial metabolism, and imaging of the cardiac autonomic nervous system.

224 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

, Dragan Kovacevic2

, Slobodan Obradovic3

,

assessment new therapeutic effect (HBO + EPO) of heart failure.

, Igor Ivanov2

1 Private "Clinic Dr Baskot", Belgrade, Serbia

drejevic foundation; 2006.

The McGroaw-Hill Companies, Inc. 2004

and Miodrag Zivkovic4

2 Institute for Cardiovascular Disease Sremska Kamenica, Serbia

3 Clinic for Urgent Medicine, Medical Military Academy, Belgrade, Serbia

4 HBO Medical Center, Medical Practice for Hyperbaric Oxygenation Therapy, Belgrade,

[1] ACC/AHA/ASNC Guidelines for the Clinical Use of Cardiac Radionuclide Imaging. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of cardiac Radionuclide Imaging). Journal of the American Coll Cardiol October. 1. 2003. ACC/AHA/ASNC Practice Guidelines 01–69.

[2] Branislav Baskot: Nuclear cardiology - determination of culprit lesion. Belgrade: An‐

[3] Garry V. Heller, Robert C. Hendel: Nuclear Cardiology – practical application 259-71

**Author details**

Branislav Baskot1

Nenad Ratkovic3

Serbia

**References**


[15] Leslee J Shaw, Allen Taylor, Paolo Raggi, Daniel S Berman: Role of noninvasive imaging in asymptomatic high/risk patients. J Nucl Cardiol 2006; vol 13 No2(156-62).

**Section 3**

**Invasive Approach and Interventional**

**Cardiology**


**Invasive Approach and Interventional Cardiology**

[15] Leslee J Shaw, Allen Taylor, Paolo Raggi, Daniel S Berman: Role of noninvasive imaging in asymptomatic high/risk patients. J Nucl Cardiol 2006; vol 13 No2(156-62).

226 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

[16] AN Clarc, GA Beller: The present role of nuclear cardiology in clinical practice. The quarterly journal of Nuclear Medicine and Molecular Imaging. vol. 49 No 1(43-58)

[17] Barry L. Zaret, George A. Beller: Clinical Nuclear Cardiology; state of the art and fu‐

[18] Vasken Dilsizian, Jagat Narula; Atlas of Nuclear Cardiology – second edition. Cur‐

[19] Baskot B, Zivković M, Tepić S, Obradović S.: Evaluation of the therapeutic effect of hyperbaric oxygenation and erithropoietin in the treatment of chronic heart failure using myocardial perfusion scintigraphy G/SPECT. Vojnosanit Pregl. 2009 May;66(5):

[20] Zivkovic Miodrag: Guide for Hyperbaric Medicine. Serbian Health Organization,

[21] Zivkovic M., Todorovic V., Tepic S., Jakovljevic V. Synergistic application of hyper‐ baric oxygenation therapy and erythropoietin in treatment of ch ronic heart failure.

Medical review, No. 1-2, pp. 19/24. Novi Sad Serbia, 2007

March 2005.

399-402.

ture directions. Elsevier Mosby. 2005.

rent medicine LLC 2006.

Belgrade, Serbia. - 2010.

**Chapter 11**

**Coronary Angiography**

Additional information is available at the end of the chapter

Our understanding of the concept of cardiac anatomy and physiology has been greatly en‐ hanced in the last 70 years due to tremendous advances in the field of cardiac catheteriza‐ tion. Cardiac catheterization was first performed methodically and with careful application of scientific methods, by Claude Bernard in 1844. He entered both the left and right ventri‐ cles of a horse through the retrograde approach via the carotid artery and jugular vein.[1]

**Figure 1.** The first fluoroscopic guided view of the right heart catheterization. Klin Wochenschr 1929; 8:2085-87.

and reproduction in any medium, provided the original work is properly cited.

© 2013 Shah; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

This led to a period of intense investigation into the cardiac physiology of animals.

Azarisman Mohd Shah

http://dx.doi.org/10.5772/54043

Springer-Verlag, Berlin, Heidelberg, New York.

**1. Introduction**

**Chapter 11**

## **Coronary Angiography**

Azarisman Mohd Shah

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54043

## **1. Introduction**

Our understanding of the concept of cardiac anatomy and physiology has been greatly en‐ hanced in the last 70 years due to tremendous advances in the field of cardiac catheteriza‐ tion. Cardiac catheterization was first performed methodically and with careful application of scientific methods, by Claude Bernard in 1844. He entered both the left and right ventri‐ cles of a horse through the retrograde approach via the carotid artery and jugular vein.[1] This led to a period of intense investigation into the cardiac physiology of animals.

**Figure 1.** The first fluoroscopic guided view of the right heart catheterization. Klin Wochenschr 1929; 8:2085-87. Springer-Verlag, Berlin, Heidelberg, New York.

© 2013 Shah; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The next step into investigating human physiology was aided greatly by Werner Forssmann who performed the first cardiac catheterization on a living person, having passed a 65 cm catheter through his left antecubital vein and into his right atrium under fluoroscopic guid‐ ance in 1929 (Figure 1).[2] Further development in selective coronary arteriography was generated by Sones and others by 1959 with greater emphasis on better catheterization tech‐ niques, improved radiographic images and less toxic radio-contrast agents. Cumulatively, these developments led to marked improvement in the adoption of cardiac catheterization as an important diagnostic tool.

Andreas Grüntzig then heralded the next great step in cardiac catheterization when he in‐ troduced balloon angioplasty of the coronary arteries in 1977.[3- 5] This led to the mush‐ rooming of cardiac catheterization into the new field of interventional cardiology with ever expanding indications and improved results.[6]

**Figure 3.** The cranial and caudal projections which when combined with the oblique planes, ensures the capture of

Coronary Angiography

231

http://dx.doi.org/10.5772/54043

most normal segments.

**Figure 4.**

**3. Viewing the LAD and LCx**

### **2. Coronary angiographic views**

Accurate diagnosis of a coronary stenosis is dependent on acquiring multiple views to ena‐ ble accurate visualization of all the coronary segments without foreshortening or overlap. This is achieved by maneuvering the image intensifier into the right and left anterior oblique planes and either the cranial or caudal projections as is seen in Figures 2 and 3 below.

**Figure 2.** The right and left anterior oblique planes corresponding to the planes of the AV valves and the interventric‐ ular septum respectively.

**Figure 3.** The cranial and caudal projections which when combined with the oblique planes, ensures the capture of most normal segments.

## **3. Viewing the LAD and LCx**

The next step into investigating human physiology was aided greatly by Werner Forssmann who performed the first cardiac catheterization on a living person, having passed a 65 cm catheter through his left antecubital vein and into his right atrium under fluoroscopic guid‐ ance in 1929 (Figure 1).[2] Further development in selective coronary arteriography was generated by Sones and others by 1959 with greater emphasis on better catheterization tech‐ niques, improved radiographic images and less toxic radio-contrast agents. Cumulatively, these developments led to marked improvement in the adoption of cardiac catheterization

230 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Andreas Grüntzig then heralded the next great step in cardiac catheterization when he in‐

rooming of cardiac catheterization into the new field of interventional cardiology with ever

Accurate diagnosis of a coronary stenosis is dependent on acquiring multiple views to ena‐ ble accurate visualization of all the coronary segments without foreshortening or overlap. This is achieved by maneuvering the image intensifier into the right and left anterior oblique planes and either the cranial or caudal projections as is seen in Figures 2 and 3 below.

**Figure 2.** The right and left anterior oblique planes corresponding to the planes of the AV valves and the interventric‐

5] This led to the mush‐

troduced balloon angioplasty of the coronary arteries in 1977.[3-

as an important diagnostic tool.

expanding indications and improved results.[6]

**2. Coronary angiographic views**

ular septum respectively.

### **4. Viewing the RCA**

[2] Forssmann W. Die Sondierung des rechten Herzens [Probing of the right heart]. Klin

Coronary Angiography

233

http://dx.doi.org/10.5772/54043

[3] Sones FM, Shirley EK, Proudfit WL, Wescott RN. Cine coronary arteriography. Cir‐

[4] Ryan TJ. The coronary angiogram and its seminal contribution to cardiovascular

[5] Grüntzig A, et al. Coronary transluminal angioplasty. Circulation 1977; 56(II):319 (ab‐

[6] King SB 3rd. The development of interventional cardiology. J Am Coll Cardiol 1998;

medicine over five decades. Circulation 2002; 106: 752–56

Wochenschr 1929; 8:2085-87

culation 1959; 20:773 (abstract)

15:31(4 Suppl B):64B-88B

stract)

**Figure 5.**

## **Author details**

Azarisman Mohd Shah

Department of Internal Medicine, Faculty of Medicine, International Islamic University Ma‐ laysia, Pahang, Malaysia

#### **References**

[1] Cournand A. Cardiac catheterization; development of the technique, its contributions to experimental medicine, and its initial applications in man. Acta Med Scand Suppl. 1975; 579:3-32

[2] Forssmann W. Die Sondierung des rechten Herzens [Probing of the right heart]. Klin Wochenschr 1929; 8:2085-87

**4. Viewing the RCA**

232 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Figure 5.**

**Author details**

**References**

Azarisman Mohd Shah

laysia, Pahang, Malaysia

1975; 579:3-32

Department of Internal Medicine, Faculty of Medicine, International Islamic University Ma‐

[1] Cournand A. Cardiac catheterization; development of the technique, its contributions to experimental medicine, and its initial applications in man. Acta Med Scand Suppl.


**Chapter 12**

**Coronary Angiography (IJECCE)**

Additional information is available at the end of the chapter

sions were also included on the committee [1].

The ACC/AHA Task Force on Practice Guidelines herein revises and updates the original "Guidelines for Coronary Angiography," published in 1987 The frequent and still-growing use of coronary angiography, its relatively high costs, its inherent risks and the ongoing evo‐

The expert committee appointed included private practitioners and academicians. Commit‐ tee members were selected to represent both experts in coronary angiography and senior clinician consultants. Representatives from the family practice and internal medicine profes‐

Coronary angiography is defined as the radiographic visualization of the coronary vessels after the injection of radiopaque contrast media. The radiographic images are permanently recorded for future review with either 35 mm cine film or digital recording. Percutaneous or cutdown techniques, usually from the femoral or brachial artery, are used for insertion of special intravascular catheters. Coronary angiography further requires selective cannulation of the ostium of the left and right coronary arteries and, if present, each saphenous vein graft or internal mammary artery graft to obtain optimal selective contrast injection and imaging. Numerous specialized catheters have been designed for this purpose. Physicians performing these procedures must be technically proficient in all aspects of the procedure and have a complete understanding of the clinical indications and risks of the procedure and of coronary anatomy, physiology and pathology. It is also important that these physi‐ cians understand the fundamentals of optimal radiographic imaging and radiation safety. Coronary angiography is usually performed as part of cardiac catheterization, which may also involve angiography of other vessels or cardiac chambers, and hemodynamic assess‐

> © 2013 Wu and Juan; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

lution of its indications have given this revision urgency and priority.

Chiu-Lung Wu and Chi-Wen Juan

http://dx.doi.org/10.5772/54080

**1. Introduction**

**1.1. Definitions**

**Chapter 12**

## **Coronary Angiography (IJECCE)**

Chiu-Lung Wu and Chi-Wen Juan

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54080

## **1. Introduction**

The ACC/AHA Task Force on Practice Guidelines herein revises and updates the original "Guidelines for Coronary Angiography," published in 1987 The frequent and still-growing use of coronary angiography, its relatively high costs, its inherent risks and the ongoing evo‐ lution of its indications have given this revision urgency and priority.

The expert committee appointed included private practitioners and academicians. Commit‐ tee members were selected to represent both experts in coronary angiography and senior clinician consultants. Representatives from the family practice and internal medicine profes‐ sions were also included on the committee [1].

#### **1.1. Definitions**

Coronary angiography is defined as the radiographic visualization of the coronary vessels after the injection of radiopaque contrast media. The radiographic images are permanently recorded for future review with either 35 mm cine film or digital recording. Percutaneous or cutdown techniques, usually from the femoral or brachial artery, are used for insertion of special intravascular catheters. Coronary angiography further requires selective cannulation of the ostium of the left and right coronary arteries and, if present, each saphenous vein graft or internal mammary artery graft to obtain optimal selective contrast injection and imaging. Numerous specialized catheters have been designed for this purpose. Physicians performing these procedures must be technically proficient in all aspects of the procedure and have a complete understanding of the clinical indications and risks of the procedure and of coronary anatomy, physiology and pathology. It is also important that these physi‐ cians understand the fundamentals of optimal radiographic imaging and radiation safety. Coronary angiography is usually performed as part of cardiac catheterization, which may also involve angiography of other vessels or cardiac chambers, and hemodynamic assess‐

© 2013 Wu and Juan; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ment as needed for a complete invasive diagnostic evaluation of the individual patient's car‐ diovascular condition[2,3].

discomfort due to myocardial ischemia, often described as a transient squeezing, pressurelike precordial discomfort. Angina is generally provoked by physical effort (particularly during the postprandial state), with exposure to cold environment or by emotional stress. The discomfort on effort is relieved by rest, its duration being a matter of minutes. The ease of provocation, frequency and duration of episodes may remain relatively unchanged in in‐

Coronary Angiography (IJECCE) http://dx.doi.org/10.5772/54080 237

**Recommendations for Coronary Angiography in Patients With Nonspecific Chest Pain**

Patients with recurrent hospitalizations for chest pain who have abnormal (but not high-

The acute coronary syndromes include unstable angina, non–Q-wave MI, and acute Q-wave MI. The diagnosis of unstable angina has been complicated by a broad range of presenta‐ tions that can vary between atypical chest pain and acute MI. An expert panel of clinicians attempted to clarify the definition of unstable angina in the recently published "Clinical Practice Guideline for Unstable Angina"[129,130]. Three possible presentations are descri‐

**•** Recent (<2 months) acceleration of angina as reflected by an increase in severity of at least

Variant angina, non–Q-wave MI and recurrent angina24 hours after MI are considered part of the spectrum of unstable angina. However, in this document, non–Q-wave MI is dis‐

**Recommendations for Coronary Angiography in Patients With Postrevascularization Is‐**

**1.** Suspected abrupt closure or subacute stent thrombosis after percutaneous revasculari‐

dividuals for extended time periods, leading to the term "stable angina pectoris."

High-risk findings on noninvasive testing. *(Level of Evidence: B)*

risk) or equivocal findings on noninvasive testing. *(Level of Evidence: B)*

All other patients with nonspecific chest pain. *(Level of Evidence: C)*

**•** Symptoms of angina at rest (usually prolonged 20 minutes);

one CCS class to at least CCS class III.[4,5]

cussed in the section on acute MI. [4,5]

zation. *(Level of Evidence: B)*

**•** New-onset (<2 months) exertional angina of at least CCS class III in severity;

**Class I**

**Class IIa: None.**

**Class IIb:**

**Class III:**

bed:

**chemia**

**Class I**

**2.3. Unstable angina**

#### **1.2. Purpose**

The purpose of coronary angiography is to define coronary anatomy and the degree of lumi‐ nal obstruction of the coronary arteries. Information obtained from the procedure includes identification of the location, length, diameter, and contour of the coronary arteries; the presence and severity of coronary luminal obstruction(s); characterization of the nature of the obstruction (including the presence of atheroma, thrombus, dissection, spasm, or myo‐ cardial bridging), and an assessment of blood flow. In addition, the presence and extent of coronary collateral vessels can be assessed.

Coronary angiography remains the standard for assessment of anatomic coronary disease, because no other currently available test can accurately define the extent of coronary lumi‐ nal obstruction. Because the technique can only provide information about abnormalities that narrow the lumen, it is limited in its ability to accurately define the etiology of the ob‐ struction or detect the presence of nonobstructive atherosclerotic disease.A coronary angiog‐ raphy, which can help diagnose heart conditions, is the most common type of heart catheter procedure. [2,3]

## **2. Coronary angiography for specific conditions**

#### **2.1. General considerations**

Coronary atherosclerosis is a slowly progressive process that can be clinically inapparent for long periods of time [78–80]. Coronary disease often becomes clinically evident because of the occurrence of symptoms, such as angina or those associated with MI. Patients with known CAD are those in whom the disease has been documented by either angiography or MI. "Suspected coronary disease" means that a patient's symptoms or other clinical charac‐ teristics suggest a high likelihood for significant CAD and its related adverse outcomes but that evidence of CAD has not yet been documented as defined above.

Patients may develop symptoms at one point in time but may become asymptomatic there‐ after as the result of a change in the disease or as the result of therapy. For instance, many patients are symptomatic after an uncomplicated MI, as are patients with mild angina, who can be rendered asymptomatic by medications. The severity of clinical presentations and the degree of provocable ischemia on noninvasive testing are the principal factors used in deter‐ mining the appropriateness of coronary angiography.

#### **2.2. Stable angina**

Patients with CAD may become symptomatic in many different ways but most commonly develop angina pectoris. In this document, angina pectoris (or simply angina) means a chest discomfort due to myocardial ischemia, often described as a transient squeezing, pressurelike precordial discomfort. Angina is generally provoked by physical effort (particularly during the postprandial state), with exposure to cold environment or by emotional stress. The discomfort on effort is relieved by rest, its duration being a matter of minutes. The ease of provocation, frequency and duration of episodes may remain relatively unchanged in in‐ dividuals for extended time periods, leading to the term "stable angina pectoris."

### **Recommendations for Coronary Angiography in Patients With Nonspecific Chest Pain Class I**

High-risk findings on noninvasive testing. *(Level of Evidence: B)*

#### **Class IIa: None.**

#### **Class IIb:**

ment as needed for a complete invasive diagnostic evaluation of the individual patient's car‐

236 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The purpose of coronary angiography is to define coronary anatomy and the degree of lumi‐ nal obstruction of the coronary arteries. Information obtained from the procedure includes identification of the location, length, diameter, and contour of the coronary arteries; the presence and severity of coronary luminal obstruction(s); characterization of the nature of the obstruction (including the presence of atheroma, thrombus, dissection, spasm, or myo‐ cardial bridging), and an assessment of blood flow. In addition, the presence and extent of

Coronary angiography remains the standard for assessment of anatomic coronary disease, because no other currently available test can accurately define the extent of coronary lumi‐ nal obstruction. Because the technique can only provide information about abnormalities that narrow the lumen, it is limited in its ability to accurately define the etiology of the ob‐ struction or detect the presence of nonobstructive atherosclerotic disease.A coronary angiog‐ raphy, which can help diagnose heart conditions, is the most common type of heart catheter

Coronary atherosclerosis is a slowly progressive process that can be clinically inapparent for long periods of time [78–80]. Coronary disease often becomes clinically evident because of the occurrence of symptoms, such as angina or those associated with MI. Patients with known CAD are those in whom the disease has been documented by either angiography or MI. "Suspected coronary disease" means that a patient's symptoms or other clinical charac‐ teristics suggest a high likelihood for significant CAD and its related adverse outcomes but

Patients may develop symptoms at one point in time but may become asymptomatic there‐ after as the result of a change in the disease or as the result of therapy. For instance, many patients are symptomatic after an uncomplicated MI, as are patients with mild angina, who can be rendered asymptomatic by medications. The severity of clinical presentations and the degree of provocable ischemia on noninvasive testing are the principal factors used in deter‐

Patients with CAD may become symptomatic in many different ways but most commonly develop angina pectoris. In this document, angina pectoris (or simply angina) means a chest

diovascular condition[2,3].

coronary collateral vessels can be assessed.

**2. Coronary angiography for specific conditions**

that evidence of CAD has not yet been documented as defined above.

mining the appropriateness of coronary angiography.

**1.2. Purpose**

procedure. [2,3]

**2.2. Stable angina**

**2.1. General considerations**

Patients with recurrent hospitalizations for chest pain who have abnormal (but not highrisk) or equivocal findings on noninvasive testing. *(Level of Evidence: B)*

#### **Class III:**

All other patients with nonspecific chest pain. *(Level of Evidence: C)*

#### **2.3. Unstable angina**

The acute coronary syndromes include unstable angina, non–Q-wave MI, and acute Q-wave MI. The diagnosis of unstable angina has been complicated by a broad range of presenta‐ tions that can vary between atypical chest pain and acute MI. An expert panel of clinicians attempted to clarify the definition of unstable angina in the recently published "Clinical Practice Guideline for Unstable Angina"[129,130]. Three possible presentations are descri‐ bed:


Variant angina, non–Q-wave MI and recurrent angina24 hours after MI are considered part of the spectrum of unstable angina. However, in this document, non–Q-wave MI is dis‐ cussed in the section on acute MI. [4,5]

#### **Recommendations for Coronary Angiography in Patients With Postrevascularization Is‐ chemia**

#### **Class I**

**1.** Suspected abrupt closure or subacute stent thrombosis after percutaneous revasculari‐ zation. *(Level of Evidence: B)*

**2.** Recurrent angina or high-risk criteria on noninvasive evaluation (Table 5) within nine months of percutaneous revascularization. *(Level of Evidence: C)*

amine in detail the merits of these two reperfusion strategies, this is a rapidly evolving area,

Coronary Angiography (IJECCE) http://dx.doi.org/10.5772/54080 239

**Recommendations for coronary angiography during the initial management of acute MI**

**1.** As an alternative to thrombolytic therapy in patients who can undergo angioplasty of the infarct artery within 12 hours of the onset of symptoms or beyond 12 hours if ische‐

**2.** In patients who are within 36 hours of an acute ST elevation/Q-wave or new LBBB MI who develop cardiogenic shock, are less than 75 years of age and revascularization can

**1.** As a reperfusion strategy in patients who are candidates for reperfusion but who have a contraindication to fibrinolytic therapy, if angioplasty can be performed as outlined

**1.** In patients who are beyond 12 hours from onset of symptoms and who have no evi‐

**2.** In patients who are eligible for thrombolytic therapy and are undergoing primary an‐ gioplasty by an unskilled operator in a laboratory that does not have surgical capability.

**Recommendations for early coronary angiography in the patient with suspected MI (ST-**

**1.** Evolving large or anterior infarction after Thrombolytic treatment when it is believed that reperfusion has not occurred and rescue PTCA is planned. (Level of Evidence: B)

**2.** Marginal hemodynamic status but not actual cardiogenic shock.(Level of Evidence: C)

**1.** In patients who have received thrombolytic therapy and have no symptoms of ische‐

**2.** Routine use of angiography and subsequent PTCA within 24 hours of administration of

**Class IIa:** Cardiogenic shock or persistent hemodynamic instability.*(Level of Evidence: B)*

**segment elevation or BBB present) who has not undergone primary PTCA**

**(MI suspected and ST-segment elevation or bundle-branch block present) Coronary angiography coupled with the intent to perform primary PTCA**

be performed within 18 hours of the onset of shock

dence of myocardial ischemia. (Level of Evidence: A)

above in class I. (Level of Evidence: C)

and some new information exists.

mic symptoms persist.

(Level of Evidence: B)

mia. *(Level of Evidence:A)*

thrombolytic agents. *(Level of Evidence: A)*

**Class I**

**Class IIa**

**Class III**

**Class I: None.**

**Class IIb:**

**Class III**

#### **Class IIa**


#### **Class IIb**


#### **Class III**


#### **Coronary angiography during the initial management of patients in the emergency de‐ partment**

Patients Presenting With Suspected MI and ST- segment Elevation or Bundle-Branch Block Of all patients who ultimately are diagnosed with acute MI, those resenting with ST-seg‐ ment elevation have been studied most extensively. Patients with ST-segment elevation have a high likelihood of thrombus occluding the infarct-related artery [6,7]. Considerable data exist showing that coronary reperfusion can be accomplished either by intravenous thrombolytic therapy or direct mechanical intervention within the infarct-related artery. Be‐ cause the benefit obtained is directly linked to the time required to reestablish normal distal blood flow [8–10], rapid triage decisions are mandatory, and delays in instituting reperfu‐ sion therapy must be minimized. The "ACC/AHA Guidelines for the Management of Pa‐ tients with Acute Myocardial Infarction" provide a comprehensive discussion of the indications, contraindications, advantages, and disadvantages of thrombolytic therapy and direct coronary angioplasty [11]. Although it is not the purpose of these guidelines to re-ex‐ amine in detail the merits of these two reperfusion strategies, this is a rapidly evolving area, and some new information exists.

#### **Recommendations for coronary angiography during the initial management of acute MI (MI suspected and ST-segment elevation or bundle-branch block present)**

#### **Coronary angiography coupled with the intent to perform primary PTCA**

## **Class I**

**2.** Recurrent angina or high-risk criteria on noninvasive evaluation (Table 5) within nine

**1.** Recurrent symptomatic ischemia within 12 months of CABG. (Level of Evidence: B)

**2.** Noninvasive evidence of high-risk criteria occurring at any time postoperatively. (Level

**3.** Recurrent angina inadequately controlled by medical means after revascularization.

**1.** Asymptomatic post-PTCA patient suspected of having restenosis within the first months after angioplasty because of an abnormal noninvasive test but without noninva‐

**2.** Recurrent angina without high-risk criteria on noninvasive testing occurring >1 year

**3.** Asymptomatic postbypass patient in whom a deterioration in serial noninvasive testing has been documented but who is not high risk on noninvasive testing. *(Level of Evidence:*

**1.** Symptoms in a postbypass patient who is not a candidate for repeat revascularization.

**2.** Routine angiography in asymptomatic patients after PTCA or other surgery, unless as

**Coronary angiography during the initial management of patients in the emergency de‐**

Patients Presenting With Suspected MI and ST- segment Elevation or Bundle-Branch Block Of all patients who ultimately are diagnosed with acute MI, those resenting with ST-seg‐ ment elevation have been studied most extensively. Patients with ST-segment elevation have a high likelihood of thrombus occluding the infarct-related artery [6,7]. Considerable data exist showing that coronary reperfusion can be accomplished either by intravenous thrombolytic therapy or direct mechanical intervention within the infarct-related artery. Be‐ cause the benefit obtained is directly linked to the time required to reestablish normal distal blood flow [8–10], rapid triage decisions are mandatory, and delays in instituting reperfu‐ sion therapy must be minimized. The "ACC/AHA Guidelines for the Management of Pa‐ tients with Acute Myocardial Infarction" provide a comprehensive discussion of the indications, contraindications, advantages, and disadvantages of thrombolytic therapy and direct coronary angioplasty [11]. Although it is not the purpose of these guidelines to re-ex‐

part of an approved research protocol. *(Level of Evidence: C)*

months of percutaneous revascularization. *(Level of Evidence: C)*

238 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Class IIa**

**Class IIb**

*C)*

**Class III**

**partment**

of Evidence:B)

(Level of Evidence: C)

*(Level of Evidence: C)*

sive high-risk criteria. *(Level of Evidence: B)*

postoperatively. *(Level of Evidence: C)*


#### **Class IIa**

**1.** As a reperfusion strategy in patients who are candidates for reperfusion but who have a contraindication to fibrinolytic therapy, if angioplasty can be performed as outlined above in class I. (Level of Evidence: C)

#### **Class III**


#### **Recommendations for early coronary angiography in the patient with suspected MI (STsegment elevation or BBB present) who has not undergone primary PTCA**

#### **Class I: None.**

**Class IIa:** Cardiogenic shock or persistent hemodynamic instability.*(Level of Evidence: B)*

#### **Class IIb:**


#### **Class III**


#### **Recommendations for early coronary angiography in acute MI (MI suspected but no stsegment elevation)**

**2.** In asymptomatic patients when cardiac surgery is not being considered. (Level of Evi‐

Coronary Angiography (IJECCE) http://dx.doi.org/10.5772/54080 241

**3.** Before cardiac surgery when preoperative hemodynamic assessment by catheterization is unnecessary, and there is neither preexisting evidence for coronary disease, nor risk

Although there are no large trials to support its use, coronary angiography is performed in congenital heart disease for two broad categorical indications. The first indication is to as‐ sess the hemodynamic impact of congenital coronary lesions (375). The second is to assess the presence of coronary anomalies, which by themselves may be innocent but whose pres‐ ence, if unrecognized, may lead to coronary injury during the correction of other congenital heart lesions. Congenital anomalies with hemodynamic significance include congenital coro‐ nary artery stenosis or atresia, coronary artery fistula [11], anomalous left coronary artery arising from the pulmonary artery [12], and anomalous left coronary artery arising from the right coronary artery or right sinus of Valsalva and passing between the aorta and right ven‐ tricular outflow tract [13]. Patients with congenital coronary stenosis may present with angi‐ na or unexplained sudden death in childhood, whereas patients whose left coronary passes between the pulmonary artery and aorta often have the same symptoms later in life. Patients with a coronary arteriovenous fistula often present with a continuous murmur or may have unexplained angina or congestive heart failure. Anomalous origin of the left coronary artery from the pulmonary artery should be suspected when there is unexplained MI or heart fail‐ ure in early childhood. Other coronary anomalies of position or origin may cause no physio‐ logic abnormality by themselves. Some, such as origin of the circumflex artery from the right sinus of Valsalva, are not associated with other congenital anomalies and present only as incidental findings and are significant only because they complicate the performance and

**Recommendations for use of coronary angiography in patients with congenital heart dis‐**

**1.** Before surgical correction of congenital heart disease when chest discomfort or nonin‐

**2.** Before surgical correction of suspected congenital coronary anomalies such as congeni‐ tal coronary artery stenosis, coronary arteriovenous fistula and anomalous origin of left

**3.** Forms of congenital heart disease frequently associated with coronary artery anomalies

vasive evidence is suggestive of associated CAD. (Level of Evidence: C)

that may complicate surgical management. (Level of Evidence: C)

**4.** Unexplained cardiac arrest in a young patient. (Level of Evidence: B)

dence: C)

**Congenital heart disease**

factors for CAD. (Level of Evidence: C)

interpretation of coronary angiograms.

coronary artery. (Level of Evidence: C)

**ease**

**Class I**

#### **Class I**


**Class II:** None.

**Class III:** None.

#### **Hospital-management phase of acute MI**

The hospital-management phase of acute MI can encompass several clinical situations. Some patients with acute MI present too late in their course to be candidates for reperfusion thera‐ py, and in others, the occurrence of infarction may not be appreciated at he time of presenta‐ tion. These groups skip the acute-treatment phase of MI and enter the hospital-management phase directly. During the hospital management phase, the actions of the clinician are driv‐ en by the consequences of the infarction, such as congestive heart failure, hemodynamic in‐ stability, recurrent ischemia or arrhythmias. Although it is still convenient to divide patients into those with Q-wave and non–Q-wave infarctions, some indications for coronary angiog‐ raphy are common to all patients with MI regardless of how they have been treated initially and whether or not Q waves ultimately develop.

#### **Recommendations for use of coronary angiography in patients with valvular heart dis‐ ease Class I**


#### **Class IIa**

None.

#### **Class IIb**

During left-heart catheterization performed for hemodynamic evaluation before aortic or mitral valve surgery in patients without preexisting evidence of coronary disease, multiple CAD risk factors or advanced age. (Level of Evidence: C)

#### **Class III**

**1.** Before cardiac surgery for infective endocarditis when there are no risk factors for coro‐ nary disease and no evidence of coronary embolization. (Level of Evidence: C)


### **Congenital heart disease**

**Recommendations for early coronary angiography in acute MI (MI suspected but no st-**

**1.** Persistent or recurrent (stuttering) episodes of symptomatic ischemia, spontaneous or

**2.** The presence of shock, severe pulmonary congestion,or continuing hypotension. (Level

The hospital-management phase of acute MI can encompass several clinical situations. Some patients with acute MI present too late in their course to be candidates for reperfusion thera‐ py, and in others, the occurrence of infarction may not be appreciated at he time of presenta‐ tion. These groups skip the acute-treatment phase of MI and enter the hospital-management phase directly. During the hospital management phase, the actions of the clinician are driv‐ en by the consequences of the infarction, such as congestive heart failure, hemodynamic in‐ stability, recurrent ischemia or arrhythmias. Although it is still convenient to divide patients into those with Q-wave and non–Q-wave infarctions, some indications for coronary angiog‐ raphy are common to all patients with MI regardless of how they have been treated initially

**Recommendations for use of coronary angiography in patients with valvular heart dis‐**

**1.** Before valve surgery or balloon valvotomy in an adult with chest discomfort, ischemia

**2.** Before valve surgery in an adult free of chest pain but with multiple risk factors for cor‐

**3.** Infective endocarditis with evidence of coronary embolization. (Level of Evidence: C)

During left-heart catheterization performed for hemodynamic evaluation before aortic or mitral valve surgery in patients without preexisting evidence of coronary disease, multiple

**1.** Before cardiac surgery for infective endocarditis when there are no risk factors for coro‐ nary disease and no evidence of coronary embolization. (Level of Evidence: C)

induced, with or without associated ECG changes. (Level of Evidence:A)

240 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**segment elevation)**

of Evidence: B)

**Hospital-management phase of acute MI**

and whether or not Q waves ultimately develop.

onary disease. (Level of Evidence: C)

by noninvasive imaging, or both. (Level of Evidence: B)

CAD risk factors or advanced age. (Level of Evidence: C)

**Class II:** None. **Class III:** None.

**ease Class I**

**Class IIa** None. **Class IIb**

**Class III**

**Class I**

Although there are no large trials to support its use, coronary angiography is performed in congenital heart disease for two broad categorical indications. The first indication is to as‐ sess the hemodynamic impact of congenital coronary lesions (375). The second is to assess the presence of coronary anomalies, which by themselves may be innocent but whose pres‐ ence, if unrecognized, may lead to coronary injury during the correction of other congenital heart lesions. Congenital anomalies with hemodynamic significance include congenital coro‐ nary artery stenosis or atresia, coronary artery fistula [11], anomalous left coronary artery arising from the pulmonary artery [12], and anomalous left coronary artery arising from the right coronary artery or right sinus of Valsalva and passing between the aorta and right ven‐ tricular outflow tract [13]. Patients with congenital coronary stenosis may present with angi‐ na or unexplained sudden death in childhood, whereas patients whose left coronary passes between the pulmonary artery and aorta often have the same symptoms later in life. Patients with a coronary arteriovenous fistula often present with a continuous murmur or may have unexplained angina or congestive heart failure. Anomalous origin of the left coronary artery from the pulmonary artery should be suspected when there is unexplained MI or heart fail‐ ure in early childhood. Other coronary anomalies of position or origin may cause no physio‐ logic abnormality by themselves. Some, such as origin of the circumflex artery from the right sinus of Valsalva, are not associated with other congenital anomalies and present only as incidental findings and are significant only because they complicate the performance and interpretation of coronary angiograms.

#### **Recommendations for use of coronary angiography in patients with congenital heart dis‐ ease**

#### **Class I**


#### **Class IIa**

Before corrective open heart surgery for congenital heart disease in an adult whose risk pro‐ file increases the likelihood of coexisting coronary disease. (Level of Evidence: C)

**2.** Before cardiac transplantation. (Level of Evidence: C)

**Class IIa**

**Class III**

dence: C)

**1. Aortic dissection**

performed [23].

**3. Arteritis**

**2. Hypertrophic cardiomyopathy**

chanical complications of MI. (Level of Evidence: C)

mediated left ventricular dysfunction. (Level of Evidence: C)

**3.** Congestive heart failure secondary to postinfarction ventricular aneurysm or other me‐

Coronary Angiography (IJECCE) http://dx.doi.org/10.5772/54080 243

**1.** Systolic dysfunction with unexplained cause despite noninvasive testing. (Level of Evi‐

**2.** Normal systolic function, but episodic heart failure raises suspicion of ischemically

Congestive heart failure with previous coronary angiograms showing normal coronary ar‐

The need for coronary angiography before surgical treatment for aortic dissection re‐ mains controversial because there are no large trials to support its use. In young patients with dissection due to Marfan syndrome or in dissection in peripartum females, coronary angiography is unnecessary unless there is suspicion that the dissection has affected one or both coronary ostia. In older patients, in whom dissection is usually related to hyper‐ tension, coronary angiography is often necessary, especially if patients are suspected of having coronary disease because of a history of angina or objective evidence of myocar‐ dial ischemia. In patients who have no history of coronary disease, the indications for cor‐ onary angiography are much less certain. Because of the high incidence of coronary disease in older patients with dissection, some studies have advocated routine coronary angiography [22], whereas others have found increased mortality when angiography is

Significant CAD due to atherosclerosis is found in 25% of patients aged >45 years with hy‐ pertrophic cardiomyopathy [26]. Because symptoms due to CAD and hypertrophic cardio‐ myopathy are similar, patients with ischemic symptoms not well controlled with medical therapy may require coronary angiography to resolve the cause of chest pain. Coronary an‐ giography also is indicated in patients with chest discomfort and hypertrophic cardiomyop‐

Some patients with inflammatory processes affecting the aorta, such as Takayasu arteritis, may have coronary artery involvement requiring coronary artery revascularization. In such patients, coronary angiography is required before the surgical procedure. Kawasaki disease can result in coronary artery aneurysm and coronary artery stenosis producing myocardial ischemia or silent occlusion and may require coronary angiographic assessment [24,25].

athy in whom a surgical procedure is planned to correct outflow tract obstruction.

teries, with no new evidence to suggest ischemic heart disease. (Level of Evidence: C)

#### **Class IIb**

During left-heart catheterization for hemodynamic assessment of congenital heart disease in an adult in whom the risk of coronary disease is not high. (Level of Evidence: C)

#### **Class III**

In the routine evaluation of congenital heart disease in asymptomatic patients for whom heart surgery is not planned. (Level of Evidence: C)

#### **Congestive heart failure**

#### **1. Systolic dysfunction**

Although it was once believed that myocardial ischemia was either short-lived and resulted in little or no muscle dysfunction or resulted in infarction with permanent damage, it is now clear that a middle state may exist in which chronic ischemic nonfunctioning myocardium is present, to which function may return after myocardial revascularizations [15,16]. This inter‐ mediate state has been termed "myocardial hibernation." Although most cases of myocar‐ dial dysfunction resulting from CAD are probably irreversible when due to infarction and subsequent deleterious ventricular remodeling (ischemic cardiomyopathy) [17], some pa‐ tients with hibernating myocardium have been shown to experience a doubling of resting ejection fraction with resolution of congestive heart failure after coronary revascularization [18,19]. However, in most cases of hibernation, a more modest improvement in ejection frac‐ tion of 5% occurs after revascularization [20].

#### **2. Diastolic dysfunction**

Isolated diastolic dysfunction is the cause of heart failure in 10% to 30% of affected patients. This disorder is common in older patients with hypertension and often is suspected because of echocardiographically detected concentric left ventricular hypertrophy, normal systolic func‐ tion and abnormal transmitral flow velocity patterns [21]. However, in some patients with nor‐ mal systolic function, the abrupt onset of pulmonary edema raises the suspicion that transient ischemia was the cause of decompensation, because elderly patients with hypertension have, by definition, at least two risk factors for coronary disease. In these patients, who are often too ill to undergo stress testing, coronary angiography may be necessary to establish or rule out the diagnosis of ischemically related diastolic dysfunction and heart failure.

#### **Recommendations for use of coronary angiography in patients with congestive heart fail‐ ure**

#### **Class I**

**1.** Congestive heart failure due to systolic dysfunction with angina or with regional wall motion abnormalities and/or scintigraphic evidence of reversible myocardial ischemia when revascularization is being considered. (Level of Evidence: B)


#### **Class IIa**

**Class IIa**

**Class IIb**

**Class III**

**Congestive heart failure**

**1. Systolic dysfunction**

**2. Diastolic dysfunction**

**ure**

**Class I**

Before corrective open heart surgery for congenital heart disease in an adult whose risk pro‐

During left-heart catheterization for hemodynamic assessment of congenital heart disease in

In the routine evaluation of congenital heart disease in asymptomatic patients for whom

Although it was once believed that myocardial ischemia was either short-lived and resulted in little or no muscle dysfunction or resulted in infarction with permanent damage, it is now clear that a middle state may exist in which chronic ischemic nonfunctioning myocardium is present, to which function may return after myocardial revascularizations [15,16]. This inter‐ mediate state has been termed "myocardial hibernation." Although most cases of myocar‐ dial dysfunction resulting from CAD are probably irreversible when due to infarction and subsequent deleterious ventricular remodeling (ischemic cardiomyopathy) [17], some pa‐ tients with hibernating myocardium have been shown to experience a doubling of resting ejection fraction with resolution of congestive heart failure after coronary revascularization [18,19]. However, in most cases of hibernation, a more modest improvement in ejection frac‐

Isolated diastolic dysfunction is the cause of heart failure in 10% to 30% of affected patients. This disorder is common in older patients with hypertension and often is suspected because of echocardiographically detected concentric left ventricular hypertrophy, normal systolic func‐ tion and abnormal transmitral flow velocity patterns [21]. However, in some patients with nor‐ mal systolic function, the abrupt onset of pulmonary edema raises the suspicion that transient ischemia was the cause of decompensation, because elderly patients with hypertension have, by definition, at least two risk factors for coronary disease. In these patients, who are often too ill to undergo stress testing, coronary angiography may be necessary to establish or rule out the

**Recommendations for use of coronary angiography in patients with congestive heart fail‐**

**1.** Congestive heart failure due to systolic dysfunction with angina or with regional wall motion abnormalities and/or scintigraphic evidence of reversible myocardial ischemia

diagnosis of ischemically related diastolic dysfunction and heart failure.

when revascularization is being considered. (Level of Evidence: B)

file increases the likelihood of coexisting coronary disease. (Level of Evidence: C)

242 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

an adult in whom the risk of coronary disease is not high. (Level of Evidence: C)

heart surgery is not planned. (Level of Evidence: C)

tion of 5% occurs after revascularization [20].


#### **Class III**

Congestive heart failure with previous coronary angiograms showing normal coronary ar‐ teries, with no new evidence to suggest ischemic heart disease. (Level of Evidence: C)

#### **1. Aortic dissection**

The need for coronary angiography before surgical treatment for aortic dissection re‐ mains controversial because there are no large trials to support its use. In young patients with dissection due to Marfan syndrome or in dissection in peripartum females, coronary angiography is unnecessary unless there is suspicion that the dissection has affected one or both coronary ostia. In older patients, in whom dissection is usually related to hyper‐ tension, coronary angiography is often necessary, especially if patients are suspected of having coronary disease because of a history of angina or objective evidence of myocar‐ dial ischemia. In patients who have no history of coronary disease, the indications for cor‐ onary angiography are much less certain. Because of the high incidence of coronary disease in older patients with dissection, some studies have advocated routine coronary angiography [22], whereas others have found increased mortality when angiography is performed [23].

#### **2. Hypertrophic cardiomyopathy**

Significant CAD due to atherosclerosis is found in 25% of patients aged >45 years with hy‐ pertrophic cardiomyopathy [26]. Because symptoms due to CAD and hypertrophic cardio‐ myopathy are similar, patients with ischemic symptoms not well controlled with medical therapy may require coronary angiography to resolve the cause of chest pain. Coronary an‐ giography also is indicated in patients with chest discomfort and hypertrophic cardiomyop‐ athy in whom a surgical procedure is planned to correct outflow tract obstruction.

#### **3. Arteritis**

Some patients with inflammatory processes affecting the aorta, such as Takayasu arteritis, may have coronary artery involvement requiring coronary artery revascularization. In such patients, coronary angiography is required before the surgical procedure. Kawasaki disease can result in coronary artery aneurysm and coronary artery stenosis producing myocardial ischemia or silent occlusion and may require coronary angiographic assessment [24,25].

#### **4. Chest trauma**

Patients who have an acute MI shortly after blunt or penetrating chest trauma may have atherosclerotic CAD, but coronary artery obstruction or damage has been reported in the ab‐ sence of coronary atherosclerosis [27]. Furthermore, myocardial contusion may simulate acute MI. Infrequently, coronary angiography is indicated in the management of such pa‐ tients.

dicates the precision of coronary angiography to be 0.02 to 0.04 mm. Factors that limit reso‐ lution in the clinical setting include grainy films from "quantum mottling" and motion artifact that, in a clinical setting, limit resolution to 0.2 mm, far less than that realized from static images of known phantoms. Other factors, such as angulation, overlap of vessels and image tube resolution can also influence accuracy in the clinical setting. Nevertheless, the accuracy of coronary angiography does allow for anatomic detail that is not obtainable by current noninvasive or other invasive technology. Only intravascular ultrasound, which is discussed in Appendix C, has an image resolution greater than that of coronary angiogra‐ phy. However, intravascular ultrasound cannot visualize the entire coronary tree nor define the anatomic course of the coronary vessels. It is also limited by shadowing from heavy cal‐

Coronary Angiography (IJECCE) http://dx.doi.org/10.5772/54080 245

Recent advances in computer storage technology have made feasible digital acquisition, processing and archival storage of angiographic images obtained during cardiac catheteriza‐ tion. Widespread conversion from cineangiographic film to digital archiving and storage is anticipated during the next decade. Analog storage technologies such as super VHS video‐ tape and analog optical disks have inadequate resolution to faithfully record coronary an‐ giography. Digital storage methods are generally adequate but until recently have lacked standardization, which precluded easy exchange of digital angiograms between centers with different equipment. The development of the Digital Imaging and Communication standard (DICOM) for cardiac angiography ensures compatibility between equipment from

In the interventional era, the advantages of digital angiography are important. The image quality provided by digital angiography is better than any common videotape format. Im‐ provements in computer speed and processing capability enable rapid replay of coronary injection sequences, as well as evaluation of the results of each intervention and identifica‐ tion of complications such as intraluminal thrombus and dissection. In many laboratories, the availability of high-quality images during catheterization permits diagnostic and thera‐ peutic catheterization to consist of a single procedure, a capability with significant implica‐ tions for the cost of interventional procedures. Industry sources now estimate that >75% of

The ACC Cardiac Catheterization Committee is coordinating efforts to develop and pro‐ mote a standard for archival storage and exchange of digital cardiac angiography. The com‐ mittee has joined in this common cause with an industry organization, the National Electrical Manufacturers Association (NEMA), and representatives of the American College of Radiology (ACR). The ACR and NEMA have recently released an interim standard

The initial efforts of the standards committee have focused on adoption of a file format and physical medium for interchange of digital angiographic studies. To transfer images be‐ tween medical centers, the sender would generate a DICOM-compatible file for review by the receiver. Recently, this working group has chosen a recordable form of the common CD-

existing laboratories are equipped with digital imaging capability.

known as Digital Imaging Communication in Medicine (DICOM version 3.0).

cification and by its inability to image very small vessels or very severe stenosis.

**3.2. Digital imaging of coronary angiography**

participating vendors.

#### **Recommendations for use of coronary angiography in other conditions**

#### **Class I**


#### **Class IIa**


## **3. Special considerations regarding coronary angiography**

#### **3.1. Accuracy**

Cineangiographic images of coronary arteries have been the principal clinical tool for deter‐ mining the severity of coronary luminal stenosis. Modern angiographic equipment has a resolution of four to five line pairs per millimeter with a six-inch field of view, the usual im‐ age magnification for coronary angiography [28]. Validation studies that use known phan‐ toms show a high correlation between actual size and that measured by quantitative coronary angiography (QCA) (r = 0.95) [29–32]. The resolution of these phantom studies in‐ dicates the precision of coronary angiography to be 0.02 to 0.04 mm. Factors that limit reso‐ lution in the clinical setting include grainy films from "quantum mottling" and motion artifact that, in a clinical setting, limit resolution to 0.2 mm, far less than that realized from static images of known phantoms. Other factors, such as angulation, overlap of vessels and image tube resolution can also influence accuracy in the clinical setting. Nevertheless, the accuracy of coronary angiography does allow for anatomic detail that is not obtainable by current noninvasive or other invasive technology. Only intravascular ultrasound, which is discussed in Appendix C, has an image resolution greater than that of coronary angiogra‐ phy. However, intravascular ultrasound cannot visualize the entire coronary tree nor define the anatomic course of the coronary vessels. It is also limited by shadowing from heavy cal‐ cification and by its inability to image very small vessels or very severe stenosis.

#### **3.2. Digital imaging of coronary angiography**

**4. Chest trauma**

tients.

**Class I**

**Class IIa**

ease.

**3.1. Accuracy**

Evidence: B)

Patients who have an acute MI shortly after blunt or penetrating chest trauma may have atherosclerotic CAD, but coronary artery obstruction or damage has been reported in the ab‐ sence of coronary atherosclerosis [27]. Furthermore, myocardial contusion may simulate acute MI. Infrequently, coronary angiography is indicated in the management of such pa‐

**1.** Diseases affecting the aorta when knowledge of the presence or extent of coronary ar‐ tery involvement is necessary for management (e.g., aortic dissection or aneurysm with

**2.** Hypertrophic cardiomyopathy with angina despite medical therapy when knowledge

**3.** Hypertrophic cardiomyopathy with angina when heart surgery is planned. (Level of

**1.** High risk for coronary disease when other cardiac surgical procedures are planned (e.g., pericardiectomy or removal of chronic pulmonary emboli). (Level of Evidence: C)

**2.** Prospective immediate cardiac transplant donors whose risk profile increases the likeli‐

**3.** Asymptomatic patients with Kawasaki disease who have coronary artery aneurysms on

**4.** Before surgery for aortic aneurysm/dissection in patients without known coronary dis‐

**5.** Recent blunt chest trauma and suspicion of acute MI, without evidence of preexisting

Cineangiographic images of coronary arteries have been the principal clinical tool for deter‐ mining the severity of coronary luminal stenosis. Modern angiographic equipment has a resolution of four to five line pairs per millimeter with a six-inch field of view, the usual im‐ age magnification for coronary angiography [28]. Validation studies that use known phan‐ toms show a high correlation between actual size and that measured by quantitative coronary angiography (QCA) (r = 0.95) [29–32]. The resolution of these phantom studies in‐

**3. Special considerations regarding coronary angiography**

**Recommendations for use of coronary angiography in other conditions**

244 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

of coronary anatomy might affect therapy. (Level of Evidence: C)

known coronary disease). (Level of Evidence: B)

hood of coronary disease. (Level of Evidence: B)

echocardiography. (Level of Evidence: B)

CAD. (Level of Evidence: C)

Recent advances in computer storage technology have made feasible digital acquisition, processing and archival storage of angiographic images obtained during cardiac catheteriza‐ tion. Widespread conversion from cineangiographic film to digital archiving and storage is anticipated during the next decade. Analog storage technologies such as super VHS video‐ tape and analog optical disks have inadequate resolution to faithfully record coronary an‐ giography. Digital storage methods are generally adequate but until recently have lacked standardization, which precluded easy exchange of digital angiograms between centers with different equipment. The development of the Digital Imaging and Communication standard (DICOM) for cardiac angiography ensures compatibility between equipment from participating vendors.

In the interventional era, the advantages of digital angiography are important. The image quality provided by digital angiography is better than any common videotape format. Im‐ provements in computer speed and processing capability enable rapid replay of coronary injection sequences, as well as evaluation of the results of each intervention and identifica‐ tion of complications such as intraluminal thrombus and dissection. In many laboratories, the availability of high-quality images during catheterization permits diagnostic and thera‐ peutic catheterization to consist of a single procedure, a capability with significant implica‐ tions for the cost of interventional procedures. Industry sources now estimate that >75% of existing laboratories are equipped with digital imaging capability.

The ACC Cardiac Catheterization Committee is coordinating efforts to develop and pro‐ mote a standard for archival storage and exchange of digital cardiac angiography. The com‐ mittee has joined in this common cause with an industry organization, the National Electrical Manufacturers Association (NEMA), and representatives of the American College of Radiology (ACR). The ACR and NEMA have recently released an interim standard known as Digital Imaging Communication in Medicine (DICOM version 3.0).

The initial efforts of the standards committee have focused on adoption of a file format and physical medium for interchange of digital angiographic studies. To transfer images be‐ tween medical centers, the sender would generate a DICOM-compatible file for review by the receiver. Recently, this working group has chosen a recordable form of the common CD- ROM, termed CD-R, as the official exchange medium. Nearly all equipment vendors have announced support for this format.

angiogram. When the atherosclerotic plaque becomes severe, luminal encroachment be‐ comes evident. Although such mild lesions do not restrict blood flow, clinical studies have demonstrated that these minimal or even unseen angiographic lesions represent an impor‐

Coronary Angiography (IJECCE) http://dx.doi.org/10.5772/54080 247

Third, assessment of luminal diameter narrowing is complicated by the frequent absence of a normal reference segment[56]. Angiography visualizes only the lumen of the vessel and cannot determine if the wall of the reference segment has atherosclerosis [38–42]. In the presence of diffuse reference segment disease, percent stenosis will predictably underesti‐

Finally, in the setting of percutaneous intervention, the assumptions underlying simple pro‐ jection imaging of the lumen are further impaired. Necropsy studies and intravascular ultra‐ sound demonstrate that most mechanical coronary interventions exaggerate the extent of luminal eccentricity by fracturing or dissecting the atheroma within the lesion [45– 49]. The angiographic appearance of the postintervention vessel often consists of an enlarged, al‐ though frequently "hazy" lumen [46]. In this setting, the lumen size on angiography may overestimate the vessel cross-sectional area and misrepresent the actual gain in lumen size.

Experimental and clinical studies have shown that when percent stenosis is >50%, the ability to increase blood flow in response to metabolic demands is impaired [50]. This augmenta‐ tion of coronary blood flow to demand is termed the coronary flow reserve. Determination of CFR requires measurement of blood flow at rest and after induction of reactive hypere‐ mia, usually by administration of a coronary vasodilator. Several methods for measurement of CFR in patients have been developed, including intracoronary Doppler flow probes, digi‐

Coronary collaterals can provide significant additional blood flow to territories served by stenotic vessels [58]. In general, collaterals are not evident unless resting ischemia is present, such as that which occurs with a stenosis.90%. In many patients, collateral flow merely re‐ stores normal resting blood flow but does not provide adequate flow when metabolic de‐ mand increases. The presence of collaterals, however, is associated with preservation of myocardial function after MI, reduced myocardial ischemia on noninvasive stress testing, and reduced ischemia during angioplasty [59,60]. Paradoxically, a greater ischemic response on noninvasive functional testing with adenosine than with exercise has been reported in the presence of collaterals, presumably due to an increase in the coronary steal phenomenon [61]. Collateral blood flow can only be semiquantified by angiography [62], and precise as‐ sessment of perfusion by angiography is poor. This inability to adequately measure collater‐ al flow is one of the factors that prevent accurate assessment of the functional significance of

For an understanding of the pharmacologic properties and adverse effects of contrast agents, the reader is referred to the 1993 review of the subject by the ACC Cardiovascular

tant predisposing cause of acute coronary syndromes, including MI [55].

mate the true amount of diameter narrowing.

tal angiography and quantitative PET [51– 54].

coronary stenosis by angiography alone [57].

Imaging Committee [63] and the 1996 review by Hirshfeld [64].

**3.5. Contrast agents**

#### **3.3. Reproducibility**

In clinical practice, the degree of coronary artery obstruction is commonly expressed as the percent diameter stenosis. This is done by comparing the diameter of the site of greatest nar‐ rowing (minimal lumen diameter) to an adjacent segment assumed to be free of disease. In clinical practice, the most common method used to estimate the percent diameter narrowing is subjective visual assessment. Because vasomotor tone can alter the reference diameter, ni‐ troglycerin is frequently administered before angiography to improve the reproducibility of the measurement. Several studies have shown that measurement of the degree and extent of luminal narrowing correlates with symptoms as well as with assessments of coronary flow reserve (CFR) and abnormalities on treadmill exercise testing, perfusion imaging with Tl or sestamibi, stress echocardiography and fast computerized tomography [33– 37]. In addition, the percent diameter reduction and the number of stenosis of >50% to 70% correlate with long-term outcome [33–37].

#### **3.4. Limitations**

Although coronary angiography is considered the reference standard for anatomic assess‐ ment of coronary obstructions, there are limitations to the technique. When luminal narrow‐ ings are present on coronary angiography (in the absence of spasm), pathological analyses almost always demonstrate severe atherosclerotic obstruction. Even minor angiographic ab‐ normalities are associated with a poorer long-term outcome than are completely normal ap‐ pearing angiograms. Coronary angiography has a high predictive value for the presence of CAD when abnormalities are present. However, the converse is not true. A normal coronary angiogram does not exclude atherosclerosis, and in fact, most pathological studies suggest that angiography grossly underestimates the extent and severity of atherosclerosis [38–42]. Several factors contribute to this discrepancy.

First, angiography depicts coronary anatomy from a planar two-dimensional silhouette of the contrast-filled vessel lumen. However, coronary lesions are often geometrically complex, with an eccentric luminal shape such that one angle of view may misrepresent the extent of narrowing [39]. Two orthogonal angiograms should demonstrate more correctly the severity of most lesions, but adequate orthogonal views are frequently unobtainable because the stenosis may be obscured by overlapping side branches, disease at bifurcation sites, dio‐ graphic foreshortening or tortuosity. This can be especially difficult in the left main coronary artery, where identifying a significant stenosis is of utmost clinical importance [43].

Second, an adaptive phenomenon, coronary remodeling," contributes to the inability of cor‐ onary angiography to identify mild atherosclerosis [44]. Remodeling was initially observed on histology as the outward displacement of the external vessel wall in vascular segments with significant atherosclerosis. In the early phases of atherosclerosis, this vessel enlarge‐ ment "compensates" for luminal encroachment, thereby concealing the atheroma from the angiogram. When the atherosclerotic plaque becomes severe, luminal encroachment be‐ comes evident. Although such mild lesions do not restrict blood flow, clinical studies have demonstrated that these minimal or even unseen angiographic lesions represent an impor‐ tant predisposing cause of acute coronary syndromes, including MI [55].

Third, assessment of luminal diameter narrowing is complicated by the frequent absence of a normal reference segment[56]. Angiography visualizes only the lumen of the vessel and cannot determine if the wall of the reference segment has atherosclerosis [38–42]. In the presence of diffuse reference segment disease, percent stenosis will predictably underesti‐ mate the true amount of diameter narrowing.

Finally, in the setting of percutaneous intervention, the assumptions underlying simple pro‐ jection imaging of the lumen are further impaired. Necropsy studies and intravascular ultra‐ sound demonstrate that most mechanical coronary interventions exaggerate the extent of luminal eccentricity by fracturing or dissecting the atheroma within the lesion [45– 49]. The angiographic appearance of the postintervention vessel often consists of an enlarged, al‐ though frequently "hazy" lumen [46]. In this setting, the lumen size on angiography may overestimate the vessel cross-sectional area and misrepresent the actual gain in lumen size.

Experimental and clinical studies have shown that when percent stenosis is >50%, the ability to increase blood flow in response to metabolic demands is impaired [50]. This augmenta‐ tion of coronary blood flow to demand is termed the coronary flow reserve. Determination of CFR requires measurement of blood flow at rest and after induction of reactive hypere‐ mia, usually by administration of a coronary vasodilator. Several methods for measurement of CFR in patients have been developed, including intracoronary Doppler flow probes, digi‐ tal angiography and quantitative PET [51– 54].

Coronary collaterals can provide significant additional blood flow to territories served by stenotic vessels [58]. In general, collaterals are not evident unless resting ischemia is present, such as that which occurs with a stenosis.90%. In many patients, collateral flow merely re‐ stores normal resting blood flow but does not provide adequate flow when metabolic de‐ mand increases. The presence of collaterals, however, is associated with preservation of myocardial function after MI, reduced myocardial ischemia on noninvasive stress testing, and reduced ischemia during angioplasty [59,60]. Paradoxically, a greater ischemic response on noninvasive functional testing with adenosine than with exercise has been reported in the presence of collaterals, presumably due to an increase in the coronary steal phenomenon [61]. Collateral blood flow can only be semiquantified by angiography [62], and precise as‐ sessment of perfusion by angiography is poor. This inability to adequately measure collater‐ al flow is one of the factors that prevent accurate assessment of the functional significance of coronary stenosis by angiography alone [57].

#### **3.5. Contrast agents**

ROM, termed CD-R, as the official exchange medium. Nearly all equipment vendors have

246 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

In clinical practice, the degree of coronary artery obstruction is commonly expressed as the percent diameter stenosis. This is done by comparing the diameter of the site of greatest nar‐ rowing (minimal lumen diameter) to an adjacent segment assumed to be free of disease. In clinical practice, the most common method used to estimate the percent diameter narrowing is subjective visual assessment. Because vasomotor tone can alter the reference diameter, ni‐ troglycerin is frequently administered before angiography to improve the reproducibility of the measurement. Several studies have shown that measurement of the degree and extent of luminal narrowing correlates with symptoms as well as with assessments of coronary flow reserve (CFR) and abnormalities on treadmill exercise testing, perfusion imaging with Tl or sestamibi, stress echocardiography and fast computerized tomography [33– 37]. In addition, the percent diameter reduction and the number of stenosis of >50% to 70% correlate with

Although coronary angiography is considered the reference standard for anatomic assess‐ ment of coronary obstructions, there are limitations to the technique. When luminal narrow‐ ings are present on coronary angiography (in the absence of spasm), pathological analyses almost always demonstrate severe atherosclerotic obstruction. Even minor angiographic ab‐ normalities are associated with a poorer long-term outcome than are completely normal ap‐ pearing angiograms. Coronary angiography has a high predictive value for the presence of CAD when abnormalities are present. However, the converse is not true. A normal coronary angiogram does not exclude atherosclerosis, and in fact, most pathological studies suggest that angiography grossly underestimates the extent and severity of atherosclerosis [38–42].

First, angiography depicts coronary anatomy from a planar two-dimensional silhouette of the contrast-filled vessel lumen. However, coronary lesions are often geometrically complex, with an eccentric luminal shape such that one angle of view may misrepresent the extent of narrowing [39]. Two orthogonal angiograms should demonstrate more correctly the severity of most lesions, but adequate orthogonal views are frequently unobtainable because the stenosis may be obscured by overlapping side branches, disease at bifurcation sites, dio‐ graphic foreshortening or tortuosity. This can be especially difficult in the left main coronary

Second, an adaptive phenomenon, coronary remodeling," contributes to the inability of cor‐ onary angiography to identify mild atherosclerosis [44]. Remodeling was initially observed on histology as the outward displacement of the external vessel wall in vascular segments with significant atherosclerosis. In the early phases of atherosclerosis, this vessel enlarge‐ ment "compensates" for luminal encroachment, thereby concealing the atheroma from the

artery, where identifying a significant stenosis is of utmost clinical importance [43].

announced support for this format.

**3.3. Reproducibility**

long-term outcome [33–37].

Several factors contribute to this discrepancy.

**3.4. Limitations**

For an understanding of the pharmacologic properties and adverse effects of contrast agents, the reader is referred to the 1993 review of the subject by the ACC Cardiovascular Imaging Committee [63] and the 1996 review by Hirshfeld [64].

Except for a less potent anticoagulant effect, nonionic agents are better tolerated and have fewer side effects than ionic agents [63]. Several randomized trials have compared their use during cardiac angiography. Barrett et al. [65] compared a nonionic low-osmolar contrast agent with an ionic high-osmolar contrast agent. Although adverse events were reduced, se‐ vere reactions were confined to patients with underlying severe cardiac disease. These au‐ thors supported the use of nonionic low-osmolar agents in these high-risk patients. Steinberg et al. [66]

**•** Disease of the heart valve causing symptoms (syncope, shortness of breath)

**•** Generally the risk of serious complications ranges from 1 in 1,000 to 1 in 500. Risks of the

Coronary Angiography (IJECCE) http://dx.doi.org/10.5772/54080 249

**•** Abnormal heart rhythm that continues for a long time. This may need an electric shock to

**•** Arrhythmias. These irregular heartbeats often go away on their own. However, your doc‐

**•** Syncope or loss of consciousness in patients with aortic valve disease

**•** To monitor rejection in heart transplant patients

**•** Pain in the Jaw,Neck or Arm

procedure include the following **:**

**Risks**

**•** Stroke

**•** Heart attack

**•** A stroke.

correct.

**•** Fever

**•** Low blood pressure.[2]

**•** Kidney failure or dysfunction

**•** Heart attack.

**•** Irregular heart beats **•** Low blood pressure

**•** Injury to the coronary artery

**•** Allergic reaction to contrast dye[3] **Rare risks and complications include:**

**•** An allergic reaction to the x-ray dye.[2]

**Coronary angiography contraindications**

**Other, less common complications include:**

tor may recommend treatment if they persist.

**•** Problems with blood coagulation (Coagulopathy)

**•** Need for emergency heart surgery or angioplasty.

**•** Surgical repair of the groin/arm puncture site or blood vessel.

**•** Kidney damage caused by the dye that's used during the test.

**•** Blood clots that can trigger a stroke,heart stroke, or other serious problems.

The difference in the incidence of any major contrast reaction is proportional to the New York Heart Association clinical function class, rising from 0.5% for class I patients to 3.6% for class IV patients [68]. Given these observations, it has been suggested that nonionic agents should be reserved for patients who are at high risk for adverse reactions and that ionic agents should be used for all other patients [64].

Factors that have been associated with high risk of adverse reactions to contrast media in‐ clude prior adverse reaction to contrast agents, age >65 years, New York Heart Association functional class IV (or hemodynamic evidence of congestive heart failure), impaired renal function (creatinine >2.0 mg/dL), acute coronary syndromes (unstable angina or acute MI) and severe valvular disease (aortic valve area <0.7 cm2 or mitral valve area <1.25 cm2 ) [64]. It is recommended that the individual practitioner appropriately assess the cost and benefit re‐ lationship when selecting contrast agents in any individual patient and that a strategy of re‐ serving nonionic agents for patients who are at high risk of adverse reactions is prudent and cost-effective.[69]

#### **ACC/AHA classifications of class I, II, and III. These classes summarize the indications for coronary angiography as follows:**

**Class I:** Conditions for which there is evidence and/or general agreement that this proce‐ dure is useful and effective.

**Class II:** Conditions for which there is conflicting evidence and/or a divergence of opin‐ ion about the usefulness/efficacy of performing the procedure. *Class IIa:* Weight of evi‐ dence/opinion is in favor of usefulness/ efficacy. *Class IIb:* Usefulness/efficacy is less well established by evidence/opinion. *Class III:* Conditions for which there is evidence and/or general agreement that the procedure is not useful/effective and in some cases may be harmful.[70,71]

#### **Coronary angiography indications**


#### **Risks**

Except for a less potent anticoagulant effect, nonionic agents are better tolerated and have fewer side effects than ionic agents [63]. Several randomized trials have compared their use during cardiac angiography. Barrett et al. [65] compared a nonionic low-osmolar contrast agent with an ionic high-osmolar contrast agent. Although adverse events were reduced, se‐ vere reactions were confined to patients with underlying severe cardiac disease. These au‐ thors supported the use of nonionic low-osmolar agents in these high-risk patients.

248 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The difference in the incidence of any major contrast reaction is proportional to the New York Heart Association clinical function class, rising from 0.5% for class I patients to 3.6% for class IV patients [68]. Given these observations, it has been suggested that nonionic agents should be reserved for patients who are at high risk for adverse reactions and that

Factors that have been associated with high risk of adverse reactions to contrast media in‐ clude prior adverse reaction to contrast agents, age >65 years, New York Heart Association functional class IV (or hemodynamic evidence of congestive heart failure), impaired renal function (creatinine >2.0 mg/dL), acute coronary syndromes (unstable angina or acute MI)

is recommended that the individual practitioner appropriately assess the cost and benefit re‐ lationship when selecting contrast agents in any individual patient and that a strategy of re‐ serving nonionic agents for patients who are at high risk of adverse reactions is prudent and

**ACC/AHA classifications of class I, II, and III. These classes summarize the indications**

**Class I:** Conditions for which there is evidence and/or general agreement that this proce‐

**Class II:** Conditions for which there is conflicting evidence and/or a divergence of opin‐ ion about the usefulness/efficacy of performing the procedure. *Class IIa:* Weight of evi‐ dence/opinion is in favor of usefulness/ efficacy. *Class IIb:* Usefulness/efficacy is less well established by evidence/opinion. *Class III:* Conditions for which there is evidence and/or general agreement that the procedure is not useful/effective and in some cases may be

**•** Unstable angina or Chest pain [uncontrolled with medications or after a heart attack]

and severe valvular disease (aortic valve area <0.7 cm2 or mitral valve area <1.25 cm2

Steinberg et al. [66]

cost-effective.[69]

harmful.[70,71]

**•** Heart attack **•** Aortic Stenosis

**•** Before a bypass surgery

**•** Abnormal treadmill test results

**•** Determine the extent of coronary artery disease

**for coronary angiography as follows:**

**Coronary angiography indications**

dure is useful and effective.

ionic agents should be used for all other patients [64].


#### **Rare risks and complications include:**


) [64]. It


#### **Other, less common complications include:**


#### **Coronary angiography contraindications**


[5] Braunwald E, Jones RH, Mark DB, et al. Diagnosing and managing unstable angina:

Coronary Angiography (IJECCE) http://dx.doi.org/10.5772/54080 251

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## **Author details**

Chiu-Lung Wu1 and Chi-Wen Juan1,2

\*Address all correspondence to: juanchiwen@yahoo.com.tw

1 Department of Emergency Medicine, Kuang Tien General Hospital, Sha-Lu,Taichung, Tai‐ wan, R.O.C.

2 Department of Nursing,Hungkuang University, Taichung, Taiwan, R.O.C.

#### **References**


[5] Braunwald E, Jones RH, Mark DB, et al. Diagnosing and managing unstable angina: Agency for Health Care Policy and Research.Circulation 1994;90:613–22.

**•** Active systemic infection

**•** Transient Ischemic attack

**•** Electrolyte imbalance

**•** Severe anemia

**Author details**

Chiu-Lung Wu1

wan, R.O.C.

**References**

50.

**•** Allergy to contrast (dye) medium

**•** Uncompensated heart failure[4]

**•** Uncontrolled Blood Pressure (Hypertension)

**•** Uncontrolled rhythm disturbances (arrhythmias)

and Chi-Wen Juan1,2

Philadelphia, Pa: Lea & Febiger, 1991.

AHCPR publication 94-0602.

\*Address all correspondence to: juanchiwen@yahoo.com.tw

1 Department of Emergency Medicine, Kuang Tien General Hospital, Sha-Lu,Taichung, Tai‐

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(abstr). Circulation 1994;90:I-58.

reserve. Circulation 1986;73:562–71.

onary artery disease? Circulation 1988;78:1157– 66.

pendent myocardium. J Am Coll Cardiol 1995; 26:615–23.

tricular dysfunction. Cardiovasc Drugs Ther 1994; 8:327–34.

lation 1994;90(pt 2):I-550.


[72] Simes RJ, Topol EJ, Holmes DR Jr, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion: impor‐ tance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circu‐ lation 1995; 91:1923– 8.

**Chapter 13**

**Improving the Utility of Coronary Angiography: The**

Alexander Incani, Anthony C. Camuglia, Karl K. Poon, O. Christopher Raffel and

Additional information is available at the end of the chapter

Darren L. Walters

**1. Introduction**

http://dx.doi.org/10.5772/54041

cult to wire than soft thrombus.

and stent performance over time.

**Use of Adjuvant Imaging and Physiological Assessment**

The most important role of coronary angiography is to delineate coronary lesions that cause inducible ischaemia. It remains the primary tool influencing the decision to undertake revas‐ cularization and patient outcomes [1] [2-4]. However, there are inherent limitations to diag‐ nostic angiography. These pitfalls include difficulties delineating eccentric plaque (that can be underappreciated in the absence of multiple angiographic views), difficulty assessing le‐ sions of moderate severity, the assessment of overall plaque burden and the composition, appreciation of ostial lesions, culprit lesion assessment in acute infarct patients and side branch analysis in bifurcation lesions. Heavily calcified lesions can also produce hazy angio‐ graphic appearances which often leaves the operator at a loss to determine the actual true lumen path and in some circumstances even misdiagnose calcification as "pseudothrom‐ bus" [5]. This latter phenomenon significantly changes the approach to intervention. The ar‐ tery can be put at risk of perforation in the absence of adequate lesion preparation or wire induced dissection as calcified plaque is often undermined, complex and much more diffi‐

Furthermore, angiography is usually used in isolation to guide intervention and ensure an adequate final stent result. FFR, IVUS and OCT can all be used to assess final PCI results

To aid decision making processes, adjunctive tools are becoming essential in "getting it right" in the catheterization laboratory. In this chapter, the use of FFR, IVUS and OCT for

and reproduction in any medium, provided the original work is properly cited.

© 2013 Incani et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

assessing left main and non left-main coronary artery disease will be discussed.

## **Improving the Utility of Coronary Angiography: The Use of Adjuvant Imaging and Physiological Assessment**

Alexander Incani, Anthony C. Camuglia, Karl K. Poon, O. Christopher Raffel and Darren L. Walters

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54041

## **1. Introduction**

[72] Simes RJ, Topol EJ, Holmes DR Jr, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion: impor‐ tance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circu‐

256 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

lation 1995; 91:1923– 8.

The most important role of coronary angiography is to delineate coronary lesions that cause inducible ischaemia. It remains the primary tool influencing the decision to undertake revas‐ cularization and patient outcomes [1] [2-4]. However, there are inherent limitations to diag‐ nostic angiography. These pitfalls include difficulties delineating eccentric plaque (that can be underappreciated in the absence of multiple angiographic views), difficulty assessing le‐ sions of moderate severity, the assessment of overall plaque burden and the composition, appreciation of ostial lesions, culprit lesion assessment in acute infarct patients and side branch analysis in bifurcation lesions. Heavily calcified lesions can also produce hazy angio‐ graphic appearances which often leaves the operator at a loss to determine the actual true lumen path and in some circumstances even misdiagnose calcification as "pseudothrom‐ bus" [5]. This latter phenomenon significantly changes the approach to intervention. The ar‐ tery can be put at risk of perforation in the absence of adequate lesion preparation or wire induced dissection as calcified plaque is often undermined, complex and much more diffi‐ cult to wire than soft thrombus.

Furthermore, angiography is usually used in isolation to guide intervention and ensure an adequate final stent result. FFR, IVUS and OCT can all be used to assess final PCI results and stent performance over time.

To aid decision making processes, adjunctive tools are becoming essential in "getting it right" in the catheterization laboratory. In this chapter, the use of FFR, IVUS and OCT for assessing left main and non left-main coronary artery disease will be discussed.

© 2013 Incani et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **2. An overview of FFR**

Fractional Flow Reserve (FFR) is the ratio of two flows - maximal flow in the diseased vessel expressed as a ratio to maximal flow if the vessel was theoretically normal[6]. During the procedure, a 0.014 inch pressure sensor coronary guide wire is advanced beyond a coronary stenosis and under conditions of maximal hyperaemia, distal pressure recorded and divided by guiding catheter pressure. The procedure requires routine anticoagulation, a calibration process [zeroing and equalization of the aortic (guiding catheter pressure Pa) with the pres‐ sure wire (Pd) and attainment of maximal hyperaemia (this is usually achieved by intrave‐ nous or intracoronary adenosine)[6]. FFR is a robust technique and reproducible which is remarkable in that the microcirculation is able to vasodilate to the same degree each time and is independent of heart rate and blood pressure [7,8]. It takes into account length of le‐ sion, lesion severity, amount of myocardium supplied, viability and contribution of collater‐ al blood flow [3,9,10]. It is now considered the gold standard for invasive functional assessment of the physiological significance of coronary stenosis. |It has recently been given a Class Ia indication for guiding PCI in multivessel coronary disease by the European Soci‐ ety of Cardiology [6].

Catheters: In general, 5Fr or 6 Fr guiding catheters are used for performing FFR. This then allows the operator to immediately go on to perform an intervention based on the FFR result or indeed fix a wire induced dissection without needing to change catheters. The latter is a rare phenomenon in experienced hands and with modern steerable soft tip pressure wires. Larger French sizes are generally avoided on account of increased risk of catheter induced

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259

Given Pv is assumed to be negligible equal and at maximal hyperaemia R (resistance) is minimal then FFR = Pd/Pa

**8.** Cross stenosis with the pressure wire (N.B. the pressure sensor is at the junction of the

**9.** Run intravenous adenosine (our preferred method) to achieve maximal hyperaemia

ostial spasm and the possibility of reducing proximal coronary artery pressure.

Qs = flow in diseased artery and Qn = flow in artery if theoretically normal

Pd = pressure distal to stenosis; Pa = aortic or guiding catheter pressure

**2.2. Summary for the sequence of events for performing FFR**

**5.** Intracoronary GTN to overcome epicardial conduit resistance

**7.** Equalize pressure wire and guiding catheter transducers

radiolucent and radio-opaque segments of the wire)

**10.** Record FFR tracing with at least 2-3 min of adenosine

**11.** Remain vigilant for pressure signal drift and catheter damping

**12.** Pullback recording is reasonable across tandem stenoses or diffuse plaque

**2.** Guiding Catheter sitting at ostium of coronary artery without damping

**1.** Systemic Heparin to achieve ACT of at least 250 sec

Basic Formula for FFR:

Therefore: FFR = [Pd-Pv/R] / [Pa-Pv/R]

Pv = venous or right atrial pressure

**3.** Zero guide and pressure wire

**4.** Remove wire introducer

**6.** Flush with saline

FFR = Qs/Qn

R = resistance

#### **2.1. Practicalities of FFR**

Pressure Transducers: The current pressure transducers usually comprise a regular trans‐ ducer for aortic pressure (Pa) recorded through the guiding catheter and the second pres‐ sure (Pd beyond the stenosis) via a miniaturized sensor-tipped pressure wire that is connected to a small computerized interface. Of note, a new wireless system is also about to enter the commercial arena. Mean pressure recordings are essential as these form the nu‐ merator and denominator of the FFR formula, not peak systolic pressure. It is optional to re‐ cord Pv (central venous or right atrial pressure) via a central line if the operator wishes to correct FFR for right atrial pressure – a concept that has been reborn in the modern FFR era whereby filling pressures in cardiac failure patients may be significantly elevated and can affect FFR recordings.

Medications: As is usual in any case where coronary wires are placed down coronary arter‐ ies, systemic anticoagulation (unfractionated heparin, low molecular weight heparin or bi‐ valirudin) is essential to avoid wire induced coronary thrombus. At our institution, the usual practice is to administer heparin to achieve an ACT of at least 250 seconds. Intracoro‐ nary nitrate is then administered to overcome epicardial vessel vasospasm and for achieving hyperaemia, either intracoronary or intravenous adenosine. Our preference is for intrave‐ nous adenosine via a femoral venous sheath, although all that is required is to achieve hy‐ peraemia – the route of administration is not as important. Intracoronary adenosine can also be given, however, this is not suitable when there are side holes in the guiding catheter, when ostial disease exists and when the aim of the study is to achieve a "pull-back" over the course of a coronary artery. Alternative agents for achieving maximal hyperaemia include intracoronary papaverine, intracoronary ATP, intravenous dipyridamole and intravenous dobutamine, however these have not been as widely adopted.

Catheters: In general, 5Fr or 6 Fr guiding catheters are used for performing FFR. This then allows the operator to immediately go on to perform an intervention based on the FFR result or indeed fix a wire induced dissection without needing to change catheters. The latter is a rare phenomenon in experienced hands and with modern steerable soft tip pressure wires. Larger French sizes are generally avoided on account of increased risk of catheter induced ostial spasm and the possibility of reducing proximal coronary artery pressure.

Basic Formula for FFR:

#### FFR = Qs/Qn

**2. An overview of FFR**

ety of Cardiology [6].

**2.1. Practicalities of FFR**

affect FFR recordings.

Fractional Flow Reserve (FFR) is the ratio of two flows - maximal flow in the diseased vessel expressed as a ratio to maximal flow if the vessel was theoretically normal[6]. During the procedure, a 0.014 inch pressure sensor coronary guide wire is advanced beyond a coronary stenosis and under conditions of maximal hyperaemia, distal pressure recorded and divided by guiding catheter pressure. The procedure requires routine anticoagulation, a calibration process [zeroing and equalization of the aortic (guiding catheter pressure Pa) with the pres‐ sure wire (Pd) and attainment of maximal hyperaemia (this is usually achieved by intrave‐ nous or intracoronary adenosine)[6]. FFR is a robust technique and reproducible which is remarkable in that the microcirculation is able to vasodilate to the same degree each time and is independent of heart rate and blood pressure [7,8]. It takes into account length of le‐ sion, lesion severity, amount of myocardium supplied, viability and contribution of collater‐ al blood flow [3,9,10]. It is now considered the gold standard for invasive functional assessment of the physiological significance of coronary stenosis. |It has recently been given a Class Ia indication for guiding PCI in multivessel coronary disease by the European Soci‐

258 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Pressure Transducers: The current pressure transducers usually comprise a regular trans‐ ducer for aortic pressure (Pa) recorded through the guiding catheter and the second pres‐ sure (Pd beyond the stenosis) via a miniaturized sensor-tipped pressure wire that is connected to a small computerized interface. Of note, a new wireless system is also about to enter the commercial arena. Mean pressure recordings are essential as these form the nu‐ merator and denominator of the FFR formula, not peak systolic pressure. It is optional to re‐ cord Pv (central venous or right atrial pressure) via a central line if the operator wishes to correct FFR for right atrial pressure – a concept that has been reborn in the modern FFR era whereby filling pressures in cardiac failure patients may be significantly elevated and can

Medications: As is usual in any case where coronary wires are placed down coronary arter‐ ies, systemic anticoagulation (unfractionated heparin, low molecular weight heparin or bi‐ valirudin) is essential to avoid wire induced coronary thrombus. At our institution, the usual practice is to administer heparin to achieve an ACT of at least 250 seconds. Intracoro‐ nary nitrate is then administered to overcome epicardial vessel vasospasm and for achieving hyperaemia, either intracoronary or intravenous adenosine. Our preference is for intrave‐ nous adenosine via a femoral venous sheath, although all that is required is to achieve hy‐ peraemia – the route of administration is not as important. Intracoronary adenosine can also be given, however, this is not suitable when there are side holes in the guiding catheter, when ostial disease exists and when the aim of the study is to achieve a "pull-back" over the course of a coronary artery. Alternative agents for achieving maximal hyperaemia include intracoronary papaverine, intracoronary ATP, intravenous dipyridamole and intravenous

dobutamine, however these have not been as widely adopted.

Qs = flow in diseased artery and Qn = flow in artery if theoretically normal

Therefore: FFR = [Pd-Pv/R] / [Pa-Pv/R]

Pd = pressure distal to stenosis; Pa = aortic or guiding catheter pressure

Pv = venous or right atrial pressure

R = resistance

Given Pv is assumed to be negligible equal and at maximal hyperaemia R (resistance) is minimal then FFR = Pd/Pa

#### **2.2. Summary for the sequence of events for performing FFR**


**c. Damping of pressure by the guiding catheter:** this is particularly true with diseased ostia and when using large guiding catheters. It creates a gradient between the guiding catheter and the proximal segment of the coronary artery and may only be unmasked during maximal hyperaemia. It is important to monitor the Pa waveform at baseline and during the FFR measurement and if indeed there is damping, the guiding catheter needs to be "backed out" over the wire to ensure the Pa measurement is valid. This usu‐ ally necessitates the use of intravenous adenosine to maintain maximal hyperaemia during the FFR recording. If guiding catheter damping is not appreciated, the obtained FFR value will be artificially higher and the true severity of the stenosis underestimat‐

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261

**d. Guiding Catheter with Side Holes:** it is technically obvious to avoid intracoronary ade‐ nosine in this setting however it is also important to always disengage the guide be‐ cause the side holes may actually confound true proximal coronary pressure measurement. Therefore, if side holes are used, intravenous adenosine and a guiding

**e. Signal Drift:** High fidelity equipment make problems of signal drift less likely. Howev‐ er the problem can still occur. This issue is detected when an apparent gradient appears between Pd and Pa without a change in waveform of the distal pressure. It should be checked for at the end of the FFR procedure by ensuring that equalization still holds true when the coronary wire is withdrawn back into the guiding catheter. This is an in‐ ternal check for the operator to ensure the final FFR reading is valid. In practical terms

**f. Maximal Hyperaemia:** It cannot be emphasized enough that there is no such thing as a resting FFR. It is only at maximal hyperaemia that resistance is minimal and that flow develops a linear relationship to pressure – a vital prerequisite for the FFR equation to hold true. Not achieving maximal hyperaemia will usually overestimate the FFR value and therefore underestimate the true severity of a coronary stenosis. At the usual dose of intravenous adenosine 140mcg/kg/min via a central sheath, all patients usually ach‐ ieve maximal hyperaemia within 2 minutes. Patients will often complain of chest tight‐ ness and dyspnoea and there will be a transient rise in blood pressure before the Pd value reduces and adopts an ischaemic waveform with diastolic blunting. At this stage, increasing the dose of adenosine will not alter the FFR value and the clinician will be comfortable that maximal hyperaemia is achieved. It is not unusual for PR prolongation or transient heart block to occur which can also be used as surrogate measures of maxi‐

Intravascular ultrasound is a catheter based pullback technique that provides invasive crosssectional tomographic imaging [13,14]. The ultrasound signal is produced by sending an electrical current through a crystal element on the transducer. Sound waves are reflected or

catheter sitting out of the ostium are imperative for an accurate FFR recording.

however, a pullback curve will also overcome this limitation.

ed.

mal hyperaemia [12].

**3. An overview of IVUS**

**Figure 1.** Typical Example of FFR Recording (n.b. mean Pd and Pa pressures and automatic FFR recording as well as transient bradycardia consistent with adenosine)

#### **2.3. Pitfalls in FFR**

Like most tools in coronary intervention, Fractional Flow Reserve is not immune to technical mistakes [11]. It is important to be aware of the following various pitfalls to ensure that the FFR measurement is both valid and reproducible.


## **3. An overview of IVUS**

**Figure 1.** Typical Example of FFR Recording (n.b. mean Pd and Pa pressures and automatic FFR recording as well as

260 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Like most tools in coronary intervention, Fractional Flow Reserve is not immune to technical mistakes [11]. It is important to be aware of the following various pitfalls to ensure that the

**a. Use of a guide wire introducer:** when used through the Y connector, there is a subtle leak of aortic guiding catheter pressure. Although it tends to only be small (<10mmHg), when the FFR is near the ischemic zone, this small difference may have important im‐ plications. It is therefore recommended that when equalizing, measuring FFR and checking for drift at the end of the procedure, that the wire introducer be removed.

**b. Not clearing the catheter of contrast:** ensuring that the guiding catheter is cleared of contrast during equalization and FFR measurement is important to avoid subtle con‐ trast induced damping of pressure waveform. To overcome this, the guiding catheter should be flushed with saline at the time of equalization and FFR measurement. It is im‐ portant to note ST changes at this time as over-enthusiastic flushing of the guiding cath‐ eter can lead to ischaemia induced ventricular fibrillation. It is advisable to flush in stages giving the patient a break between 5-second flushes until the catheter is clear of

transient bradycardia consistent with adenosine)

contrast on fluoroscopy.

FFR measurement is both valid and reproducible.

**2.3. Pitfalls in FFR**

Intravascular ultrasound is a catheter based pullback technique that provides invasive crosssectional tomographic imaging [13,14]. The ultrasound signal is produced by sending an electrical current through a crystal element on the transducer. Sound waves are reflected or pass through structures depending on their acoustic impedance. The scanning process pro‐ vides both a qualitative and quantitative assessment of the artery. Vessel wall, atherosclerot‐ ic burden and plaque composition can all be assessed and with a well defined lumen-intima interface, measurements made of lesion severity such as minimum lumen area.

#### **3.1. IVUS assessment of wall layers**

The intima is a single layer of endothelial cells that is largely defined by its interface with blood in the lumen [15]. Saline or contrast flush can help delineate this interface in complex undermined plaque or when this interface may be ambiguous in cases such as lumen filling defects or intramural haematoma.

The media is composed of smooth muscle cells and does not reflect ultrasound and there‐ fore appears as a dark ring during the pullback [15]. It is often used to help size stents along with reference lumen dimensions.

The adventitia is a matrix of collagen and elastin and reflects ultrasound markedly to give a whitish appearance on the outer segments of the vessel wall [15].

#### **3.2. IVUS transducer type**

There are two main types of transducers commercially available - a rotational single trans‐ ducer and multiple stationary transducers in a phased array system [16]. The following table compares the current commercially available products.

**Figure 2.** Panel 1: Adventitia (A), Media (M), Intima (I) and Catheter (C), Panel 2: NURD (N), Panel 3: Wire Artifact, Pan‐

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263

Calcified Plaque has marked acoustic shadowing with signal drop out and appears white on IVUS [15]. If circumferential calcification exists, this may prompt the operator to perform ro‐ tablation to ensure full stent expansion. Eccentric masses of bulky calcified plaque should also alert the operator to the potential risk of vessel perforation during percutaneous coro‐ nary intervention (particularly if a cutting balloon is used or if aggressive postdilation is performed) or focal stent under expansion. Generally, when only part of the vessel perime‐ ter is rigid, aggressive postdilation will force stent expansion into the direction of least re‐

IVUS is also able to detect soft plaque, fibrous tissue and in-stent restenosis. Positive and

Definition of diagnostic IVUS parameters for describing parameters of lesion significance as

negative remodeling are also easily identified and generally best identified by IVUS.

el 4: Eccentric fibrous plaque (P)

sistance.

**3.3. Plaque morphology by IVUS**

per the "JACC IVUS Consensus Document" [17]:


**Table 1.**

The most commonly used device in our institution is the rotational system. There is a drive cable that rotates a single transducer element at the tip. The imaging system is located with‐ in a protective sheath that is very soft and creates a fluid interface for the imaging transduc‐ er. The two main artifacts that are encountered include wire artifact and occasionally NURD (Non-uniform Rotational Distortion) [16].

**Figure 2.** Panel 1: Adventitia (A), Media (M), Intima (I) and Catheter (C), Panel 2: NURD (N), Panel 3: Wire Artifact, Pan‐ el 4: Eccentric fibrous plaque (P)

#### **3.3. Plaque morphology by IVUS**

pass through structures depending on their acoustic impedance. The scanning process pro‐ vides both a qualitative and quantitative assessment of the artery. Vessel wall, atherosclerot‐ ic burden and plaque composition can all be assessed and with a well defined lumen-intima

The intima is a single layer of endothelial cells that is largely defined by its interface with blood in the lumen [15]. Saline or contrast flush can help delineate this interface in complex undermined plaque or when this interface may be ambiguous in cases such as lumen filling

The media is composed of smooth muscle cells and does not reflect ultrasound and there‐ fore appears as a dark ring during the pullback [15]. It is often used to help size stents along

The adventitia is a matrix of collagen and elastin and reflects ultrasound markedly to give a

There are two main types of transducers commercially available - a rotational single trans‐ ducer and multiple stationary transducers in a phased array system [16]. The following table

**Comparison Boston Scientific Volcano Volcano** Commercial Name iCross Eagle Eye Platinum Revolution Imaging Method IVUS IVUS IVUS Scanning Design Rotational Phased Array Rotational Frequency 40 MHz 20 MHz 45 MHz Overall Profile 3.2 Fr 3.5 Fr 3.2 Fr

Guide Catheter 6Fr 5Fr 6Fr Delivery Monorail Rapid Exchange Monorail

The most commonly used device in our institution is the rotational system. There is a drive cable that rotates a single transducer element at the tip. The imaging system is located with‐ in a protective sheath that is very soft and creates a fluid interface for the imaging transduc‐ er. The two main artifacts that are encountered include wire artifact and occasionally NURD

whitish appearance on the outer segments of the vessel wall [15].

Tip Entry Profile 0.022" 0.019"

(Non-uniform Rotational Distortion) [16].

compares the current commercially available products.

interface, measurements made of lesion severity such as minimum lumen area.

262 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**3.1. IVUS assessment of wall layers**

defects or intramural haematoma.

with reference lumen dimensions.

**3.2. IVUS transducer type**

**Table 1.**

Calcified Plaque has marked acoustic shadowing with signal drop out and appears white on IVUS [15]. If circumferential calcification exists, this may prompt the operator to perform ro‐ tablation to ensure full stent expansion. Eccentric masses of bulky calcified plaque should also alert the operator to the potential risk of vessel perforation during percutaneous coro‐ nary intervention (particularly if a cutting balloon is used or if aggressive postdilation is performed) or focal stent under expansion. Generally, when only part of the vessel perime‐ ter is rigid, aggressive postdilation will force stent expansion into the direction of least re‐ sistance.

IVUS is also able to detect soft plaque, fibrous tissue and in-stent restenosis. Positive and negative remodeling are also easily identified and generally best identified by IVUS.

Definition of diagnostic IVUS parameters for describing parameters of lesion significance as per the "JACC IVUS Consensus Document" [17]:


**3.4. IVUS to guide intervention**

tional area whereby the use of IVUS improves outcomes [18].

OPTICUS [25] 550 6 mth angio;

**Table 3.** IVUS vs Angiographic Guidance of Bare Metal Stent Implantation

**4. Overview of optical coherence tomography**

pathology behind restenosis.

Despite the relatively attractive ability to size stents and ensure adequate apposition and full stent expansion, there is unfortunately a lack of evidence that IVUS improves the incidence of MACE in patients undergoing stenting although 6-month angiographic diameters may be improved (refer to table below). The exception to this however is in the left main interven‐

Improving the Utility of Coronary Angiography: The Use of Adjuvant Imaging and Physiological Assessment

**Study Number (N) End Point Result** Albiero et al [19] 312 6mth angio IVUS better Blasini et al [20] 212 6 mth angio IVUS better Choi et al [21] 278 Acute closure; 6 month angio IVUS better Gaster et al [22] 108 6 mth angio IVUS better AVID [23] 759 12 mth TLR IVUS better CRUISE [24] 499 9 mth TVR IVUS better

PRESTO [26] 9070 9 mth MACE NO DIFFERENCE

SIPS [28] 269 2 year TLR IVUS better TULIP [29] 144 12 mth MACE IVUS better

The use of IVUS in elucidating the mechanism of instent restenosis is also important particu‐ larly given that it may not be as benign as initially thought. Walters et al. have described that an acute coronary syndrome is a common presentation for in-stent restenosis [30]. An‐ giography alone tends to overestimate the degree of restenosis and usually offers little infor‐ mation regarding the mechanism such as stent undersizing, incomplete expansion, strut fracture and geographic miss. Now that we have arrived in the OCT era, we may gain fur‐ ther insights into neoatherosclerosis as apposed to proliferative fibrous neointima as the

OCT is an intravascular imaging modality akin to intravascular ultrasound (IVUS), howev‐ er, where IVUS uses sound, OCT uses light. The use of near infrared frequency (1300 nm) light waves has remarkably increased resolution. OCT, unlike IVUS, requires a bloodless field. This was originally achieved with proximal occlusion (i.e. time-domain OCT) but in its

RESIST [27] 155 18mth MACE NO SIGNIFICANT DIFFERENCE

12mth MACE

NO DIFFERENCE

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265

#### **Table 2.**

Reference segments can be proximal and distal to the tightest point of the lesion and are usually arbitrarily defined to be within 10 mm of the MLA at a point with the least disease and not involving any side-branches.

**Figure 3.** Panel 1: 180 degree arc of calcium (C), Panel 2: Near 360 degree ring of calcium (C) – this would warrant rotablator, Panel 3: Post Rota-PCI with full stent expansion (S), Panel 4: Plaque rupture (PR) – unstable plaque during ACS

#### **3.4. IVUS to guide intervention**

**Term Description** Lumen Cross-Sectional Area (CSA) The area defined by the luminal border

264 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Minimum Lumen Diameter (MLD) The shortest diameter through the centre point of the

Maximum Lumen Diameter The maximum diameter through the centre point of the

Lumen Eccentricity (Maximum lumen – MLD)/Maximum Lumen Diameter Lumen Area Stenosis (Reference Lumen CSA – Minimum lumen CSA)/Reference

Lumen Diameter Stenosis (Reference Diameter – MLD)/Reference Diameter

Reference segments can be proximal and distal to the tightest point of the lesion and are usually arbitrarily defined to be within 10 mm of the MLA at a point with the least disease

**Figure 3.** Panel 1: 180 degree arc of calcium (C), Panel 2: Near 360 degree ring of calcium (C) – this would warrant rotablator,

Panel 3: Post Rota-PCI with full stent expansion (S), Panel 4: Plaque rupture (PR) – unstable plaque during ACS

**Table 2.**

and not involving any side-branches.

lumen

lumen

Lumen CSA

Despite the relatively attractive ability to size stents and ensure adequate apposition and full stent expansion, there is unfortunately a lack of evidence that IVUS improves the incidence of MACE in patients undergoing stenting although 6-month angiographic diameters may be improved (refer to table below). The exception to this however is in the left main interven‐ tional area whereby the use of IVUS improves outcomes [18].


**Table 3.** IVUS vs Angiographic Guidance of Bare Metal Stent Implantation

The use of IVUS in elucidating the mechanism of instent restenosis is also important particu‐ larly given that it may not be as benign as initially thought. Walters et al. have described that an acute coronary syndrome is a common presentation for in-stent restenosis [30]. An‐ giography alone tends to overestimate the degree of restenosis and usually offers little infor‐ mation regarding the mechanism such as stent undersizing, incomplete expansion, strut fracture and geographic miss. Now that we have arrived in the OCT era, we may gain fur‐ ther insights into neoatherosclerosis as apposed to proliferative fibrous neointima as the pathology behind restenosis.

## **4. Overview of optical coherence tomography**

OCT is an intravascular imaging modality akin to intravascular ultrasound (IVUS), howev‐ er, where IVUS uses sound, OCT uses light. The use of near infrared frequency (1300 nm) light waves has remarkably increased resolution. OCT, unlike IVUS, requires a bloodless field. This was originally achieved with proximal occlusion (i.e. time-domain OCT) but in its most recent iteration, has been achieved by contrast injection with Fourier Domain OCT. This has significantly improved the user-friendliness of OCT. The characteristics of IVUS, TD-OCT and FD-OCT are detailed below:

rich plaque, fibrous plaque, calcified nodules, macrophages, intimal disruption, red and white thrombus and thin capped fibroatheroma. OCT has revolutionized the assessment of stent performance with an unrivalled ability to detect malapposition, stent expansion, edge dissection, prolapse, filling defects, strut appearance and strut coverage. It can even discrim‐ inate between neointima and neo-atherosclerosis with regard to in-stent restenosis and de‐ tect neorevascularisation. OCT is in its infancy in its ability to define flow-limiting stenoses

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**Figure 4.** Panel 1: Blood swirl artifact ; Panel 2: Wire artifact (W) ; Panel 3: Stitch artifact from catheter movement (arrow) ; Panel 4: Spontaneous coronary dissection with visible false lumen (FL) ; Panel 5: Fibrous Plaque ; Panel 6:

on the basis of lesion parameters for severity (akin to IVUS measurements).

**Table 5.**

Proliferative neointima within a stent


#### **Table 4.**

#### **4.1. Procedural detail**

The currently available OCT catheter is a rapid exchange catheter compatible with a 6Fr guiding catheter. The OCT catheter has several markers and the position of the imaging op‐ tical lens is noted to be 25 mm from the tip of the catheter and 5 mm proximal to the proxi‐ mal marker. It appears as a radiolucent gap in the imaging catheter. It is thus important to note that a considerable length of catheter is needed to be placed beyond a stenosis and therefore a suitable landing zone is required that is of reasonable caliber and not excessively tortuous. A calibration process is performed prior to image acquisition – z offset or auto-cal‐ ibration whereby marker fiducials are placed equidistant around the border of the catheter on the computer interface. With an automated injection system, we advocate a contrast in‐ jection of 4mL/sec, 14mL volume for the left coronary system; 3mL/sec, 12 mL for the right coronary system. For manual injection, usually 10mL contrast at reasonably sustained injec‐ tion pressure will be sufficient to opacify the vessel. Ischemic electrocardiographic changes are not infrequent but almost always self-limiting; arrhythmia is rare and less frequent than with TD-OCT. REF Other complications such as those from guiding catheters and coronary wires are not attributable to OCT per se but are a part of the inherent risk of the procedure. The main advantages with the FD-OCT over TD-OCT are the faster pullback speed (20mm/ sec) and the avoidance of proximal vessel occlusion, with potentially clearer images and larger reference segment dimensions [31]. The safety and feasibility of FD-OCT has been widely reported [32-34]. Slowing the pullback speed to 10 mm/sec can enhance the imaging detail particularly if imaging for stent complications at the end of a PCI.

#### **4.2. Current uses of OCT**

Sine 1996, a lot of work has been performed evaluating the correlation of OCT with histopa‐ thology – an essential prerequisite to describing vessel pathology. Exquisite images and de‐ tailed analysis of plaque composition [35] can be achieved including clarification of lipid rich plaque, fibrous plaque, calcified nodules, macrophages, intimal disruption, red and white thrombus and thin capped fibroatheroma. OCT has revolutionized the assessment of stent performance with an unrivalled ability to detect malapposition, stent expansion, edge dissection, prolapse, filling defects, strut appearance and strut coverage. It can even discrim‐ inate between neointima and neo-atherosclerosis with regard to in-stent restenosis and de‐ tect neorevascularisation. OCT is in its infancy in its ability to define flow-limiting stenoses on the basis of lesion parameters for severity (akin to IVUS measurements).


**Table 5.**

most recent iteration, has been achieved by contrast injection with Fourier Domain OCT. This has significantly improved the user-friendliness of OCT. The characteristics of IVUS,

266 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Axial resolution, micron 100 10-15 10-15

Frame rate, frames/sec 30 20 100 Maximum scan diameter, mm 10 6.8 9.7 Proximal occlusion No Yes No Pullback rate, mm/s 1 1-3 20

The currently available OCT catheter is a rapid exchange catheter compatible with a 6Fr guiding catheter. The OCT catheter has several markers and the position of the imaging op‐ tical lens is noted to be 25 mm from the tip of the catheter and 5 mm proximal to the proxi‐ mal marker. It appears as a radiolucent gap in the imaging catheter. It is thus important to note that a considerable length of catheter is needed to be placed beyond a stenosis and therefore a suitable landing zone is required that is of reasonable caliber and not excessively tortuous. A calibration process is performed prior to image acquisition – z offset or auto-cal‐ ibration whereby marker fiducials are placed equidistant around the border of the catheter on the computer interface. With an automated injection system, we advocate a contrast in‐ jection of 4mL/sec, 14mL volume for the left coronary system; 3mL/sec, 12 mL for the right coronary system. For manual injection, usually 10mL contrast at reasonably sustained injec‐ tion pressure will be sufficient to opacify the vessel. Ischemic electrocardiographic changes are not infrequent but almost always self-limiting; arrhythmia is rare and less frequent than with TD-OCT. REF Other complications such as those from guiding catheters and coronary wires are not attributable to OCT per se but are a part of the inherent risk of the procedure. The main advantages with the FD-OCT over TD-OCT are the faster pullback speed (20mm/ sec) and the avoidance of proximal vessel occlusion, with potentially clearer images and larger reference segment dimensions [31]. The safety and feasibility of FD-OCT has been widely reported [32-34]. Slowing the pullback speed to 10 mm/sec can enhance the imaging

detail particularly if imaging for stent complications at the end of a PCI.

Sine 1996, a lot of work has been performed evaluating the correlation of OCT with histopa‐ thology – an essential prerequisite to describing vessel pathology. Exquisite images and de‐ tailed analysis of plaque composition [35] can be achieved including clarification of lipid

Wavelength Ultrasound Near-infrared Near-infrared

**IVUS TD-OCT FD-OCT**

TD-OCT and FD-OCT are detailed below:

**Table 4.**

**4.1. Procedural detail**

**4.2. Current uses of OCT**

**Figure 4.** Panel 1: Blood swirl artifact ; Panel 2: Wire artifact (W) ; Panel 3: Stitch artifact from catheter movement (arrow) ; Panel 4: Spontaneous coronary dissection with visible false lumen (FL) ; Panel 5: Fibrous Plaque ; Panel 6: Proliferative neointima within a stent

**•** In the early phases of operator inexperience, there can be difficulty identifying calcium

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269

The presence of myocardial ischemia is an important determinant of adverse cardiac out‐ come [36,37]. Revascularization of stenotic coronary lesions, by eliminating myocardial is‐ chemia can improve patient symptoms, functional status and in patients with proven ischaemia, reduce death and major adverse cardiovascular events [38-40]. Importantly, for stenotic lesions that do not induce ischemia, medical therapy alone is likely to be equally ef‐ fective with less benefit for revascularization [2,3,40]. While most patients undergo non-in‐ vasive testing to detect the presence of myocardial ischemia prior to consideration of angiography many patients with high clinical likelihood of CAD are catheterized without functional testing. Additionally, noninvasive stress imaging studies may be non-diagnostic and are limited in their ability to accurately localize culprit lesions in patients with multives‐ sel CAD [41]. Ultimately where revascularization is considered, patients undergo coronary

Proving ischaemic burden in intermediate lesions requires invasive adjunctive tools – pres‐ sure derived measurements using FFR aim at functional evaluation whilst intravascular ul‐ trasound (IVUS) and OCT provide anatomical clarification of the vessel anatomy and lesion dimensions. Both intracoronary IVUS and OCT can be used to measure lesion and vessel pa‐ rameters such as minimum luminal area and diameter. Unlike IVUS, OCT has only just be‐ gun to be validated against FFR. Given FFR is now the gold standard of invasive physiological assessment of the stenosis functional significance, there are studies underway to validate lesion parameters for severity on OCT with the physiological information ob‐

Coronary angiography is a 2-dimensional lumenogram of a 3-dimensional vascular lumen. It reports stenosis severity as a ratio of the lesion minimal lumen diameter to the adjacent "normal" reference segment. But, coronary atherosclerosis is a diffuse process and the accu‐ racy of angiographic assessment is limited by the inability to identify both "diseased" and "normal" vessel segments. Histopathological studies have demonstrated that angiography fails to detect atheroma until the area stenosis approaches 40-50% as this is the approximate critical level at which further expansion of the external elastic membrane is not possible and so plaque begins to encroach upon the lumen. Furthermore, eccentric plaque produces an eccentric lumen that can give conflicting degrees of angiographic narrowing dependant on the viewing angulations. Despite improvements in quantitative coronary angiographic (QCA) techniques, coronary angiography frequently fails to identify the accurate hemody‐ namic significance of coronary stenoses, particularly those between 30% and 70% diameter stenosis [42-44]. The assessment and management of these "intermediate coronary lesions",

**5. Assessment of moderate coronary artery disease – Non Left Main**

and differentiating it from lipid rich plaque

**5.1. Coronary angiography and stenosis significance**

angiography.

tained by FFR.

**Figure 5.** Panel 1: Calcified Nodule (arrow); Panel 2: Red thrombus (arrow) ; Panel 3: Vasa Vasorum (arrow) ; Panel 4: Covered stent – uncovered 7 years post deployment; Panel 5: Lipid rich plaque that is catheter hugging ; Panel 6: dis‐ rupted intima with a small cavity

#### **4.3. Despite the overall attractiveness of OCT, some drawbacks include**


**•** In the early phases of operator inexperience, there can be difficulty identifying calcium and differentiating it from lipid rich plaque

## **5. Assessment of moderate coronary artery disease – Non Left Main**

The presence of myocardial ischemia is an important determinant of adverse cardiac out‐ come [36,37]. Revascularization of stenotic coronary lesions, by eliminating myocardial is‐ chemia can improve patient symptoms, functional status and in patients with proven ischaemia, reduce death and major adverse cardiovascular events [38-40]. Importantly, for stenotic lesions that do not induce ischemia, medical therapy alone is likely to be equally ef‐ fective with less benefit for revascularization [2,3,40]. While most patients undergo non-in‐ vasive testing to detect the presence of myocardial ischemia prior to consideration of angiography many patients with high clinical likelihood of CAD are catheterized without functional testing. Additionally, noninvasive stress imaging studies may be non-diagnostic and are limited in their ability to accurately localize culprit lesions in patients with multives‐ sel CAD [41]. Ultimately where revascularization is considered, patients undergo coronary angiography.

Proving ischaemic burden in intermediate lesions requires invasive adjunctive tools – pres‐ sure derived measurements using FFR aim at functional evaluation whilst intravascular ul‐ trasound (IVUS) and OCT provide anatomical clarification of the vessel anatomy and lesion dimensions. Both intracoronary IVUS and OCT can be used to measure lesion and vessel pa‐ rameters such as minimum luminal area and diameter. Unlike IVUS, OCT has only just be‐ gun to be validated against FFR. Given FFR is now the gold standard of invasive physiological assessment of the stenosis functional significance, there are studies underway to validate lesion parameters for severity on OCT with the physiological information ob‐ tained by FFR.

#### **5.1. Coronary angiography and stenosis significance**

**Figure 5.** Panel 1: Calcified Nodule (arrow); Panel 2: Red thrombus (arrow) ; Panel 3: Vasa Vasorum (arrow) ; Panel 4: Covered stent – uncovered 7 years post deployment; Panel 5: Lipid rich plaque that is catheter hugging ; Panel 6: dis‐

**•** Limited ability to image very large vessels given limited depth of penetration (imaging

**•** Blood pool artifact (this occurs when the lumen is not devoid of blood because of inade‐

**•** Stitch artifact (usually only subtle and not a major issue; this artifact relates mostly to catheter movement within the vessel and appears as an abrupt step in the vessel wall)

**•** If the catheter does not sit coaxially within the vessel then an oblique cut may be made

**•** Given the imaging catheter remains in the artery, there may be a tendency to straighten the vessel, cause vessel concertina and perhaps even distort stents of questionable longi‐

**•** Difficulty to image true aorto-ostial disease (IVUS is preferred in this scenario)

quate contrast injection – the erythrocytes cause a severe scatter of light)

**4.3. Despite the overall attractiveness of OCT, some drawbacks include**

268 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

rupted intima with a small cavity

**•** Need for extra contrast

>4.5 mm diameter vessels is difficult)

through the lumen and vessel wall

tudinal strength

Coronary angiography is a 2-dimensional lumenogram of a 3-dimensional vascular lumen. It reports stenosis severity as a ratio of the lesion minimal lumen diameter to the adjacent "normal" reference segment. But, coronary atherosclerosis is a diffuse process and the accu‐ racy of angiographic assessment is limited by the inability to identify both "diseased" and "normal" vessel segments. Histopathological studies have demonstrated that angiography fails to detect atheroma until the area stenosis approaches 40-50% as this is the approximate critical level at which further expansion of the external elastic membrane is not possible and so plaque begins to encroach upon the lumen. Furthermore, eccentric plaque produces an eccentric lumen that can give conflicting degrees of angiographic narrowing dependant on the viewing angulations. Despite improvements in quantitative coronary angiographic (QCA) techniques, coronary angiography frequently fails to identify the accurate hemody‐ namic significance of coronary stenoses, particularly those between 30% and 70% diameter stenosis [42-44]. The assessment and management of these "intermediate coronary lesions", then becomes a dilemma for the clinician. In this context, a more reliable technique at the time of angiography is vital to direct appropriate revascularization or medical therapy in a single setting. Fractional flow reserve (FFR) assessment and Intravascular ultrasound (IVUS) are two such techniques which are now part of standard clinical practice in guiding treat‐ ment of patients with intermediate coronary lesions [43,44] [45].

**5.3. Fractional flow reserve corrected for right atrial pressure and stenosis significance**

parameters for lesion severity.

cross-sectional area ≤3.0 - 4.0mm2

preference to FFR when:

**5.4. Intravascular ultrasound (IVUS) and stenosis significance**

gree of calcification and accurate vessel size are required.

rhythmia or severe asthma precluding the use of adenosine.

The original FFR calculation was derived from the following formula: FFR= (Pd-Pv)/(Pa-Pv) where Pd is distal mean pressure, Pa is aortic/guiding catheter mean pressure and Pv is cen‐ tral venous/RA (right atrial) pressure [48,49]. Effectively, this is an FFR corrected for right atrial pressure (FFRRA). FFRRA was used in some [49,50] but not all of the original validation studies to determine which FFR values best predicts an ischaemic burden [51-53]. In all re‐ cent studies validating IVUS with FFR and FFR with revascularisation/outcomes, FFR was never corrected for RA pressure. The simplified formula FFR = Pd/Pa was used largely based on the assumption that Pv was minimal and therefore did not greatly influence the final FFR result. Furthermore, previous data suggested that a correlation existed between FFR and positron emmission tomography (PET) derived myocardial blood flow indices even when RA pressure was ommitted [50]. However, this was a small series of low risk pa‐ tients with a mean RA pressure of 5 mmHg. This does not necessarily reflect the cohort of patients coming through a high volume tertiary hospital with congestive cardiac failure pa‐ tients in which filling pressure may not be insignificant. This lead Layland et al to compare FFRRA with FFR in assessing coronary stenoses in a real world cohort. They demonstrated that right atrial pressure does in fact influence the FFR and tends to shift it downward into the ischaemic threshold [54]. It is not known however, whether FFRRA (as opposed to FFR) can be used to guide intervention or whether it would better correlate with IVUS or OCT

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271

As previously described, intravascular ultrasound is a catheter-based technique that pro‐ vides high-resolution (up to 150microns) cross-sectional tomographic images of the coro‐ nary lumen and the coronary arterial wall that can be visualized in real time. It is currently the commonest intravascular imaging modality used as an adjunct to coronary angiography and PCI. Intravascular ultrasound is simple to perform, and its use is associated with very low complication rates [55]. IVUS does not provide direct hemodynamic data of a coronary lesion. However, several studies have demonstrated a strong correlation between IVUS le‐ sion parameter and ischemia by myocardial perfusion imaging [56], and FFR [57,58]. Param‐ eters that correlated with an FFR value ≤0.75 were area stenosis (>60-70%), minimal lumen

**1.** Precise information on extent of the atherosclerosis, plaque characteristics including de‐

**2.** FFR assessment is contraindicated; significant conducting system disease or bradyar‐

**3.** Situations where FFR values may be misleading; previous MI with significant scar, dif‐ fuse coronary disease, microvascular disease, significant left ventricular hypertrophy. The traditional cutoff of MLA <4 mm2 on IVUS has been questioned in recent studies, and it is now thought that an MLA of <2.4 mm2 may better predict a significant lesion [57-59]. Ulti‐

and minimal lumen diameter ≤1.8 mm. IVUS is used in

#### **5.2. Fractional flow reserve and stenosis significance**

Coronary pressure wire-derived FFR is now the technique of choice used in the cardiac cathe‐ terization laboratory to determine the functional significance of a coronary stenosis [45]. This method relies on the decrease in intra-arterial pressure induced by a stenosis to determine whether the lesion is producing physiologically significant ischemia. As described previously, Fractional flow reserve (FFR) is defined as the ratio of flow in the stenotic artery to the flow in the same artery in the theoretic absence of the stenosis [46]. Pressure is used as a surrogate of flow and FFR can be calculated by measuring the pressure difference across a stenosis under maxi‐ mal hyperemia induced usually by adenosine. The pressure distal to the stenosis is accurately measured by a 0.014-inch pressure sensor angioplasty guidewire passed distal to the stenosis. FFR in a normal coronary artery = 1.0. FFR values of <0.75 (normal 1.0) are associated with posi‐ tive functional stress tests in numerous comparative studies [sensitivity (88%), specificity (100%), positive predictive value (100%), and overall accuracy (93%)[45]. FFR values >0.80 are associated with negative ischemic results with a predictive accuracy of 95% [45]. Deferring re‐ vascularisation based on non-significant FFR values (>0.75) are associated with rates of death or myocardial infarction lower than that after routine stenting [3]. In patients with multivessel cor‐ onary artery disease FFR-guided PCI is associated with reduced major adverse cardiac events [40]. Furthermore, De Bruyne et al have recently demonstrated that managing patients medical‐ ly (deferring PCI) with lesions that have documented ischaemic burden (defined as FFR < 0.80) have an increased risk of urgent revascularisation [47].


**Table 6.**

#### **5.3. Fractional flow reserve corrected for right atrial pressure and stenosis significance**

then becomes a dilemma for the clinician. In this context, a more reliable technique at the time of angiography is vital to direct appropriate revascularization or medical therapy in a single setting. Fractional flow reserve (FFR) assessment and Intravascular ultrasound (IVUS) are two such techniques which are now part of standard clinical practice in guiding treat‐

270 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Coronary pressure wire-derived FFR is now the technique of choice used in the cardiac cathe‐ terization laboratory to determine the functional significance of a coronary stenosis [45]. This method relies on the decrease in intra-arterial pressure induced by a stenosis to determine whether the lesion is producing physiologically significant ischemia. As described previously, Fractional flow reserve (FFR) is defined as the ratio of flow in the stenotic artery to the flow in the same artery in the theoretic absence of the stenosis [46]. Pressure is used as a surrogate of flow and FFR can be calculated by measuring the pressure difference across a stenosis under maxi‐ mal hyperemia induced usually by adenosine. The pressure distal to the stenosis is accurately measured by a 0.014-inch pressure sensor angioplasty guidewire passed distal to the stenosis. FFR in a normal coronary artery = 1.0. FFR values of <0.75 (normal 1.0) are associated with posi‐ tive functional stress tests in numerous comparative studies [sensitivity (88%), specificity (100%), positive predictive value (100%), and overall accuracy (93%)[45]. FFR values >0.80 are associated with negative ischemic results with a predictive accuracy of 95% [45]. Deferring re‐ vascularisation based on non-significant FFR values (>0.75) are associated with rates of death or myocardial infarction lower than that after routine stenting [3]. In patients with multivessel cor‐ onary artery disease FFR-guided PCI is associated with reduced major adverse cardiac events [40]. Furthermore, De Bruyne et al have recently demonstrated that managing patients medical‐ ly (deferring PCI) with lesions that have documented ischaemic burden (defined as FFR < 0.80)

ment of patients with intermediate coronary lesions [43,44] [45].

**5.2. Fractional flow reserve and stenosis significance**

have an increased risk of urgent revascularisation [47].

**Table 6.**

The original FFR calculation was derived from the following formula: FFR= (Pd-Pv)/(Pa-Pv) where Pd is distal mean pressure, Pa is aortic/guiding catheter mean pressure and Pv is cen‐ tral venous/RA (right atrial) pressure [48,49]. Effectively, this is an FFR corrected for right atrial pressure (FFRRA). FFRRA was used in some [49,50] but not all of the original validation studies to determine which FFR values best predicts an ischaemic burden [51-53]. In all re‐ cent studies validating IVUS with FFR and FFR with revascularisation/outcomes, FFR was never corrected for RA pressure. The simplified formula FFR = Pd/Pa was used largely based on the assumption that Pv was minimal and therefore did not greatly influence the final FFR result. Furthermore, previous data suggested that a correlation existed between FFR and positron emmission tomography (PET) derived myocardial blood flow indices even when RA pressure was ommitted [50]. However, this was a small series of low risk pa‐ tients with a mean RA pressure of 5 mmHg. This does not necessarily reflect the cohort of patients coming through a high volume tertiary hospital with congestive cardiac failure pa‐ tients in which filling pressure may not be insignificant. This lead Layland et al to compare FFRRA with FFR in assessing coronary stenoses in a real world cohort. They demonstrated that right atrial pressure does in fact influence the FFR and tends to shift it downward into the ischaemic threshold [54]. It is not known however, whether FFRRA (as opposed to FFR) can be used to guide intervention or whether it would better correlate with IVUS or OCT parameters for lesion severity.

#### **5.4. Intravascular ultrasound (IVUS) and stenosis significance**

As previously described, intravascular ultrasound is a catheter-based technique that pro‐ vides high-resolution (up to 150microns) cross-sectional tomographic images of the coro‐ nary lumen and the coronary arterial wall that can be visualized in real time. It is currently the commonest intravascular imaging modality used as an adjunct to coronary angiography and PCI. Intravascular ultrasound is simple to perform, and its use is associated with very low complication rates [55]. IVUS does not provide direct hemodynamic data of a coronary lesion. However, several studies have demonstrated a strong correlation between IVUS le‐ sion parameter and ischemia by myocardial perfusion imaging [56], and FFR [57,58]. Param‐ eters that correlated with an FFR value ≤0.75 were area stenosis (>60-70%), minimal lumen cross-sectional area ≤3.0 - 4.0mm2 and minimal lumen diameter ≤1.8 mm. IVUS is used in preference to FFR when:


The traditional cutoff of MLA <4 mm2 on IVUS has been questioned in recent studies, and it is now thought that an MLA of <2.4 mm2 may better predict a significant lesion [57-59]. Ulti‐ mately, it is still unclear which of the two MLA cuttoff's is more efficient in predicting sign‐ ficant stenoses, and future IVUS and OCT studies may also suffer from this "shifting goalpost" phenomenon. This reflects the need for more studies validating anatomical with physiological data.

OCT and IVUS were indeed much smaller than the traditional 4 mm2

requisite before OCT can be validly used to establish stenosis significance.

id. Specific in vivo validation data against FFR is required.

by a simple approach to the side-branch is usually all that is required.

vasculature pressures are high and thereby the FFR falsely elevated [6].

**6. Other uses for FFR**

struction post ACS is detrimental [69].

**7.1. Background**

**7. Assessment of the ambiguous left main**

not correct FFR for right atrial pressure nor did it include OCT values indexed to the size of the patient or reference vessel (in a bid to roughly adjust for mass of myocardium supplied) – two corrections that may improve the correlation between OCT and FFR and affect the anatomical parameter and its value that best predicts an FFR ≤0.80. Further studies are therefore a vital pre-

Improving the Utility of Coronary Angiography: The Use of Adjuvant Imaging and Physiological Assessment

In-vitro studies with a vascular phantom have shown that not only do OCT luminal meas‐ urements correlate strongly with IVUS but they are more accurate than IVUS [63]. Both in vitro and in vivo studies suggest, however, that OCT measurements tend to be smaller than IVUS measurements probably because of its better luminal definition [62,64]. Therefore, di‐ rect translation of IVUS parameters of stenosis significance to OCT is not appropriate or val‐

FFR can be used to guide PCI formally to ensure full stent expansion based on FFR >0.94 [65] and can also be used to evaluate side branch "pinching" post PCI. Koo et al demonstrated that when the side branch was <75% stenosed post PCI, the FFR was never in the ischaemic range and when it was >75% stenosed, it only fell into the ischaemic range approximately 1/3 of the time [66]. This emphasizes a common issue of over-interpreting the side branch appearance in PCI cases and vindicates bifurcation studies such as Nordic-Baltic Bifurcation Study III [67] where‐

The use of FFR in vein grafts or in cases of severe left ventricular hypertrophy has not yet been validated. Nor, is it a useful tool in the acute setting such as a STEMI when the micro‐

The pressure sensor wire also has a temperature sensing function that enables it to detect changes in temperature with saline flushes. Although beyond the scope of this chapter, it has allowed the FFR wire to also measure microcirculatory function (Index of Microcircula‐ tory Resistance or IMR). The basic physiology behind IMR relates to transit time and tem‐ perature change detected by the wire sensor after flushing 3mls of saline via the guiding catheter. Ultimately, transit time is inversely proportional to microcirculatory resistance [68]. Although IMR is still largely a research tool, it has been shown to correlate with peak CK enzyme rise post STEMI and therefore offers a proof of concept that microvascular ob‐

The accurate detection and description of disease of the left main coronary artery (LMCA) is of fundamental importance in the evaluation of patients in the catheterization laboratory.

. However, this study did

http://dx.doi.org/10.5772/54041

273

In our catheterization laboratory about half of the stenosis assessments are done with IVUS. In some centers' it is the primary tool used [60]. There is a growing trend in our labarotory now for using OCT instead of IVUS for plaque characterisation and vessel dimensions.

#### **5.5. Optical coherence tomography and stenosis significance**

Optical coherence tomography (OCT) is a recently introduced medical imaging technology. It is an optical analogue of IVUS and measures the back-reflection of near-infrared light di‐ rected at tissues and generates images with a resolution close to 10micron; 10-15X greater than IVUS. With the current generation of FD-OCT imaging engines, it is also up to 20 times faster in imaging [35]. The safety of OCT imaging has been well described [61,62]. Given its significantly higher resolution, OCT has many advantages over IVUS both in atherosclerotic plaque assessment and in evaluating the acute and long-term effects of PCI [35]. It is likely to replace IVUS as the primary intravascular imaging modality.


#### **Table 7.**

With its better definition of the intimal-luminal interface and higher resolution compared to IVUS, OCT may improve accuracy and reduce observer variability in intravascular luminal cross-sectional measurements; in this context OCT may be particularly useful in assessing (in‐ termediate) coronary stenosis severity. However, unlike IVUS which has many studies validat‐ ing it against FFR albeit with differing MLA results, there has only been one such trial using OCT [59]. In this study, it was demonstrated that an MLA of 1.95 mm2 was most efficient at pre‐ dicting physiological significance. Gonzalo et al. [59] also demonstrated that OCT was more ef‐ ficient than IVUS in predicting stenosis severity and that the geometric cutoff values for both OCT and IVUS were indeed much smaller than the traditional 4 mm2 . However, this study did not correct FFR for right atrial pressure nor did it include OCT values indexed to the size of the patient or reference vessel (in a bid to roughly adjust for mass of myocardium supplied) – two corrections that may improve the correlation between OCT and FFR and affect the anatomical parameter and its value that best predicts an FFR ≤0.80. Further studies are therefore a vital prerequisite before OCT can be validly used to establish stenosis significance.

In-vitro studies with a vascular phantom have shown that not only do OCT luminal meas‐ urements correlate strongly with IVUS but they are more accurate than IVUS [63]. Both in vitro and in vivo studies suggest, however, that OCT measurements tend to be smaller than IVUS measurements probably because of its better luminal definition [62,64]. Therefore, di‐ rect translation of IVUS parameters of stenosis significance to OCT is not appropriate or val‐ id. Specific in vivo validation data against FFR is required.

## **6. Other uses for FFR**

mately, it is still unclear which of the two MLA cuttoff's is more efficient in predicting sign‐ ficant stenoses, and future IVUS and OCT studies may also suffer from this "shifting goalpost" phenomenon. This reflects the need for more studies validating anatomical with

272 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

In our catheterization laboratory about half of the stenosis assessments are done with IVUS. In some centers' it is the primary tool used [60]. There is a growing trend in our labarotory now for using OCT instead of IVUS for plaque characterisation and vessel dimensions.

Optical coherence tomography (OCT) is a recently introduced medical imaging technology. It is an optical analogue of IVUS and measures the back-reflection of near-infrared light di‐ rected at tissues and generates images with a resolution close to 10micron; 10-15X greater than IVUS. With the current generation of FD-OCT imaging engines, it is also up to 20 times faster in imaging [35]. The safety of OCT imaging has been well described [61,62]. Given its significantly higher resolution, OCT has many advantages over IVUS both in atherosclerotic plaque assessment and in evaluating the acute and long-term effects of PCI [35]. It is likely

With its better definition of the intimal-luminal interface and higher resolution compared to IVUS, OCT may improve accuracy and reduce observer variability in intravascular luminal cross-sectional measurements; in this context OCT may be particularly useful in assessing (in‐ termediate) coronary stenosis severity. However, unlike IVUS which has many studies validat‐ ing it against FFR albeit with differing MLA results, there has only been one such trial using

dicting physiological significance. Gonzalo et al. [59] also demonstrated that OCT was more ef‐ ficient than IVUS in predicting stenosis severity and that the geometric cutoff values for both

was most efficient at pre‐

OCT [59]. In this study, it was demonstrated that an MLA of 1.95 mm2

**5.5. Optical coherence tomography and stenosis significance**

to replace IVUS as the primary intravascular imaging modality.

physiological data.

**Table 7.**

FFR can be used to guide PCI formally to ensure full stent expansion based on FFR >0.94 [65] and can also be used to evaluate side branch "pinching" post PCI. Koo et al demonstrated that when the side branch was <75% stenosed post PCI, the FFR was never in the ischaemic range and when it was >75% stenosed, it only fell into the ischaemic range approximately 1/3 of the time [66]. This emphasizes a common issue of over-interpreting the side branch appearance in PCI cases and vindicates bifurcation studies such as Nordic-Baltic Bifurcation Study III [67] where‐ by a simple approach to the side-branch is usually all that is required.

The use of FFR in vein grafts or in cases of severe left ventricular hypertrophy has not yet been validated. Nor, is it a useful tool in the acute setting such as a STEMI when the micro‐ vasculature pressures are high and thereby the FFR falsely elevated [6].

The pressure sensor wire also has a temperature sensing function that enables it to detect changes in temperature with saline flushes. Although beyond the scope of this chapter, it has allowed the FFR wire to also measure microcirculatory function (Index of Microcircula‐ tory Resistance or IMR). The basic physiology behind IMR relates to transit time and tem‐ perature change detected by the wire sensor after flushing 3mls of saline via the guiding catheter. Ultimately, transit time is inversely proportional to microcirculatory resistance [68]. Although IMR is still largely a research tool, it has been shown to correlate with peak CK enzyme rise post STEMI and therefore offers a proof of concept that microvascular ob‐ struction post ACS is detrimental [69].

## **7. Assessment of the ambiguous left main**

### **7.1. Background**

The accurate detection and description of disease of the left main coronary artery (LMCA) is of fundamental importance in the evaluation of patients in the catheterization laboratory. Significant LMCA stenosis carries a poor prognosis without appropriate revascularization. [70-72] Therefore, the presence or absence of left main disease has a critical impact on thera‐ peutic decision making following angiographic evaluation.

adenosine infusion, care should be taken to ensure that the peripheral intravenous site is flushing normally and appropriately connected. Maximal hyperaemia will be achieved in most patients by two to three minutes, at which point the infusion can be ceased. An alterna‐ tive to the infusion of adenosine is intracoronary bolus injection, but this is potentially a less robust [85] method and can be practically difficult if guide catheter pressure damping man‐ dates catheter disengagement. A further potential confounder is the role of right atrial pres‐ sure in FFR assessment. Although FFR adjusted for right atrial pressure was tested by Layland et al in the non-left main subset, adjusting for assessment of left main has not been conducted although a similar phenomenon would be expected – that being as FFR ap‐ proaches the ischaemic zone, right atrial pressure becomes increasingly important.[54] This

Improving the Utility of Coronary Angiography: The Use of Adjuvant Imaging and Physiological Assessment

Intravascular ultrasound (IVUS) of the LMCA provides sonographically derived images of the LMCA lumen and vessel wall. As a result, IVUS provides real time anatomical and pathological information in 2 dimensions. IVUS parameters have been evaluated in multiple studies in the setting of LMCA disease. Initial work that correlated IVUS data with clinical outcomes demonstrated a relationship between IVUS derived minimal luminal diameter (MLD) and minimal lumen area (MLA) at a lesion site with major adverse cardiovascular events (MACE).[86] [87]These initial studies, however, did not mandate any specific cut off values for treatment decisions. A clinical outcome based study by Fassa et al subsequently demonstrated that deferral of revascularization is the appropriate strategy where the LMCA

Given the clinically validated findings for FFR, IVUS has also been investigated utilizing FFR as a gold standard comparator. In a cohort of 51 North American patients Jasti et al

<0.75. This study also correlated FFR measurements with clinical outcomes and confirmed the appropriateness of an FFR cut off of <0.75. [90]Kang et al performed a similar correlation

evaluation of clinical outcomes was not performed as was done in the study by Jasti et al. In addition, the applicability of the study by Kang et al to patients of European ethnicity is un‐ clear. Both studies also demonstrated that relative disease burden metrics such as plaque burden and area stenosis were insufficiently predictive of FFR measurements to be useful in

Based on the above data, a cut off of ≤5.9 mm<sup>2</sup> for MLA, if using IVUS alone, should be used in determining referral for LMCA revascularization following IVUS evaluation. Where there is uncertainty or ambiguity around measurements or their relevance in specific patients,

study in 55 South Korean patients. They found a MLA cut off of <4.1 mm2

strong consideration should be given to adjunctive FFR evaluation.

or an MLA ≤5.9 mm2

. [88]More recent work has revised this measurement down to ≥6 mm<sup>2</sup>

. [89]

correlated well

correlated strongly with a FFR

http://dx.doi.org/10.5772/54041

275

correlated with a FFR of <0.8. However,

is an area that requires further investigation.

**7.3. Intravascular ultrasound assessment**

demonstrated that an MLD ≤2.8 mm2

with a FFR <0.75 and a MLA cut off of <4.8 mm2

MLA is ≥7.5 mm<sup>2</sup>

clinical practice.

Angiographic assessment of the LMCA can be challenging. The anatomical plane of the LMCA, issues with vessel overlap, elliptical vessel configuration and plaque eccentricity all contribute to potential difficulty in accurately quantifying LMCA disease with conventional coronary angiography alone. In cases where LMCA disease severity is ambiguous, indeter‐ minate or equivocal, adjunctive intravascular imaging or physiological assessment is of key importance.[18]

Fractional flow reserve (FFR) offers a real time stress physiological assessment of coronary pressure dynamics. Intravascular ultrasound (IVUS) is able to define the anatomy of the LMCA. Both of these technologies allow for the potential to improve LMCA assessment and attendant clinical outcomes and are discussed further below. Optical coherence tomography (OCT) has a limited role in LMCA assessment, especially for ostial LMCA disease, largely due to the dependence on having a contrast filled lumen to allow satisfactory imaging reso‐ lution to occur. [73]

#### **7.2. Fractional flow reserve physiological assessment**

FFR has been evaluated in several studies in the setting of LMCA disease. A cut off value for the Pd/Pa (pressure distal/pressure aortic) ratio, following induction of hyperaemia, of <0.75 – 0.8 has been demonstrated to safely discriminate between patients who should be referred for revascularization, usually coronary artery bypass grafting, as opposed to ongoing medi‐ cal therapy and observation. [74-81] Patients with readings between 0.75 – 0.8 have physiol‐ ogy in a range that requires further study. In patients with intermediate readings of this kind the clinical context, as well consideration to additional evaluation with intravascular ultrasound become important.

The FFR technique involves the placement of a high fidelity pressure sensor beyond the left main plaque just as described in the "non left main" section previously. Consideration should be given to performing the procedure in both the left anterior descending and left circumflex artery to ensure concordance of results – this is particularly important if the cir‐ cumflex is dominant [18]. Once the wire is in position and the catheter flushed with 100 – 200 mcg of intracoronary nitroglycerine followed by saline, hyperaemia is induced with the use of adenosine, 140 - 180 mcg/kg/min via intravenous infusion (central or peripheral). Higher doses may be required if a systemic response is not demonstrated. Venous infusion is preferred, however, adenosine can also be delivered by intracoronary bolus and studies in the area suggest no major difference between the three administration methods, [82,83] al‐ though intracoronary bolus doses of up to 720 mcg on each injection may be required.[84]

There are several potential pitfalls to FFR evaluation of the left main. Of utmost importance is the particular issue of guiding catheter damping and potential obstructive interference with coronary flow. Disengagement of the guide catheter is required for accurate evaluation in order to not underestimate the significance of the FFR. If a peripheral line is used for the adenosine infusion, care should be taken to ensure that the peripheral intravenous site is flushing normally and appropriately connected. Maximal hyperaemia will be achieved in most patients by two to three minutes, at which point the infusion can be ceased. An alterna‐ tive to the infusion of adenosine is intracoronary bolus injection, but this is potentially a less robust [85] method and can be practically difficult if guide catheter pressure damping man‐ dates catheter disengagement. A further potential confounder is the role of right atrial pres‐ sure in FFR assessment. Although FFR adjusted for right atrial pressure was tested by Layland et al in the non-left main subset, adjusting for assessment of left main has not been conducted although a similar phenomenon would be expected – that being as FFR ap‐ proaches the ischaemic zone, right atrial pressure becomes increasingly important.[54] This is an area that requires further investigation.

#### **7.3. Intravascular ultrasound assessment**

Significant LMCA stenosis carries a poor prognosis without appropriate revascularization. [70-72] Therefore, the presence or absence of left main disease has a critical impact on thera‐

274 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Angiographic assessment of the LMCA can be challenging. The anatomical plane of the LMCA, issues with vessel overlap, elliptical vessel configuration and plaque eccentricity all contribute to potential difficulty in accurately quantifying LMCA disease with conventional coronary angiography alone. In cases where LMCA disease severity is ambiguous, indeter‐ minate or equivocal, adjunctive intravascular imaging or physiological assessment is of key

Fractional flow reserve (FFR) offers a real time stress physiological assessment of coronary pressure dynamics. Intravascular ultrasound (IVUS) is able to define the anatomy of the LMCA. Both of these technologies allow for the potential to improve LMCA assessment and attendant clinical outcomes and are discussed further below. Optical coherence tomography (OCT) has a limited role in LMCA assessment, especially for ostial LMCA disease, largely due to the dependence on having a contrast filled lumen to allow satisfactory imaging reso‐

FFR has been evaluated in several studies in the setting of LMCA disease. A cut off value for the Pd/Pa (pressure distal/pressure aortic) ratio, following induction of hyperaemia, of <0.75 – 0.8 has been demonstrated to safely discriminate between patients who should be referred for revascularization, usually coronary artery bypass grafting, as opposed to ongoing medi‐ cal therapy and observation. [74-81] Patients with readings between 0.75 – 0.8 have physiol‐ ogy in a range that requires further study. In patients with intermediate readings of this kind the clinical context, as well consideration to additional evaluation with intravascular

The FFR technique involves the placement of a high fidelity pressure sensor beyond the left main plaque just as described in the "non left main" section previously. Consideration should be given to performing the procedure in both the left anterior descending and left circumflex artery to ensure concordance of results – this is particularly important if the cir‐ cumflex is dominant [18]. Once the wire is in position and the catheter flushed with 100 – 200 mcg of intracoronary nitroglycerine followed by saline, hyperaemia is induced with the use of adenosine, 140 - 180 mcg/kg/min via intravenous infusion (central or peripheral). Higher doses may be required if a systemic response is not demonstrated. Venous infusion is preferred, however, adenosine can also be delivered by intracoronary bolus and studies in the area suggest no major difference between the three administration methods, [82,83] al‐ though intracoronary bolus doses of up to 720 mcg on each injection may be required.[84]

There are several potential pitfalls to FFR evaluation of the left main. Of utmost importance is the particular issue of guiding catheter damping and potential obstructive interference with coronary flow. Disengagement of the guide catheter is required for accurate evaluation in order to not underestimate the significance of the FFR. If a peripheral line is used for the

peutic decision making following angiographic evaluation.

**7.2. Fractional flow reserve physiological assessment**

importance.[18]

lution to occur. [73]

ultrasound become important.

Intravascular ultrasound (IVUS) of the LMCA provides sonographically derived images of the LMCA lumen and vessel wall. As a result, IVUS provides real time anatomical and pathological information in 2 dimensions. IVUS parameters have been evaluated in multiple studies in the setting of LMCA disease. Initial work that correlated IVUS data with clinical outcomes demonstrated a relationship between IVUS derived minimal luminal diameter (MLD) and minimal lumen area (MLA) at a lesion site with major adverse cardiovascular events (MACE).[86] [87]These initial studies, however, did not mandate any specific cut off values for treatment decisions. A clinical outcome based study by Fassa et al subsequently demonstrated that deferral of revascularization is the appropriate strategy where the LMCA MLA is ≥7.5 mm<sup>2</sup> . [88]More recent work has revised this measurement down to ≥6 mm<sup>2</sup> . [89]

Given the clinically validated findings for FFR, IVUS has also been investigated utilizing FFR as a gold standard comparator. In a cohort of 51 North American patients Jasti et al demonstrated that an MLD ≤2.8 mm2 or an MLA ≤5.9 mm2 correlated strongly with a FFR <0.75. This study also correlated FFR measurements with clinical outcomes and confirmed the appropriateness of an FFR cut off of <0.75. [90]Kang et al performed a similar correlation study in 55 South Korean patients. They found a MLA cut off of <4.1 mm2 correlated well with a FFR <0.75 and a MLA cut off of <4.8 mm2 correlated with a FFR of <0.8. However, evaluation of clinical outcomes was not performed as was done in the study by Jasti et al. In addition, the applicability of the study by Kang et al to patients of European ethnicity is un‐ clear. Both studies also demonstrated that relative disease burden metrics such as plaque burden and area stenosis were insufficiently predictive of FFR measurements to be useful in clinical practice.

Based on the above data, a cut off of ≤5.9 mm<sup>2</sup> for MLA, if using IVUS alone, should be used in determining referral for LMCA revascularization following IVUS evaluation. Where there is uncertainty or ambiguity around measurements or their relevance in specific patients, strong consideration should be given to adjunctive FFR evaluation.

## **8. Case examples**

#### Case #1: FFR and IVUS of Left Main

A 48 year-old gentleman presents with ischaemic sounding chest pain, troponin 1.3 ng/L and subtle precordial ST depression on his ECG. He has a background history of smoking, dyslipidaemia and a strong family history of premature coronary disease.

A 65 year old female presented with a long history of exertional chest discomfort and dysp‐ noea. A stress echocardiogram demonstrated possible mild exercise induced basal inferior wall hypokinesia. She had a background history of severe uncontrolled hypertension. Her left coronary tree was unremarkable. A 50% mid RCA lesion was interrogated by OCT and

Improving the Utility of Coronary Angiography: The Use of Adjuvant Imaging and Physiological Assessment

mendation was for improved blood pressure control. This case highlights the importance of thorough assessment of moderate lesions despite a typical symptom profile of angina. This patient almost certainly had hypertensive heart disease as a cause of her shortness of breath

A 37 year-old female with a family history of coronary disease presents with chest pain, ele‐ vated biomarkers and ST praecordial T wave inversion on her 12 lead ECG a few months

Angiography revealed diffuse narrowing of distal left anterior descending artery (refer to

Case #3: Use of IVUS and OCT to diagnose spontaneous coronary dissection:

**Figure 7.** FFR of Left Main into LAD – dramatic drop in FFR to 0.71

on OCT and FFR > 0.80, the lesion was not stented. The recom‐

http://dx.doi.org/10.5772/54041

277

FFR – refer to figures 8 and 9.

Given an MLA > 1.95mm2

and chest discomfort.

postpartum.

figure 10).

Angiography revealed an ambiguous left main with a complex hazy calcified roof. There was an impression of severe ostial plaque with only a narrow jet of contrast effluxing back into the left coronary cusp.

**Figure 6.** Angiographic (A and B) views and IVUS of left main (panels C and D)

The patient clearly had a left main lesion with an MLD < 2.8 mm and MLA < 5.9 mm2 and an FFR <0.71 which was all consistent with a haemodynamically significant lesion. On the basis of physiological and anatomical confirmation of severity, the patient was sent for CABG and made an uneventful recovery. This case highlights the importance of careful inspection of the angiogram in multiple views, consideration of the pitfalls of angiography and the com‐ bined use of IVUS and FFR to assess ambiguous left main plaque.

Case #2: FFR and OCT of a moderate RCA lesion:

A 65 year old female presented with a long history of exertional chest discomfort and dysp‐ noea. A stress echocardiogram demonstrated possible mild exercise induced basal inferior wall hypokinesia. She had a background history of severe uncontrolled hypertension. Her left coronary tree was unremarkable. A 50% mid RCA lesion was interrogated by OCT and FFR – refer to figures 8 and 9.

Given an MLA > 1.95mm2 on OCT and FFR > 0.80, the lesion was not stented. The recom‐ mendation was for improved blood pressure control. This case highlights the importance of thorough assessment of moderate lesions despite a typical symptom profile of angina. This patient almost certainly had hypertensive heart disease as a cause of her shortness of breath and chest discomfort.

Case #3: Use of IVUS and OCT to diagnose spontaneous coronary dissection:

**8. Case examples**

into the left coronary cusp.

Case #1: FFR and IVUS of Left Main

A 48 year-old gentleman presents with ischaemic sounding chest pain, troponin 1.3 ng/L and subtle precordial ST depression on his ECG. He has a background history of smoking,

Angiography revealed an ambiguous left main with a complex hazy calcified roof. There was an impression of severe ostial plaque with only a narrow jet of contrast effluxing back

dyslipidaemia and a strong family history of premature coronary disease.

276 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Figure 6.** Angiographic (A and B) views and IVUS of left main (panels C and D)

bined use of IVUS and FFR to assess ambiguous left main plaque.

Case #2: FFR and OCT of a moderate RCA lesion:

The patient clearly had a left main lesion with an MLD < 2.8 mm and MLA < 5.9 mm2

FFR <0.71 which was all consistent with a haemodynamically significant lesion. On the basis of physiological and anatomical confirmation of severity, the patient was sent for CABG and made an uneventful recovery. This case highlights the importance of careful inspection of the angiogram in multiple views, consideration of the pitfalls of angiography and the com‐

and an

A 37 year-old female with a family history of coronary disease presents with chest pain, ele‐ vated biomarkers and ST praecordial T wave inversion on her 12 lead ECG a few months postpartum.

Angiography revealed diffuse narrowing of distal left anterior descending artery (refer to figure 10).

**Figure 7.** FFR of Left Main into LAD – dramatic drop in FFR to 0.71

**Figure 8.** Panel A: Moderate RCA lesion with yellow line through the tightest point, Panel B: Proximal Reference Di‐ mensions, Panel C: Distal Reference Dimensions, Panel D: MLA and MLD

**Figure 9.** FFR clearly not in the ischaemic zone

Improving the Utility of Coronary Angiography: The Use of Adjuvant Imaging and Physiological Assessment

http://dx.doi.org/10.5772/54041

279

Improving the Utility of Coronary Angiography: The Use of Adjuvant Imaging and Physiological Assessment http://dx.doi.org/10.5772/54041 279

**Figure 9.** FFR clearly not in the ischaemic zone

**Figure 8.** Panel A: Moderate RCA lesion with yellow line through the tightest point, Panel B: Proximal Reference Di‐

278 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

mensions, Panel C: Distal Reference Dimensions, Panel D: MLA and MLD

**References**

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[6] Pijls NHJ, Sels JWEM. Functional Measurement of Coronary Stenosis. JAC. Elsevier

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**Figure 10.** Angiogram, IVUS and OCT of the mid to distal LAD, Panel A: Arrow points to abrupt change in vessel cali‐ ber, Panel B: IVUS with intramural haematoma (arrow), Panel C: OCT with intramural haematoma (arrow)

IVUS and OCT both confirmed spontaneous coronary dissection as the cause of the angio‐ graphic appearance with clear evidence of intramural haematoma. The patient was man‐ aged conservatively and made an uneventful recovery.

## **9. Concluding statement**

This chapter has highlighted some of the most important points regarding FFR, OCT and IVUS. In essence, these modalities are complimentary and it is up to the experienced opera‐ tor to decide on when one modality may have a clear advantage over another (e.g. IVUS be‐ ing more appropriate than OCT for imaging true aorto-ostial disease). It is generally accepted that FFR is the most useful tool to help decide when to revascularise and IVUS/OCT to help decide on pathology, guide the intervention and optimise the PCI result.

## **Author details**

Alexander Incani1 , Anthony C. Camuglia1 , Karl K. Poon1 , O. Christopher Raffel1 and Darren L. Walters1

1 The Prince Charles Hospital, Rode Rd, Chermside, Brisbane, Queensland, Australia

2 University of Queensland, St Lucia, Brisbane, Queensland, Australia

## **References**

**Figure 10.** Angiogram, IVUS and OCT of the mid to distal LAD, Panel A: Arrow points to abrupt change in vessel cali‐

IVUS and OCT both confirmed spontaneous coronary dissection as the cause of the angio‐ graphic appearance with clear evidence of intramural haematoma. The patient was man‐

This chapter has highlighted some of the most important points regarding FFR, OCT and IVUS. In essence, these modalities are complimentary and it is up to the experienced opera‐ tor to decide on when one modality may have a clear advantage over another (e.g. IVUS be‐ ing more appropriate than OCT for imaging true aorto-ostial disease). It is generally accepted that FFR is the most useful tool to help decide when to revascularise and IVUS/OCT to help decide on pathology, guide the intervention and optimise the PCI result.

, Karl K. Poon1

1 The Prince Charles Hospital, Rode Rd, Chermside, Brisbane, Queensland, Australia

, O. Christopher Raffel1

and

ber, Panel B: IVUS with intramural haematoma (arrow), Panel C: OCT with intramural haematoma (arrow)

280 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

aged conservatively and made an uneventful recovery.

, Anthony C. Camuglia1

2 University of Queensland, St Lucia, Brisbane, Queensland, Australia

**9. Concluding statement**

**Author details**

Alexander Incani1

Darren L. Walters1


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288 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

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657.

5(4):402-8

204–211.

**Chapter 14**

**Coronary Angiography –**

Additional information is available at the end of the chapter

derstanding of the operative field prior to the procedure.

computed tomography, magnetic resonance and also echocardiography.

Maria Anna Staniszewska

http://dx.doi.org/10.5772/54034

attention has to be paid to CAD.

coronary angiography.

**1. Introduction**

**Technical Recommendations and Radiation Protection**

According to recent World Health Organization statistics for 2007, cardiovascular deaths ac‐ count for 33.7% of all deaths worldwide, whereas cancer represents 29.5%, other chronic dis‐ eases 26.5%, injury and communicable diseases 4.3%. [1]. Coronary artery disease (CAD) is the leading cause of cardiovascular death throughout the world. In the light of this, special

Imaging is an integral part of diagnostics and treatment of the disease, especially of surgical and transcatheter cardiological interventions. Pre-procedural imaging provides detailed un‐

Traditional two-dimensional (2D) imaging, i.e. standard echocardiography and convention‐ al angiography, relies on acquisition of a limited number of planes/projections, which can‐ not be changed during the review, while three-dimentional (3D) imaging allows fast acquisition of volumetric data sets and subsequent off-line reconstructions along unlimited 2D planes and 3D volumes. 3D imaging of the cardiovascular structures is pursued with

Cardiovascular surgery is a dynamically developing field and many procedures are per‐ formed under control of dedicated imaging systems but most of these procedures start from

Quantitative coronary angiography is the method for visualization of coronary vessels dur‐ ing exposure to x-rays, after their filling up with contrast agents. This allows to assess coro‐ nary artery stenoses for hybrid revascularization or quantifying stenoses in bypass grafts. Depending on a further proceeding expected for a patient two versions of the procedure are

and reproduction in any medium, provided the original work is properly cited.

© 2013 Staniszewska; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

possible: CCA – conventional coronary angiography and CTA- CT angiography.

## **Coronary Angiography – Technical Recommendations and Radiation Protection**

Maria Anna Staniszewska

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54034

## **1. Introduction**

According to recent World Health Organization statistics for 2007, cardiovascular deaths ac‐ count for 33.7% of all deaths worldwide, whereas cancer represents 29.5%, other chronic dis‐ eases 26.5%, injury and communicable diseases 4.3%. [1]. Coronary artery disease (CAD) is the leading cause of cardiovascular death throughout the world. In the light of this, special attention has to be paid to CAD.

Imaging is an integral part of diagnostics and treatment of the disease, especially of surgical and transcatheter cardiological interventions. Pre-procedural imaging provides detailed un‐ derstanding of the operative field prior to the procedure.

Traditional two-dimensional (2D) imaging, i.e. standard echocardiography and convention‐ al angiography, relies on acquisition of a limited number of planes/projections, which can‐ not be changed during the review, while three-dimentional (3D) imaging allows fast acquisition of volumetric data sets and subsequent off-line reconstructions along unlimited 2D planes and 3D volumes. 3D imaging of the cardiovascular structures is pursued with computed tomography, magnetic resonance and also echocardiography.

Cardiovascular surgery is a dynamically developing field and many procedures are per‐ formed under control of dedicated imaging systems but most of these procedures start from coronary angiography.

Quantitative coronary angiography is the method for visualization of coronary vessels dur‐ ing exposure to x-rays, after their filling up with contrast agents. This allows to assess coro‐ nary artery stenoses for hybrid revascularization or quantifying stenoses in bypass grafts.

Depending on a further proceeding expected for a patient two versions of the procedure are possible: CCA – conventional coronary angiography and CTA- CT angiography.

© 2013 Staniszewska; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

CCA is performed under the control of x-ray unit with C-arm and is preferred if further car‐ diovascular surgery is planned for the patient.

**c.** The long periods of exposure can be recorded in so-called "cine-mode" (if x-ray system

Coronary Angiography – Technical Recommendations and Radiation Protection

http://dx.doi.org/10.5772/54034

293

The results of CCA procedure are analyzed by cardiologists during its performance and also

Cardiovascular surgery covers a wide array of procedures and methods, each with specific imaging requirements. Consequently, x-ray systems are offered by the vendors in many ver‐

Two types of construction are proposed generally: a fixed C-arm system and mobile C-arm. A fixed C-arm system can be floor-mounted or ceiling-mounted. The solution is chosen by the user in dependence on the space condition of operating room. Fixed C-arm systems are required for CCA and further surgery procedures such as: percutaneous coronary interven‐

A powerful mobile C-arm can be used for pacemakers or defibrillator implants and carotid artery stenting. However, fixed C-arm systems can offer added security and are preferred

Diagnostic procedures and a structural heart disease treatment in children using imaging system require a high temporal resolution, which is provided by dedicated fixed C-arm sys‐

**•** high frequency converter generator of minimum 80 kW (in possibly rectangular pulses),

**•** x-ray tube – image detector distance tracking (minimum focus skin distance 30 cm),

**•** display of fluoroscopy time, total dose-area product (fluoroscopy and radiographic) and

**•** image hold system (for example default storage of the last 20 sec. of fluoroscopy for refer‐

**•** generator should be controlled by microprocessor, power switch accurately controlled, with short switching time (about 1 ms); voltage should cover the range of (40-120) kV,

Despite of the general features, the system should fulfil the following requirements:

Any x-ray system used for CCA procedures should be equipped as follows:

**•** minimum two dose-rate modes (Low-Medium-High or Low- Standard),

is technically predicted to this mode of work).

**2.2. Technical requirements for x-ray systems with C-arm**

tions (PCI) and endovascular aortic repair (EVAR).

for complex cases and lengthier procedures.

**•** x-ray tube focuses not larger than 1.2/0.5mm,

**•** patient table made from low-attenuating materials,

**•** a high power tube with high heat dissipation,

**•** dose-area product meter with display visible for operator,

tems with very high frame rates.

estimated skin entrance dose,

ence or archiving).

retrospectively after that.

sions.

CTA is performed under the control of computerized tomography (CT scanner) and has on‐ ly diagnostic meaning.

This chapter is divided into three parts concerning both: the techniques of coronary angiog‐ raphy (CCA and CTA) and the new technical solutions in this field. Some details concerning the standards of CCA and CTA performance have already been published [2] and are used here with addition of new information.

## **2. CCA**

#### **2.1. Description of the procedure**

A patient lies in supine position on the table being a part of C-arm unit. X-ray tube moves rotationally in two perpendicular planes (horizontal and vertical) which makes any required type of projection possible. (The most common projections are: LAO, LAO/Cranial, LAO/ Caudal, RAO). The principal current-voltage parameters are chosen automatically.

Good practice rules require that the x-ray tube is kept under the table. This allows to avoid unnecessary irradiation of the staff and makes the doses to patient lower.

In order to visualize coronary vessels a contrast agent is administered intravenously: a thin catheter is previously introduced to the brachial artery or the femoral artery (there are two alternative access routes) and its movement is traced by fluoroscopy and observed on moni‐ tor by the operator.

(The physiological parameters of a patient are permanently monitored during the procedure.)

The operating team consists of 3 to 4 persons: usually they are an operator (with an assistant if necessary), a scrub nurse and an anaesthetic nurse. All the persons stay around the patient table and thus may be exposed to even high doses of radiation. (There are scattered x-rays mainly.) An especially exposed member of the team is the operator: the doses registered for such persons may achieve the highest level measured for occupational exposures [3,4].

Patient exposure results mainly from primary x-ray beam which covers a part of back sur‐ face (the area of left shoulder) by most time of the procedure. The remaining body of a pa‐ tient is exposed to rather scattered radiation.

Three types of images can be created during the procedure:


**c.** The long periods of exposure can be recorded in so-called "cine-mode" (if x-ray system is technically predicted to this mode of work).

The results of CCA procedure are analyzed by cardiologists during its performance and also retrospectively after that.

#### **2.2. Technical requirements for x-ray systems with C-arm**

CCA is performed under the control of x-ray unit with C-arm and is preferred if further car‐

292 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

CTA is performed under the control of computerized tomography (CT scanner) and has on‐

This chapter is divided into three parts concerning both: the techniques of coronary angiog‐ raphy (CCA and CTA) and the new technical solutions in this field. Some details concerning the standards of CCA and CTA performance have already been published [2] and are used

A patient lies in supine position on the table being a part of C-arm unit. X-ray tube moves rotationally in two perpendicular planes (horizontal and vertical) which makes any required type of projection possible. (The most common projections are: LAO, LAO/Cranial, LAO/

Good practice rules require that the x-ray tube is kept under the table. This allows to avoid

In order to visualize coronary vessels a contrast agent is administered intravenously: a thin catheter is previously introduced to the brachial artery or the femoral artery (there are two alternative access routes) and its movement is traced by fluoroscopy and observed on moni‐

(The physiological parameters of a patient are permanently monitored during the procedure.)

The operating team consists of 3 to 4 persons: usually they are an operator (with an assistant if necessary), a scrub nurse and an anaesthetic nurse. All the persons stay around the patient table and thus may be exposed to even high doses of radiation. (There are scattered x-rays mainly.) An especially exposed member of the team is the operator: the doses registered for such persons may achieve the highest level measured for occupational exposures [3,4].

Patient exposure results mainly from primary x-ray beam which covers a part of back sur‐ face (the area of left shoulder) by most time of the procedure. The remaining body of a pa‐

**a.** Real-time images (fluoroscopic images) observed by the operator (visible also on the

**b.** Radiographic images for saving some chosen moments of the procedure (so-called

Caudal, RAO). The principal current-voltage parameters are chosen automatically.

unnecessary irradiation of the staff and makes the doses to patient lower.

diovascular surgery is planned for the patient.

here with addition of new information.

**2.1. Description of the procedure**

ly diagnostic meaning.

**2. CCA**

tor by the operator.

tient is exposed to rather scattered radiation.

technical console),

acquisition),

Three types of images can be created during the procedure:

Cardiovascular surgery covers a wide array of procedures and methods, each with specific imaging requirements. Consequently, x-ray systems are offered by the vendors in many ver‐ sions.

Two types of construction are proposed generally: a fixed C-arm system and mobile C-arm.

A fixed C-arm system can be floor-mounted or ceiling-mounted. The solution is chosen by the user in dependence on the space condition of operating room. Fixed C-arm systems are required for CCA and further surgery procedures such as: percutaneous coronary interven‐ tions (PCI) and endovascular aortic repair (EVAR).

A powerful mobile C-arm can be used for pacemakers or defibrillator implants and carotid artery stenting. However, fixed C-arm systems can offer added security and are preferred for complex cases and lengthier procedures.

Diagnostic procedures and a structural heart disease treatment in children using imaging system require a high temporal resolution, which is provided by dedicated fixed C-arm sys‐ tems with very high frame rates.

Any x-ray system used for CCA procedures should be equipped as follows:


Despite of the general features, the system should fulfil the following requirements:


**•** should be equipped with additional filtration (Cu preferred), enabling to select a proper filtration in dependence on x-ray spectrum,

**2.3. Dosimetric quantities**

tion of real value.

dence angle variation.

following approaches:

dren as well as adults).

sis of CT human images.

cine). (Dose Area Product= DAP [Gy.m2

chamber placed on the x-ray tube output.

1Gy and exceeds the threshold of deterministic skin effects.)

**b.** with Monte Carlo simulations using mathematical phantoms,

coefficient averaged for multiple scanners.

Presently used fluoroscopic equipment measures air kerma with the use of an ionization chamber incorporated into the x-ray tube envelope and reports the dose-area product (DAP), equal to air kerma (dose) multiplied by x-ray beam cross-sectional area. (This is legal requirement.) X-ray systems used for fluoroscopic procedures are obligatory equipped in DAP-meter to summarize emission in all the modes of work (i.e. fluoroscopy, radiography,

DAP is independent on the distance from x-ray source ( according to the inverse-square law). Some systems show also peak skin dose (in grays) treated as the highest dose received by any location on the patient's skin, including both incident and back-scattered radiation. Although thought to be the best predictor of skin injury, peak skin dose is difficult to meas‐ ure in practice and the values displayed by the x-ray system can be treated as an approxima‐

DAP (and entrance air kerma) values have to be displayed on the monitors of x-ray system and should be registered in the patient record. (Especially when entrance air kerma is over

For a given projection mean entrance skin dose (or entrance air kerma) can be calculated as the ratio of DAP and the area of the incident x-ray beam (at the level of patient's skin). The relationship is not valid for DAP summarized for the whole procedure because of the inci‐

The actual dose received by a patient from a given x-ray procedure can be evaluated by the

**c.** with DLP values provided by the x-ray system and a body region-specific conversion

Dosimetric measurements are commonly made with termoluminescent dosimeters (lithium fluoride or calcium fluoride) or solid state detectors. The detectors are distributed inside the phantom which is exposed as a patient. The most popular are Rando Man or Rando Woman phantoms (representing adult humans) and the family of CIRS phantoms (representing chil‐

Monte Carlo simulation assumes a mathematical phantom representing a patient from a giv‐ en age group and model photon transitions through this phantom. The older solutions used the "family" of Cristy' phantoms for simulation, modelling organs as geometrical solids. The newer studies use voxel phantoms which are more anatomical being created on the ba‐

The last approach, i.e. taking some conversion coefficients from literature and multiplying by DAP is the simplest but on the condition that the values are really adequate for the given

**a.** with calculation based on dosimetric measurements made in physical phantoms,

]). Measurements are performed by the transmission

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295


Additionally in some x-ray systems are also available partially absorbent contoured filters (so-called wedge filters) to absorb radiation in the low density areas surrounding the heart.

Another proposal for coronary angiography appears in 2009 [5], i.e. biplane system in which simultaneous accurate images of the heart are provided from two different points of view. This allows to reduced contrast volume and radiation exposure. Biplane angiog‐ raphy helps to visualize complex coronary or structural cardiac anatomy. The clinical set‐ tings in which biplane system is the most critical occur in the paediatric population and in those patients with renal failure. The value of biplane angiography must be balanced against cost and difficulty of use: such system requires the patient's heart to be in the ex‐ act centre of the two planes (the isocentre) and then AP and lateral planes were properly angled in orthogonal protections.

#### *2.2.1. Image recording*

Most of x-ray units used in cardiology nowadays are equipped with the digital image re‐ cording system. There are two types of it: (1) an image intensifier based system and (2) a flat-panel fluoroscopy system. The first one utilizes conventional technology: the output screen of image intensifier is projected in a video camera or a CCD camera to produce an electronic information. Such systems are still used in many interventional labs. The older systems have got image intensifiers, which cause a significant loss of signal intensity be‐ cause of the construction principle.

The digital Flat Detectors (FD) are smaller and easier to operate. Image quality may be bet‐ ter, but the modern x-ray systems have much higher output capacity and thus higher doses are probable.

Maximum field of view FD has to be large enough: 30x36 cm (11.8x14.4 inch), but the used area may be part of the maximum in dependence on current medical needs.

Image matrix size should be also large – especially for the acquisitions recording, and can be smaller for fluoroscopic observations (the signals are then summarized).

Nyquist frequency of FD fluoroscopy systems are better than 3 lp/mm.

Quite important are the monitors in the system: they can be monochrome or colour LCD of 18-19 inch.

#### **2.3. Dosimetric quantities**

**•** should be equipped with additional filtration (Cu preferred), enabling to select a proper

294 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**•** flexibility of pulsed fluoroscopy mode (grid- switched and individually programmed with a different composition of x-ray dose rate, digital processing and filter settings),

Additionally in some x-ray systems are also available partially absorbent contoured filters (so-called wedge filters) to absorb radiation in the low density areas surrounding the heart. Another proposal for coronary angiography appears in 2009 [5], i.e. biplane system in which simultaneous accurate images of the heart are provided from two different points of view. This allows to reduced contrast volume and radiation exposure. Biplane angiog‐ raphy helps to visualize complex coronary or structural cardiac anatomy. The clinical set‐ tings in which biplane system is the most critical occur in the paediatric population and in those patients with renal failure. The value of biplane angiography must be balanced against cost and difficulty of use: such system requires the patient's heart to be in the ex‐ act centre of the two planes (the isocentre) and then AP and lateral planes were properly

Most of x-ray units used in cardiology nowadays are equipped with the digital image re‐ cording system. There are two types of it: (1) an image intensifier based system and (2) a flat-panel fluoroscopy system. The first one utilizes conventional technology: the output screen of image intensifier is projected in a video camera or a CCD camera to produce an electronic information. Such systems are still used in many interventional labs. The older systems have got image intensifiers, which cause a significant loss of signal intensity be‐

The digital Flat Detectors (FD) are smaller and easier to operate. Image quality may be bet‐ ter, but the modern x-ray systems have much higher output capacity and thus higher doses

Maximum field of view FD has to be large enough: 30x36 cm (11.8x14.4 inch), but the used

Image matrix size should be also large – especially for the acquisitions recording, and can be

Quite important are the monitors in the system: they can be monochrome or colour LCD of

area may be part of the maximum in dependence on current medical needs.

smaller for fluoroscopic observations (the signals are then summarized). Nyquist frequency of FD fluoroscopy systems are better than 3 lp/mm.

**•** a possibility of AEC mode choice by the user (IMAGE or DOSE weighted).

filtration in dependence on x-ray spectrum,

**•** collimators incorporating circular shutters,

**•** overcouch image detector,

**•** staff protective shielding,

angled in orthogonal protections.

cause of the construction principle.

*2.2.1. Image recording*

are probable.

18-19 inch.

Presently used fluoroscopic equipment measures air kerma with the use of an ionization chamber incorporated into the x-ray tube envelope and reports the dose-area product (DAP), equal to air kerma (dose) multiplied by x-ray beam cross-sectional area. (This is legal requirement.) X-ray systems used for fluoroscopic procedures are obligatory equipped in DAP-meter to summarize emission in all the modes of work (i.e. fluoroscopy, radiography, cine). (Dose Area Product= DAP [Gy.m2 ]). Measurements are performed by the transmission chamber placed on the x-ray tube output.

DAP is independent on the distance from x-ray source ( according to the inverse-square law). Some systems show also peak skin dose (in grays) treated as the highest dose received by any location on the patient's skin, including both incident and back-scattered radiation. Although thought to be the best predictor of skin injury, peak skin dose is difficult to meas‐ ure in practice and the values displayed by the x-ray system can be treated as an approxima‐ tion of real value.

DAP (and entrance air kerma) values have to be displayed on the monitors of x-ray system and should be registered in the patient record. (Especially when entrance air kerma is over 1Gy and exceeds the threshold of deterministic skin effects.)

For a given projection mean entrance skin dose (or entrance air kerma) can be calculated as the ratio of DAP and the area of the incident x-ray beam (at the level of patient's skin). The relationship is not valid for DAP summarized for the whole procedure because of the inci‐ dence angle variation.

The actual dose received by a patient from a given x-ray procedure can be evaluated by the following approaches:


Dosimetric measurements are commonly made with termoluminescent dosimeters (lithium fluoride or calcium fluoride) or solid state detectors. The detectors are distributed inside the phantom which is exposed as a patient. The most popular are Rando Man or Rando Woman phantoms (representing adult humans) and the family of CIRS phantoms (representing chil‐ dren as well as adults).

Monte Carlo simulation assumes a mathematical phantom representing a patient from a giv‐ en age group and model photon transitions through this phantom. The older solutions used the "family" of Cristy' phantoms for simulation, modelling organs as geometrical solids. The newer studies use voxel phantoms which are more anatomical being created on the ba‐ sis of CT human images.

The last approach, i.e. taking some conversion coefficients from literature and multiplying by DAP is the simplest but on the condition that the values are really adequate for the given procedure and type of x-ray system. The range of conversion factor reported for CCA varies from 0.12 to 0.26 mSv/(Gy.cm2 ) [6].

Paediatric patients also undergone CCA procedures. The doses for 50 children examined us‐ ing Allura Xper F20 system are given in Table 2 (the own data from the paediatric clinic).

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**Number of patients The range of PSD [mGy] (\*)** 6 0-20 7 20-40 2 40-60 7 60-80 5 80-100 11 100-200 4 200-300 4 300-400 3 400-500 1 "/>500

The values of effective doses in non-paediatric population undergoing CCA is presented and discussed in [6]. The values were published during ten years (from 1997 to 2007). The mean value is 7.4 mSv but standard deviation is very high (5.4 mSv) because of a wide range of reported doses (from 2.3 to 22.7 mSv). Similar value of ≈7mSv as typical effective dose for

Radiation risk to staff in CCA procedures is caused by necessity to work in the radiation filed, standing near patient during exposure. Staff is exposed mainly to scattered radiation

(\*) the value of Peak Skin Dose is displayed by x-ray system

**2.5. Doses to staff**

**Table 2.** The values of PSD [mGy] for paediatric patients during CCA

adult patients in CCA is also cited by the UNSCEAR [6].

although accidentally can be irradiated by primary x-rays.

The factors affecting staff dose are as follows:

**•** relative position with respect to patient,

**•** effective use of protection shielding.

**•** patient architecture (BMI),

**•** irradiated patient volume,

**•** x-ray tube position,

**•** time of exposure,

Regardless of the way, the effective dose estimates the radiation charge for some "typical" (standard) patient, without taking into consideration the anatomy of a given human, and thus should be referred to the category of patients undergoing the given x-ray procedure.

#### **2.4. Doses to patients**

The doses obtained by the patients undergoing CCA procedures depend on:


Doses received by patients in CCA are evaluated both for the whole body and to the skin.

The entrance surface dose to patient dramatically increases when the focus-to-skin distance becomes too short.

The patient doses are significantly higher when the high dose-rate mode is activated or if pulsed fluoroscopy of high number of pulses per second is chosen. These doses are also in‐ versely proportional to the size of image detector.

During coronarography an entrance dose for a small area of patient's back can be very high while a dose to the remaining part of the trunk can be very low. In consequence, the effec‐ tive dose may be low and the deterministic effects can appear. (Skin injuries for patients un‐ dergoing interventional procedures are reported [7].)


**Table 1.** The doses to patients in CCA procedures (according to [8])

Paediatric patients also undergone CCA procedures. The doses for 50 children examined us‐ ing Allura Xper F20 system are given in Table 2 (the own data from the paediatric clinic).


(\*) the value of Peak Skin Dose is displayed by x-ray system

**Table 2.** The values of PSD [mGy] for paediatric patients during CCA

The values of effective doses in non-paediatric population undergoing CCA is presented and discussed in [6]. The values were published during ten years (from 1997 to 2007). The mean value is 7.4 mSv but standard deviation is very high (5.4 mSv) because of a wide range of reported doses (from 2.3 to 22.7 mSv). Similar value of ≈7mSv as typical effective dose for adult patients in CCA is also cited by the UNSCEAR [6].

#### **2.5. Doses to staff**

procedure and type of x-ray system. The range of conversion factor reported for CCA varies

296 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Regardless of the way, the effective dose estimates the radiation charge for some "typical" (standard) patient, without taking into consideration the anatomy of a given human, and thus should be referred to the category of patients undergoing the given x-ray procedure.

Doses received by patients in CCA are evaluated both for the whole body and to the skin.

The entrance surface dose to patient dramatically increases when the focus-to-skin distance

The patient doses are significantly higher when the high dose-rate mode is activated or if pulsed fluoroscopy of high number of pulses per second is chosen. These doses are also in‐

During coronarography an entrance dose for a small area of patient's back can be very high while a dose to the remaining part of the trunk can be very low. In consequence, the effec‐ tive dose may be low and the deterministic effects can appear. (Skin injuries for patients un‐

**Number of patients DAP [Gy.cm2] Time of fluoroscopy [min] Number of frames**

130 72 +/-55 0.35+/-0.25 1550+/-775

78 73 9.9 1079 100 60.6 - 412 117 1.1 – 11.3 0.3 - 22 -

 35 - 160 4.8+/-3.5 39+/-11 37-190 4.2+/-3.0 30+/-10 3.1-57.2 1.5-5.1 639 64 - 281 0.4 - 33 200-1911

) [6].

**•** mode of work (number of acquisitions -radiographic or cine).

The doses obtained by the patients undergoing CCA procedures depend on:

from 0.12 to 0.26 mSv/(Gy.cm2

**•** patient architecture (BMI-body mass index),

**•** emission effectiveness of the x-ray system,

versely proportional to the size of image detector.

dergoing interventional procedures are reported [7].)

**Table 1.** The doses to patients in CCA procedures (according to [8])

**2.4. Doses to patients**

**•** applied dose-rate mode,

**•** total exposure time,

becomes too short.

Radiation risk to staff in CCA procedures is caused by necessity to work in the radiation filed, standing near patient during exposure. Staff is exposed mainly to scattered radiation although accidentally can be irradiated by primary x-rays.

The factors affecting staff dose are as follows:


Thus, staff and patient doses are partially linked: higher exposure for a patient means higher irradiation to staff. This is especially true for the operator and the person standing nearby him (an assistant or scrub nurse). Additional factor determining the doses to staff is profes‐ sional experience and good training in the procedure performance: good manual skills cause the exposure time shorter.

**3. CTA**

Cardiac CT procedures were an engine for development of new technical solutions in CT: visualization of quickly moving anatomical structures needs extremely short time for ac‐ quisition and reconstruction of images. This is available in the new multislice CT scanners, with rotation time not longer than 0.4s and slice collimation 8 cm or more (up to 16 cm). Im‐ provements in spatial and temporal resolution, scan time, scan range and advanced image postprocessing (very important in clinical practice) have made CT angiography (CTA) an excellent tool for identifying patients in need of invasive therapy and for mapping out the best percutaneous or surgical approach. In some cases CTA provides complementary infor‐

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Although history of cardiac CT began with the four-slice scanners, the real development started with 64-slice scanners with appropriate combination of spatial and temporal resolu‐ tion. However, the intensity of x-rays emitted in the multislice CT scanners has to be higher and then a number of dose-reduction mechanisms is implemented for patients' safety.

According the American College of Cardiology Foundation (ACCF) the principal indica‐

**•** noncontrast CT calcium scoring for patients at intermediate risk of coronary heart disease

**•** coronary CT is especially recommended for patients with reduced left ventricular ejection

**•** preoperative CT angiography for both heart surgery and noncoronary indications in the

The current role of coronary CT angiography in the assessment of coronary artery disease is based on its high negative predictive value in ruling out significant stenosis in intermediate risk populations. [12]. A precise preprocedural visualization of complex coronary lesions with CT angiography would be complementary to conventional angiography and allow op‐

The main benefit from CTA is evaluation of cardiac structure and function and also evalua‐

From technological reasons the possibilities of CT are limited to diagnostics, without further

**•** low and intermediate pretest probability of obstructive coronary artery disease (CAD),

mation to that of conventional angiography (CCA).

and for low-risk patients with a family history of disease,

fraction at low or intermediate pretest probability of disease,

timization of the interventional approach during subsequent PCI [13].

tion of anatomical structures surrounding the heart.

The main stages of CT study protocol are as follows:

tions to cardiac CT are as follows [11]:

setting of risk of CAD.

**3.1. Description of the procedure**

**2.** calcium scoring,

therapeutic activity (means angioplasty).

**1.** the heart rate control and regulation,

The problem of radiation risk to staff in interventional cardiology had been widely dis‐ cussed many times.The essential conclusions resulted from that are the recommendations concerning performance of the interventional procedures and elaboration of the methodolo‐ gy for evaluation radiation risk for the staff [4, 9].

According results of the survey performed by European research group SENTINEL in a sample of European cardiac centres [10] doses for the first operator are as follows:


Although the above values are rather low it should be underlined that these values may be higher many times (even up the annual limits), especially for inexperienced staff or in a case of clinically difficult patient.

Currently Philips as the only global healthcare company offered a real-time dosimetric sys‐ tem Dose Aware. The system does not replace the thermoluminescence dosimeter (TLD) as a legal dose meter. TLD reports accumulated x-ray dose from the exposure for a period of time but does not include any time stamp or awareness where and when the x-ray dose was acquired.

Dose Aware is a system that gives real-time feedback of scattered x-ray dose reception and instant access to time-stamped dose history. The system is completed from:


Staff working in an x-ray environment wears a PDM. This PDM measures x-ray dose re‐ ception and is wirelessly connected to the Base Station. The Base Station is mounted in the examination room where all staff can directly see whether received dose is in red, yellow or green area. The "yellow" or "red" status means a necessity of immediate ac‐ tion to reduce x-ray exposure. X-ray dose history information can be automatically re‐ trieved from any Base Station or from any PDM by using a Cradle with Dose View software or Dose Manager software.

## **3. CTA**

Thus, staff and patient doses are partially linked: higher exposure for a patient means higher irradiation to staff. This is especially true for the operator and the person standing nearby him (an assistant or scrub nurse). Additional factor determining the doses to staff is profes‐ sional experience and good training in the procedure performance: good manual skills cause

298 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The problem of radiation risk to staff in interventional cardiology had been widely dis‐ cussed many times.The essential conclusions resulted from that are the recommendations concerning performance of the interventional procedures and elaboration of the methodolo‐

According results of the survey performed by European research group SENTINEL in a

Although the above values are rather low it should be underlined that these values may be higher many times (even up the annual limits), especially for inexperienced staff or in a case

Currently Philips as the only global healthcare company offered a real-time dosimetric sys‐ tem Dose Aware. The system does not replace the thermoluminescence dosimeter (TLD) as a legal dose meter. TLD reports accumulated x-ray dose from the exposure for a period of time but does not include any time stamp or awareness where and when the x-ray dose was

Dose Aware is a system that gives real-time feedback of scattered x-ray dose reception and

**•** Base Station : an LCD touchscreen displays real time dose data from all PDMs within range. The Base Station stores PDM data as well. Multiple Base Stations can be network

**•** Personal Dose Meter (PDM) –worn by the staff; smart badge measures scatter radiation

Staff working in an x-ray environment wears a PDM. This PDM measures x-ray dose re‐ ception and is wirelessly connected to the Base Station. The Base Station is mounted in the examination room where all staff can directly see whether received dose is in red, yellow or green area. The "yellow" or "red" status means a necessity of immediate ac‐ tion to reduce x-ray exposure. X-ray dose history information can be automatically re‐ trieved from any Base Station or from any PDM by using a Cradle with Dose View

sample of European cardiac centres [10] doses for the first operator are as follows:

**b.** equivalent dose over the apron: median 11.1mSv, third quartile 14mSv.

instant access to time-stamped dose history. The system is completed from:

linked to a computer running Dose Manager software for analysis.

and transmit this information to the Base Station where is displayed.

**•** Dose View: PC software package is included together with the Base Station.

**•** Cradle: for placement of the PDM (outside of the exposure time)

**a.** annual effective dose: median 1.3mSv, third quartile 1.4mSv,

the exposure time shorter.

of clinically difficult patient.

software or Dose Manager software.

acquired.

gy for evaluation radiation risk for the staff [4, 9].

Cardiac CT procedures were an engine for development of new technical solutions in CT: visualization of quickly moving anatomical structures needs extremely short time for ac‐ quisition and reconstruction of images. This is available in the new multislice CT scanners, with rotation time not longer than 0.4s and slice collimation 8 cm or more (up to 16 cm). Im‐ provements in spatial and temporal resolution, scan time, scan range and advanced image postprocessing (very important in clinical practice) have made CT angiography (CTA) an excellent tool for identifying patients in need of invasive therapy and for mapping out the best percutaneous or surgical approach. In some cases CTA provides complementary infor‐ mation to that of conventional angiography (CCA).

Although history of cardiac CT began with the four-slice scanners, the real development started with 64-slice scanners with appropriate combination of spatial and temporal resolu‐ tion. However, the intensity of x-rays emitted in the multislice CT scanners has to be higher and then a number of dose-reduction mechanisms is implemented for patients' safety.

According the American College of Cardiology Foundation (ACCF) the principal indica‐ tions to cardiac CT are as follows [11]:


The current role of coronary CT angiography in the assessment of coronary artery disease is based on its high negative predictive value in ruling out significant stenosis in intermediate risk populations. [12]. A precise preprocedural visualization of complex coronary lesions with CT angiography would be complementary to conventional angiography and allow op‐ timization of the interventional approach during subsequent PCI [13].

The main benefit from CTA is evaluation of cardiac structure and function and also evalua‐ tion of anatomical structures surrounding the heart.

#### **3.1. Description of the procedure**

From technological reasons the possibilities of CT are limited to diagnostics, without further therapeutic activity (means angioplasty).

The main stages of CT study protocol are as follows:


As coronary disease is jointed with calcification of coronary arteries, evaluation of this proc‐ ess is a good indicator of pathology. CTA gives possibility to display calcifications (3D) and to assess them quantitatively: it is so-called "calcium scoring".

A dose-length-product (DLP) is directly measured by a dosemeter with a pencil chamber. Measured in units of mGy.cm, DLP reflects the integrated radiation dose (in a given posi‐

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The first estimation of a dose received by a patient during the CT procedure is the value of the CTDIvol displayed on the console monitor of the scanner. The CTDIvol represents an aver‐ age dose over the scanned volume. The quantity is computed on the basis of exposure pa‐ rameters (voltage, mAs per scan, pitch) according to the calibration stored in the computer memory of the scanner. The calibration is performed for the standard dosimetric cylindrical phantom from PMMA. By convention, a phantom 16 cm in diameter is used to model the head, and a 32 cm phantom is used to model the body (for adult patient). The displayed

CTDIvol can be computed on the basis of DLP measurements using a practical formula given

where DLPave= (1/3)DLPc +(2/3)DLPp, L- the accurate length of scan., i.e. the difference be‐

DLPc and DLPp are measured in the centrum and at periphery of the adequate PMMA phan‐

The absorbed organ doses and then the effective dose received by a patient from a given CT

**c.** with CTDIvol values provided on the scanner console and a body region-specific conver‐

Dosimetric measurements are commonly made with termoluminescent dosimeters (lithium fluoride or calcium fluoride) or solid state detectors. The detectors are distributed inside the phantom which is exposed as a patient. The most popular are Rando Man or Rando Woman phantoms (representing adult humans) and the family of CIRS phantoms (representing chil‐

Monte Carlo simulation assumes a mathematical phantom representing a patient from a giv‐ en age group and model photon transitions through this phantom. The older solutions used the "family" of Cristy' phantoms for simulation, modelling organs as geometrical solids. The newer studies use voxel phantoms which are more anatomical being created on the ba‐

The last approach, i.e. taking some conversions coefficient from literature and multiplying by CTDIvol is the simplest, but under condition, that the both values are really adequate for

**a.** with calculation based on dosimetric measurements made in physical phantoms,

CTDIvol is used as a measure of radiation charge in the procedure.

tion) for the total length of scanning.

below:

CTDIvol= (DLPave/L) mGy

dren as well as adults).

sis of CT human images.

the given scanner.

tween start and end positions of the table.

tom (i.e. "HEAD" Ø=16cm or "BODY" Ø=32cm).

procedure may be evaluated by the following approaches:

sion coefficient averaged for multiple scanners.

**b.** with Monte Carlo simulations using mathematical phantoms,

Generally, the heart can be imaged well if its structures do not move significantly during the scanning time. This condition is fulfilled during the diastolic phase of cardiac cycle. For se‐ lection of the proper phase for CT images recording ECG gating (triggering) is applied.

General rules for exposure parameters:

Slice thickness <1mm, pitch<1, trot≤0.5sec, kilovoltage U≥100kV, mAs and physical filtration are dependent on the CT scanner, ECG-gating.

Set of parameters for a given CT scanner is determined by the model of a scanner and the version of software dedicated to coronary procedures and offered by the vendor on a user's requirement.

The parameters have also be optimal for the patient's clinical status. The heart rate has here spe‐ cial importance: at the high cardiac rate the registered imaging data have also to be reconstruct‐ ed very quickly (practically immediately). This is available only for the newest scanners and is applied for paediatric procedures. As usual, it does not exceed 65 bpm but the required value de‐ pends on the scanner software. Lowering of the heart rate is achieved pharmacologically.

After completing acquisition of primary data elaboration on them begins, i.e. post-processing.

The possibilities of CT scanner are determined by the installed version of software which may be changed.

The principal algorithms for image post-processing are [14]:


The axial images produced by hardware (so-called row data) are essential and should be used but reformed images may improve lesion detection and classification (particularly co‐ ronal and oblique views). The axial images and MPRs are used for diagnosis and the SSD and MIPs are for display purposes.

The results of CTA are evaluated or consulted by a cardiologist.

#### **3.2. Dosimetric quantites**

Practical dosimetric quantities used for CT are a dose-length-product (DLP) and computedtomography-dose- index (CTDI).

A dose-length-product (DLP) is directly measured by a dosemeter with a pencil chamber. Measured in units of mGy.cm, DLP reflects the integrated radiation dose (in a given posi‐ tion) for the total length of scanning.

The first estimation of a dose received by a patient during the CT procedure is the value of the CTDIvol displayed on the console monitor of the scanner. The CTDIvol represents an aver‐ age dose over the scanned volume. The quantity is computed on the basis of exposure pa‐ rameters (voltage, mAs per scan, pitch) according to the calibration stored in the computer memory of the scanner. The calibration is performed for the standard dosimetric cylindrical phantom from PMMA. By convention, a phantom 16 cm in diameter is used to model the head, and a 32 cm phantom is used to model the body (for adult patient). The displayed CTDIvol is used as a measure of radiation charge in the procedure.

CTDIvol can be computed on the basis of DLP measurements using a practical formula given below:

CTDIvol= (DLPave/L) mGy

**3.** i.v. injection of contrast agent,

General rules for exposure parameters:

are dependent on the CT scanner, ECG-gating.

As coronary disease is jointed with calcification of coronary arteries, evaluation of this proc‐ ess is a good indicator of pathology. CTA gives possibility to display calcifications (3D) and

300 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Generally, the heart can be imaged well if its structures do not move significantly during the scanning time. This condition is fulfilled during the diastolic phase of cardiac cycle. For se‐ lection of the proper phase for CT images recording ECG gating (triggering) is applied.

Slice thickness <1mm, pitch<1, trot≤0.5sec, kilovoltage U≥100kV, mAs and physical filtration

Set of parameters for a given CT scanner is determined by the model of a scanner and the version of software dedicated to coronary procedures and offered by the vendor on a user's requirement.

The parameters have also be optimal for the patient's clinical status. The heart rate has here spe‐ cial importance: at the high cardiac rate the registered imaging data have also to be reconstruct‐ ed very quickly (practically immediately). This is available only for the newest scanners and is applied for paediatric procedures. As usual, it does not exceed 65 bpm but the required value de‐ pends on the scanner software. Lowering of the heart rate is achieved pharmacologically.

After completing acquisition of primary data elaboration on them begins, i.e. post-processing.

The possibilities of CT scanner are determined by the installed version of software which

The axial images produced by hardware (so-called row data) are essential and should be used but reformed images may improve lesion detection and classification (particularly co‐ ronal and oblique views). The axial images and MPRs are used for diagnosis and the SSD

Practical dosimetric quantities used for CT are a dose-length-product (DLP) and computed-

to assess them quantitatively: it is so-called "calcium scoring".

The principal algorithms for image post-processing are [14]:

The results of CTA are evaluated or consulted by a cardiologist.

**•** curved and multiplanar reformats (MPR),

**•** maximum intensity projection (MIP),

**•** shaded-surface display (SSD),

and MIPs are for display purposes.

tomography-dose- index (CTDI).

**•** volume rendering (VR).

**3.2. Dosimetric quantites**

**4.** CT angiography.

may be changed.

where DLPave= (1/3)DLPc +(2/3)DLPp, L- the accurate length of scan., i.e. the difference be‐ tween start and end positions of the table.

DLPc and DLPp are measured in the centrum and at periphery of the adequate PMMA phan‐ tom (i.e. "HEAD" Ø=16cm or "BODY" Ø=32cm).

The absorbed organ doses and then the effective dose received by a patient from a given CT procedure may be evaluated by the following approaches:


Dosimetric measurements are commonly made with termoluminescent dosimeters (lithium fluoride or calcium fluoride) or solid state detectors. The detectors are distributed inside the phantom which is exposed as a patient. The most popular are Rando Man or Rando Woman phantoms (representing adult humans) and the family of CIRS phantoms (representing chil‐ dren as well as adults).

Monte Carlo simulation assumes a mathematical phantom representing a patient from a giv‐ en age group and model photon transitions through this phantom. The older solutions used the "family" of Cristy' phantoms for simulation, modelling organs as geometrical solids. The newer studies use voxel phantoms which are more anatomical being created on the ba‐ sis of CT human images.

The last approach, i.e. taking some conversions coefficient from literature and multiplying by CTDIvol is the simplest, but under condition, that the both values are really adequate for the given scanner.

Regardless of the way, the effective dose estimates the radiation charge for some "typical" (standard) patient, without taking into consideration the anatomy of a given human, and thus should be referred to the category of patients undergoing the given x-ray procedure.

The special solution for dose reduction being dedicated to cardiac CT examinations is the

Coronary Angiography – Technical Recommendations and Radiation Protection

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303

RGH = Retrospectively Gated Helical: the patient and table move through the gantry at a steady speed. A low pitch (0.2 to 0.4) is needed to cover the entire cardiac volume, especially to compensate for any ectopic beats, which can result in misregistration and gaps in cover‐ age. Thus, the same anatomy can be exposed to the x-ray beam many times (up to five) to

PGA= Prospectively Gated Axial: the table is stationary during PGA image acquisition, then moves to the next location for another scan that is initiated by the next normal cardiac cycle.

Diagnostic value of images obtained for PGA protocol was found not lower than for RGH while the doses where substantially lower [8]. In the same study including 203 CTA exams (82 with routine RGH and 121 with the PGA) the doses were evaluated for protocol includ‐ ing scout images, low-dose calcium scoring scans, test-bolus scan and CT coronary angio‐ gram. The exams were performed using 64-slice CT scanner (LightSpeed VCT XT, GE). The

The similar dose values (16.3 mSv and 3.5 mSv for RGH and PGA, respectively) are drawn as a conclusion from the papers published from 2007 to 2011 [1] and prospective ECG-trig‐ gering is recommended as the most commonly applied technique for dose reduction [16, 17]. Lowering of tube voltage is another technique frequently proposed for dose reduction. The results of multicenter, multivendor randomized trial using 80 kVp was published by LaB‐ ounty et. al. [18]. The authors concluded that CTA using 80 kVp instead of 100 kVp was as‐ sociated with a nearly 50% reduction in radiation dose with no significant difference in interpretability and noniferior image quality despite lower signal-to-noise and contrast-to-

The newest technique for cardiac imaging is so-called C-arm CT (also Rotational Angio, dy‐ na-CT). This is a special option of the new models of C-arm units introduced as a potential modality for intra-operative 3D imaging. This is possible for C-arm systems equipped with

The C-arm is rotated over a wide range (>180°) with or without continuous contrast injec‐ tion, acquiring multiple views of the cardiovascular structure with subsequent 3D recon‐ struction. This is advanced post processing giving images like 3D reconstructions from CT. For ECG-referenced cardiac imaging, identical alternating forward and backward rotations

flat panel detectors and appropriate software for image reconstructions.

The x-rays emission is then dynamically predicted on the basis of ECG signal.

change of image acquisition technique from RGH to PGA [8].

ensure enough coverage, causing high absorbed doses.

effective doses were as follows:

noise ratios.

**4. C-arm CT**

RGH: (8.7-23.2) mSv, mean: 18.4 mSv; PGA: (0.75-6.67) mSv; mean: 2.84 mSv.

#### **3.3. Doses to patients and radiation protection in CTA**

Computerized tomography is treated as a high-dose imaging technique although in the cur‐ rently produced scanners a lot of mechanisms for dose reduction is implemented and the high doses can be avoided.

Because of exposure conditions in CTA (thin slices and low pitch) the doses to patients are relatively high, especially at 64-slice scanners. It was an inspiration to implement the meth‐ ods of dose reduction without loss of image quality. (According to Sun et.al [1] 64-slice CT scanners are the most commonly used for coronary CT angiography, although 16-slice are still in use. The next place have dual-source CT scanners as dedicated to angiographic proce‐ dures.)

The mean effective doses in CTA for adult patients undergoing the procedure using 64-slice scanners are from 8 mSv to 21.4 mSv [6].

The doses can be reduced through lowering current-voltage parameters, implementation of x-rays intensity modulation (for three axis), shortening of scanned body length and ECG gating ( specially for cardiac procedures). ECG-controlled tube current modulation is very common approach utilized in CTA [1].

An example of the impact of different scan protocols on radiation dose and image quality is taken from [15]. The data concern the randomly selected adult patients examined for the evaluation of coronary artery disease. Two CT scanners were used: 16-slice and 64-slice.


**Table 3.** Data for different protocols of CTA (from [15])

The special solution for dose reduction being dedicated to cardiac CT examinations is the change of image acquisition technique from RGH to PGA [8].

RGH = Retrospectively Gated Helical: the patient and table move through the gantry at a steady speed. A low pitch (0.2 to 0.4) is needed to cover the entire cardiac volume, especially to compensate for any ectopic beats, which can result in misregistration and gaps in cover‐ age. Thus, the same anatomy can be exposed to the x-ray beam many times (up to five) to ensure enough coverage, causing high absorbed doses.

PGA= Prospectively Gated Axial: the table is stationary during PGA image acquisition, then moves to the next location for another scan that is initiated by the next normal cardiac cycle.

The x-rays emission is then dynamically predicted on the basis of ECG signal.

Diagnostic value of images obtained for PGA protocol was found not lower than for RGH while the doses where substantially lower [8]. In the same study including 203 CTA exams (82 with routine RGH and 121 with the PGA) the doses were evaluated for protocol includ‐ ing scout images, low-dose calcium scoring scans, test-bolus scan and CT coronary angio‐ gram. The exams were performed using 64-slice CT scanner (LightSpeed VCT XT, GE). The effective doses were as follows:

RGH: (8.7-23.2) mSv, mean: 18.4 mSv;

PGA: (0.75-6.67) mSv; mean: 2.84 mSv.

The similar dose values (16.3 mSv and 3.5 mSv for RGH and PGA, respectively) are drawn as a conclusion from the papers published from 2007 to 2011 [1] and prospective ECG-trig‐ gering is recommended as the most commonly applied technique for dose reduction [16, 17].

Lowering of tube voltage is another technique frequently proposed for dose reduction. The results of multicenter, multivendor randomized trial using 80 kVp was published by LaB‐ ounty et. al. [18]. The authors concluded that CTA using 80 kVp instead of 100 kVp was as‐ sociated with a nearly 50% reduction in radiation dose with no significant difference in interpretability and noniferior image quality despite lower signal-to-noise and contrast-tonoise ratios.

## **4. C-arm CT**

Regardless of the way, the effective dose estimates the radiation charge for some "typical" (standard) patient, without taking into consideration the anatomy of a given human, and thus should be referred to the category of patients undergoing the given x-ray procedure.

302 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Computerized tomography is treated as a high-dose imaging technique although in the cur‐ rently produced scanners a lot of mechanisms for dose reduction is implemented and the

Because of exposure conditions in CTA (thin slices and low pitch) the doses to patients are relatively high, especially at 64-slice scanners. It was an inspiration to implement the meth‐ ods of dose reduction without loss of image quality. (According to Sun et.al [1] 64-slice CT scanners are the most commonly used for coronary CT angiography, although 16-slice are still in use. The next place have dual-source CT scanners as dedicated to angiographic proce‐

The mean effective doses in CTA for adult patients undergoing the procedure using 64-slice

The doses can be reduced through lowering current-voltage parameters, implementation of x-rays intensity modulation (for three axis), shortening of scanned body length and ECG gating ( specially for cardiac procedures). ECG-controlled tube current modulation is very

An example of the impact of different scan protocols on radiation dose and image quality is taken from [15]. The data concern the randomly selected adult patients examined for the evaluation of coronary artery disease. Two CT scanners were used: 16-slice and 64-slice.

> 100 kV with EGC

No. of patients 30 50 50 50 50 30 Heart rate [bpm] 61.3±11.3 60.7±9.5 57.8±5.3 61.1±10.4 57.5±7.2 57.0±8.2

CTDIvol [Gy] 42.1±3.6 25.2±2.9 19.4±1.0 58.8±6.5 38.3±3.11 22.0±1.8

16 –slice CT 64-slice CT

510.0±40.3 304.5±42.3 387.6±18.9 870.0±55.6 551.0±58.2 537.8±50.7

11.1±3.9 11.9±4.3 11.9±3.7 8.9±2.5 9.2±2.8 9.2±2.5

10.6±1.2 6.4±0.9 5.0±0.3 14.8±1.8 9.4±1.0 5.4±1.1

120 kV without EGC

120 kV with EGC

100 kV with EGC

**3.3. Doses to patients and radiation protection in CTA**

high doses can be avoided.

scanners are from 8 mSv to 21.4 mSv [6].

common approach utilized in CTA [1].

120 kV without EGC

**Table 3.** Data for different protocols of CTA (from [15])

120 kV with EGC

dures.)

Tube current [mA]

Signal-to-noise

Effective dose [mSv]

ratio

The newest technique for cardiac imaging is so-called C-arm CT (also Rotational Angio, dy‐ na-CT). This is a special option of the new models of C-arm units introduced as a potential modality for intra-operative 3D imaging. This is possible for C-arm systems equipped with flat panel detectors and appropriate software for image reconstructions.

The C-arm is rotated over a wide range (>180°) with or without continuous contrast injec‐ tion, acquiring multiple views of the cardiovascular structure with subsequent 3D recon‐ struction. This is advanced post processing giving images like 3D reconstructions from CT. For ECG-referenced cardiac imaging, identical alternating forward and backward rotations are triggered by the ECG signal to acquire projections covering the entire acquisition range at a similar cardiac phase [19, 20, 21].

[6] Einstein AJ, Moser KW, Thompson RC, Cerqueira MD, Hezlova MJ. *Contemporary Re‐*

Coronary Angiography – Technical Recommendations and Radiation Protection

http://dx.doi.org/10.5772/54034

305

[7] Vano E, Arranz L, Sastre JM, et al: *Dosimetric and radiation protection considerations based on some cases of patient skin injuries in interventional cardiology*. Br.J.Radiol., 71,

[8] Bor D, Olgar T, Toklu T, et al.: *Patient doses and dosimetric evaluations in interventional*

[9] International Commission on Radiological Protection, Publication 75, General Princi‐

[10] Padovani R: Optimisation of patient and staff exposure in interventional radiology. In: Radiation Protection in Medical Physics, edited by Y.Lemoigne and A.Caner, Springer in Cooperation with NATO Public Diplomacy Division, The Netherlands,

[11] Taylor A, Cerquiera M in Journal of the American College of Cardiology, October 2010: according to AuntMinnie.com (November 1,2010): *New cardiac CT guidelines ex‐*

[12] Hamon M, Biondi-Zoccai GG, Malagutti P, Agostoni P, Morello R, Valgimigli M, Ha‐ mon M. *Diagnostic performance of multi slice spiral computed tomography of coronary ar‐ teries as compared with conventional invasive coronary angiography. A meta-analysis*. J Am

[13] Wink O. Hecht HS, Ruijters D. *Coronary computed tomographic angiography in the car‐ diac catheterization laboratory: current applications and future developments*. Cardiol Clin

[15] Hausleiter J, Meyer T, Hademitzky M, Huber E, Zankl M, Martinoff S, Kastrati A, Schomig A. *Radiation Dose Estimates From Cardiac Multislice Computed Tomography in*

[16] Sabarudin A, Sun Z, Ng K-H. *Radiation dose associated with coronary CT angiography and invasive coronary angiography: an experimental study of the effect of dose-saving strat‐*

[17] Hong YJ, Kim SJ, Lee SM, Min PK, Yoon YW, Lee BK, Kim TH. *Low-dose coronary computed tomography angiography using prospective ECG-triggering compared to invasive*

[18] LaBounty TM, Leipsic J, Poulter R, Wood D, Johnson M, Srichai MB, Cury RC, Hei‐ bron B, Hague C, Lin FY, et al. *Coronary CT angiography of patients with a normal body mass index using 80 kVp versus 100 kVp: a prospective, multicenter, multivendor random‐*

*coronary angiography*. Int J Cardiovasc Imaging, 2011 Mar; 27(3): 425-431

[14] W.A.Kalender: Computed Tomography. Publicis MCD Verlag, Munich 2000

*Daily Practice*. Circulation, 2006, March; 113:1305-1310

*egies*. Radiat Prot Dosimetry, 2012; 150(2): 180-187

*ized trial*. Am J Radiol, 2011, Nov,; 197(5): W860-867

*views in Cardiovascular Medicine*. Circulation, 2007; 116: 1290-1305

ples of Monitoring for Radiation Protection of Workers, 1997.

*cardiology*. Physica Medica, 25,31-42, 2009.

510-516, 1998.

2011.

*pand use for low-risk patients*.

Coll Cardiol 2006; 48: 1896-1910

2009; 27: 513-529

Because of the relatively slow rotation of the C-arm, the temporal resolution of these sys‐ tems is significantly inferior to the new multislice CT scanners [19].

The acquisition of 3D data directly from the angiography system may facilitate co-registra‐ tion of angiographic data with pre-procedurally acquired 3D CT images, with subsequent automatic registration to the 2D-fluoroscopy images obtained using the same system. The availability of real-time 3D anatomical information from the patient may offer advantages beyond those of pre-procedural images.

C-arm CT as a technical solution joins some benefits of CT with C-arm techniques, giving possibility to continue the diagnostic procedure (angiography) as a therapeutic one, and subsequently to provide CT-like images during an interventional procedure without mov‐ ing the patient to a CT or MRI scanner.

The results of comparison of both CA modes (CCA and rotational angiography) performed for the same patients (over 200) revealed a hih degree of diagnostic agreement for 3 inde‐ pendent cardiologist and for each coronary segment [22]. Contrast medium volume during rotational CA and conventional CA amounted to 31.9± 4.5 mL versus 52.2±8.0 mL, and pa‐ tient radiation exposure amounted to 5.0±2.6 Gy.cm2 versus 11.5±5.5 Gy.cm2 , respectively.

## **Author details**

Maria Anna Staniszewska

Dept. of Medical Imaging Techniques, Medical University, Lodz, Poland

## **References**


[6] Einstein AJ, Moser KW, Thompson RC, Cerqueira MD, Hezlova MJ. *Contemporary Re‐ views in Cardiovascular Medicine*. Circulation, 2007; 116: 1290-1305

are triggered by the ECG signal to acquire projections covering the entire acquisition range

304 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Because of the relatively slow rotation of the C-arm, the temporal resolution of these sys‐

The acquisition of 3D data directly from the angiography system may facilitate co-registra‐ tion of angiographic data with pre-procedurally acquired 3D CT images, with subsequent automatic registration to the 2D-fluoroscopy images obtained using the same system. The availability of real-time 3D anatomical information from the patient may offer advantages

C-arm CT as a technical solution joins some benefits of CT with C-arm techniques, giving possibility to continue the diagnostic procedure (angiography) as a therapeutic one, and subsequently to provide CT-like images during an interventional procedure without mov‐

The results of comparison of both CA modes (CCA and rotational angiography) performed for the same patients (over 200) revealed a hih degree of diagnostic agreement for 3 inde‐ pendent cardiologist and for each coronary segment [22]. Contrast medium volume during rotational CA and conventional CA amounted to 31.9± 4.5 mL versus 52.2±8.0 mL, and pa‐

[1] Sun Z, Ng K-H. *Coronary CT angiography in coronary artery disease*. WJC, 2011 Septem‐

[2] Advances in the Diagnosis of Coronary Atherosclerosis, Edited by Suna F.Kirac. In‐ Tech, 2011. Chapter 5: Coronary Angiography- Physical and Technical Aspects, by

[3] Vano E, Gonzales L, Guibelalde E, et al:Radiation exposure to medical staff in inter‐

[4] International Commission on Radiological Protection, Publication 85, Avoidance of

[5] http://www.cathlabdigest.com/articles/Biplane-Coronary-Angiography, by M.Kern

versus 11.5±5.5 Gy.cm2

, respectively.

tems is significantly inferior to the new multislice CT scanners [19].

at a similar cardiac phase [19, 20, 21].

beyond those of pre-procedural images.

ing the patient to a CT or MRI scanner.

**Author details**

**References**

Maria Anna Staniszewska

ber 26; 3(9): 303-310

M.A.Staniszewska

tient radiation exposure amounted to 5.0±2.6 Gy.cm2

Dept. of Medical Imaging Techniques, Medical University, Lodz, Poland

ventional and cardiac radiology. Br.J.Radio., 71,954-960,1998.

Radiation Injuries from Medical Interventional Procedures, 2001.


[19] Schoenhagen P, Numburi U, Halliburton SS, Aulbach P, von Roden M, Desai MY, Rodriguez LL, Kapadia SR, Tuzcu EM, Lytle BW. *Three-dimensional imaging in the con‐ text of minimally invasive and tanscatheter cardiovascular interventions using multi-detector computed tomography: from pre-operative planning to intra-operative guidance*. European Heart Journal, 2010; 31: 2727-2741

**Chapter 15**

**Transradial Versus Transfemoral**

Additional information is available at the end of the chapter

ventional procedures, and suitable for most patients.

vascular access for coronary angiography and intervention.

and intervention regarding their applicability, feasibility and safety.

Although trans-brachial approach via brachial cut done, that has been introduced by Sones in 1959, was the prefer method for coronary angiography in the 1950s and 1960s, because of the complexity of the procedure, it lost its popularity during last decades. Meanwhile trans-femoral (TF) approach became popular and dominant method for cathe‐ terization and angiography, because of the simplicity of the technique and operatorfriendly. Whereas trans-radial (TR) approach in aortography for the first time was reported by Radner S, in 1948 [1], due to small vessel size, this technique has been aban‐ doned until 1989, that Campeau did relive this technique and introduced it as an ideal approach for coronary angiography [2]. Although TF approach still is dominant approach worldwide, during the last decade TR approach has emerged as a new method for coro‐ nary angiography and angioplasty, mostly in European countries and Japan. Because of its advantages, less vascular complication and early mobilization of patients, TR ap‐ proach is going to be the method of choice for cardiac catheterization and angiography. TR technique encompasses vast majority of procedures, including diagnostic and inter‐

There is no doubt that all three above mentioned approaches are applicable in invasive and interventional cardiology but we are looking for the most feasible and safest approach for

The purpose of this chapter is to compare the different approaches in coronary angiography

and reproduction in any medium, provided the original work is properly cited.

© 2013 Zand Parsa; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Coronary Angiography**

Amir Farhang Zand Parsa

http://dx.doi.org/10.5772/54077

**1. Introduction**


**Chapter 15**

## **Transradial Versus Transfemoral Coronary Angiography**

Amir Farhang Zand Parsa

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54077

## **1. Introduction**

[19] Schoenhagen P, Numburi U, Halliburton SS, Aulbach P, von Roden M, Desai MY, Rodriguez LL, Kapadia SR, Tuzcu EM, Lytle BW. *Three-dimensional imaging in the con‐ text of minimally invasive and tanscatheter cardiovascular interventions using multi-detector computed tomography: from pre-operative planning to intra-operative guidance*. European

306 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

[20] Neubauer AM, Garcia JA, Messenger JC, Hansis E, Kim MS, Klein AJ, Schoonenberg GA, Grass M, Carroll JD. *Clinical feasibility of a fully automated 3D reconstructions of ro‐*

[21] Tommassini G, Camerini A, Gatti A, Derelli G, Bruzzone A, Veccio G. *Panoramic coro‐*

[22] Empen K, Kuon E, Hummel A, Gebauer C, Dorr M, Konemann R, Hoffmann W, Staudt A, Weitmann K, Reffelmann T, Felix SB. *Comparison of rotational with conven‐*

*tational coronary X-ray angiograms*. Circ Cardiovasc Interv, 2010; 3: 71-79

*tional coronary angiography*. Am Heart J, 2010, Sept.; 160(3): 552-563

*nary angiography*. J Am Coll Cardiol, 1998; 31: 871-877

Heart Journal, 2010; 31: 2727-2741

Although trans-brachial approach via brachial cut done, that has been introduced by Sones in 1959, was the prefer method for coronary angiography in the 1950s and 1960s, because of the complexity of the procedure, it lost its popularity during last decades. Meanwhile trans-femoral (TF) approach became popular and dominant method for cathe‐ terization and angiography, because of the simplicity of the technique and operatorfriendly. Whereas trans-radial (TR) approach in aortography for the first time was reported by Radner S, in 1948 [1], due to small vessel size, this technique has been aban‐ doned until 1989, that Campeau did relive this technique and introduced it as an ideal approach for coronary angiography [2]. Although TF approach still is dominant approach worldwide, during the last decade TR approach has emerged as a new method for coro‐ nary angiography and angioplasty, mostly in European countries and Japan. Because of its advantages, less vascular complication and early mobilization of patients, TR ap‐ proach is going to be the method of choice for cardiac catheterization and angiography. TR technique encompasses vast majority of procedures, including diagnostic and inter‐ ventional procedures, and suitable for most patients.

There is no doubt that all three above mentioned approaches are applicable in invasive and interventional cardiology but we are looking for the most feasible and safest approach for vascular access for coronary angiography and intervention.

The purpose of this chapter is to compare the different approaches in coronary angiography and intervention regarding their applicability, feasibility and safety.

© 2013 Zand Parsa; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **2. Anatomical considerations**

Operators should be prepared for these approaches theoretically. The knowledge of anatomy of the femoral, brachial and radial arteries is necessary and helpful for doing these techniques successfully.

**3. Technical aspects**

to the radial styloid.

3 centimeter (cm) from the inguinal ligament.

Awareness of operators of instruments and devices (catheters, wires and etc.…) compatible

Transradial Versus Transfemoral Coronary Angiography

http://dx.doi.org/10.5772/54077

309

**Arterial puncture:** For doing catheterization and angiography the most important job is to find an accesses route. All cardiologists and interventionists are familiar with the transfemoral access. It is a large caliber artery and easy to be punctured and it is the advantage of this rout over the transbrachial or transradial approach. The only point that should be mentioned regarding TF approach is that the arterial puncture must be done in the groin not farther than

The most difficulty in the transradial technique that operators confront with is the arterial puncture and almost always it is responsible for the failure of the procedure. This is the main reason that this technique needs more experience. Learning curve in this technique dose has profound impact on the procedural success rate and procedural time [7, 8]. Access to the radial

Before trying to do radial puncture, it is necessary to do Allen's test for making sure that ulnar artery is patent and collateral supply of the hand is sufficient. The Allen's test for the first time was described by Dr.Allen in 1929 to evaluate collateral circulation of pa‐ tients suffering from thromboangitis obliterans [9]. For this purpose the patient will be asked to clench his/her hand. Meanwhile operator compresses both the radial and the ul‐ nar arteries by thumb fingers and again the patient will be asked to open his/her hand. After a few second compression on the ulnar artery will be released. In normal situation red color of finger tips will be restored within 10 seconds (positive Allen's test). Pulse Oxymetery of fingers is an alternative method. The test considered positive if the pulse waveform reappeared after releasing compression on the ulnar artery while compressing the radial artery (figure 2) [10, 11]. However the necessity of the evaluation of collateral

Before doing radial puncture, the wrist should be prepared by hyperextending it over an arm board or positioned the arm beside the body with the wrist expanded. Sterilization with betadine must be done from elbow to the tips of fingers. Then the skin of the area is anaesthe‐ tized with 2-3 ml lidocain 1%-2%. The puncture site is approximately 1-2 centimeter proximal

After identifying the radial artery a small incision of the skin of the prepared puncture site is done, and then the radial artery is punctured with a 20- 21- gauge (G) needle through the incision. Appearances of pulsatile flow from the end of the needle con‐ firmed that the needle is inside the lumen of the artery. It can be occurred when the nee‐ dle is pushing inside the radial artery or when the needle that deeply seated in the posterior wall of the artery is pulling back until pulsatile flow from the needle reap‐ pears. Then a 0.018 – 0.035- inch hydrophilic guide wire is introduced through the nee‐ dle for inserting 5 to 6- French (Fr), 11-25- cm long sheath in the radial artery (figure 3). Just after the insertion of a sheath, a cocktail consisted of 2mg verapamil, 100 microgram

artery is a challenging job and needs learning curve for getting skill and to be expert.

blood flow to the hand before TR approach is controversial [12].

with each approach and method is crucial for doing these procedures successfully.

**Femoral Access:** Common femoral artery is the continuation of external iliac artery. It begins just below the inguinal ligament outside the femoral vein and inside to the femoral nerve. Com‐ mon femoral artery and vein enclosed in a fibrous sheath that has been called, femoral sheath. It lies anterior and adjacent to the one third of internal aspect of the head of femur and crosses to the median side of the body of the femur (figure 1, A). One of the reasons that TF approach is prone to more complication is its proximity to the femoral nerve, femoral vein and pelvic cavity. Because puncturing of superficial femoral artery is more susceptible to pseudo-aneurysm, com‐ mon femoral artery (first 3 centimeter) must be chosen for arterial puncture.

**Radial access:** The radial artery is the continuation of the brachial artery. It begins at the bifurcation of the brachial artery in the cubital fossa, and passes along the radial side of the forearm to the wrist toward the styloid process of the radius [3]. Then it passes between the two heads of the first Interosseous dorsalis into the palm of the hand (figure 1, B). At the wrist where arterial puncture should be done there is no nerve, vein or cavity at the vicinity of the radial artery, i.e. they are not enclosed in the same fibrous sheath. Deep palmar arch is a connection between the radial and the ulnar artery that protect hand from ischemia due to the occlusion of each branches. The radial artery serves mainly as an arterial conduit to the hand [4]. These are the reasons that radial approach is less prone to complication. The radial artery diameter is about 3.1mm±0.2mm [5]. However, its size is variable and depends on patients' race, gender and size.

**Figure 1.** A; The femoral artery, femoral vein and femoral nerve at the groin, B; The radial and the ulnar arteries at the wrist (adapted from: R. Putzand, R. pubast, Sobotta Atlas of Human Anatomy, Urban & Fisher, 14th edition, 2008, p. 245, 614) [6]

## **3. Technical aspects**

**2. Anatomical considerations**

successfully.

race, gender and size.

245, 614) [6]

Operators should be prepared for these approaches theoretically. The knowledge of anatomy of the femoral, brachial and radial arteries is necessary and helpful for doing these techniques

308 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Femoral Access:** Common femoral artery is the continuation of external iliac artery. It begins just below the inguinal ligament outside the femoral vein and inside to the femoral nerve. Com‐ mon femoral artery and vein enclosed in a fibrous sheath that has been called, femoral sheath. It lies anterior and adjacent to the one third of internal aspect of the head of femur and crosses to the median side of the body of the femur (figure 1, A). One of the reasons that TF approach is prone to more complication is its proximity to the femoral nerve, femoral vein and pelvic cavity. Because puncturing of superficial femoral artery is more susceptible to pseudo-aneurysm, com‐

**Radial access:** The radial artery is the continuation of the brachial artery. It begins at the bifurcation of the brachial artery in the cubital fossa, and passes along the radial side of the forearm to the wrist toward the styloid process of the radius [3]. Then it passes between the two heads of the first Interosseous dorsalis into the palm of the hand (figure 1, B). At the wrist where arterial puncture should be done there is no nerve, vein or cavity at the vicinity of the radial artery, i.e. they are not enclosed in the same fibrous sheath. Deep palmar arch is a connection between the radial and the ulnar artery that protect hand from ischemia due to the occlusion of each branches. The radial artery serves mainly as an arterial conduit to the hand [4]. These are the reasons that radial approach is less prone to complication. The radial artery diameter is about 3.1mm±0.2mm [5]. However, its size is variable and depends on patients'

**A B** 

**Figure 1.** A; The femoral artery, femoral vein and femoral nerve at the groin, B; The radial and the ulnar arteries at the wrist (adapted from: R. Putzand, R. pubast, Sobotta Atlas of Human Anatomy, Urban & Fisher, 14th edition, 2008, p.

mon femoral artery (first 3 centimeter) must be chosen for arterial puncture.

Awareness of operators of instruments and devices (catheters, wires and etc.…) compatible with each approach and method is crucial for doing these procedures successfully.

**Arterial puncture:** For doing catheterization and angiography the most important job is to find an accesses route. All cardiologists and interventionists are familiar with the transfemoral access. It is a large caliber artery and easy to be punctured and it is the advantage of this rout over the transbrachial or transradial approach. The only point that should be mentioned regarding TF approach is that the arterial puncture must be done in the groin not farther than 3 centimeter (cm) from the inguinal ligament.

The most difficulty in the transradial technique that operators confront with is the arterial puncture and almost always it is responsible for the failure of the procedure. This is the main reason that this technique needs more experience. Learning curve in this technique dose has profound impact on the procedural success rate and procedural time [7, 8]. Access to the radial artery is a challenging job and needs learning curve for getting skill and to be expert.

Before trying to do radial puncture, it is necessary to do Allen's test for making sure that ulnar artery is patent and collateral supply of the hand is sufficient. The Allen's test for the first time was described by Dr.Allen in 1929 to evaluate collateral circulation of pa‐ tients suffering from thromboangitis obliterans [9]. For this purpose the patient will be asked to clench his/her hand. Meanwhile operator compresses both the radial and the ul‐ nar arteries by thumb fingers and again the patient will be asked to open his/her hand. After a few second compression on the ulnar artery will be released. In normal situation red color of finger tips will be restored within 10 seconds (positive Allen's test). Pulse Oxymetery of fingers is an alternative method. The test considered positive if the pulse waveform reappeared after releasing compression on the ulnar artery while compressing the radial artery (figure 2) [10, 11]. However the necessity of the evaluation of collateral blood flow to the hand before TR approach is controversial [12].

Before doing radial puncture, the wrist should be prepared by hyperextending it over an arm board or positioned the arm beside the body with the wrist expanded. Sterilization with betadine must be done from elbow to the tips of fingers. Then the skin of the area is anaesthe‐ tized with 2-3 ml lidocain 1%-2%. The puncture site is approximately 1-2 centimeter proximal to the radial styloid.

After identifying the radial artery a small incision of the skin of the prepared puncture site is done, and then the radial artery is punctured with a 20- 21- gauge (G) needle through the incision. Appearances of pulsatile flow from the end of the needle con‐ firmed that the needle is inside the lumen of the artery. It can be occurred when the nee‐ dle is pushing inside the radial artery or when the needle that deeply seated in the posterior wall of the artery is pulling back until pulsatile flow from the needle reap‐ pears. Then a 0.018 – 0.035- inch hydrophilic guide wire is introduced through the nee‐ dle for inserting 5 to 6- French (Fr), 11-25- cm long sheath in the radial artery (figure 3). Just after the insertion of a sheath, a cocktail consisted of 2mg verapamil, 100 microgram (μgr) nitroglycerin and 2500 unit unfractionated heparin (UFH) or 200 μgr nitroglycerin and 2500 unit UFH should be administered through the side arm of the sheath, for pre‐ venting vasospasm and thrombus formation. Right radial artery was preferred rout by the majority of operators so far but recently left radial artery has been introduced by some operators as a preferred method.

Although conventional catheters (pigtail, judkin's (left and right), XB, EB and etc….) can be used for catheterization and coronary angiography via radial access, usually new catheters such as Tiger (terumo) are used for coronary angiography (figure 3). The advantage of new catheters is that both left and right coronary arteries can be opacified by one catheter.

**Figure 3.** 5-Fr ˟ Tiger catheter, 50-Cm ˟ 0.018-inch˟Nitinol hydrophilic guide wire, 21-G ˟ needle and 5-Fr ˟ 19-Cm

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**Transbrachial approach:** The transbrachial approach that for the first time was introduced by F Mason Sones in 1958 has been done via arteriotomy (cut done) technique [14, 15]. Due to the complexity of the procedure this approach lost its popularity and no longer has been used as a routine approach for coronary angiography and intervention. However in recent years this approach is used for selected cases (in the presence of severe peripheral vascular disease and ect…) percutaneously. But the dominant approaches are either radial or femoral approach.

**Transfemoral approach:** Transfemoral approach that was introduced by Sven Ivar Seldinger in 1953 has been done percutaneously, figure 4 [16]. Because Seldinger's method was feasible and easy to do, very soon did get popularity among invasive and /interventional cardiologists and radiologists. For more than 50 years it has been the method of choice for angiography and/

Step 1 Step 2 Step 3 Step 4

**Figure 4.** Steps of percutaneous technique for coronary angiography, Seldinger's method. (from Seldinger SI. Catheter replacement of the needle in percutaneous arteriography. A new technique. Acta Radiologica 1953; 39:

sheath, from top to below respectively.

angioplasty worldwide.

368-76) [16].

**4. Limitations of each approach**

**Figure 2.** Pulse waveform and oxygen saturation before (A), during (B) and after (C) Allen's test. (Adapted from: Na‐ tarajan D. Coronary Angiography – The Need for Improvement in Medical and Interventional Therapy. Edited by Brani‐ *slav Baškot, Publisher: InTech, 2011; p=55*) [13]

**Figure 3.** 5-Fr ˟ Tiger catheter, 50-Cm ˟ 0.018-inch˟Nitinol hydrophilic guide wire, 21-G ˟ needle and 5-Fr ˟ 19-Cm sheath, from top to below respectively.

## **4. Limitations of each approach**

(μgr) nitroglycerin and 2500 unit unfractionated heparin (UFH) or 200 μgr nitroglycerin and 2500 unit UFH should be administered through the side arm of the sheath, for pre‐ venting vasospasm and thrombus formation. Right radial artery was preferred rout by the majority of operators so far but recently left radial artery has been introduced by

310 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Although conventional catheters (pigtail, judkin's (left and right), XB, EB and etc….) can be used for catheterization and coronary angiography via radial access, usually new catheters such as Tiger (terumo) are used for coronary angiography (figure 3). The advantage of new

**Figure 2.** Pulse waveform and oxygen saturation before (A), during (B) and after (C) Allen's test. (Adapted from: Na‐ tarajan D. Coronary Angiography – The Need for Improvement in Medical and Interventional Therapy. Edited by Brani‐

catheters is that both left and right coronary arteries can be opacified by one catheter.

some operators as a preferred method.

*slav Baškot, Publisher: InTech, 2011; p=55*) [13]

**Transbrachial approach:** The transbrachial approach that for the first time was introduced by F Mason Sones in 1958 has been done via arteriotomy (cut done) technique [14, 15]. Due to the complexity of the procedure this approach lost its popularity and no longer has been used as a routine approach for coronary angiography and intervention. However in recent years this approach is used for selected cases (in the presence of severe peripheral vascular disease and ect…) percutaneously. But the dominant approaches are either radial or femoral approach.

**Transfemoral approach:** Transfemoral approach that was introduced by Sven Ivar Seldinger in 1953 has been done percutaneously, figure 4 [16]. Because Seldinger's method was feasible and easy to do, very soon did get popularity among invasive and /interventional cardiologists and radiologists. For more than 50 years it has been the method of choice for angiography and/ angioplasty worldwide.

**Figure 4.** Steps of percutaneous technique for coronary angiography, Seldinger's method. (from Seldinger SI. Catheter replacement of the needle in percutaneous arteriography. A new technique. Acta Radiologica 1953; 39: 368-76) [16].

Limitations for TF approach are: 1) severe peripheral vascular disease, 2) obese patients, 3) presence of severe musculoskeletal abnormalities such as spine or hip malformation, 4) coagulopathies or patients who received high doses of anticoagulation. Not only these limitations decrease the success rate of procedures but also increase the complication rates that will be discussed later.

bleeding occurred in 13 (0.05%) of 2,390 patients in the radial access group compared to 48 (2.3%) of 2,068 patients in the femoral access group (OR 0.27, 95% CI 0.16-0.45; P <0.001), figure 5 [23]. Also according to this meta-analysis of trials occurrence of haematomas was significantly lower in the radial access group compared with femoral

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**2.** Pseudoaneurysm; pseudoaneurysmcan is a potentially life threatening complication that particularly occurred in the TF approach. Its incidence in the TF approach was about 0.03% to 0.2% [24]. But it seems to be more prevalent in the era of intervention. Although in the above mentioned meta-analysis, that included all trials of percutaneous coronary inter‐ vention, few cases [7 0f 3507 patients) in the radial group has been reported [23], its

Anticoagulation is the main risk factor for occurring pseudoaneurysm that followed by; receiving thrombolytic agents or potent antiplatelet (Gp IIb/IIa), obesity, female gender, large sheath size, interventional procedures and multipuncture of the left groin. Although the size of the pseudoaneurysm is not an absolute predictor of the need for surgical repair, pseudoa‐ neurysm smaller than 18 mm in diameter is safe and will be closed spontaneously. Ultrasound-

**Figure 5.** Forest plot for major bleeding of radial versus femoral access. (from; Jolly SS, Amlani S, Haman M, Yusuf S, Mehta SR. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: A systematic review and meta-analysis of randomized trials. Am Heart J 2009;157:132-40) [23]

**3.** Arteriovenous fistula; Occurrence of arteiovenous fistula (AVF) after catheterization is more infrequent than pseudoaneurysm and such as other vascular access complications

access group (HR 0 40, 95% CI 0 28-0 57; p<0 0001) [23].

incidence in the TR approach in coronary angiography is near zero.

guided compression is the first choice treatment of this complication.

**Major bleeding**

**Transradial approach:** Since the first time in1989 that Campeau L reported 100 cases of coro‐ nary angiography via getting access through the radial artery without major complication [2] and in 1993 that Ferdinand Keimeneij and colleagues did percutaneous coronary angioplasty (PTCA) by TR approach, that was comparable with TF approach, TR approach emerged as a new technique for coronary angiography and angioplasty. In 1997 Ferdinant Keimeneij et al,re‐ ported comparison between transradial, transbrachial and transfemoral PTCA in 900 patients. Although in their study access failure in TR approach was more common than transbracial and TF approaches, major access site complication were more frequent in the two latters [17]. How‐ ever, with getting more experience the rate of failure in the TR approach has declined signifi‐ cantly [18]. Indeed transradial success rate depends to the operator learning curve.

TR approach is suitable for most patients and limitation of this approach is very low; however, there is some limitations for this approach that are as below: 1) inadequate ulnar artery collateral circulation (abnormal Allen's test), 2) needs for using large sheath, catheter and / devices, 3) the other limitation of this approach is need for repeating the procedure; however, it has been reported by Sakai and colleagues that transradial approach can be repeated for three to five times in the same access site, especially in men [19]. 4) The other limitation is the need for right heart catheterization and / endomyocardial biopsy simultaneously. However, some studies proposed forearm vein for right heart catheterization in the same time [20, 21].

## **5. Complications**

Usually complications are vascular and mostly dependent to the access site. Although access site complication is more common in the TF approach compared to TR approach, it can occur in both approaches.These complications are:

**1.** Bleeding and hematomas; the most common complications in these approaches are bleeding and hematomas and their occurrence increase in the setting of anticoagulant and antiplatelet therapy that is usual in these patients. Bleeding complication in the femoral approach in the era of intervention is about 3% that 1% of them need blood transfusion; however, in the radial approach it is nearly 0% [22, 17]. Keimeneij et al in a randomized study involving 900 patients did compare TF, transbrchial and TR approaches in patients undergoing percutaneous coronary intervention. In their study access site complications were significantly lower in the TR approach (Major access site bleeding occurred in seven patients (2.3%) in the transbrachial group, six (2.0%) in the transfemoral group and none in the transradial group, p = 0.035 [17]. A systematic review of randomized trials has shown reduction of access site complications by 73% when TR approach was employed instead of TF approach. In this met-analysis major bleeding occurred in 13 (0.05%) of 2,390 patients in the radial access group compared to 48 (2.3%) of 2,068 patients in the femoral access group (OR 0.27, 95% CI 0.16-0.45; P <0.001), figure 5 [23]. Also according to this meta-analysis of trials occurrence of haematomas was significantly lower in the radial access group compared with femoral access group (HR 0 40, 95% CI 0 28-0 57; p<0 0001) [23].

**2.** Pseudoaneurysm; pseudoaneurysmcan is a potentially life threatening complication that particularly occurred in the TF approach. Its incidence in the TF approach was about 0.03% to 0.2% [24]. But it seems to be more prevalent in the era of intervention. Although in the above mentioned meta-analysis, that included all trials of percutaneous coronary inter‐ vention, few cases [7 0f 3507 patients) in the radial group has been reported [23], its incidence in the TR approach in coronary angiography is near zero.

Anticoagulation is the main risk factor for occurring pseudoaneurysm that followed by; receiving thrombolytic agents or potent antiplatelet (Gp IIb/IIa), obesity, female gender, large sheath size, interventional procedures and multipuncture of the left groin. Although the size of the pseudoaneurysm is not an absolute predictor of the need for surgical repair, pseudoa‐ neurysm smaller than 18 mm in diameter is safe and will be closed spontaneously. Ultrasoundguided compression is the first choice treatment of this complication.

#### **Major bleeding**

Limitations for TF approach are: 1) severe peripheral vascular disease, 2) obese patients, 3) presence of severe musculoskeletal abnormalities such as spine or hip malformation, 4) coagulopathies or patients who received high doses of anticoagulation. Not only these limitations decrease the success rate of procedures but also increase the complication rates that

312 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**Transradial approach:** Since the first time in1989 that Campeau L reported 100 cases of coro‐ nary angiography via getting access through the radial artery without major complication [2] and in 1993 that Ferdinand Keimeneij and colleagues did percutaneous coronary angioplasty (PTCA) by TR approach, that was comparable with TF approach, TR approach emerged as a new technique for coronary angiography and angioplasty. In 1997 Ferdinant Keimeneij et al,re‐ ported comparison between transradial, transbrachial and transfemoral PTCA in 900 patients. Although in their study access failure in TR approach was more common than transbracial and TF approaches, major access site complication were more frequent in the two latters [17]. How‐ ever, with getting more experience the rate of failure in the TR approach has declined signifi‐

TR approach is suitable for most patients and limitation of this approach is very low; however, there is some limitations for this approach that are as below: 1) inadequate ulnar artery collateral circulation (abnormal Allen's test), 2) needs for using large sheath, catheter and / devices, 3) the other limitation of this approach is need for repeating the procedure; however, it has been reported by Sakai and colleagues that transradial approach can be repeated for three to five times in the same access site, especially in men [19]. 4) The other limitation is the need for right heart catheterization and / endomyocardial biopsy simultaneously. However, some studies proposed forearm vein for right heart catheterization in the same time [20, 21].

Usually complications are vascular and mostly dependent to the access site. Although access site complication is more common in the TF approach compared to TR approach, it can occur

**1.** Bleeding and hematomas; the most common complications in these approaches are bleeding and hematomas and their occurrence increase in the setting of anticoagulant and antiplatelet therapy that is usual in these patients. Bleeding complication in the femoral approach in the era of intervention is about 3% that 1% of them need blood transfusion; however, in the radial approach it is nearly 0% [22, 17]. Keimeneij et al in a randomized study involving 900 patients did compare TF, transbrchial and TR approaches in patients undergoing percutaneous coronary intervention. In their study access site complications were significantly lower in the TR approach (Major access site bleeding occurred in seven patients (2.3%) in the transbrachial group, six (2.0%) in the transfemoral group and none in the transradial group, p = 0.035 [17]. A systematic review of randomized trials has shown reduction of access site complications by 73% when TR approach was employed instead of TF approach. In this met-analysis major

cantly [18]. Indeed transradial success rate depends to the operator learning curve.

will be discussed later.

**5. Complications**

in both approaches.These complications are:

**Figure 5.** Forest plot for major bleeding of radial versus femoral access. (from; Jolly SS, Amlani S, Haman M, Yusuf S, Mehta SR. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: A systematic review and meta-analysis of randomized trials. Am Heart J 2009;157:132-40) [23]

**3.** Arteriovenous fistula; Occurrence of arteiovenous fistula (AVF) after catheterization is more infrequent than pseudoaneurysm and such as other vascular access complications is more common in the TF approach. Its incidence in the femoral access site particularly in the era of interventional procedures according to some studies is about 0.3% to 0.8% [25, 26]. Although occurrence of AVF is very rare in the TR approach, there is sporadic case report of its occurrence after using radial access for coronary angioplasty but not in diagnostic coronary angiography. In my best knowledge four cases of AVF after TR approach for intervention have been reported, table 4 [27]. Interestingly majority of catheter induced AVFs, either in the femoral access site or in the radial access site are asymptomatic.

Although as randomized trials did reveal significant reduction of access site complication by using TR approach [23], many invasive and/ interventional cardiologist do perceive that the decrease in vascular complications with TR approach are balanced by technical difficulties and

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As a whole TR approach was associated with a little bit longer procedural duration compare to TF approach, but in the hand of expert operators there was no significant difference (12.4±5.8min versus 11.2±3.3min), CARAFE study [7]. In the recent study that has been done by Bruek et al that was larger than CARAFE study and involved operators who were in their early learning curves of TR approach [8]. The median procedural duration for TR and TF approaches were 40.2min and 37min respectively, that difference was statistically significant (p=0.046). Also in a meta-analysis of randomized trials that has been done by Jolly et al, TR approach was associated with longer procedural duration, when weighted mean difference, 3.1 minutes (95% CI 2.4-3.8 p<0.001). When comparing non-radial expert (4.8min, 95% CI 3.7-5.8min) to radial expert (1.7min, 95% CI 07-2.6min), there is significant heterogeneity [23]. It means that operator experience plays a major role in the procedural duration for TR

Usually procedural success rate in the TR approach is less than TF approach that generally is due to failed radial puncture. The success rate (successful angiography without occurrence of significant hematomas) for TR approach compare to TF approach in the Bruek et al, study [8] was 96.5% versus 99.8% respectively (p<0.0001]. However, recent studies revealed no signifi‐

Age didn't have any impact on procedural success rate on the TR approach. Procedural success in patient older than and younger than 70 years old was the same [95.1% versus 94.8% respectively, p=NS) [31]. Also there was no significant difference in the procedural success rate in patients who had prior brachial arteriotomy (cut-down) and those who didn't [93.6% versus

As mentioned above both techniques have advantages and disadvantages over each other. Advantages of TF approach over TR approach are: i) because of large caliber vessel it provides easier access site canulation for inserting different sheath size, particularly, large lumen sheaths, that is necessary in the era of interventional cardiology for using large lumen catheters and/large caliber devices. ii) The other advantageous of this technique is that it made simul‐ taneous venoul canulation possible. iii) It takes X ray tube far from operator, and iv) repeatable for unlimited and/several times. iiv) As a whole this technique was associated with higher

cant difference in procedural success rate between two techniques [30].

**7. Advantages and disadvantages of two techniques**

procedural success rate particularly in the era of interventional cardiology.

increased radiation exposure with TR approach.

**6. Procedural duration and success rate**

approach.

95.3% respectively, p=NS) [18].

**4.** Arterial occlusion is the most important but rare access site complication that more frequently occur in the TR approach. Radial artery occlusion has been reported 2%-60% in the studies using absence of pulse as a criterion for arterial occlusion [28], and 3%-6% in the studies using Doppler ultrasound findings [29]. Also Keimeneij et al reported 5% radial artery occlusion at discharge and 3% at one month follow up in their cases without any femoral artery occlusion [17]. Usually radial artery occlusion does not associate with ischemic complication. Duel arterial supply of the hand increases the safety of this procedure regarding thrombotic or traumatic occlusion of the radial artery. Generally speaking, the incidence of ischemic damage to the hand following TR approach is much lower and more infrequent compare to TF approach.


**Table 1.** Some cases which developed radial arteriovenous fistula after cardiac catheterization (adapted from: Kwac MS, Yoon SJ, Oh SJ, Jeon DW, Kim DH, and Yang JY. A rare case of radial arteriovenous fistula after coronary angiography. Korean Circ J 2010;40:677-79) [23]

AVF: arteriovenous fistula, Rt: right

**5.** Nerve injury; because of superficial course of radial artery and being far from nerve, in contrast to femoral artery (figure 1), nerve injury is more infrequent in TR approach compare to TF approach.

Although as randomized trials did reveal significant reduction of access site complication by using TR approach [23], many invasive and/ interventional cardiologist do perceive that the decrease in vascular complications with TR approach are balanced by technical difficulties and increased radiation exposure with TR approach.

## **6. Procedural duration and success rate**

is more common in the TF approach. Its incidence in the femoral access site particularly in the era of interventional procedures according to some studies is about 0.3% to 0.8% [25, 26]. Although occurrence of AVF is very rare in the TR approach, there is sporadic case report of its occurrence after using radial access for coronary angioplasty but not in diagnostic coronary angiography. In my best knowledge four cases of AVF after TR approach for intervention have been reported, table 4 [27]. Interestingly majority of catheter induced AVFs, either in the femoral access site or in the radial access site are

314 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

**4.** Arterial occlusion is the most important but rare access site complication that more frequently occur in the TR approach. Radial artery occlusion has been reported 2%-60% in the studies using absence of pulse as a criterion for arterial occlusion [28], and 3%-6% in the studies using Doppler ultrasound findings [29]. Also Keimeneij et al reported 5% radial artery occlusion at discharge and 3% at one month follow up in their cases without any femoral artery occlusion [17]. Usually radial artery occlusion does not associate with ischemic complication. Duel arterial supply of the hand increases the safety of this procedure regarding thrombotic or traumatic occlusion of the radial artery. Generally speaking, the incidence of ischemic damage to the hand following TR approach is much

**Authers Year Age/Sex Lession & site Symptom or sign Diagnostic tool Surgical**

1-Venous dilation & palpable thrill at puncture site

Painless pulsatile mass at puncture site

Painless pulsatile mass at puncture site

Pulsatile mass & thrill at puncture site

Doppler ultrasound imaging

Doppler ultrasound imaging

Doppler ultrasound imaging

Doppler ultrasound imaging

**repair**

yes

yes

yes

yes

lower and more infrequent compare to TF approach.

2005 64/male AVF of Rt radial

2007 59/male Radial artery

2007 61/male AVF of radial

**Case 4** Kwac et al 2010 67/male AVF of radial

angiography. Korean Circ J 2010;40:677-79) [23]

AVF: arteriovenous fistula, Rt: right

compare to TF approach.

artery

artery

artery

pseudoaneurysm

**Table 1.** Some cases which developed radial arteriovenous fistula after cardiac catheterization (adapted from: Kwac MS, Yoon SJ, Oh SJ, Jeon DW, Kim DH, and Yang JY. A rare case of radial arteriovenous fistula after coronary

**5.** Nerve injury; because of superficial course of radial artery and being far from nerve, in contrast to femoral artery (figure 1), nerve injury is more infrequent in TR approach

asymptomatic.

**Case 1** Pulikal et al

**Case 2** Spence et al

**Case 3** Spence et al

As a whole TR approach was associated with a little bit longer procedural duration compare to TF approach, but in the hand of expert operators there was no significant difference (12.4±5.8min versus 11.2±3.3min), CARAFE study [7]. In the recent study that has been done by Bruek et al that was larger than CARAFE study and involved operators who were in their early learning curves of TR approach [8]. The median procedural duration for TR and TF approaches were 40.2min and 37min respectively, that difference was statistically significant (p=0.046). Also in a meta-analysis of randomized trials that has been done by Jolly et al, TR approach was associated with longer procedural duration, when weighted mean difference, 3.1 minutes (95% CI 2.4-3.8 p<0.001). When comparing non-radial expert (4.8min, 95% CI 3.7-5.8min) to radial expert (1.7min, 95% CI 07-2.6min), there is significant heterogeneity [23]. It means that operator experience plays a major role in the procedural duration for TR approach.

Usually procedural success rate in the TR approach is less than TF approach that generally is due to failed radial puncture. The success rate (successful angiography without occurrence of significant hematomas) for TR approach compare to TF approach in the Bruek et al, study [8] was 96.5% versus 99.8% respectively (p<0.0001]. However, recent studies revealed no signifi‐ cant difference in procedural success rate between two techniques [30].

Age didn't have any impact on procedural success rate on the TR approach. Procedural success in patient older than and younger than 70 years old was the same [95.1% versus 94.8% respectively, p=NS) [31]. Also there was no significant difference in the procedural success rate in patients who had prior brachial arteriotomy (cut-down) and those who didn't [93.6% versus 95.3% respectively, p=NS) [18].

## **7. Advantages and disadvantages of two techniques**

As mentioned above both techniques have advantages and disadvantages over each other.

Advantages of TF approach over TR approach are: i) because of large caliber vessel it provides easier access site canulation for inserting different sheath size, particularly, large lumen sheaths, that is necessary in the era of interventional cardiology for using large lumen catheters and/large caliber devices. ii) The other advantageous of this technique is that it made simul‐ taneous venoul canulation possible. iii) It takes X ray tube far from operator, and iv) repeatable for unlimited and/several times. iiv) As a whole this technique was associated with higher procedural success rate particularly in the era of interventional cardiology.

However; disadvantages of TF approach are: i) bleeding that is common in the setting of antiplatelet and anticoagulation therapy, that is usual in these patients, is the most important and prevalent complication of TF approach. Major bleeding results >3 fold increases in-hospital and one year mortality (odds ratio= 3.5) and re-infarction [32]. ii) Pseudoaneurysm, atriove‐ nous fistula and retroperitoneal hemorrhage are serious and life-threatening complication of this procedure. iii) Another disadvantageous of TF approach, albeit rare, is thromboembolic or ischemic events of lower extremities, that more often occurred in the presence of peripheral vascular disease or as a result of traumatization and/ dissection of iliac or illeofemoral arteries.

the presence of severe atherosclerosis and small diameter of the femoral artery closure device

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Both transfemoral and transradial techniques are safe, feasible and comparable techniques for cardiac catheterization, angiography and intervention. However, each of these two techniques has own applications and limitations. Although TF approach is dominant ap‐ proach worldwide, TR approach is going to be the technique of choice for coronary an‐ giography and percutaneous coronary intervention in the near future. TR approach reduces hospital stay, procedural cost and vascular complications and also increases pa‐ tients comfort and satisfaction. However, this approach needs more experience and great‐ er learning curve compare to TF approach. In another word, TF approach is the easier and more operator-friendly technique for catheterization and angiography; but with sub‐ stantial access site complications. On the other hand, TR approach is safer and more pa‐ tient-friendly technique for catheterization and angiography but it needs more experience

Case selection is mater in this regard. For example obese patients, patients with severe peripheral vascular disease and / severe musculoskeletal abnormalities and patients with coagulopathies or under aggressive anticoagulation are not good candidate for TF approach. The prefer approach for these patients is TR approach. On the other hand patients with abnormal Allen's test, patients who need simultaneous right and left heart catheterization and when insertion of a large sheath is needed are not good candidate for TR approach. The prefer approach for these patients is TF approach. Indeed these two vascular access techniques can

Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

port of a new technique. Acta Radiol 1948; 29: 178-80

Cardiovasc Diagn 1989; 16: 3-7

[1] Rander S. Thoracal aortography by catheterization from radial artery; preliminary re‐

[2] Campeau L. Percutaneous radial artery approach for coronary angiography. Cathet

shouldn't be used.

**8. Summary**

and higher learning curve.

be reconciled.

**Author details**

**References**

Amir Farhang Zand Parsa

TR approach has gained popularity in recent years and is going to be the technique of choice in coronary angiography and even coronary intervention due to its advantages over TF approach.

The advantages of TR approach over TF approach are; i) reduction of vascular complications in terms of hematomas, bleeding and etc…, even in the setting of acute coronary syndrome (ACS) and/ in patients receiving antithrombotic and antiplatelet therapies. Due to achieving easy hemostasis the bleeding complication and need for transfusion have decreased dramat‐ ically by this technique compare to TF approach. In the MORTAL (Mortality Benefit of Reduced Transfusion after PCI via the Arm or Leg) TR approach was associated with 50% reduction in blood transfusion rate, and 29% and 17% reduction in 30-day and one year mortality respectively (p<0.001) [33]. Although in the RIVAL study TR approach was superior to TF approach regarding access site complications (bleeding, hematoma, pseudoaneurysm, etc...), and the incidence of access site complications even in the presence of aggressive anticoagulant regimen were negligible, they concluded that both techniques are safe and effective [34]. ii) Early ambulation and hospital discharge of patients, decreasing hospital cost and increasing patient comfort and satisfaction are other advantages of TR approach over TF approach. In a meta- analysis of more than 20 randomized trials [23], TR approach reduced hospital stay by 0.4 day (95% CI 0.2-0.5, p=0.0001).

The most important disadvantages of TR approach are; the increasing radiation exposure of the operator, access failure and procedural failure, which is higher in comparison with the TF approach and absolutely depend to the operator's learning curve and skill.

#### **7.1. Post procedural hemostasis**

Because of the small size and superficiality of the radial artery, hemostasis can be achieved by manual compression. Usually the arterial sheath is removed at the catheterization laboratory at the end of procedure. Hemostasis is obtained by manual compression of the puncture site, and then compression is applied with a cotton pillow tourniquet or by using pressure bandage with elastic sticky straps. In any way the bandage is removed after 6 hours.

In the TF approach also the sheath is removed in the catheterization laboratory and hemostasis is obtained by manual compression, then a bandage and sandbag is applied proximal to the puncture site. The patient should be restricted to bed rest for at least 6 hours. In the case of extensive anticoagulation, vascular closure device can be used for hemostasis. However, in the presence of severe atherosclerosis and small diameter of the femoral artery closure device shouldn't be used.

## **8. Summary**

However; disadvantages of TF approach are: i) bleeding that is common in the setting of antiplatelet and anticoagulation therapy, that is usual in these patients, is the most important and prevalent complication of TF approach. Major bleeding results >3 fold increases in-hospital and one year mortality (odds ratio= 3.5) and re-infarction [32]. ii) Pseudoaneurysm, atriove‐ nous fistula and retroperitoneal hemorrhage are serious and life-threatening complication of this procedure. iii) Another disadvantageous of TF approach, albeit rare, is thromboembolic or ischemic events of lower extremities, that more often occurred in the presence of peripheral vascular disease or as a result of traumatization and/ dissection of iliac or illeofemoral arteries.

316 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

TR approach has gained popularity in recent years and is going to be the technique of choice in coronary angiography and even coronary intervention due to its advantages over TF

The advantages of TR approach over TF approach are; i) reduction of vascular complications in terms of hematomas, bleeding and etc…, even in the setting of acute coronary syndrome (ACS) and/ in patients receiving antithrombotic and antiplatelet therapies. Due to achieving easy hemostasis the bleeding complication and need for transfusion have decreased dramat‐ ically by this technique compare to TF approach. In the MORTAL (Mortality Benefit of Reduced Transfusion after PCI via the Arm or Leg) TR approach was associated with 50% reduction in blood transfusion rate, and 29% and 17% reduction in 30-day and one year mortality respectively (p<0.001) [33]. Although in the RIVAL study TR approach was superior to TF approach regarding access site complications (bleeding, hematoma, pseudoaneurysm, etc...), and the incidence of access site complications even in the presence of aggressive anticoagulant regimen were negligible, they concluded that both techniques are safe and effective [34]. ii) Early ambulation and hospital discharge of patients, decreasing hospital cost and increasing patient comfort and satisfaction are other advantages of TR approach over TF approach. In a meta- analysis of more than 20 randomized trials [23], TR approach reduced

The most important disadvantages of TR approach are; the increasing radiation exposure of the operator, access failure and procedural failure, which is higher in comparison with the TF

Because of the small size and superficiality of the radial artery, hemostasis can be achieved by manual compression. Usually the arterial sheath is removed at the catheterization laboratory at the end of procedure. Hemostasis is obtained by manual compression of the puncture site, and then compression is applied with a cotton pillow tourniquet or by using pressure bandage

In the TF approach also the sheath is removed in the catheterization laboratory and hemostasis is obtained by manual compression, then a bandage and sandbag is applied proximal to the puncture site. The patient should be restricted to bed rest for at least 6 hours. In the case of extensive anticoagulation, vascular closure device can be used for hemostasis. However, in

approach and absolutely depend to the operator's learning curve and skill.

with elastic sticky straps. In any way the bandage is removed after 6 hours.

approach.

hospital stay by 0.4 day (95% CI 0.2-0.5, p=0.0001).

**7.1. Post procedural hemostasis**

Both transfemoral and transradial techniques are safe, feasible and comparable techniques for cardiac catheterization, angiography and intervention. However, each of these two techniques has own applications and limitations. Although TF approach is dominant ap‐ proach worldwide, TR approach is going to be the technique of choice for coronary an‐ giography and percutaneous coronary intervention in the near future. TR approach reduces hospital stay, procedural cost and vascular complications and also increases pa‐ tients comfort and satisfaction. However, this approach needs more experience and great‐ er learning curve compare to TF approach. In another word, TF approach is the easier and more operator-friendly technique for catheterization and angiography; but with sub‐ stantial access site complications. On the other hand, TR approach is safer and more pa‐ tient-friendly technique for catheterization and angiography but it needs more experience and higher learning curve.

Case selection is mater in this regard. For example obese patients, patients with severe peripheral vascular disease and / severe musculoskeletal abnormalities and patients with coagulopathies or under aggressive anticoagulation are not good candidate for TF approach. The prefer approach for these patients is TR approach. On the other hand patients with abnormal Allen's test, patients who need simultaneous right and left heart catheterization and when insertion of a large sheath is needed are not good candidate for TR approach. The prefer approach for these patients is TF approach. Indeed these two vascular access techniques can be reconciled.

## **Author details**

Amir Farhang Zand Parsa

Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

### **References**


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[24] Souka H, Burkenham T. Management plan of post-angiography false aneurysm of

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[3] Karlsson S, Neichajev IA. Arterial anatomy of the upper extremity. Acta Radiol Di‐

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[8] Brueck M, Bandorski D, Kramer W, Wieczorek M, Holtgen R, Tillmans H. A random‐ ized comparison trasradial versus transfemoral approach for coronary angiography

[9] Allen E. Thromboangitis obliterans: methods of chronic occlusive arterial lesions dis‐

[10] Benit E, Vranckx P, Jaspers L, Jackmaer TR, Poelmans C, Coninx R. Frequency of a positive modified Allen's test in 1000 consecutive patients undergoing cardiac cathe‐

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[14] Sones FM Jr, Shirely EK. Cine coronary angiography. Mod Concepts Cardiovasc Dis

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[31] Caputo RR, Simons A, Giambartolomei A, Grant W, Fedele K, Abraham S, Rejer MJ, Walford GD, Esente P. Transradial cardiac catheterization in elderly patients. Cathet Cardivasc Interv 2000; 51: 287-90

**Chapter 16**

**Contrast-Induced Nephropathy**

Additional information is available at the end of the chapter

Diagnostic and therapeutic angiographic procedures are increasingly performed. Many complex interventions are lengthy and require large dosages of contrast medium (CM). Radiological procedures such as coronary angiography require intravascular administra‐ tion of iodinated CM is becoming a great source of an iatrogenic disease known as con‐ trast-induced nephropathy (CIN). The pathogenesis of CIN is unclear. The proposed mechanisms are outer-medullary hypoxia due to decreased renal blood flow secondary to renal artery vasoconstriction. Tubular obstruction, apoptosis and oxidative damage, endo‐ thelial dysfunction, defective prostaglandin synthesis, and autonomic dysfunction are oth‐

Patients who develop CIN have higher complication rates, longer hospital stays, and higher mortality than patients who not develop CIN. Nearly one-third of the patients who require in-hospital dialysis because of CIN die prior to discharge. No current treat‐ ment can reverse or ameliorate CIN once it occurs. The occurrence of CIN is directly re‐ lated to the number of pre-existing patient risk markers. After the high-risk patient population has been identified and risk markers addressed, the next step in preventing CIN is the use of different prophylactic therapies. The strongly associated risk markers for CIN are pre-existing renal failure, diabetes mellitus, age greater than 70 years, concur‐ rent use of nephrotoxic drugs, hypovolemia, use of a large amount of CM or an ionic hy‐

Aim of the present chapter is to summarize the knowledge about the risk factors and pro‐ phylactic treatments of CIN according to the ultimate clinical research and developments.

and reproduction in any medium, provided the original work is properly cited.

© 2013 Toprak; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

Omer Toprak

**1. Introduction**

er proposed mechanisms.

perosmolar CM, and congestive heart failure.

http://dx.doi.org/10.5772/54032


## **Chapter 16**

## **Contrast-Induced Nephropathy**

## Omer Toprak

[31] Caputo RR, Simons A, Giambartolomei A, Grant W, Fedele K, Abraham S, Rejer MJ, Walford GD, Esente P. Transradial cardiac catheterization in elderly patients. Cathet

320 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

[32] Fei T, Voeltz MD, Attubato MI, Lincoff AM, Chew DP, Bittl JA, Topol EJ, Manoukian SV. Predictors and impact of major hemorrhage on mortality following percutaneous

[33] Chase AJ, Fretz EB, Warburton WP, Klinke WP, Carere RG, Pi D, Berry B, Hilton JD. Association of the arterial access sites at angioplasty with transfusion and mortality study (mortality benefit of reduced transfusion after percutaneous coronary inter‐

[34] Jolly SS, Yusuf S, Cairns J, Neimelä K, Xarier D, Widimsky p, Budaj A, Neimelä M, Valentin V, Lewis BS, Avezum A, Step PG, Rao SV, Gao P, Afzal R, Joyner CD, Chro‐ lacius S, Mehta SR; RIVAL trial group. Radial versus femoral access for coronary an‐ giography and intervention in patients with acute coronary syndrome (RIVAL): a

randomized parallel group multicenter trial. Lancet 2011; 377:1409-20

coronary intervention from Replace-2 trial. Am J Cardiol 2007; 100: 1364-69

Cardivasc Interv 2000; 51: 287-90

vention via the arm or leg). Heart 2008, 91: 1019-25

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54032

## **1. Introduction**

Diagnostic and therapeutic angiographic procedures are increasingly performed. Many complex interventions are lengthy and require large dosages of contrast medium (CM). Radiological procedures such as coronary angiography require intravascular administra‐ tion of iodinated CM is becoming a great source of an iatrogenic disease known as con‐ trast-induced nephropathy (CIN). The pathogenesis of CIN is unclear. The proposed mechanisms are outer-medullary hypoxia due to decreased renal blood flow secondary to renal artery vasoconstriction. Tubular obstruction, apoptosis and oxidative damage, endo‐ thelial dysfunction, defective prostaglandin synthesis, and autonomic dysfunction are oth‐ er proposed mechanisms.

Patients who develop CIN have higher complication rates, longer hospital stays, and higher mortality than patients who not develop CIN. Nearly one-third of the patients who require in-hospital dialysis because of CIN die prior to discharge. No current treat‐ ment can reverse or ameliorate CIN once it occurs. The occurrence of CIN is directly re‐ lated to the number of pre-existing patient risk markers. After the high-risk patient population has been identified and risk markers addressed, the next step in preventing CIN is the use of different prophylactic therapies. The strongly associated risk markers for CIN are pre-existing renal failure, diabetes mellitus, age greater than 70 years, concur‐ rent use of nephrotoxic drugs, hypovolemia, use of a large amount of CM or an ionic hy‐ perosmolar CM, and congestive heart failure.

Aim of the present chapter is to summarize the knowledge about the risk factors and pro‐ phylactic treatments of CIN according to the ultimate clinical research and developments.

© 2013 Toprak; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **2. Definition of CIN**

A universally accepted definition of CIN does not exist. The most commonly used definition for CIN is the elevation of serum creatinine by ≥0.5mg/dl or ≥25% occurring within 48 hours after administration of CM, and the absence of an alternative etiology. Using the Cockcroft-Gault and the Modification of Diet in Renal Disease equations are useful in estimation of the GFR. Serum cystatin C has been proposed as an alternative endogenous marker of GFR showing higher correlation to standard clearance methods such as inulin or iohexol clear‐ ance. Serum cystatin C may detect CIN one to two days earlier than creatinine. Recent stud‐ ies documented that serum and urine neutrophil gelatinase-associated lipocalin is an early predictive biomarker of CIN (Shaker et al., 2010). Urinary interleukin 18 and urinary livertype fatty acid-binding protein are new potential biomarkers of CIN (Perrin et al., 2012). Cholesterol atheroemboli, volume depletion, and interstitial nephritis should consider in differential diagnosis of CIN. The incidence of CIN is reported to be 0.6-2.3% in general pop‐ ulation who do not have any risk factor for CIN, but the incidence can be increased to 90% in patients at high risk for CIN (Toprak, 2007).

#### **2.1. Pathophysiology of CIN**

The potential pathophysiologic mechanisms of CIN were summarized in Figure 1. Medul‐ lary hypoxia due to decreased renal blood flow secondary to renal artery vasoconstriction, tubular obstruction, direct tubular toxicity of the CM due to apoptosis, oxidative damage, endothelial dysfunction, and renal microcirculatory alterations may play a role in the patho‐ genesis of CIN.

F ree radicalsand e ndothelial dysfunction

Decrease of NO and prostaglandins

Release of adenosine and endothelin

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 323

Microvascular stasis

Renal vasoconstriction

Renal medullary Hypoxia

Contrast - induced Nephropathy

Specific factors that increase the risks for development of CIN are related to the patient, the

**Risk Factors Odds Ratio (95%CI) p Value**

Preprocedural creatinine 2.0-2.9 mg/dl 7.37 (4.78-11.39) <0.0001 Preprocedural creatinine ≥ 3mg/d 12.82 (8.01-20.54) <0.0001

R ed blood cell deformability

Increased viscosity

Contrast m edia

Intra - tubular precip itat ion of proteins

Tubular obstruction

Va cuolization, nec rosis, apoptosis

**Figure 1.** Pathogenesis of contrast-induced nephropathy. NO: nitric oxide.

contrast media, and the procedure (Table 1).

Direct toxic effect to proximal tubulus

**2.3. Risk Factors for CIN**

**Kidney Related Risk Factors** Pre-existing renal failure

Diabetes mellitus-Diabetic nephropathy

#### **2.2. Clinical course and outcomes**

CIN may range in severity from asymptomatic, nonoliguric transient renal dysfunction to oliguric severe renal failure that necessitates permanent dialysis. CIN is reported to be the third leading cause of in-hospital acute renal failure after hypotension and surgery. Approx‐ imately \$180 million is spent annually to manage CIN in the US. Dangas et al. showed that in-hospital outcomes such as death (6.3% vs 0.8%), cardiac death (4.0% vs 0.5%), coronary artery bypass grafting (5.8% vs 0.5%), major adverse cardiac event (9.3% vs 1.1%), packed red cell transfusion (28% vs 6%), vascular surgery of access site (5.6% vs 2.6%), post-proce‐ dure length of stay (6.8±7.1 vs 2.3±2.5) were significantly higher in CIN developed patients compare with control (p<0.0001). In cumulative one-year outcome death, out-of-hospital death and major adverse cardiac events were significantly higher in CIN developed patients (p<0.0001) (Dangas et al., 2005). In a study of acute myocardial infarction patients undergo‐ ing primary angioplasty, it was found that CIN developed patients have significantly higher incidence of high-rate atrial fibrillation (p=0.01), high-degree conduction disturbances re‐ quiring permanent pacemaker (p=0.04), acute pulmonary edema (p=0.008), respiratory fail‐ ure requiring mechanical ventilation (p<0.0001), cardiogenic shock requiring intra-aortic balloon (p<0.0001), and acute renal failure requiring renal replacement therapy (p<0.0001) (Marenzi et al., 2004).

**Figure 1.** Pathogenesis of contrast-induced nephropathy. NO: nitric oxide.

#### **2.3. Risk Factors for CIN**

**2. Definition of CIN**

in patients at high risk for CIN (Toprak, 2007).

**2.1. Pathophysiology of CIN**

**2.2. Clinical course and outcomes**

genesis of CIN.

(Marenzi et al., 2004).

A universally accepted definition of CIN does not exist. The most commonly used definition for CIN is the elevation of serum creatinine by ≥0.5mg/dl or ≥25% occurring within 48 hours after administration of CM, and the absence of an alternative etiology. Using the Cockcroft-Gault and the Modification of Diet in Renal Disease equations are useful in estimation of the GFR. Serum cystatin C has been proposed as an alternative endogenous marker of GFR showing higher correlation to standard clearance methods such as inulin or iohexol clear‐ ance. Serum cystatin C may detect CIN one to two days earlier than creatinine. Recent stud‐ ies documented that serum and urine neutrophil gelatinase-associated lipocalin is an early predictive biomarker of CIN (Shaker et al., 2010). Urinary interleukin 18 and urinary livertype fatty acid-binding protein are new potential biomarkers of CIN (Perrin et al., 2012). Cholesterol atheroemboli, volume depletion, and interstitial nephritis should consider in differential diagnosis of CIN. The incidence of CIN is reported to be 0.6-2.3% in general pop‐ ulation who do not have any risk factor for CIN, but the incidence can be increased to 90%

322 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The potential pathophysiologic mechanisms of CIN were summarized in Figure 1. Medul‐ lary hypoxia due to decreased renal blood flow secondary to renal artery vasoconstriction, tubular obstruction, direct tubular toxicity of the CM due to apoptosis, oxidative damage, endothelial dysfunction, and renal microcirculatory alterations may play a role in the patho‐

CIN may range in severity from asymptomatic, nonoliguric transient renal dysfunction to oliguric severe renal failure that necessitates permanent dialysis. CIN is reported to be the third leading cause of in-hospital acute renal failure after hypotension and surgery. Approx‐ imately \$180 million is spent annually to manage CIN in the US. Dangas et al. showed that in-hospital outcomes such as death (6.3% vs 0.8%), cardiac death (4.0% vs 0.5%), coronary artery bypass grafting (5.8% vs 0.5%), major adverse cardiac event (9.3% vs 1.1%), packed red cell transfusion (28% vs 6%), vascular surgery of access site (5.6% vs 2.6%), post-proce‐ dure length of stay (6.8±7.1 vs 2.3±2.5) were significantly higher in CIN developed patients compare with control (p<0.0001). In cumulative one-year outcome death, out-of-hospital death and major adverse cardiac events were significantly higher in CIN developed patients (p<0.0001) (Dangas et al., 2005). In a study of acute myocardial infarction patients undergo‐ ing primary angioplasty, it was found that CIN developed patients have significantly higher incidence of high-rate atrial fibrillation (p=0.01), high-degree conduction disturbances re‐ quiring permanent pacemaker (p=0.04), acute pulmonary edema (p=0.008), respiratory fail‐ ure requiring mechanical ventilation (p<0.0001), cardiogenic shock requiring intra-aortic balloon (p<0.0001), and acute renal failure requiring renal replacement therapy (p<0.0001)

Specific factors that increase the risks for development of CIN are related to the patient, the contrast media, and the procedure (Table 1).


*2.3.1. Patient-related risk factors*

*2.3.1.1. Pre-existing renal disease*

(McCullough et al., 1997).

*2.3.1.2. Diabetes mellitus*

The major risk factor for CIN is a GFR<60 ml/min/1.73 m2

slightly higher risk of CIN than the general population.

sociated with decreased vasodilatory response, which is important in developing CIN, and in patients with renal insufficiency, the clearance of CM is slower than in normal subjects. In a study of 7586 patients who underwent coronary intervention, CIN devel‐ oped in 22.4% of the patients who had serum creatinine levels of 2.0 to 2.9 mg/dl and in 30.6% of those with serum creatinine levels of 3.0 mg/dl or higher, compared with 2.4% of patients with serum creatinine levels <1.1 mg/dl ( Rihal et al., 2002). Two other stud‐ ies (Moore et al., 1992; Barrett et al., 1992) reported that the incidence of CIN increased from 4% to 20% as the baseline serum creatinine increased from 1.2 to 2.9 mg/dl. In an‐ other study, the incidence of CIN increased from 8% to 92% as the serum creatinine in‐ creased from 1.5 to 6.8 mg/dl. Furthermore, the probability of CIN requiring dialysis increases from 0.04% to 48% as the baseline GFR decreases from 50 to 10 ml/min

Nitric oxide-dependent renal vasodilatation is characteristically altered and renal outer medullary pO2 is significantly reduced in diabetes mellitus. Chronic kidney disease and DM are associated with endothelial dysfunction and decreased vasodilatory responses. Diabetic nephropathy has been identified as a powerful and independent risk factor for CIN. Patients with diabetic nephropathy and a mean serum creatinine of 6.8 mg/dl had a 92% incidence of CIN after coronary angiography (Weinrauch et al., 1977). Patients with diabetes who have advanced chronic renal failure because of causes other than diabetic nephropathy are at significantly higher risk of developing CIN like diabetic nephropathy. On the other hand, studies have shown that when pre-existing renal disease is present, patients with and without diabetes are similarly at risk of CIN, which correlates with the degree of renal disease. Some authors have suggested that DM in the absence of nephrop‐ athy, particularly in insulin-dependent patients with diabetes, is associated with an in‐ creased risk of CIN (McCullough et al., 1997; Toprak 2007). In a study, it was found that the incidence of CIN was rather low (2%) in patients with neither diabetes nor azotemia, significantly higher (16%) in individuals with diabetes but preserved renal function, and much higher (38%) in patients who had both diabetes and azotemia (Lautin et al., 1991). In another study, the incidence of CIN was found to be 2% in patients without diabetes and 3.7% in patients with diabetes with a baseline creatinine of 1.1 mg/dl or less (OR=1.86, p=0.005). When renal function is mildly impaired (serum creatinine level 1.2 to 1.9 mg/dl), the risk of CIN in patients with diabetes mellitus increases to 4.5% (OR=2.42, p<0.001) (Rihal et al., 2002). Other studies have failed to corroborate this connection (Par‐ frey et al., 1989). However, given that, those with diabetes alone were found to be at

. Chronic kidney disease is as‐

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 325


**Table 1.** Risk factors for the development of contrast-induced nephropathy

#### *2.3.1. Patient-related risk factors*

**Risk Factors Odds Ratio (95%CI) p Value** Preprocedural creatinine≤ 1.1mg/dl 1.86 (1.20-2.89) 0.005 Preprocedural creatinine 1.2-1.9 mg/dl 2.42 (1.54-3.79) <0.001

324 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Low effective circulatory volume 1.19 (0.72-1.95) 0.05

Class III-IV congestive heart failure 2.20 (1.60-2.90) <0.0001 Left ventricle ejection fraction<40% 1.57 (1.14-2.16) 0.005 Acute myocardial infarction ≤ 24 h 1.85 (1.31-2.63) 0.0006 Hypertension 2.00 (1.40-2.80) 0.0001 Periprocedural hypotension 2.50 (1.70-3.69) <0.00001 Multi-vessel coronary involvement 3.24 (1.07-9.82) 0.038 Peripheral vascular disease 1.90 (1.40-2.70) <0.0001 Preprocedure shock 1.19 (0.72-1.96) 0.05 Using intra-aortic balloon pump 15.51 (4.65-51.64) <0.0001 Bypass graft intervention 4.94 (1.16-20.9) 0.03 Time-to-reperfusion ≥6 h 2.51 (1.01-6.16) 0.04 Pulmonary edema 2.56 (1.42-4.52) 0.001

Age "/>75 years 5.28 (1.98-14.05) 0.0009 Female gender 1.4 (1.25-1.60) 0.0001

High total dose of contrast agent ("/>300 ml) 2.8 (1.17-6.68) 0.02

Short duration of two contrast administration 4.4 (2.9-6.5) <0.0001

Procedural success 0.27 (0.19-0.38) <0.0001 Baseline hematocrit 0.95 (0.92-0.97) <0.00001 Hyperuricemia 4.71 (1.29-17.21) 0.019 ACE inhibitors 3.37 (1.14-9.94) 0.028 Angiotensin Receptor Blockers 2.70 (1.25-5.81) 0.011 Metabolic Syndrome 426 (1.19-15.25) 0.026 Hypoalbuminemia 5.79 (1.71-19.64) 0.005

Osmolality (Low- vs. high-osmolality) 0.50 (0.36-0.68)

**Table 1.** Risk factors for the development of contrast-induced nephropathy

Use of nephrotoxic drugs

**Demographic Risk Factors**

**Other Possible Risk Factors**

Hypercholesterolemia Renal transplant Multiple myeloma

Intra-arterial contrast administration

Diuretics

Sepsis, cirrhosis

Contrast Media Related Risk Factors

**Cardiovascular System Related Risk Factors**

#### *2.3.1.1. Pre-existing renal disease*

The major risk factor for CIN is a GFR<60 ml/min/1.73 m2 . Chronic kidney disease is as‐ sociated with decreased vasodilatory response, which is important in developing CIN, and in patients with renal insufficiency, the clearance of CM is slower than in normal subjects. In a study of 7586 patients who underwent coronary intervention, CIN devel‐ oped in 22.4% of the patients who had serum creatinine levels of 2.0 to 2.9 mg/dl and in 30.6% of those with serum creatinine levels of 3.0 mg/dl or higher, compared with 2.4% of patients with serum creatinine levels <1.1 mg/dl ( Rihal et al., 2002). Two other stud‐ ies (Moore et al., 1992; Barrett et al., 1992) reported that the incidence of CIN increased from 4% to 20% as the baseline serum creatinine increased from 1.2 to 2.9 mg/dl. In an‐ other study, the incidence of CIN increased from 8% to 92% as the serum creatinine in‐ creased from 1.5 to 6.8 mg/dl. Furthermore, the probability of CIN requiring dialysis increases from 0.04% to 48% as the baseline GFR decreases from 50 to 10 ml/min (McCullough et al., 1997).

#### *2.3.1.2. Diabetes mellitus*

Nitric oxide-dependent renal vasodilatation is characteristically altered and renal outer medullary pO2 is significantly reduced in diabetes mellitus. Chronic kidney disease and DM are associated with endothelial dysfunction and decreased vasodilatory responses. Diabetic nephropathy has been identified as a powerful and independent risk factor for CIN. Patients with diabetic nephropathy and a mean serum creatinine of 6.8 mg/dl had a 92% incidence of CIN after coronary angiography (Weinrauch et al., 1977). Patients with diabetes who have advanced chronic renal failure because of causes other than diabetic nephropathy are at significantly higher risk of developing CIN like diabetic nephropathy. On the other hand, studies have shown that when pre-existing renal disease is present, patients with and without diabetes are similarly at risk of CIN, which correlates with the degree of renal disease. Some authors have suggested that DM in the absence of nephrop‐ athy, particularly in insulin-dependent patients with diabetes, is associated with an in‐ creased risk of CIN (McCullough et al., 1997; Toprak 2007). In a study, it was found that the incidence of CIN was rather low (2%) in patients with neither diabetes nor azotemia, significantly higher (16%) in individuals with diabetes but preserved renal function, and much higher (38%) in patients who had both diabetes and azotemia (Lautin et al., 1991). In another study, the incidence of CIN was found to be 2% in patients without diabetes and 3.7% in patients with diabetes with a baseline creatinine of 1.1 mg/dl or less (OR=1.86, p=0.005). When renal function is mildly impaired (serum creatinine level 1.2 to 1.9 mg/dl), the risk of CIN in patients with diabetes mellitus increases to 4.5% (OR=2.42, p<0.001) (Rihal et al., 2002). Other studies have failed to corroborate this connection (Par‐ frey et al., 1989). However, given that, those with diabetes alone were found to be at slightly higher risk of CIN than the general population.

#### *2.3.1.3. Pre-diabetes*

In a study of 421 patients who underwent coronary angiography with renal insufficiency, we presented that pre-DM increase the incidence of CIN 2.1-fold in comparison to patients with normal fasting glucose (NFG) but pre-DM is not as strong as DM as a risk of develop‐ ing CIN. CIN occurred in 20% of the DM (RR=3.6, p=0.001), 11.4% of the pre-DM (RR 2.1, p=0.314) and 5.5% of the NFG group. The decrease of GFR was higher in DM and pre-DM (p=0.001 and p=0.002, respectively). Length of hospital stay was 2.45 ± 1.45 day in DM, 2.27 ± 0.68 day in pre-DM, and 1.97 ± 0.45 day in NFG (p<0.001, DM vs. NFG and p=0.032, pre-DM vs. NFG). The rate of major adverse cardiac events was 8.7% in DM, 5% in pre-DM, and 2.1% in NFG (*P*=0.042, DM vs. NFG). Hemodialysis was required in 3.6% of DM, and 0.7% in pre-DM (*P*=0.036, DM vs. NFG), and the total number of hemodialysis sessions during 3 months was higher in DM and pre-DM (*P*<0.001). Serum glucose ≥124 mg/dl was the best cut-off point for prediction of CIN (Toprak et al., 2007).

*2.3.1.7. Multivessel Coronary involvement, peripheral vascular disease, and renal artery stenosis*

ment is a risk for CIN (OR=3.24, p=0.038) (Toprak et al., 2006).

gender as an independent risk factor for CIN (Rudnick et al., 1995).

*2.3.1.8. Older age*

in elderly patients.

*2.3.1.9. Gender*

If a patient has multivessel coronary involvement, the other vessels in the body, such as the renal artery, can be involved. If the renal artery is involved, the renal blood supply may decrease and the kidneys may be more susceptible to CIN. Factors related to acceler‐ ated or diffuse atherosclerosis are linked to the development of CIN. The treatment of multivessel disease, challenging chronic total occlusions and extensively diseased coro‐ nary segments, may require high doses of CM for providing an optimal image quality, thus enhancing the potential toxic effects on the renal function. In a study of 177 patients who underwent cardiac catheterization, subjects were also evaluated for renal artery stenosis. Coronary artery disease was detected in 110 patients (62%), and significant renal artery stenosis was detected in 19 patients (11%). Using multivariate analysis, it was found that the extent of coronary artery disease was an independent predictor of renal ar‐ tery stenosis (Weber-Mzell et al., 2002). In a study a total of 5571 patients who under‐ went PCI were evaluated for CIN risk factors, and it was found that multivessel coronary involvement was only a univariate predictor of CIN (p=0.003) (Mehran et al., 2004). In two other cohort studies it was found that peripheral vascular disease is a risk for CIN in patients who underwent PCI (OR=1.9, p<0.0001 and OR=1.71, p=0.001, respectively) (Bar‐ tholomew et al., 2004; Rihal et al., 2002). In a study a total of 219 non-diabetic patients who underwent coronary angiography we have found that multivessel coronary involve‐

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 327

In a prospective study in which elderly patients (≥70 years) were subjected to cardiac cathe‐ terization, 11% developed CIN (Rich & Crecelius, 1990). In another study, CIN incidence was 17% in elderly patients (>60 years) as compared with 4% in younger patients (Kohli et al., 2000). In 208 patients with acute myocardial infarction who underwent coronary inter‐ vention, it was found that an age of ≥75 years was an independent risk for CIN (OR=5.28, p=0.0009) (Marenzi et al., 2004). The possible reasons of the high incidence of CIN in elderly were age-related changes in renal function, more difficult vascular access following tortuosi‐ ty, calcification of the vessels requiring greater amount of CM, defective prostaglandin syn‐ thesis, and the presence of renovascular disease. Furthermore, hypovolemia is very common

Ovarian hormones can affect the renin–angiotensin system and renal blood flow. In a retro‐ spective study of 8628 patients who underwent PCI, female sex was an independent predic‐ tor of CIN (OR=1.4, p<0.0001). One-year outcome analyses by gender showed a higher mortality among females than among males in a cohort of CIN patients (14% vs 10%, p=0.05) (Iakovou et al., 2003). The findings of this study contradict those of a previous randomized controlled trial of ionic vs nonionic CM, in which a multivariate analysis identified male

#### *2.3.1.4. Metabolic syndrome, impaired fasting glucose and hypertriglyceridemia*

In a prospective cohort study of 219 non-diabetic elderly patients with reduced kidney func‐ tion who underwent elective coronary angiography, we reported that metabolic syndrome was a risk indicator of CIN (OR=4.26, p=0.026). CIN occurred in 14% of the metabolic syn‐ drome group and 3.6% of the non-metabolic syndrome group (relative risk 3.93, p=0.007). Impaired fasting glucose (OR=4.72, p=0.007), high triglyceride (OR=4.06, p=0.022); and multivessel involvement (OR=3.24, p=0.038) in the metabolic syndrome group were predictors of CIN (Toprak et al., 2006).

#### *2.3.1.5. Hyperuricemia*

Contrast agents have a uricosuric effect, which appears to be caused by enhanced renal tub‐ ular secretion of uric acid. Furthermore, hyperuricemia is accompanied by enhanced synthe‐ sis of reactive oxygen species, tubular obstruction by uric acid, an activated renin– angiotensin–aldosterone system, increased endothelin-1, and an inhibited nitric oxide sys‐ tem which plays a role in the pathogenesis of CIN. In a prospective cohort study we evaluat‐ ed 266 patients who undergoing elective coronary angiography and we found that patients with hyperuricemia are at risk of developing CIN (OR=4.71, p=0.019). CIN occurred in 15.1% of the hyperuricemic group and 2.9% of the normouricemic group (p<0.001). Length of hos‐ pital stay (p<0.001) and CIN requiring renal replacement therapy (p=0.017) were significant‐ ly higher in hyperuricemic group. Serum uric acid ≥7 mg/dl in males and ≥5.9 mg/dl in females were found the best cut-off value for prediction of CIN (Toprak et al., 2006).

#### *2.3.1.6. Hypercholesterolemia*

Altered nitric oxide-dependent renal vasodilatation is prevalent in hypercholesterolemia. Hypercholesterolemia aggravates CIN through the reduced production of nitric oxide (Yang et al., 2004).

#### *2.3.1.7. Multivessel Coronary involvement, peripheral vascular disease, and renal artery stenosis*

If a patient has multivessel coronary involvement, the other vessels in the body, such as the renal artery, can be involved. If the renal artery is involved, the renal blood supply may decrease and the kidneys may be more susceptible to CIN. Factors related to acceler‐ ated or diffuse atherosclerosis are linked to the development of CIN. The treatment of multivessel disease, challenging chronic total occlusions and extensively diseased coro‐ nary segments, may require high doses of CM for providing an optimal image quality, thus enhancing the potential toxic effects on the renal function. In a study of 177 patients who underwent cardiac catheterization, subjects were also evaluated for renal artery stenosis. Coronary artery disease was detected in 110 patients (62%), and significant renal artery stenosis was detected in 19 patients (11%). Using multivariate analysis, it was found that the extent of coronary artery disease was an independent predictor of renal ar‐ tery stenosis (Weber-Mzell et al., 2002). In a study a total of 5571 patients who under‐ went PCI were evaluated for CIN risk factors, and it was found that multivessel coronary involvement was only a univariate predictor of CIN (p=0.003) (Mehran et al., 2004). In two other cohort studies it was found that peripheral vascular disease is a risk for CIN in patients who underwent PCI (OR=1.9, p<0.0001 and OR=1.71, p=0.001, respectively) (Bar‐ tholomew et al., 2004; Rihal et al., 2002). In a study a total of 219 non-diabetic patients who underwent coronary angiography we have found that multivessel coronary involve‐ ment is a risk for CIN (OR=3.24, p=0.038) (Toprak et al., 2006).

#### *2.3.1.8. Older age*

*2.3.1.3. Pre-diabetes*

CIN (Toprak et al., 2006).

*2.3.1.6. Hypercholesterolemia*

et al., 2004).

*2.3.1.5. Hyperuricemia*

In a study of 421 patients who underwent coronary angiography with renal insufficiency, we presented that pre-DM increase the incidence of CIN 2.1-fold in comparison to patients with normal fasting glucose (NFG) but pre-DM is not as strong as DM as a risk of develop‐ ing CIN. CIN occurred in 20% of the DM (RR=3.6, p=0.001), 11.4% of the pre-DM (RR 2.1, p=0.314) and 5.5% of the NFG group. The decrease of GFR was higher in DM and pre-DM (p=0.001 and p=0.002, respectively). Length of hospital stay was 2.45 ± 1.45 day in DM, 2.27 ± 0.68 day in pre-DM, and 1.97 ± 0.45 day in NFG (p<0.001, DM vs. NFG and p=0.032, pre-DM vs. NFG). The rate of major adverse cardiac events was 8.7% in DM, 5% in pre-DM, and 2.1% in NFG (*P*=0.042, DM vs. NFG). Hemodialysis was required in 3.6% of DM, and 0.7% in pre-DM (*P*=0.036, DM vs. NFG), and the total number of hemodialysis sessions during 3 months was higher in DM and pre-DM (*P*<0.001). Serum glucose ≥124 mg/dl was the best

326 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

In a prospective cohort study of 219 non-diabetic elderly patients with reduced kidney func‐ tion who underwent elective coronary angiography, we reported that metabolic syndrome was a risk indicator of CIN (OR=4.26, p=0.026). CIN occurred in 14% of the metabolic syn‐ drome group and 3.6% of the non-metabolic syndrome group (relative risk 3.93, p=0.007). Impaired fasting glucose (OR=4.72, p=0.007), high triglyceride (OR=4.06, p=0.022); and multivessel involvement (OR=3.24, p=0.038) in the metabolic syndrome group were predictors of

Contrast agents have a uricosuric effect, which appears to be caused by enhanced renal tub‐ ular secretion of uric acid. Furthermore, hyperuricemia is accompanied by enhanced synthe‐ sis of reactive oxygen species, tubular obstruction by uric acid, an activated renin– angiotensin–aldosterone system, increased endothelin-1, and an inhibited nitric oxide sys‐ tem which plays a role in the pathogenesis of CIN. In a prospective cohort study we evaluat‐ ed 266 patients who undergoing elective coronary angiography and we found that patients with hyperuricemia are at risk of developing CIN (OR=4.71, p=0.019). CIN occurred in 15.1% of the hyperuricemic group and 2.9% of the normouricemic group (p<0.001). Length of hos‐ pital stay (p<0.001) and CIN requiring renal replacement therapy (p=0.017) were significant‐ ly higher in hyperuricemic group. Serum uric acid ≥7 mg/dl in males and ≥5.9 mg/dl in

females were found the best cut-off value for prediction of CIN (Toprak et al., 2006).

Altered nitric oxide-dependent renal vasodilatation is prevalent in hypercholesterolemia. Hypercholesterolemia aggravates CIN through the reduced production of nitric oxide (Yang

cut-off point for prediction of CIN (Toprak et al., 2007).

*2.3.1.4. Metabolic syndrome, impaired fasting glucose and hypertriglyceridemia*

In a prospective study in which elderly patients (≥70 years) were subjected to cardiac cathe‐ terization, 11% developed CIN (Rich & Crecelius, 1990). In another study, CIN incidence was 17% in elderly patients (>60 years) as compared with 4% in younger patients (Kohli et al., 2000). In 208 patients with acute myocardial infarction who underwent coronary inter‐ vention, it was found that an age of ≥75 years was an independent risk for CIN (OR=5.28, p=0.0009) (Marenzi et al., 2004). The possible reasons of the high incidence of CIN in elderly were age-related changes in renal function, more difficult vascular access following tortuosi‐ ty, calcification of the vessels requiring greater amount of CM, defective prostaglandin syn‐ thesis, and the presence of renovascular disease. Furthermore, hypovolemia is very common in elderly patients.

#### *2.3.1.9. Gender*

Ovarian hormones can affect the renin–angiotensin system and renal blood flow. In a retro‐ spective study of 8628 patients who underwent PCI, female sex was an independent predic‐ tor of CIN (OR=1.4, p<0.0001). One-year outcome analyses by gender showed a higher mortality among females than among males in a cohort of CIN patients (14% vs 10%, p=0.05) (Iakovou et al., 2003). The findings of this study contradict those of a previous randomized controlled trial of ionic vs nonionic CM, in which a multivariate analysis identified male gender as an independent risk factor for CIN (Rudnick et al., 1995).

#### *2.3.1.10. Hypovolemia*

Hypovolemia leads to active sodium reabsorbtion, which is an oxygen-demanding process, and increases neurohumoral vasoconstrictive stimuli that might compromise medullary oxygenation. The toxic effects of CM on the renal tubular lumen may be exacerbated in hy‐ povolemia. Decreased effective circulating volume and reduced renal perfusion potentiate renal vasoconstriction after administration of intravascular CM. Volume expansion reduces the activity of the renin–angiotensin system, minimizes increases in blood viscosity and os‐ molality, and increases medullary perfusion. At present the most convincing preventive procedure of CIN is adequate hydration with isotonic saline or sodium bicarbonate. Before coronary angiography, the volume status of patients can be assessed through the inferior vena cava index, mean atrial pressure, noninvasive pulmonary-capillary wedge pressure or bioimpedance spectroscopy (Toprak & Cirit, 2005).

intensify medullary hypoxia, and cisplatin can attach to sulfhydryl groups. Mannitol can in‐ crease the metabolic workload in the kidney, and amphotericin B can cause the effect of a combination of mannitol and cyclosporine A. Nonselective NSAIDs and selective COX-2 in‐ hibitors decrease the vasodilatory prostaglandins in the kidney and potentiate the vasocon‐

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 329

Patients who are receiving metformin may develop lactic acidosis as a result of CIN. A de‐ cline in renal function after contrast exposure could adversely affect the clearance of metfor‐ min. The complication was almost always observed in diabetic patients with decreased renal function before injection of CM. A meta-analysis by the Cochrane Library with pooled data from 176 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 35,619 patient-years of metformin use or in 30,002 patients-years in the non-met‐ formin group. It seems safer to instruct patients especially at high risk for CIN not to take this drug for 48 h or so after CM administration and resume taking the drug only if there are

ACE inhibitors have been identified as a risk factor for CIN because of their potential to re‐ duce renal function. On the other hand, some small studies have shown that the nephrotox‐ icity of CM may be reduced because of decreased renal vasoconstriction by inhibition of angiotensin II. Renal vasoconstriction occurs after the CM administration and the renin–an‐ giotensin system is responsible for this vasoconstriction. In a randomized controlled study with 71 patients with diabetes who underwent coronary angiography randomized to capto‐ pril or control, 25-mg captopril was given three times daily. There was a significant decrease in CIN in the patients who received captopril compared with the control group (6% vs 29%, respectively, p<0.02) (Gupta et al., 1999). We have performed a randomized controlled study in 80 patients with serum creatinine below 2 mg/dl who underwent coronary angiography. Captopril was administered in 48 patients before coronary angiography. Five patients (10.4%) in the captopril group developed CIN, compared with only one patient (3.1%) in the control group (p=0.02) (Toprak et al., 2003). In a study of 230 patients with renal insufficien‐ cy and age ≥65 years we found that chronic ACE inhibitor administration was a risk for de‐ veloping CIN. CIN occurred in 17 patients (15.6%) in the ACE inhibitor group and 7 patients (5.8%) in the control group (p=0.015). Serum creatinine level increased from 1.34 ± 0.20 to 1.53 ± 0.27 mg/dl in the ACE inhibitor group and from 1.33 ± 0.18 to 1.45 ± 0.19 mg/dl in the control group (p<0.001). Chronic ACE inhibitor administration was a risk indicator of CIN (OR=3.37, p=0.028) (Cirit et al., 2006). In another study, 421 patients with renal insufficiency who underwent coronary angiography, use of ACE inhibitors or ARB was a risk for CIN in multivariate analysis (OR=2.7, p=0.011) (Toprak et al., 2007). In a recent study, the impact of renin-angiotensin and aldosterone system blockade on the frequency of CIN was assessed retrospectively. Patients treated with ACE inhibitors or ARB (n=269) and were not treated with them (n=143) underwent coronary angiography included to the study. CIN developed

strictive effect of CM.

no signs of nephrotoxicity.

*2.3.1.15. ACE inhibitors and angiotensin receptor blockers*

*2.3.1.14. Metformin*

#### *2.3.1.11. Congestive heart failure and reduced left ventricular ejection fraction*

Advanced heart failure and reduced LVEF are characterized by effective volume depletion caused by low cardiac output and increased neurohumoral vasoconstrictive stimuli and im‐ paired nitric oxide-dependent renal vasodilatation that might compromise medullary oxy‐ genation. Studies have shown that reduced left ventricular ejection fraction (LVEF) (≤49%) and advanced congestive heart failure (New York Heart Association class III or IV) are inde‐ pendent risk factors for CIN. In a study, Dangas et al. showed that LVEF below 40% is an independent predictor of CIN (Dangas et al., 2005). We have previously reported that if the LVEF is greater than 30%, this condition does not show any significant effect on the devel‐ opment of CIN (Toprak et al., 2003). In a study it was shown that congestive heart failure was an independent risk for CIN (OR=1.53, p=0.007) (Rihal et al., 2002). In a cohort study it was found that congestive heart failure is a risk for CIN in patients who underwent PCI (OR=2.2, p<0.0001) (Bartholomew et al., 2004).

#### *2.3.1.12. Hypertension*

An explanation for hypertension as a risk factor for CIN is: alterations in the intrarenal ex‐ pression of vasoactive mediators, such as the renin-angiotensin system or nitric oxide, may be contributing factors. Impaired nitric oxide-dependent renal vasodilatation is prevalent in individuals who are hypertensive. Finally, a reduced number of nephrons could predispose hypertensive patients to CIN. In a study of 8628 patients who underwent percutaneous in‐ terventions, hypertension was found to be an independent predictor of CIN (OR=1.2, p=0.0035). In a cohort study Bartholomew et al. found that hypertension is a risk for CIN in patients who underwent PCI (OR=2.0, p=0.0001) (Bartholomew et al., 2004).

#### *2.3.1.13. Nephrotoxic drugs*

Directly, nephrotoxic drugs and those that inhibit the vasodilatory effects of prostaglandins have been reported to render the kidney more vulnerable to CM. Sulfonamides, aminogly‐ cosides, and their combinations with furosemide are particularly potent. Cyclosporin A may intensify medullary hypoxia, and cisplatin can attach to sulfhydryl groups. Mannitol can in‐ crease the metabolic workload in the kidney, and amphotericin B can cause the effect of a combination of mannitol and cyclosporine A. Nonselective NSAIDs and selective COX-2 in‐ hibitors decrease the vasodilatory prostaglandins in the kidney and potentiate the vasocon‐ strictive effect of CM.

#### *2.3.1.14. Metformin*

*2.3.1.10. Hypovolemia*

bioimpedance spectroscopy (Toprak & Cirit, 2005).

(OR=2.2, p<0.0001) (Bartholomew et al., 2004).

*2.3.1.12. Hypertension*

*2.3.1.13. Nephrotoxic drugs*

*2.3.1.11. Congestive heart failure and reduced left ventricular ejection fraction*

Hypovolemia leads to active sodium reabsorbtion, which is an oxygen-demanding process, and increases neurohumoral vasoconstrictive stimuli that might compromise medullary oxygenation. The toxic effects of CM on the renal tubular lumen may be exacerbated in hy‐ povolemia. Decreased effective circulating volume and reduced renal perfusion potentiate renal vasoconstriction after administration of intravascular CM. Volume expansion reduces the activity of the renin–angiotensin system, minimizes increases in blood viscosity and os‐ molality, and increases medullary perfusion. At present the most convincing preventive procedure of CIN is adequate hydration with isotonic saline or sodium bicarbonate. Before coronary angiography, the volume status of patients can be assessed through the inferior vena cava index, mean atrial pressure, noninvasive pulmonary-capillary wedge pressure or

328 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Advanced heart failure and reduced LVEF are characterized by effective volume depletion caused by low cardiac output and increased neurohumoral vasoconstrictive stimuli and im‐ paired nitric oxide-dependent renal vasodilatation that might compromise medullary oxy‐ genation. Studies have shown that reduced left ventricular ejection fraction (LVEF) (≤49%) and advanced congestive heart failure (New York Heart Association class III or IV) are inde‐ pendent risk factors for CIN. In a study, Dangas et al. showed that LVEF below 40% is an independent predictor of CIN (Dangas et al., 2005). We have previously reported that if the LVEF is greater than 30%, this condition does not show any significant effect on the devel‐ opment of CIN (Toprak et al., 2003). In a study it was shown that congestive heart failure was an independent risk for CIN (OR=1.53, p=0.007) (Rihal et al., 2002). In a cohort study it was found that congestive heart failure is a risk for CIN in patients who underwent PCI

An explanation for hypertension as a risk factor for CIN is: alterations in the intrarenal ex‐ pression of vasoactive mediators, such as the renin-angiotensin system or nitric oxide, may be contributing factors. Impaired nitric oxide-dependent renal vasodilatation is prevalent in individuals who are hypertensive. Finally, a reduced number of nephrons could predispose hypertensive patients to CIN. In a study of 8628 patients who underwent percutaneous in‐ terventions, hypertension was found to be an independent predictor of CIN (OR=1.2, p=0.0035). In a cohort study Bartholomew et al. found that hypertension is a risk for CIN in

Directly, nephrotoxic drugs and those that inhibit the vasodilatory effects of prostaglandins have been reported to render the kidney more vulnerable to CM. Sulfonamides, aminogly‐ cosides, and their combinations with furosemide are particularly potent. Cyclosporin A may

patients who underwent PCI (OR=2.0, p=0.0001) (Bartholomew et al., 2004).

Patients who are receiving metformin may develop lactic acidosis as a result of CIN. A de‐ cline in renal function after contrast exposure could adversely affect the clearance of metfor‐ min. The complication was almost always observed in diabetic patients with decreased renal function before injection of CM. A meta-analysis by the Cochrane Library with pooled data from 176 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 35,619 patient-years of metformin use or in 30,002 patients-years in the non-met‐ formin group. It seems safer to instruct patients especially at high risk for CIN not to take this drug for 48 h or so after CM administration and resume taking the drug only if there are no signs of nephrotoxicity.

#### *2.3.1.15. ACE inhibitors and angiotensin receptor blockers*

ACE inhibitors have been identified as a risk factor for CIN because of their potential to re‐ duce renal function. On the other hand, some small studies have shown that the nephrotox‐ icity of CM may be reduced because of decreased renal vasoconstriction by inhibition of angiotensin II. Renal vasoconstriction occurs after the CM administration and the renin–an‐ giotensin system is responsible for this vasoconstriction. In a randomized controlled study with 71 patients with diabetes who underwent coronary angiography randomized to capto‐ pril or control, 25-mg captopril was given three times daily. There was a significant decrease in CIN in the patients who received captopril compared with the control group (6% vs 29%, respectively, p<0.02) (Gupta et al., 1999). We have performed a randomized controlled study in 80 patients with serum creatinine below 2 mg/dl who underwent coronary angiography. Captopril was administered in 48 patients before coronary angiography. Five patients (10.4%) in the captopril group developed CIN, compared with only one patient (3.1%) in the control group (p=0.02) (Toprak et al., 2003). In a study of 230 patients with renal insufficien‐ cy and age ≥65 years we found that chronic ACE inhibitor administration was a risk for de‐ veloping CIN. CIN occurred in 17 patients (15.6%) in the ACE inhibitor group and 7 patients (5.8%) in the control group (p=0.015). Serum creatinine level increased from 1.34 ± 0.20 to 1.53 ± 0.27 mg/dl in the ACE inhibitor group and from 1.33 ± 0.18 to 1.45 ± 0.19 mg/dl in the control group (p<0.001). Chronic ACE inhibitor administration was a risk indicator of CIN (OR=3.37, p=0.028) (Cirit et al., 2006). In another study, 421 patients with renal insufficiency who underwent coronary angiography, use of ACE inhibitors or ARB was a risk for CIN in multivariate analysis (OR=2.7, p=0.011) (Toprak et al., 2007). In a recent study, the impact of renin-angiotensin and aldosterone system blockade on the frequency of CIN was assessed retrospectively. Patients treated with ACE inhibitors or ARB (n=269) and were not treated with them (n=143) underwent coronary angiography included to the study. CIN developed 11.9% in ACE-inhibitor using group and 4.2% in control group (p=0.006). Use of ARB or ACE inhibitors was found as a risk for CIN (OR=3.08, p=0.016) (Kiski et al., 2010). Checking the use of ACE inhibitors or ARB before coronary angiography seems to be a useful guide in tracking risk assessment for CIN. It is reasonable to suggest that there is a need to hold ACE inhibitor or ARB use before coronary angiography.

between low hematocrit levels and CIN has been investigated in a prospective study of 6773 patients who underwent PCI (Nikolsky et al., 2005). A lower baseline hematocrit was an in‐ dependent predictor of CIN; and each 3% decrease in baseline hematocrit resulted in a sig‐ nificant increase in the odds of CIN in patients with and without chronic kidney disease (11% and 23%, respectively). Dangas et al. showed that the baseline hematocrit level is an independent predictor of CIN in patients with chronic kidney disease (OR=0.95, p<0.00001)

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 331

Hypoalbuminemia impairs endothelial function, enhances renal vasoconstriction, impairs the synthesis and release of nitric oxide, and decreases antioxidant enzyme activity. In a study, low serum albumin (<3.5 g/dl) was identified as a risk factor for CIN in patients 70 years of age or older who underwent cardiac catheterization (Rich, et al., 1990). Also we have found that in 230 patients who underwent coronary angiography with renal in‐ sufficiency, serum albumin level ≤3.5 g/dl was a risk factor for CIN (OR=5.79, p=0.005)

A systolic blood pressure of less than 80 mm Hg for at least 1 h that requires inotropic support with medications is a risk factor for CIN. A study by Dangas et al showed that periprocedural hypotension and pulmonary edema are independent predictors of CIN in patients with chronic kidney disease (OR=2.50, p<0.00001 and OR=2.56, p=0.001, respec‐ tively) (Dangas et al., 2005) Sepsis, through direct damage by bacterial toxins to renal tu‐ bules and impairment of circulation, has also been reported as a risk factor. Reduction of effective intravascular volume caused by liver cirrhosis has been reported as contribu‐ ting to pre-renal reduction in renal perfusion, thus enhancing the ischemic insult of CM

*2.3.2.1. Short duration of the two contrast administration and urgent/emergency procedure*

In those who have no risk factors for CIN, angiography should be delayed more than 48 hours after a previous exposure to intravascular contrast media. In patients with diabetes or preexisting renal disease, this time interval should be increased to more than 72 hours. In a cohort study, urgent/emergency procedure was found as a predictor of CIN (OR=4, p<0.0001) (Bartholomew et al., 2004). The higher risk of developing CIN in patients with ur‐

Using intra-aortic balloon pump may signify a very high-risk population due to very se‐ vere coronary atherosclerosis and/or indicate a role of atheroembolism. In 208 consecu‐

(Dangas et al., 2005).

(Cirit et al., 2006).

(Toprak, 2007).

*2.3.2. Procedure-related risk factors*

*2.3.2.2. Use of intra-aortic balloon pump*

*2.3.1.21. Hypotension, sepsis, cirrhosis, and pulmonary edema*

gent status was irrespective of baseline renal function.

*2.3.1.20. Low serum albumin*

#### *2.3.1.16. Multiple myeloma*

Multiple myeloma has been suggested as a potential risk factor for CIN. The pathomechan‐ ism of this process has been explained by the precipitation of CM molecules together with Tamm–Horsfall proteins and other abnormal proteins, tubular epithelial cells damaged and desquamated as a result of ischemia, direct contrast toxicity, or disturbed function of integ‐ rins. Intratubular light chains, particularly in the setting of intravascular volume depletion, have been found to augment the nephrotoxic potential of CM (Holland et al., 1985). Studies with a broader scope have since shown that the observed risk is linked to coexisting risk fac‐ tors, such as pre-existing renal insufficiency, low circulating volume, proteinuria, amyloido‐ sis, hyperuricemia, and hypercalcemia rather than to myeloma itself. Studies showed an incidence of CIN of only 0.6–1.25% in patients with myeloma if dehydration is avoided (Mc‐ Carthy & Becker, 1992).

#### *2.3.1.17. Renal transplantation*

Patients with renal transplantation may be at a higher risk of CIN due to concomitant use of cyclosporine and higher prevalence of diabetes and renal insufficiency. In a study, 33 pa‐ tients with a functioning renal allograft who underwent different contrast studies, the inci‐ dence of CIN was 21.2% (Ahuja et al., 2000).

#### *2.3.1.18. Acute myocardial infarction*

A study by Rihal et al. showed that acute myocardial infarction within 24 h before adminis‐ tration of the CM is a risk factor for CIN (OR=1.85, p=0.0006). This study demonstrates that CIN is a frequent complication in acute myocardial infarction, even in patients with a nor‐ mal baseline renal function. (Rihal et al., 2002). In a study of 208 acute myocardial infarction patients who underwent primary PCI, anterior acute myocardial infarction was significantly higher in patients who developed CIN (p=0.0015). However, in multivariate analysis, anteri‐ or acute myocardial infarction (OR=2.17, p=0.09) was not a risk for CIN (Marenzi et al., 2004). In 2082 percutaneous interventions for acute myocardial infarction, it was reported a more than seven-fold (3.2% vs 23.3%) increase in 1-year mortality in patients who developed CIN (Sadeghi et al., 2003).

#### *2.3.1.19. Anemia*

Anemia-induced deterioration of renal ischemia may be one plausible explanation for the higher incidence of CIN in patients with a low hematocrit level. A baseline hematocrit value of less than 39% for men and less than 36% for women is a risk for CIN. The relationship between low hematocrit levels and CIN has been investigated in a prospective study of 6773 patients who underwent PCI (Nikolsky et al., 2005). A lower baseline hematocrit was an in‐ dependent predictor of CIN; and each 3% decrease in baseline hematocrit resulted in a sig‐ nificant increase in the odds of CIN in patients with and without chronic kidney disease (11% and 23%, respectively). Dangas et al. showed that the baseline hematocrit level is an independent predictor of CIN in patients with chronic kidney disease (OR=0.95, p<0.00001) (Dangas et al., 2005).

#### *2.3.1.20. Low serum albumin*

11.9% in ACE-inhibitor using group and 4.2% in control group (p=0.006). Use of ARB or ACE inhibitors was found as a risk for CIN (OR=3.08, p=0.016) (Kiski et al., 2010). Checking the use of ACE inhibitors or ARB before coronary angiography seems to be a useful guide in tracking risk assessment for CIN. It is reasonable to suggest that there is a need to hold ACE

330 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Multiple myeloma has been suggested as a potential risk factor for CIN. The pathomechan‐ ism of this process has been explained by the precipitation of CM molecules together with Tamm–Horsfall proteins and other abnormal proteins, tubular epithelial cells damaged and desquamated as a result of ischemia, direct contrast toxicity, or disturbed function of integ‐ rins. Intratubular light chains, particularly in the setting of intravascular volume depletion, have been found to augment the nephrotoxic potential of CM (Holland et al., 1985). Studies with a broader scope have since shown that the observed risk is linked to coexisting risk fac‐ tors, such as pre-existing renal insufficiency, low circulating volume, proteinuria, amyloido‐ sis, hyperuricemia, and hypercalcemia rather than to myeloma itself. Studies showed an incidence of CIN of only 0.6–1.25% in patients with myeloma if dehydration is avoided (Mc‐

Patients with renal transplantation may be at a higher risk of CIN due to concomitant use of cyclosporine and higher prevalence of diabetes and renal insufficiency. In a study, 33 pa‐ tients with a functioning renal allograft who underwent different contrast studies, the inci‐

A study by Rihal et al. showed that acute myocardial infarction within 24 h before adminis‐ tration of the CM is a risk factor for CIN (OR=1.85, p=0.0006). This study demonstrates that CIN is a frequent complication in acute myocardial infarction, even in patients with a nor‐ mal baseline renal function. (Rihal et al., 2002). In a study of 208 acute myocardial infarction patients who underwent primary PCI, anterior acute myocardial infarction was significantly higher in patients who developed CIN (p=0.0015). However, in multivariate analysis, anteri‐ or acute myocardial infarction (OR=2.17, p=0.09) was not a risk for CIN (Marenzi et al., 2004). In 2082 percutaneous interventions for acute myocardial infarction, it was reported a more than seven-fold (3.2% vs 23.3%) increase in 1-year mortality in patients who developed

Anemia-induced deterioration of renal ischemia may be one plausible explanation for the higher incidence of CIN in patients with a low hematocrit level. A baseline hematocrit value of less than 39% for men and less than 36% for women is a risk for CIN. The relationship

inhibitor or ARB use before coronary angiography.

*2.3.1.16. Multiple myeloma*

Carthy & Becker, 1992).

*2.3.1.17. Renal transplantation*

dence of CIN was 21.2% (Ahuja et al., 2000).

*2.3.1.18. Acute myocardial infarction*

CIN (Sadeghi et al., 2003).

*2.3.1.19. Anemia*

Hypoalbuminemia impairs endothelial function, enhances renal vasoconstriction, impairs the synthesis and release of nitric oxide, and decreases antioxidant enzyme activity. In a study, low serum albumin (<3.5 g/dl) was identified as a risk factor for CIN in patients 70 years of age or older who underwent cardiac catheterization (Rich, et al., 1990). Also we have found that in 230 patients who underwent coronary angiography with renal in‐ sufficiency, serum albumin level ≤3.5 g/dl was a risk factor for CIN (OR=5.79, p=0.005) (Cirit et al., 2006).

#### *2.3.1.21. Hypotension, sepsis, cirrhosis, and pulmonary edema*

A systolic blood pressure of less than 80 mm Hg for at least 1 h that requires inotropic support with medications is a risk factor for CIN. A study by Dangas et al showed that periprocedural hypotension and pulmonary edema are independent predictors of CIN in patients with chronic kidney disease (OR=2.50, p<0.00001 and OR=2.56, p=0.001, respec‐ tively) (Dangas et al., 2005) Sepsis, through direct damage by bacterial toxins to renal tu‐ bules and impairment of circulation, has also been reported as a risk factor. Reduction of effective intravascular volume caused by liver cirrhosis has been reported as contribu‐ ting to pre-renal reduction in renal perfusion, thus enhancing the ischemic insult of CM (Toprak, 2007).

#### *2.3.2. Procedure-related risk factors*

#### *2.3.2.1. Short duration of the two contrast administration and urgent/emergency procedure*

In those who have no risk factors for CIN, angiography should be delayed more than 48 hours after a previous exposure to intravascular contrast media. In patients with diabetes or preexisting renal disease, this time interval should be increased to more than 72 hours. In a cohort study, urgent/emergency procedure was found as a predictor of CIN (OR=4, p<0.0001) (Bartholomew et al., 2004). The higher risk of developing CIN in patients with ur‐ gent status was irrespective of baseline renal function.

#### *2.3.2.2. Use of intra-aortic balloon pump*

Using intra-aortic balloon pump may signify a very high-risk population due to very se‐ vere coronary atherosclerosis and/or indicate a role of atheroembolism. In 208 consecu‐ tive acute myocardial infarction patients undergoing percutaneous coronary intervention, use of intra-aortic balloon pump was a risk predictor of CIN (OR=15.51, p<0.0001) (Mar‐ enzi et al., 2004). In a study, it has demonstrated that, intra-aortic balloon pump use is an independent predictor of CIN in patients with chronic kidney disease (OR=2.27, p=0.004) (Dangas et al., 2005). In another study, it was found that the use of intra-aortic balloon pump was a risk factor for CIN requiring dialysis after PCI (OR=1.94) (Gruberg et al., 2001). In another derivation and validation cohort study, intra-aortic balloon pump use was a risk for CIN in patients undergoing coronary intervention (OR=5.1, p<0.0001) (Bar‐ tholomew et al., 2004).

angiography. The incidence of CIN was 3% in the iodixanol group and 26% in the io‐ hexol group (p=0.002) (Aspelin et al., 2003). In another randomized study, the renal tol‐ erance of iodixanol and iohexol was compared in 124 patients with creatinine >1.7 mg/dl. The incidence of CIN was 3.7% in iodixanol group and 10% in iohexol group (p>0.05) (Chalmers et al., 1999). The available data do not provide clear evidence that the whole iso-osmolar CM class offers an improvement over the low-osmolar CM class. Other studies with iodixanol in renal failure patients have shown a higher incidence of CIN than that observed in the NEPHRIC study (21% in the RAPPID trial, 30% in the CONTRAST trial) (Baker et al., 2003: Stone et al., 2003). In addition to their osmolarity, contrast medias are characterized as ionic versus non-ionic. Small clinical trials of lowrisk patients undergoing coronary angiography have shown little difference in the risk of CIN between the 2 types of CM. However, a randomized trial of 1196 patients under‐ going coronary angiography showed that non-ionic CM reduced the incidence of CIN in patients with preexisting renal disease with or without diabetes (Rudnick et al., 1995). In addition, symptomatic or hemodynamic adverse drug events have been shown to occur less often with non-ionic, low-osmolality CM compared with ionic, high-osmolality CM. In high-risk patients, it is reasonable to don't use the high-osmolar and ionic CM to

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 333

Intra-arterial contrast administration is a risk for CIN. This effect is thought to be due to the fact that the acute intra renal concentration of CM is much higher after intra arterial rather

Mehran et al. developed a simple scoring method that integrates eight baseline clinical variables to assess the risk of CIN after percutaneous coronary intervention (PCI). These are hypotension (score 5), use of intra-aortic balloon pump (score 5), congestive heart failure (score 5), serum creatinine>1.5 mg/dl (score 4), age>75 years (score 4), anemia (score 3), diabetes mellitus (score 3), and volume of CM (score 1 per 100 ml). If the total score is 5 or less, the risk category is low; if the total score is 16 or higher, the risk cate‐

Extracellular volume expansion with intravenous saline or sodium bicarbonate, minimizing the dose of CM, using low-osmolar non-ionic CM instead of high osmolar ionic CM, stop‐ ping the intake of nephrotoxic drugs and avoiding short intervals between procedures re‐ quiring CM have all been shown to be effective in reducing CIN. Alternatives to ordinary CM, such as carbon dioxide or gadolinium chelates, can be used in patients at high risk of

minimize the risk of CIN.

than intravenous injection.

*2.3.3.3. Intra-arterial administration of the contrast media*

*2.3.4. Scoring method to predict high risk patients for CIN*

gory is very high (Mehran et al., 2004).

**2.4. Prevention Strategies for CIN**

CIN (Table 2).

#### *2.3.2.3. Bypass graft intervention and delayed reperfusion*

Procedures with bypass angiography and intervention may be associated with higher complexity, longer duration, and limited success, thus indicating an unstable post-proce‐ dural period with impaired cardiac output. Gruberg et al. showed that the risk of CIN re‐ quiring dialysis after PCI was increased with bypass graft intervention (OR=4.94) (Gruberg et al., 2001). In a study of 208 acute myocardial infarction patients undergoing primary PCI, the risk of CIN was increased if the time-to-reperfusion is ≥6 h (OR=2.51, p=0.04) (Marenzi et al., 2004)

#### *2.3.3. Contrast medium-related risk factors*

#### *2.3.3.1. Increased dose of contrast medium*

According to different sources, the relatively safe cutoff point of contrast amount varies from 70 ml up to 220ml. However, doses as low as 20 to 30 ml are capable of inducing CIN. In a study that patients undergoing coronary angiography, each 100 ml of contrast medium administered was associated with a significant increase of 12% in the risk of CIN (OR=1.12, p=0.02) (Rihal et al., 2002). Marenzi et al. showed that contrast volume >300 ml is an inde‐ pendent risk for CIN (OR=2.80, p=0.02) (Marenzi et al., 2004). In another study patients with preexisting renal failure revealed a 10-fold risk of CIN when more than 125 ml of contrast media was administered (Taliercio et al., 1986).

#### *2.3.3.2. High-osmolar and ionic CM*

Most side effects attributable to contrast medias are related to hypertonicity. Currently, four main types of contrast media are used in routine practice today, including nonionic low-osmolar, ionic low-osmolar, nonionic iso-osmolar, and ionic high-osmolar contrast media. In a large study which comparing the non-ionic low-osmolality agent iohexol to the ionic high-osmolality agent meglumine/sodium diatrizoate in patients with pre-exist‐ ing renal dysfunction undergoing angiography, patients with renal insufficiency receiv‐ ing diatrizoate were 3.3 times as likely to develop CIN compared to those receiving iohexol (Rudnick et al., 1995). NEPHRIC trial is a randomized, prospective study com‐ paring the nonionic iso-osmolar CM iodixanol with the nonionic low-osmolar CM iohex‐ ol in 129 renal impairment patients with diabetes undergoing coronary or aorto-femoral angiography. The incidence of CIN was 3% in the iodixanol group and 26% in the io‐ hexol group (p=0.002) (Aspelin et al., 2003). In another randomized study, the renal tol‐ erance of iodixanol and iohexol was compared in 124 patients with creatinine >1.7 mg/dl. The incidence of CIN was 3.7% in iodixanol group and 10% in iohexol group (p>0.05) (Chalmers et al., 1999). The available data do not provide clear evidence that the whole iso-osmolar CM class offers an improvement over the low-osmolar CM class. Other studies with iodixanol in renal failure patients have shown a higher incidence of CIN than that observed in the NEPHRIC study (21% in the RAPPID trial, 30% in the CONTRAST trial) (Baker et al., 2003: Stone et al., 2003). In addition to their osmolarity, contrast medias are characterized as ionic versus non-ionic. Small clinical trials of lowrisk patients undergoing coronary angiography have shown little difference in the risk of CIN between the 2 types of CM. However, a randomized trial of 1196 patients under‐ going coronary angiography showed that non-ionic CM reduced the incidence of CIN in patients with preexisting renal disease with or without diabetes (Rudnick et al., 1995). In addition, symptomatic or hemodynamic adverse drug events have been shown to occur less often with non-ionic, low-osmolality CM compared with ionic, high-osmolality CM. In high-risk patients, it is reasonable to don't use the high-osmolar and ionic CM to minimize the risk of CIN.

#### *2.3.3.3. Intra-arterial administration of the contrast media*

tive acute myocardial infarction patients undergoing percutaneous coronary intervention, use of intra-aortic balloon pump was a risk predictor of CIN (OR=15.51, p<0.0001) (Mar‐ enzi et al., 2004). In a study, it has demonstrated that, intra-aortic balloon pump use is an independent predictor of CIN in patients with chronic kidney disease (OR=2.27, p=0.004) (Dangas et al., 2005). In another study, it was found that the use of intra-aortic balloon pump was a risk factor for CIN requiring dialysis after PCI (OR=1.94) (Gruberg et al., 2001). In another derivation and validation cohort study, intra-aortic balloon pump use was a risk for CIN in patients undergoing coronary intervention (OR=5.1, p<0.0001) (Bar‐

332 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Procedures with bypass angiography and intervention may be associated with higher complexity, longer duration, and limited success, thus indicating an unstable post-proce‐ dural period with impaired cardiac output. Gruberg et al. showed that the risk of CIN re‐ quiring dialysis after PCI was increased with bypass graft intervention (OR=4.94) (Gruberg et al., 2001). In a study of 208 acute myocardial infarction patients undergoing primary PCI, the risk of CIN was increased if the time-to-reperfusion is ≥6 h (OR=2.51,

According to different sources, the relatively safe cutoff point of contrast amount varies from 70 ml up to 220ml. However, doses as low as 20 to 30 ml are capable of inducing CIN. In a study that patients undergoing coronary angiography, each 100 ml of contrast medium administered was associated with a significant increase of 12% in the risk of CIN (OR=1.12, p=0.02) (Rihal et al., 2002). Marenzi et al. showed that contrast volume >300 ml is an inde‐ pendent risk for CIN (OR=2.80, p=0.02) (Marenzi et al., 2004). In another study patients with preexisting renal failure revealed a 10-fold risk of CIN when more than 125 ml of contrast

Most side effects attributable to contrast medias are related to hypertonicity. Currently, four main types of contrast media are used in routine practice today, including nonionic low-osmolar, ionic low-osmolar, nonionic iso-osmolar, and ionic high-osmolar contrast media. In a large study which comparing the non-ionic low-osmolality agent iohexol to the ionic high-osmolality agent meglumine/sodium diatrizoate in patients with pre-exist‐ ing renal dysfunction undergoing angiography, patients with renal insufficiency receiv‐ ing diatrizoate were 3.3 times as likely to develop CIN compared to those receiving iohexol (Rudnick et al., 1995). NEPHRIC trial is a randomized, prospective study com‐ paring the nonionic iso-osmolar CM iodixanol with the nonionic low-osmolar CM iohex‐ ol in 129 renal impairment patients with diabetes undergoing coronary or aorto-femoral

tholomew et al., 2004).

p=0.04) (Marenzi et al., 2004)

*2.3.3. Contrast medium-related risk factors*

*2.3.3.1. Increased dose of contrast medium*

media was administered (Taliercio et al., 1986).

*2.3.3.2. High-osmolar and ionic CM*

*2.3.2.3. Bypass graft intervention and delayed reperfusion*

Intra-arterial contrast administration is a risk for CIN. This effect is thought to be due to the fact that the acute intra renal concentration of CM is much higher after intra arterial rather than intravenous injection.

#### *2.3.4. Scoring method to predict high risk patients for CIN*

Mehran et al. developed a simple scoring method that integrates eight baseline clinical variables to assess the risk of CIN after percutaneous coronary intervention (PCI). These are hypotension (score 5), use of intra-aortic balloon pump (score 5), congestive heart failure (score 5), serum creatinine>1.5 mg/dl (score 4), age>75 years (score 4), anemia (score 3), diabetes mellitus (score 3), and volume of CM (score 1 per 100 ml). If the total score is 5 or less, the risk category is low; if the total score is 16 or higher, the risk cate‐ gory is very high (Mehran et al., 2004).

#### **2.4. Prevention Strategies for CIN**

Extracellular volume expansion with intravenous saline or sodium bicarbonate, minimizing the dose of CM, using low-osmolar non-ionic CM instead of high osmolar ionic CM, stop‐ ping the intake of nephrotoxic drugs and avoiding short intervals between procedures re‐ quiring CM have all been shown to be effective in reducing CIN. Alternatives to ordinary CM, such as carbon dioxide or gadolinium chelates, can be used in patients at high risk of CIN (Table 2).


nation intravenous and oral volume supplementation on the development of CIN was studied in 425 patients undergoing percutaneous coronary intervention. Patients were ran‐ domly assigned to receive hydration with either isotonic or half-isotonic. In addition pa‐ tients were encouraged to drink plenty of fluids (at least 1500 ml). They found that applying the combination of intravenous and oral volume supplementation results in a very low inci‐ dence of CIN (1.4%) (Mueller et al., 2005). Most studies have found that hydration alone is better than hydration combined with a diuretic. In a study, 78 patients with serum creati‐ nine >1.6 mg/dl were randomized to three groups: hydration alone, hydration with mannitol and hydration with furosemide. Half-isotonic saline was used for hydration. CIN occurred in 11%, 28% and 40% of patients in the three groups, respectively (p=0.02), thus showing that forced diuresis is of no benefit in preventing CIN. In a meta-analysis it was found that the administration of sodium bicarbonate is superior to the administration of saline alone in the prevention of CIN (Solomon et al., 1994). The effectiveness of sodium bicarbonate treat‐

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 335

Antioxidant N-acetylcysteine (NAC) might scavenge oxygen free radicals, thus attenuate the cytotoxic effects of CM. NAC may also have direct vasodilating effects on the kid‐ neys through an increase in the biologic effects of nitric oxide. Tepel et al. were evaluat‐ ed the effects of NAC (600 mg orally twice daily), at first time, in 83 patients undergoing computed tomography. Two percent of the patients in the NAC group had CIN versus 21% in the placebo group (p=0.01) (Tepel et al., 2000). Since then, a number of trials have been published. Results from these trials have been inconsistent. In a randomized, place‐ bo-controlled study it was found that NAC is protective against CIN Fifty-four patients were randomized to receive either 600 mg of NAC twice daily for 4 doses or placebo. The incidence of CIN was 8% in the NAC group versus 45% in the placebo group (p=0.005) (Diaz-Sandoval et al., 2002). In addition to oral administration, intravenous ad‐ ministration of NAC to protect against CIN has also been evaluated. In a study, Baker et al. randomly assigned 80 patients to receive either NAC infusion (n=41) versus saline in‐ fusion (n=39). CIN developed in only 2 (5%) of patients in the NAC group compared with 8 (21%) in the saline group (p=0.04) (Baker et al., 2003). The authors concluded that NAC infusion protects against CIN. In a meta-analysis, evaluating more than 800 patients at high risk of developing CIN also documented a positive impact of NAC prophylaxis on CIN (Birck et al., 2003). In another meta-analysis, nine randomized controlled trials were included and the difference in mean change in creatinine between the NAC treated group and controls was -0.27 mg/dl. The relative risk of developing CIN was 0.43 in sub‐ jects randomized to NAC. They suggest that NAC helps prevent declining renal function and CIN (Liu et al., 2005). In contrast to these reports, some studies failed to find a signif‐ icant effect of NAC on the occurrence of CINA total of 183 patients with preexisting re‐ nal insufficiency undergoing contrast study were randomly assigned to receive NAC at a dose of 600 mg twice daily on the day before and the day of the contrast study plus sal‐ ine infusion or saline alone. The incidence of CIN was 6.5% in the NAC group versus 11% in the control group (p=0.22) (Briguori et al., 2002). In a multi centric double blind

ment to prevent CIN in high-risk patients remains uncertain.

*2.4.2. N-acetylcysteine*

**Table 2.** Prevention strategies for contrast-induced nephropathy in high-risk patients

#### *2.4.1. Volume expansion*

Volume expansion is the single most important measure that has been documented to be beneficial in preventing CIN. A standardized saline hydration protocol has been proven ef‐ fective in reducing the risk of CIN and should be used routinely. The most widely accepted protocol is administering isotonic saline at 1 to 1.5 ml/kg/h beginning 6 to 12 hours prior to the procedure and continuing for up to 12 hours following contrast administration. In a randomized trial, two different hydration regimens were compared in 1620 patients under‐ going coronary interventions. They showed that the incidence of CIN was significantly low‐ er among patients given an isotonic saline solution than among those given a hypotonic saline solution (0.7% vs. 2.0% respectively, p=0.04) (Mueller et al., 2002). In another trial, a total of 119 patients with serum creatinine exceeding 1.1 mg/dl were randomized to receive isotonic solution of sodium bicarbonate (n=59) or isotonic saline (n=60) at a rate of 3 ml/kg/h for 1 hour before and 1 ml/kg/h for 6 hours after contrast administration. CIN developed in only 1 patient (1.7%) compared with 8 patients (13.6%) in the saline group (p=0.02) (Merten et al., 2004). The authors postulated that a reduction in oxidative injury may have conferred protection against CIN. However, further studies are required to clarify the role of hydra‐ tion with sodium bicarbonate in preventing CIN. In a prospective study, the effect of combi‐ nation intravenous and oral volume supplementation on the development of CIN was studied in 425 patients undergoing percutaneous coronary intervention. Patients were ran‐ domly assigned to receive hydration with either isotonic or half-isotonic. In addition pa‐ tients were encouraged to drink plenty of fluids (at least 1500 ml). They found that applying the combination of intravenous and oral volume supplementation results in a very low inci‐ dence of CIN (1.4%) (Mueller et al., 2005). Most studies have found that hydration alone is better than hydration combined with a diuretic. In a study, 78 patients with serum creati‐ nine >1.6 mg/dl were randomized to three groups: hydration alone, hydration with mannitol and hydration with furosemide. Half-isotonic saline was used for hydration. CIN occurred in 11%, 28% and 40% of patients in the three groups, respectively (p=0.02), thus showing that forced diuresis is of no benefit in preventing CIN. In a meta-analysis it was found that the administration of sodium bicarbonate is superior to the administration of saline alone in the prevention of CIN (Solomon et al., 1994). The effectiveness of sodium bicarbonate treat‐ ment to prevent CIN in high-risk patients remains uncertain.

#### *2.4.2. N-acetylcysteine*

**Clinical evidence advocating their use Don't use With conflicting or limited**

334 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Low or iso-osmolar contrast Mannitol Calcium channel blockers

COX-2 inhibitors, aminoglycoside,

Metformin usage especially in patients

Volume expansion is the single most important measure that has been documented to be beneficial in preventing CIN. A standardized saline hydration protocol has been proven ef‐ fective in reducing the risk of CIN and should be used routinely. The most widely accepted protocol is administering isotonic saline at 1 to 1.5 ml/kg/h beginning 6 to 12 hours prior to the procedure and continuing for up to 12 hours following contrast administration. In a randomized trial, two different hydration regimens were compared in 1620 patients under‐ going coronary interventions. They showed that the incidence of CIN was significantly low‐ er among patients given an isotonic saline solution than among those given a hypotonic saline solution (0.7% vs. 2.0% respectively, p=0.04) (Mueller et al., 2002). In another trial, a total of 119 patients with serum creatinine exceeding 1.1 mg/dl were randomized to receive isotonic solution of sodium bicarbonate (n=59) or isotonic saline (n=60) at a rate of 3 ml/kg/h for 1 hour before and 1 ml/kg/h for 6 hours after contrast administration. CIN developed in only 1 patient (1.7%) compared with 8 patients (13.6%) in the saline group (p=0.02) (Merten et al., 2004). The authors postulated that a reduction in oxidative injury may have conferred protection against CIN. However, further studies are required to clarify the role of hydra‐ tion with sodium bicarbonate in preventing CIN. In a prospective study, the effect of combi‐

Extracellular volume expansion Nonsteroidal anti-inflammatory drugs,

Delaying contrast procedures until hemodynamic status is corrected

*2.4.1. Volume expansion*

cisplatin

Saline or sodium bicarbonate Loop diuretics Theophylline

Minimizing the dose of contrast Multiple use of contrast within 72 h Fenoldopam Alternative imaging techniques Large doses of contrast Captopril Monitoring serum creatinine High-osmolar contrast Ascorbic acid

with renal failure

**Table 2.** Prevention strategies for contrast-induced nephropathy in high-risk patients

≥48 h between contrast procedures Endothelin antagonist

**evidence**

Acetylcystein

Atrial natriuretic peptide

B-type natriuretic peptide

PGE1

Hemofiltration Nebivolol Statins

Pentoxifylline

Antioxidant N-acetylcysteine (NAC) might scavenge oxygen free radicals, thus attenuate the cytotoxic effects of CM. NAC may also have direct vasodilating effects on the kid‐ neys through an increase in the biologic effects of nitric oxide. Tepel et al. were evaluat‐ ed the effects of NAC (600 mg orally twice daily), at first time, in 83 patients undergoing computed tomography. Two percent of the patients in the NAC group had CIN versus 21% in the placebo group (p=0.01) (Tepel et al., 2000). Since then, a number of trials have been published. Results from these trials have been inconsistent. In a randomized, place‐ bo-controlled study it was found that NAC is protective against CIN Fifty-four patients were randomized to receive either 600 mg of NAC twice daily for 4 doses or placebo. The incidence of CIN was 8% in the NAC group versus 45% in the placebo group (p=0.005) (Diaz-Sandoval et al., 2002). In addition to oral administration, intravenous ad‐ ministration of NAC to protect against CIN has also been evaluated. In a study, Baker et al. randomly assigned 80 patients to receive either NAC infusion (n=41) versus saline in‐ fusion (n=39). CIN developed in only 2 (5%) of patients in the NAC group compared with 8 (21%) in the saline group (p=0.04) (Baker et al., 2003). The authors concluded that NAC infusion protects against CIN. In a meta-analysis, evaluating more than 800 patients at high risk of developing CIN also documented a positive impact of NAC prophylaxis on CIN (Birck et al., 2003). In another meta-analysis, nine randomized controlled trials were included and the difference in mean change in creatinine between the NAC treated group and controls was -0.27 mg/dl. The relative risk of developing CIN was 0.43 in sub‐ jects randomized to NAC. They suggest that NAC helps prevent declining renal function and CIN (Liu et al., 2005). In contrast to these reports, some studies failed to find a signif‐ icant effect of NAC on the occurrence of CINA total of 183 patients with preexisting re‐ nal insufficiency undergoing contrast study were randomly assigned to receive NAC at a dose of 600 mg twice daily on the day before and the day of the contrast study plus sal‐ ine infusion or saline alone. The incidence of CIN was 6.5% in the NAC group versus 11% in the control group (p=0.22) (Briguori et al., 2002). In a multi centric double blind clinical trial 156 patients undergoing coronary angiography or percutaneous coronary in‐ tervention with creatinine clearance <50 ml/min were randomly assigned to receive N-ace‐ tylcysteine 600 mg orally twice daily for two days or placebo. Sixteen patients developed CIN. Eight of 77 patients (10.4%) in the NAC group and eight of 79 patients (10.1%) in the placebo group (p=1.00). No difference was observed in the change in endogenous cre‐ atinine clearance, p=0.28). They concluded that oral NAC did not prevent CIN in patients at low to moderate risk undergoing cardiac catheterisation with ionic low osmolality CM (Gomes et al., 2005). In another study, 50 patients undergoing elective diagnostic coro‐ nary angiography with serum creatinine values above 1.3 mg/dl were included and CIN was detected in 3 of 25 patients (12%) in the NAC group and 2 of 25 patients (8%) in the control group (p>0.05). It was detected that in patients planned to undergo elective diag‐ nostic coronary angiography with renal dysfunction, oral NAC and hydration before the procedure was not more effective than hydration alone in the prevention of CIN (Gulel et al., 2005). A direct renoprotective effect of NAC remains questionable. To date, only a few trials described the effects of NAC not only on serum creatinine but also on clinical end points. The serum creatinine can be decrease in administration of NAC without reno‐ protective effect. In a prospective study, NAC was given at a dose of 600 mg every 12 h for a total of four doses to the volunteers with a normal renal function who did not re‐ ceive contrast agent. There was a significant decrease of the mean serum creatinine (p<0.05) and a significant increase of the GFR (p<0.02), whereas the cystatin C concentra‐ tion did not change significantly (Hoffmann et al., 2004). In patients undergoing emergen‐ cy diagnostic procedures, in which a full hydration protocol is not possible, an abbreviated hydration regimen plus oral or intravenous administration of NAC can be recommended. NAC may be of benefit mostly in high-risk patients. If NAC is to be used as a preventative measure, it should be given at a dose of 600 mg orally twice daily on the day before and day of the procedure.

pam group compared with 30.1% of patients in the placebo group (p=0.61) (Stone et al., 2003). The authors concluded that fenoldopam did not protect against CIN. In 2 other large studies comparing fenoldopam with NAC treatment with fenoldopam either had a similar, non significant effect as that of NAC or was inferior to it (Allaqaband et al., 2002; Briguori et al., 2004). The routine use of fenoldopam cannot be recommended at the

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 337

CM stimulate the intrarenal secretion of adenosine, which binds to the renal adenosine re‐ ceptor and acts as a potent vasoconstrictor, reducing renal blood flow and increasing the generation of oxygen free radicals as it is metabolized to xanthine and hypoxanthine. Theo‐ phylline and aminophylline, adenosine antagonists, have also been studied in the preven‐ tion of CIN in a number of trials. Studies with these agents have used varying doses and dosage forms and yielded conflicting results (Erley et al., 1999; Kapoor et al., 2001). Based on the conflicting information found in clinical studies, adenosine antagonists should not be

The calcium channel antagonists verapamil and diltiazem have been found to attenuate the renal vasoconstrictor response after exposure to CM. However, when the efficacy of the felodipine, nitrendipine and nifedipine was evaluated, results were inconsistent. Two small studies performed the use of sublingual nifedipine given prior to contrast adminis‐ tration. Patients (n=20) who received sublingual nifedipine did not have a significant in‐ crease in serum creatinine, while those in the placebo group did (Rodicio et al., 1990). In another study, patients (n=30) who received nifedipine had an increase in renal plasma flow following administration of contrast, while patients in the placebo group had a de‐ crease in renal flow (Russo et al., 1990). One other study showed that nitrendipine use cause a significant reduction in the GFR in the placebo group compared to little or no change in GFR in the nitrendipine group (Neumayer et al., 1989). In another study, 27 pa‐ tients with normal to moderately reduced renal function underwent femoral angiography randomized to receive either oral felodipine or placebo. Patients in the felodipine group had a significant increase in serum creatinine from baseline, while patients in the placebo group did not demonstrate a similar increase (Spangberg-Viklund et al., 1996). More large-scale trials are needed before calcium channel blockers can be routinely recommend‐

PGE1 has vasodilatory effects that may be beneficial in preventing CIN. In one study, 130 patients were randomly assigned to receive either placebo or one of three doses of PGE1. The increase in serum creatinine level was smaller in all of the three PGE1 groups than in the pla‐ cebo group, but the difference was significant only in the medium-dose (20 ng/kg/min) of

routinely used in patients as a preventative measure at this time.

present time.

*2.4.5. Adenosine antagonists*

*2.4.6. Calcium channel blockers*

ed in patients prior to CM administration.

*2.4.7. Prostaglandin E1*

#### *2.4.3. Ascorbic acid*

Prophylactic oral administration of ascorbic acid may protect against CIN. In a randomized, placebo-controlled trial in 231 patients with serum creatinine ≥1.2 mg/dl who undergoing coronary angiography showed that the use of ascorbic acid was associated with a significant reduction in the rate of CIN. CIN occurred in 11 of the 118 patients (9%) in the ascorbic acid group and in 23 of the 113 patients (20%) in the placebo group (OR=0.38; p=0.02) (Spargias et al., 2004). Further prospective studies are needed to validate these preliminary results.

#### *2.4.4. Fenoldopam*

Fenoldopam mesylate is a selective dopamine-1 receptor agonist that produces systemic, peripheral and renal arterial vasodilatation. Several investigators have reported a positive impact of fenoldopam against CIN in small studies. In a placebo-controlled, double-blind, multicenter trial, 315 patients with creatinine clearance of less than 60 ml/min were randomized to receive fenoldopam infusion [0.05 μg/kg/min titrated to 0.1 μg/kg/min (n=157)] or matching placebo (n=158). CIN occurred in 33.6% of patients in the fenoldo‐ pam group compared with 30.1% of patients in the placebo group (p=0.61) (Stone et al., 2003). The authors concluded that fenoldopam did not protect against CIN. In 2 other large studies comparing fenoldopam with NAC treatment with fenoldopam either had a similar, non significant effect as that of NAC or was inferior to it (Allaqaband et al., 2002; Briguori et al., 2004). The routine use of fenoldopam cannot be recommended at the present time.

#### *2.4.5. Adenosine antagonists*

clinical trial 156 patients undergoing coronary angiography or percutaneous coronary in‐ tervention with creatinine clearance <50 ml/min were randomly assigned to receive N-ace‐ tylcysteine 600 mg orally twice daily for two days or placebo. Sixteen patients developed CIN. Eight of 77 patients (10.4%) in the NAC group and eight of 79 patients (10.1%) in the placebo group (p=1.00). No difference was observed in the change in endogenous cre‐ atinine clearance, p=0.28). They concluded that oral NAC did not prevent CIN in patients at low to moderate risk undergoing cardiac catheterisation with ionic low osmolality CM (Gomes et al., 2005). In another study, 50 patients undergoing elective diagnostic coro‐ nary angiography with serum creatinine values above 1.3 mg/dl were included and CIN was detected in 3 of 25 patients (12%) in the NAC group and 2 of 25 patients (8%) in the control group (p>0.05). It was detected that in patients planned to undergo elective diag‐ nostic coronary angiography with renal dysfunction, oral NAC and hydration before the procedure was not more effective than hydration alone in the prevention of CIN (Gulel et al., 2005). A direct renoprotective effect of NAC remains questionable. To date, only a few trials described the effects of NAC not only on serum creatinine but also on clinical end points. The serum creatinine can be decrease in administration of NAC without reno‐ protective effect. In a prospective study, NAC was given at a dose of 600 mg every 12 h for a total of four doses to the volunteers with a normal renal function who did not re‐ ceive contrast agent. There was a significant decrease of the mean serum creatinine (p<0.05) and a significant increase of the GFR (p<0.02), whereas the cystatin C concentra‐ tion did not change significantly (Hoffmann et al., 2004). In patients undergoing emergen‐ cy diagnostic procedures, in which a full hydration protocol is not possible, an abbreviated hydration regimen plus oral or intravenous administration of NAC can be recommended. NAC may be of benefit mostly in high-risk patients. If NAC is to be used as a preventative measure, it should be given at a dose of 600 mg orally twice daily on

336 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

Prophylactic oral administration of ascorbic acid may protect against CIN. In a randomized, placebo-controlled trial in 231 patients with serum creatinine ≥1.2 mg/dl who undergoing coronary angiography showed that the use of ascorbic acid was associated with a significant reduction in the rate of CIN. CIN occurred in 11 of the 118 patients (9%) in the ascorbic acid group and in 23 of the 113 patients (20%) in the placebo group (OR=0.38; p=0.02) (Spargias et al., 2004). Further prospective studies are needed to validate these preliminary results.

Fenoldopam mesylate is a selective dopamine-1 receptor agonist that produces systemic, peripheral and renal arterial vasodilatation. Several investigators have reported a positive impact of fenoldopam against CIN in small studies. In a placebo-controlled, double-blind, multicenter trial, 315 patients with creatinine clearance of less than 60 ml/min were randomized to receive fenoldopam infusion [0.05 μg/kg/min titrated to 0.1 μg/kg/min (n=157)] or matching placebo (n=158). CIN occurred in 33.6% of patients in the fenoldo‐

the day before and day of the procedure.

*2.4.3. Ascorbic acid*

*2.4.4. Fenoldopam*

CM stimulate the intrarenal secretion of adenosine, which binds to the renal adenosine re‐ ceptor and acts as a potent vasoconstrictor, reducing renal blood flow and increasing the generation of oxygen free radicals as it is metabolized to xanthine and hypoxanthine. Theo‐ phylline and aminophylline, adenosine antagonists, have also been studied in the preven‐ tion of CIN in a number of trials. Studies with these agents have used varying doses and dosage forms and yielded conflicting results (Erley et al., 1999; Kapoor et al., 2001). Based on the conflicting information found in clinical studies, adenosine antagonists should not be routinely used in patients as a preventative measure at this time.

#### *2.4.6. Calcium channel blockers*

The calcium channel antagonists verapamil and diltiazem have been found to attenuate the renal vasoconstrictor response after exposure to CM. However, when the efficacy of the felodipine, nitrendipine and nifedipine was evaluated, results were inconsistent. Two small studies performed the use of sublingual nifedipine given prior to contrast adminis‐ tration. Patients (n=20) who received sublingual nifedipine did not have a significant in‐ crease in serum creatinine, while those in the placebo group did (Rodicio et al., 1990). In another study, patients (n=30) who received nifedipine had an increase in renal plasma flow following administration of contrast, while patients in the placebo group had a de‐ crease in renal flow (Russo et al., 1990). One other study showed that nitrendipine use cause a significant reduction in the GFR in the placebo group compared to little or no change in GFR in the nitrendipine group (Neumayer et al., 1989). In another study, 27 pa‐ tients with normal to moderately reduced renal function underwent femoral angiography randomized to receive either oral felodipine or placebo. Patients in the felodipine group had a significant increase in serum creatinine from baseline, while patients in the placebo group did not demonstrate a similar increase (Spangberg-Viklund et al., 1996). More large-scale trials are needed before calcium channel blockers can be routinely recommend‐ ed in patients prior to CM administration.

#### *2.4.7. Prostaglandin E1*

PGE1 has vasodilatory effects that may be beneficial in preventing CIN. In one study, 130 patients were randomly assigned to receive either placebo or one of three doses of PGE1. The increase in serum creatinine level was smaller in all of the three PGE1 groups than in the pla‐ cebo group, but the difference was significant only in the medium-dose (20 ng/kg/min) of PGE1 group (Koch et al., 2000). More studies need to be done to better understand the role of prostaglandin E1, but results from this pilot study appear promising.

*2.4.11. Statins*

renal replacement therapy.

recommended in prevention of CIN.

*2.4.13. Hemofiltration and hemodialysis*

the results of this trial.

*2.4.14. New types of contrast medias*

*2.4.12. Nebivolol*

Whether additional benefits can be achieved with the use of statin in decreasing the risk of CIN remains undetermined. In a recent meta analysis of randomised controlled trials com‐ paring statin pretreatment with non-statin pretreatment for the prevention of CIN, it was found that, the incidence of CIN was not significantly lower in statin pretreatment group as compared with control group (RR=0.76, p=0.30) (Zhang et al., 2011). The current cumulative evidence suggests that statin pretreatment may neither prevent CIN nor reduce the need for

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 339

In an experimental study we demonstrated that nebivolol have a protective role against CIN. Nebivolol leads to a decrease in the systemic and renal oxidative stres (p=0.001) and an increase in renal nitrite production (p=0.027). In addition, contrast-induced proteinuria, pro‐ teinaceous cast (*p<* 0.001), and tubular necrosis (p=0.001) are restored by nebivolol (Toprak et al., 2008). Two recent human studies demonstrated the protective effect of nebivolol on CIN. One of the study showed that the use of oral nebivolol for one week at a dose of 5 mg per day decrease the incidence of CIN in patients who underwent coronary angiography with renal dysfunction (p=0.03) (Avci et al., 2011). Another more recent study showed that the use of oral nebivolol for 4 days at a dose of 5 mg per day is protective against nephrotox‐ ic effects of CM in patients who underwent coronary angiography or ventriculography (Gu‐ nebakmaz et al., 2012). More large-scale trials are needed before nebivolol can be routinely

Currently available data do not support use of prophylactic hemodialysis for prevention of CIN. In a trial of 113 patients, reported that CIN occurred in 24% of the hemodialysis group as compared with 16% of non-hemodialysis group (Vogt et al., 2001). Clinically rel‐ evant events also were not different in two groups. Only continuous venovenous hemofil‐ tration has been shown to protect against CIN. In a study, 114 patients with chronic renal failure undergoing percutaneous coronary intervention were divided in two groups: 56 patients received normal saline and 58 patients underwent hemofiltration at a rate of 1000 ml/h (Marenzi et al., 2003). Hemofiltration seems to have a protective effect, including significant reduction in in-hospital and 1-year mortality compared with routine hydra‐ tion. The mechanisms of this benefit are not clear. Further studies are needed to confirm

Gadolinium-enhanced magnetic resonance coronary angiography is a non-invasive method for evaluation of coronary arteries. It has been suggested that gadolinum-based CM could be used in stead of iodinated CM for radiological examinations in patients with significant renal impairment. However, its use has been questioned on the basis of reports of nephro‐

#### *2.4.8. Atrial Natriuretic Peptide (ANP)*

ANP may prevent CIN by increasing renal blood flow. In a study, ANP was included in one of the four arms. In which dopamine, mannitol, and ANP caused an increase in CIN in dia‐ betic patients as compared to saline alone (Weisberg et al., 1994). In another trial patients were randomized to one of four treatment arms: fluid alone or one of three doses of ANP. Results showed no statistically significant differences in the incidence of CIN between any of the four treatment arms (Kurnik et al., 1998) Based on these results and the limited clinical data, ANP cannot be advocated in the prevention of CIN.

#### *2.4.9. Endothelin antagonists*

Endothelin-1 is a potent endogenous vasoconstrictor, is thought to play a role in the de‐ velopment of CIN. Endothelin-1 has two primary receptors. In animal studies, endothelin-A antagonists were shown to reduce the incidence of CIN (Liss et al., 2003). However, in a randomized study of 158 patients, the use of a mixed endothelin-A and B antagonist was associated with a significantly higher incidence of CIN than was placebo (56% vs. 29%, p=0.002) (Wang et al., 2000). Endothelin antagonists currently have no role in pre‐ vention of CIN.

#### *2.4.10. Low-dose of dopamine*

At low doses (1-3 mcg/kg/min), dopamine activates two types of dopamine (DA) recep‐ tors, DA-1 and DA-2. Activation of the DA-1 receptor results in an increase in natriure‐ sis and renal blood flow. Since dopamine, at low doses, is believed to be more selective for the DA-1 receptors, it has been investigated in the prevention of CIN. Kapoor et al. randomized 40 patients with diabetes scheduled to undergo a coronary angiography to either dopamine or placebo control. None of the patients in the dopamine group devel‐ oped CIN compared to 50% of patients receiving placebo (Kapoor et al., 2002). In anoth‐ er prospective, randomized trial, Hans et al. evaluated 55 patients (40% had diabetes) with chronic renal insufficiency. Patients were randomized to receive dopamine or an equal volume of saline. The group receiving dopamine had a significantly lower inci‐ dence of CIN as compared to the control group (Hans et al., 1998). In contrast to the tri‐ als showing a potential benefit of dopamine, other studies have failed to demonstrate this benefit. Abizaid et al. performed a randomized, prospective study involving patients with renal insufficiency who underwent coronary angioplasty. Patients were randomized to continue with the saline, receive aminophylline in addition to the saline, or receive dopamine plus saline. In the dopamine plus saline group, 50% of patients developed CIN, while only 30% of the patients in the saline-alone group developed CIN. This dif‐ ference did not reach statistical significance, but it appeared that use of dopamine might worsen outcomes (Abizaid et al., 1999). Low-dose dopamine use cannot be supported at this time.

#### *2.4.11. Statins*

PGE1 group (Koch et al., 2000). More studies need to be done to better understand the role of

ANP may prevent CIN by increasing renal blood flow. In a study, ANP was included in one of the four arms. In which dopamine, mannitol, and ANP caused an increase in CIN in dia‐ betic patients as compared to saline alone (Weisberg et al., 1994). In another trial patients were randomized to one of four treatment arms: fluid alone or one of three doses of ANP. Results showed no statistically significant differences in the incidence of CIN between any of the four treatment arms (Kurnik et al., 1998) Based on these results and the limited clinical

Endothelin-1 is a potent endogenous vasoconstrictor, is thought to play a role in the de‐ velopment of CIN. Endothelin-1 has two primary receptors. In animal studies, endothelin-A antagonists were shown to reduce the incidence of CIN (Liss et al., 2003). However, in a randomized study of 158 patients, the use of a mixed endothelin-A and B antagonist was associated with a significantly higher incidence of CIN than was placebo (56% vs. 29%, p=0.002) (Wang et al., 2000). Endothelin antagonists currently have no role in pre‐

At low doses (1-3 mcg/kg/min), dopamine activates two types of dopamine (DA) recep‐ tors, DA-1 and DA-2. Activation of the DA-1 receptor results in an increase in natriure‐ sis and renal blood flow. Since dopamine, at low doses, is believed to be more selective for the DA-1 receptors, it has been investigated in the prevention of CIN. Kapoor et al. randomized 40 patients with diabetes scheduled to undergo a coronary angiography to either dopamine or placebo control. None of the patients in the dopamine group devel‐ oped CIN compared to 50% of patients receiving placebo (Kapoor et al., 2002). In anoth‐ er prospective, randomized trial, Hans et al. evaluated 55 patients (40% had diabetes) with chronic renal insufficiency. Patients were randomized to receive dopamine or an equal volume of saline. The group receiving dopamine had a significantly lower inci‐ dence of CIN as compared to the control group (Hans et al., 1998). In contrast to the tri‐ als showing a potential benefit of dopamine, other studies have failed to demonstrate this benefit. Abizaid et al. performed a randomized, prospective study involving patients with renal insufficiency who underwent coronary angioplasty. Patients were randomized to continue with the saline, receive aminophylline in addition to the saline, or receive dopamine plus saline. In the dopamine plus saline group, 50% of patients developed CIN, while only 30% of the patients in the saline-alone group developed CIN. This dif‐ ference did not reach statistical significance, but it appeared that use of dopamine might worsen outcomes (Abizaid et al., 1999). Low-dose dopamine use cannot be supported at

prostaglandin E1, but results from this pilot study appear promising.

338 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

data, ANP cannot be advocated in the prevention of CIN.

*2.4.8. Atrial Natriuretic Peptide (ANP)*

*2.4.9. Endothelin antagonists*

*2.4.10. Low-dose of dopamine*

vention of CIN.

this time.

Whether additional benefits can be achieved with the use of statin in decreasing the risk of CIN remains undetermined. In a recent meta analysis of randomised controlled trials com‐ paring statin pretreatment with non-statin pretreatment for the prevention of CIN, it was found that, the incidence of CIN was not significantly lower in statin pretreatment group as compared with control group (RR=0.76, p=0.30) (Zhang et al., 2011). The current cumulative evidence suggests that statin pretreatment may neither prevent CIN nor reduce the need for renal replacement therapy.

#### *2.4.12. Nebivolol*

In an experimental study we demonstrated that nebivolol have a protective role against CIN. Nebivolol leads to a decrease in the systemic and renal oxidative stres (p=0.001) and an increase in renal nitrite production (p=0.027). In addition, contrast-induced proteinuria, pro‐ teinaceous cast (*p<* 0.001), and tubular necrosis (p=0.001) are restored by nebivolol (Toprak et al., 2008). Two recent human studies demonstrated the protective effect of nebivolol on CIN. One of the study showed that the use of oral nebivolol for one week at a dose of 5 mg per day decrease the incidence of CIN in patients who underwent coronary angiography with renal dysfunction (p=0.03) (Avci et al., 2011). Another more recent study showed that the use of oral nebivolol for 4 days at a dose of 5 mg per day is protective against nephrotox‐ ic effects of CM in patients who underwent coronary angiography or ventriculography (Gu‐ nebakmaz et al., 2012). More large-scale trials are needed before nebivolol can be routinely recommended in prevention of CIN.

#### *2.4.13. Hemofiltration and hemodialysis*

Currently available data do not support use of prophylactic hemodialysis for prevention of CIN. In a trial of 113 patients, reported that CIN occurred in 24% of the hemodialysis group as compared with 16% of non-hemodialysis group (Vogt et al., 2001). Clinically rel‐ evant events also were not different in two groups. Only continuous venovenous hemofil‐ tration has been shown to protect against CIN. In a study, 114 patients with chronic renal failure undergoing percutaneous coronary intervention were divided in two groups: 56 patients received normal saline and 58 patients underwent hemofiltration at a rate of 1000 ml/h (Marenzi et al., 2003). Hemofiltration seems to have a protective effect, including significant reduction in in-hospital and 1-year mortality compared with routine hydra‐ tion. The mechanisms of this benefit are not clear. Further studies are needed to confirm the results of this trial.

#### *2.4.14. New types of contrast medias*

Gadolinium-enhanced magnetic resonance coronary angiography is a non-invasive method for evaluation of coronary arteries. It has been suggested that gadolinum-based CM could be used in stead of iodinated CM for radiological examinations in patients with significant renal impairment. However, its use has been questioned on the basis of reports of nephro‐ toxicity and its association with nephrogenic systemic fibrosis, a rare and serious syndrome that involves fibrosis of skin, joints, eyes, and internal organs. In a study by Hoffmann et al. the effect of gadopentetate dimeglumine (iodine-based CM) was studied in 181 patients with normal renal function and the effect of gadolinium was studied in 198 patients with pre-excisting renal failure. There was no statistically significant change in serum creatinine concentration after gadopentetate dimeglumine. In contrary, serum creatinine levels de‐ creased significantly after the administration of gadolinium (p<0.01) (Hoffmann et al., 2005). In a retrospective study, the safety of gadolinium was evaluated in 91 patients with stage 3 and 4 renal failure who underwent angiographic MRI procedures. Eleven of 91 patients de‐ veloped CIN (12.1%) (Ergun et al., 2006). In another randomized study gadobutrol, a gadoli‐ nium-based CM, was compared with standard iohexol, an iodinated CM, in 21 patients with renal dysfunction. The incidence of CIN was 50% in gadobutrol group and 45% in iohexol group (p=0.70). In this study, gadolinium showed no benefit over iohexol in patients with severely impaired renal function (Erley et al., 2004). More studies need to be done to better understand the role of gadolinum on CIN. Ultrasound contrast agents are micro-bubbles which produce acoustic enhancement. They are pharmacologically almost inert and safe.

on Contrast-Induced Acute Renal Failure after Coronary Angioplasty in Patients with Preexisting Renal Insufficiency. *The American Journal of Cardiology*, Vol.83, No.2,

Contrast-Induced Nephropathy http://dx.doi.org/10.5772/54032 341

[2] Ahuja, TS., Niaz, N., & Agraharkar, M. (2000). Contrast-Induced Nephrotoxicity in Renal Allograft Recipients. *Clinical Nephrology*, Vol.54, No.1, (July 2000), pp.11-14,

[3] Allaqaband, S., Tumuluri, R., Malik, AM., Gupta, A., Volkert, P., Shalev, Y., & Bajwa, TK. (2002). Prospective Randomized Study of N-Acetylcysteine, Fenoldopam, and Saline for Prevention of Radiocontrast-Induced Nephropathy. *Catheterization and Car‐ diovascular Interventions*, Vol.57, No.3, (November 2002), pp.279-283, ISSN 1522-1946 [4] Aspelin, P., Aubry, P., Fransson, SG., Strasser, R., Willenbrock, R., & Berg, KJ. (2003). Nephrotoxic Effects in High-Risk Patients Undergoing Angiography. *The New Eng‐ land Journal of Medicine*, Vol.348, No.6, (February 2003), pp.491-499, ISSN 0028-4793 [5] Avci, E., Yeşil, M., Bayata, S., Postaci, N., Arikan, E., & Cirit, M. (2011). The Role of Nebivolol in The Prevention of Contrast-Induced Nephropathy in Patients with Re‐ nal Dysfunction. The Anatolian Journal of Cardiology, Vol.11, No.7, (November

[6] Baker, CS., Wragg, A., Kumar, S., De Palma, R., Baker, LR., & Knight, CJ. (2003). A Rapid Protocol for the Prevention of Contrast-Inducted Renal Dysfunction: The RAP‐ PID Study. *Journal of the American College of the Cardiology,* Vol. 41, No. 12, (June 2003),

[7] Bartholomew, BA., Harjai, KJ., Dukkipati, S., Boura, JA., Yerkey, MW., Glazier, S., Grines, CL., & O'Neill, WW. (2004). Impact of Nephropathy after Percutaneous Coro‐ nary Intervention and a Method for Risk Stratification, *The American Journal of Cardi‐*

[8] Barrett, BJ., Parfrey, PS., Vavasour HM., McDonald, J., Kent, G., Hefferton, D., O'Dea, F., Stone, E., Reddy, R., & McManamon, PJ. (1992). Contrast Nephropathy in Patients with Impaired Renal Function: High Versus Low Osmolar Media. *Kidney Internation‐*

[9] Birck, R., Krzossok, S., Markowetz, F., Schnulle, P., van der Woude, FJ., & Braun, C. (2003). Acetylcysteine for Prevention of Contrast Nephropathy: Meta-Analysis. *Lan‐*

[10] Briguori, C., Manganelli, F., Scarpato, P., Elia, PP., Golia, B., Riviezzo, G., Lepore, S., Librera, M., Villari, B., Colombo, A., & Ricciardelli, B. (2002). Acetylcysteine and Contrast Agent-Associated Nephrotoxicity. *Journal of the American College of the Cardi‐*

[11] Briguori, C., Colombo, A., Airoldi, F., Violante, A., Castelli, A., Balestrieri, P., Paolo Elia, P., Golia, B., Lepore, S., Riviezzo, G., Scarpato, P., Librera, M., Focaccio, A., & Ricciardelli, B. (2004). N-Acetylcysteine Versus Fenoldopam Mesylate to Prevent

*ology,* Vol.93, No.12, (June 2004), pp.1515-1519, ISSN 0002-9149

*al*, Vol.41, No.5, (May 1992), pp. 1274–1279, ISSN 0085-2538

*ology,* Vol.40, No.2, (July 2002), pp. 298-303, ISSN 0735-1097

*cet,* Vol.362, No.9384, (August 2003), pp.598-603, ISSN 0140-6736

(January 1999), pp.260-263, ISSN 0002-9149

2011), pp.613-617, ISSN 1302-8723

pp.2114-2118, ISSN 0735-1097

ISSN 0301-0430

#### **3. Conclusion**

The development of CIN is associated with adverse outcomes including prolonged hospital‐ ization, the potential need for renal replacement therapy, and most important, increased mortality. The treatment of established CIN is limited to supportive measures and dialysis. For this reason, screening for high-risk patients before CM including -cardiac procedures and taking the appropriate prophylactic regimens is important in reducing CIN. Pre-exist‐ ing renal dysfunction, especially when secondary to diabetic nephropathy, is the most im‐ portant risk factor. Extra cellular volume expansion and use of low osmolar CM are the two most effective measures to prevent CIN. Acetylcysteine may use in high-risk patients, and nebivolol may use as a new prophylactic agent for CIN, but this finding has not been uni‐ form or always demonstrated by currently available trials.

#### **Author details**

#### Omer Toprak

Department of Medicine, Division of Nephrology, Balikesir University School of Medicine, Balikesir, Turkey

#### **References**

[1] Abizaid, AS., Clark, CE., Mintz, GS., Dosa, S., Popma, JJ., Pichard, AD., Satler, LF., Harvey, M., Kent, KM., & Leon, MB. (1999). Effects of Dopamine and Aminophylline on Contrast-Induced Acute Renal Failure after Coronary Angioplasty in Patients with Preexisting Renal Insufficiency. *The American Journal of Cardiology*, Vol.83, No.2, (January 1999), pp.260-263, ISSN 0002-9149

toxicity and its association with nephrogenic systemic fibrosis, a rare and serious syndrome that involves fibrosis of skin, joints, eyes, and internal organs. In a study by Hoffmann et al. the effect of gadopentetate dimeglumine (iodine-based CM) was studied in 181 patients with normal renal function and the effect of gadolinium was studied in 198 patients with pre-excisting renal failure. There was no statistically significant change in serum creatinine concentration after gadopentetate dimeglumine. In contrary, serum creatinine levels de‐ creased significantly after the administration of gadolinium (p<0.01) (Hoffmann et al., 2005). In a retrospective study, the safety of gadolinium was evaluated in 91 patients with stage 3 and 4 renal failure who underwent angiographic MRI procedures. Eleven of 91 patients de‐ veloped CIN (12.1%) (Ergun et al., 2006). In another randomized study gadobutrol, a gadoli‐ nium-based CM, was compared with standard iohexol, an iodinated CM, in 21 patients with renal dysfunction. The incidence of CIN was 50% in gadobutrol group and 45% in iohexol group (p=0.70). In this study, gadolinium showed no benefit over iohexol in patients with severely impaired renal function (Erley et al., 2004). More studies need to be done to better understand the role of gadolinum on CIN. Ultrasound contrast agents are micro-bubbles which produce acoustic enhancement. They are pharmacologically almost inert and safe.

340 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

The development of CIN is associated with adverse outcomes including prolonged hospital‐ ization, the potential need for renal replacement therapy, and most important, increased mortality. The treatment of established CIN is limited to supportive measures and dialysis. For this reason, screening for high-risk patients before CM including -cardiac procedures and taking the appropriate prophylactic regimens is important in reducing CIN. Pre-exist‐ ing renal dysfunction, especially when secondary to diabetic nephropathy, is the most im‐ portant risk factor. Extra cellular volume expansion and use of low osmolar CM are the two most effective measures to prevent CIN. Acetylcysteine may use in high-risk patients, and nebivolol may use as a new prophylactic agent for CIN, but this finding has not been uni‐

Department of Medicine, Division of Nephrology, Balikesir University School of Medicine,

[1] Abizaid, AS., Clark, CE., Mintz, GS., Dosa, S., Popma, JJ., Pichard, AD., Satler, LF., Harvey, M., Kent, KM., & Leon, MB. (1999). Effects of Dopamine and Aminophylline

form or always demonstrated by currently available trials.

**3. Conclusion**

**Author details**

Omer Toprak

Balikesir, Turkey

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[70] Toprak, O., & Cirit, M. (2005). Investigating the Volume Status Before Contrast Nephropathy Studies. *Nephrology Dialysis Transplantation,* Vol.20, No.2, (February 2005), pp. 464, ISSN 0931-0509

**Chapter 17**

**Contrast-Induced Nephropathy in**

Chia-Ter Chao, Vin-Cent Wu and Yen-Hung Lin

Additional information is available at the end of the chapter

episodes of contrast-induced AKI are dialysis-requring.

http://dx.doi.org/10.5772/54081

**1. Introduction**

**Coronary Angiography and Intervention**

Since the advent of coronary angioplasty more than 3 decades ago, the volume of percutane‐ ous coronary interventions (PCI) has been rising progressively, with relative decrease in amount of coronary artery bypass graft (CABG) surgery. Roughly 1.4 million of catheteriza‐ tion procedures are performed in U.S. each year.[1] Contrast medium is widely used in both diagnositc coronary angiography and PCI, and intravenous use of iodinated contrast medi‐ um is a common precipitator of contrast-induced nephropathy (or contrast-induced acute kidney injury [AKI]). [2, 3] With the trend of increasing PCI use in the modern era, expected‐ ly more patients will develop contrast-induced AKI in the future. Currently contrast-in‐ duced nephropathy has been the third most common cause of hospital-acquired AKI in the large registry studies. [4] This phenomenon is worthy of our attention, since past researchers have identified that contrast-induced AKI can be associated with increased late incidence of acute myocardial infarction (AMI) and target vessel revascularization [5], longer in-hospital stay [6], a more complicated hospitalization course (bleeding episodes requiring transfusion, vascular complications) [7], and higher in-hospital mortality and morbidity [8-10]. More im‐ portantly, contrast induced AKI correlates with higher healthcare resource utilization in‐ cluding hospitalization cost [11]. The economical spending increases even further if the

We have witnessed significant advancement in the development of contrast medium within the past 7 decades. [8] The structure, osmolality and its inherent chemotoxicity have also changed tremendously, and are the focuses of experiments involving various animal models, cell culture systems, and human subjects. [12] In addition, knowledge of the pathogenesis and the relevant risk factors of contrast-induced AKI is also expandng, and this progress contributes significantly to our planning of strategies to prevent this

> © 2013 Chao et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.


**Chapter 17**

## **Contrast-Induced Nephropathy in Coronary Angiography and Intervention**

Chia-Ter Chao, Vin-Cent Wu and Yen-Hung Lin

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54081

## **1. Introduction**

[70] Toprak, O., & Cirit, M. (2005). Investigating the Volume Status Before Contrast Nephropathy Studies. *Nephrology Dialysis Transplantation,* Vol.20, No.2, (February

348 What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary Artery Disease

[71] Toprak, O., Cirit, M., Bayata, S., Yesil, M., & Aslan, SL. (2003). The Effect of Pre-pro‐ cedural Captopril on Contrast-Induced Nephropathy in Patients who Underwent Coronary Angiography. *Anadolu Kardiyoloji Dergisi,* Vol. 3, No.2, (June 2003), pp.

[72] Toprak, O., Cirit, M., Bayata, S., Aslan, SL., Sarioglu, F., & Cetinkaya, GS. (2003). Is There Any Relationship Between Left Ventricul Ejection Fraction and Contrast In‐ duced Nephropathy? *Türkiye Klinikleri Journal of Medical Sciences*, Vol 23, No. 2,

[73] Vogt, B., Ferrari, P., Schonholzer, C., Marti, HP., Mohaupt, M., Wiederkehr, M., Cere‐ ghetti, C., Serra, A., Huynh-Do, U., Uehlinger, D., & Frey, FJ. (2001). Prophylactic He‐ modialysis after Radiocontrast Media in Patients with Renal Insufficiency is Potentially Harmful. *The American Journal of Medicine,* Vol.111, No.9, (December

[74] Wang, A., Holcslaw, T., Bashore, TM., Freed, MI., Miller, D., Rudnick, MR., Szerlip, H., Thames, MD., Davidson, CJ., Shusterman, N., & Schwab, SJ. (2000). Exacerbation of Radiocontrast Nephrotoxicity by Endothelin Receptor Antagonism. *Kidney Interna‐*

[75] Weber-Mzell, D., Kotanko, P., Schumacher, M., Klein, W., & Skrabal, F. (2002). Coro‐ nary Anatomy Predicts Presence or Absence of Renal Artery Stenosis. A Prospective Study in Patients Undergoing Cardiac Catheterization for Suspected Coronary Ar‐ tery Disease. *European Heart Journal*, Vol.23, No.21, (November 2002), pp.1684–1691,

[76] Weinrauch, LA., Healy, RW., Leland, OS Jr., Goldstein, HH., Kassissieh, SD., Liberti‐ no, JA., Takacs, FJ., & D'Elia, JA. (1977). Coronary Angiography and Acute Renal Failure in Diabetic Azotemic Nephropathy. *Annals of Internal Medicine,* Vol.86, No.1,

[77] Weisberg, LS., Kurnik, PB., & Kurnik, BR. (1994). Risk of Radiocontrast Nephropathy in Patients with and without Diabetes Mellitus. Kidney International, Vol.45, No.1,

[78] Yang, DW., Jia, RH., Yang, DP., Ding, GH., & Huang, CX. (2004). Dietary Hypercho‐ lesterolemia Aggravates Contrast Media-Induced Nephropathy. *Chinese Medical Jour‐*

[79] Zhang, L., Zhang, L., Lu, Y., Wu, B., Zhang, S., Jiang, H., Ge, J., & Chen, H. (2011). Efficacy of Statin Pretreatment for the Prevention of Contrast-Induced Nephropathy: A Meta-Analysis of Randomised Controlled Trials. *International Journal of Clinical*

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ISSN 0195-668x

98-103, ISSN 1302-8723

Since the advent of coronary angioplasty more than 3 decades ago, the volume of percutane‐ ous coronary interventions (PCI) has been rising progressively, with relative decrease in amount of coronary artery bypass graft (CABG) surgery. Roughly 1.4 million of catheteriza‐ tion procedures are performed in U.S. each year.[1] Contrast medium is widely used in both diagnositc coronary angiography and PCI, and intravenous use of iodinated contrast medi‐ um is a common precipitator of contrast-induced nephropathy (or contrast-induced acute kidney injury [AKI]). [2, 3] With the trend of increasing PCI use in the modern era, expected‐ ly more patients will develop contrast-induced AKI in the future. Currently contrast-in‐ duced nephropathy has been the third most common cause of hospital-acquired AKI in the large registry studies. [4] This phenomenon is worthy of our attention, since past researchers have identified that contrast-induced AKI can be associated with increased late incidence of acute myocardial infarction (AMI) and target vessel revascularization [5], longer in-hospital stay [6], a more complicated hospitalization course (bleeding episodes requiring transfusion, vascular complications) [7], and higher in-hospital mortality and morbidity [8-10]. More im‐ portantly, contrast induced AKI correlates with higher healthcare resource utilization in‐ cluding hospitalization cost [11]. The economical spending increases even further if the episodes of contrast-induced AKI are dialysis-requring.

We have witnessed significant advancement in the development of contrast medium within the past 7 decades. [8] The structure, osmolality and its inherent chemotoxicity have also changed tremendously, and are the focuses of experiments involving various animal models, cell culture systems, and human subjects. [12] In addition, knowledge of the pathogenesis and the relevant risk factors of contrast-induced AKI is also expandng, and this progress contributes significantly to our planning of strategies to prevent this

© 2013 Chao et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

adverse event after contrast medium injection. In this sense, a thorough understanding of the epidemiology, pathophysiology, clinical manifestations, diagnosis, prevention strategy and management of contrast-induced AKI is of critical importance for both primary care physicians and intervention cardiologists.

*Potential Serum markers Time frame* **Within 2-4 hours after procedure**

Serum creatinine 1.0 mg/dL↑

Serum creatinine 50%↑from baseline

Serum cystatin C# ? 25%↑from baseline Urinary NGAL# ↑>100-150 ng/mL
