Still under investigation

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

The reported incidence of contrast-induced AKI varies widely among the existing literature, ranging from 2% to 25% after contrast medium injection [2, 13-15]. The estimations differ ac‐ cording to the cohort being studied, the definition used to identify patients with contrastinduced AKI, the distinction of the baseline risk factors of the population studied, and the intervention administered for prevention. [2] Maioli and coworkers, in a randomized con‐ trolled trial (RCT) to evaluate the effectiveness of various preventive strategies, identified a 2~2.5 fold difference in the incidence of contrast-induced AKI (control group, 12%; interven‐ tion group, 27.3%). [16] Weisbord and colleagues, in another study, demonstrated the im‐ portance of the AKI definition to the estimated incidence (ranging from 0.3% if stringently defined by serum creatinine [sCr] change of 1.0 mg/dL, to 13.7% if loosely defined by sCr change of 0.25 mg/dL). [3] Consequently, a consistent definition of contrast-induced AKI is

The definition of contrast-induced AKI can be divided into 2 main components, the predefined time frame and the change of renal function markers (Table 1). Typically contrastinduced AKI is defined by the current literature as an increase in sCr within the first 24 or 48 hours after contrast injection. [2, 14] There are arguments, however, that a period of 24 hours best captures the group of patients who develop contrast-induced AKI and car‐ ry the most favorable outcome; others claim that the elevation of sCr for clinical dignosis of contrast-induced AKI takes at least 48 hours. [17] The European Society of Urogenital Radiology (ESUR) has produced guidelines on contrast-induced AKI in 1999, and updat‐ ed the content in 2011. [18, 19] Contrast-induced AKI (then termed contrast-induced nephropathy [CIN]) is defined as "a condition in which an impairment in renal function (an increase in sCr by more than 25% or 0.5 mg/dL) occurs within 3 days following intra‐ vascular administration of a contrast medium, in the absence of an alternative etiology". [18] Recently, the threshold of sCr change for diagnosis of AKI has been challenged, since minor sCr change has been shown to correlate with outcome measures. [20] In 2007, Acute Kidney Injury Network (AKIN) group has proposed a further fine-tuned classifica‐ tion scheme for staging AKI. [21] Milder AKI was staged as an elevation of sCre of 0.3 mg/dL within 48 hours. This concept further enhances the diagnostic probability of con‐ trast-induced nephropathy, but there concerns that this criteria might be over-sensitive and leads to false positive diagnosis. [22] The researchers are now gradully adopting this

**2. Epidemiology of contrast induced acute kidney injury (AKI)**

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

physicians and intervention cardiologists.

vital for both clinical and research interest in this field.

scheme in categorzing contrast-induced AKI.

**2.1. Definition of contrast-induced acute kidney injury (AKI)**

**Table 1.** The currently available definition of contrast-induced nephropathy

Other rapidly-responsive serum markers aiming at earlier detection of renal function change also are under investigation. Cystatin C is a cationic low molecular weight cys‐ teine protease, produced at a constant rate by all nucleated cells.[23] It is not metabo‐ lized in the serum, and is freely filtered by glomeruli, thus serving as a good marker for assessing glomerular filtration rate (GFR).[24] A japanese study utilizing cystatin C and sCr in evaluating post-computed tomographic coronary angiography AKI concluded that serum cystatin C at day one after examination significantly correlates with change of sCr, indicating AKI. [25] Cystatin C is particularly useful in patients with diabetic histo‐ ry. On the other hand, Ribichini et al, in another study comparing sCr and cystatin C for detecting AKI after PCI within 12 hours, found that serum cystatin C performed signifi‐ cantly worse than sCr, with an area under curve (AUC) value of 0.48 only. [26] Neutro‐ phil gelatinase-associated lipocalin (NGAL) is a small stress protein released from injured tubular cells after various stimuli. [27] A multitude of studies have documented its role in earlier detection of AKI, with excellent sensitivity and fair specificity.[28-30] Hirsch and coworkers first demonstrated in pediatric population that, with a cut-off val‐ ue of 100 ng/mL and timeframe of 2 hours, urinary NGAL predicts contrast-induced AKI well, with 73% sensitivity and 100% specificity. [31] Another study from Austria reached similar findings, with additional benefit of improving renal outcome, possibly due to ear‐ lier detection. [32] Besides, there are other potential candidate biomarkers implicated as possessing a role in contrast-induced AKI, including kidney-injury molecules -1 (KIM-1), urinary L type fatty acid-binding protein (L-FABP), but few human studies are available currently.[33] Finally, the exact diagnostic modality of choice for contrast-induced nephr‐ opathy remains uncertain. A recent study by Erselcan and colleagues discovered that sCr-based diagnosis can in fact differ substantially from radionuclide-based GFR estima‐ tion method. [34] Consequently, the reported incidence of contrast-induced nephropathy in the literature might contain certain degree of deviation. Nonetheless, a close monitor‐ ing of sCr change and other markers of renal function change after contrast exposure is still crucial and necessary to detect any evidence of contrast-induced nephropathy after PCI.

morbidities such as coronary artery diseases also contribute to the increased susceptibili‐ ty. [37] Fluid retention in DM patients also increases the use of diuretics, which is also reportedly a risk factor for contrast-induced AKI. [38] In addition to the impact of a base‐ line DM, pre-procedural glucose level higher than 200 mg/dL s is also a risk factor for

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Advanced age is another risk factor that enhances the probability of developing contrast-in‐ duced AKI. The definition of advanced age differs between the reported studies, but gener‐ ally a range of 65-75 year-old is adopted. [15] Age higher than 75 can associate with a 1.5-5 fold elevated risk, while every one-year increment carries a 2% increased risk. [7, 15, 35] Ag‐ ing *per se* denotes the physiologic degeneration of the kidney, both structurally and func‐ tionally, and the ability of recovery after various nephrotoxic insults also dampens in this population. [40] Most experts agree that a baseline renal function should be measured in

Probably the most important risk factor for contrast-induced AKI is a baseline comorbidity of CKD. Almost all clinical trials and scoring models for predicting and stratifying risk of contrast-induced AKI have shown that CKD independently leads to more contrast-induced AKI episodes. [6, 7, 9, 13, 15, 35] The risk of renal dysfunction is directly proportional to the baseline sCr value, and further amplified by the presence of DM. [7, 15] Rihal et al, in a large PCI cohort, identified that patients with pre-procedural sCr 1.2-1.9, 2.0-2.9, >3 mg/dL, had a graded increment in risk of developing contrast-induced AKI (odds ratio [OR] 2.4, 7.4 and 12.8, respectively).[35] One-third of patients with sCr level higher than 2.0 mg/dL receiving

contrast medium for radiographic studies will develop contrast-induced AKI. [41, 42]

The definition of CKD seems to vary somewhat between studies. It is generally agreed that patients with CKD should be classified by the stages proposed by the Kidney Dis‐ ease Outcome Quality Initiative (KDOQI) according to their GFR values. [19] (Table 3) CKD is usually defined as renal function within stage 3 or higher level based on the KDOQI scheme, but there are some controversy about this. [43] GFR can be estimated by the Modification of Diet in Renal Disease (MDRD) formula, which takes account of each patient's sCr, age, ethnicity and gender. [44] However, this equation might be flawed when applied in patients with unstable or changing renal function. Patients with special dietary preference such as vegetarians and high protein diets, and ones with extreme body stature (very obese or lean) may be unsuitable by MDRD formula, too. [44] Recent‐ ly, Chronic Kidney Disease – Epidemiology Collaboration (CKD-EPI) creatinine equation is found to outperform MDRD formula in these situations, but this equation, too, does not apply during changing renal function. [45] Nonetheless, sCr-based estimation of GFR is currently still the most valuable and timely method of grading patients' baseline renal function. Patients with estimated GFR (eGFR) higher than 60 ml/min/1.73m2 should be

contrast-induced AKI (2-fold risk). [39]

*3.1.3. Pre-existing chronic kidney disease (CKD)*

older patients before their exposure to contrast medium. [2, 19]

treated as normal unless they have other renal diseases. [46]

*3.1.2. Advanced age*

## **3. Risk factors for contrast induced acute kidney injury (AKI)**

Identification of patients potentially susceptible of developing contrast-induced AKI before their exposure is important, since modification of the ways we administer contrast medium can lead to a decrease in AKI. [4] Risk factors for developing such injury can be divided into 2 parts: patient-related factors and procedure-related factors. We will give a brief overview of these factors in the following sections.

#### **3.1. Patient-related risk factors**

There are several factors identified in the literature that enhances the susceptibility of devel‐ oping contrast-induced AKI (Table 2).


Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CKD, chronic kidney disease; NSAID, non-steroidal anti-inflammatory agent

**Table 2.** Factors associated with increased risk of contrast-induced acute kidney injury

#### *3.1.1. Diabetes mellitus (DM)*

DM has been established as an independent factor for patients developing contrast-in‐ duced AKI. Presence of DM is associated with a 1.5 ~ 3 fold higher risk of renal injury af‐ ter contrast exposure, and it potentially amplifies the risk incurred by pre-existing chronic kidney disease (CKD) alone (see below). [13, 15, 35] DM putatively predisposes host kid‐ neys to ischemic injury (from macro- or micro-vascular stenosis), increases oxidatice stress and free radical damage, as well as endothelial dysfunction.[36] The accompanying co‐ morbidities such as coronary artery diseases also contribute to the increased susceptibili‐ ty. [37] Fluid retention in DM patients also increases the use of diuretics, which is also reportedly a risk factor for contrast-induced AKI. [38] In addition to the impact of a base‐ line DM, pre-procedural glucose level higher than 200 mg/dL s is also a risk factor for contrast-induced AKI (2-fold risk). [39]

#### *3.1.2. Advanced age*

ing of sCr change and other markers of renal function change after contrast exposure is still crucial and necessary to detect any evidence of contrast-induced nephropathy after

Identification of patients potentially susceptible of developing contrast-induced AKI before their exposure is important, since modification of the ways we administer contrast medium can lead to a decrease in AKI. [4] Risk factors for developing such injury can be divided into 2 parts: patient-related factors and procedure-related factors. We will give a brief overview

There are several factors identified in the literature that enhances the susceptibility of devel‐

**Patient-related risk factors Procedure-related risk factors**

Diabetes (especially with nephropathy) Higher contrast medium osmolality

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CKD, chronic kidney disease;

DM has been established as an independent factor for patients developing contrast-in‐ duced AKI. Presence of DM is associated with a 1.5 ~ 3 fold higher risk of renal injury af‐ ter contrast exposure, and it potentially amplifies the risk incurred by pre-existing chronic kidney disease (CKD) alone (see below). [13, 15, 35] DM putatively predisposes host kid‐ neys to ischemic injury (from macro- or micro-vascular stenosis), increases oxidatice stress and free radical damage, as well as endothelial dysfunction.[36] The accompanying co‐

**Table 2.** Factors associated with increased risk of contrast-induced acute kidney injury

Advanced age Higher contrast medium volumes

Pre-existing CKD Intra-arterial (vs. intravenous) route

**3. Risk factors for contrast induced acute kidney injury (AKI)**

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

of these factors in the following sections.

oping contrast-induced AKI (Table 2).

Arterial hypotension Absolute intravascular volume depletion status Relative intravascular volume depletion status Diuretic use NSAID use (?) ACE inhibitor/ARB use (?)

NSAID, non-steroidal anti-inflammatory agent

*3.1.1. Diabetes mellitus (DM)*

**3.1. Patient-related risk factors**

PCI.

Advanced age is another risk factor that enhances the probability of developing contrast-in‐ duced AKI. The definition of advanced age differs between the reported studies, but gener‐ ally a range of 65-75 year-old is adopted. [15] Age higher than 75 can associate with a 1.5-5 fold elevated risk, while every one-year increment carries a 2% increased risk. [7, 15, 35] Ag‐ ing *per se* denotes the physiologic degeneration of the kidney, both structurally and func‐ tionally, and the ability of recovery after various nephrotoxic insults also dampens in this population. [40] Most experts agree that a baseline renal function should be measured in older patients before their exposure to contrast medium. [2, 19]

#### *3.1.3. Pre-existing chronic kidney disease (CKD)*

Probably the most important risk factor for contrast-induced AKI is a baseline comorbidity of CKD. Almost all clinical trials and scoring models for predicting and stratifying risk of contrast-induced AKI have shown that CKD independently leads to more contrast-induced AKI episodes. [6, 7, 9, 13, 15, 35] The risk of renal dysfunction is directly proportional to the baseline sCr value, and further amplified by the presence of DM. [7, 15] Rihal et al, in a large PCI cohort, identified that patients with pre-procedural sCr 1.2-1.9, 2.0-2.9, >3 mg/dL, had a graded increment in risk of developing contrast-induced AKI (odds ratio [OR] 2.4, 7.4 and 12.8, respectively).[35] One-third of patients with sCr level higher than 2.0 mg/dL receiving contrast medium for radiographic studies will develop contrast-induced AKI. [41, 42]

The definition of CKD seems to vary somewhat between studies. It is generally agreed that patients with CKD should be classified by the stages proposed by the Kidney Dis‐ ease Outcome Quality Initiative (KDOQI) according to their GFR values. [19] (Table 3) CKD is usually defined as renal function within stage 3 or higher level based on the KDOQI scheme, but there are some controversy about this. [43] GFR can be estimated by the Modification of Diet in Renal Disease (MDRD) formula, which takes account of each patient's sCr, age, ethnicity and gender. [44] However, this equation might be flawed when applied in patients with unstable or changing renal function. Patients with special dietary preference such as vegetarians and high protein diets, and ones with extreme body stature (very obese or lean) may be unsuitable by MDRD formula, too. [44] Recent‐ ly, Chronic Kidney Disease – Epidemiology Collaboration (CKD-EPI) creatinine equation is found to outperform MDRD formula in these situations, but this equation, too, does not apply during changing renal function. [45] Nonetheless, sCr-based estimation of GFR is currently still the most valuable and timely method of grading patients' baseline renal function. Patients with estimated GFR (eGFR) higher than 60 ml/min/1.73m2 should be treated as normal unless they have other renal diseases. [46]

#### *3.1.4. Arterial hypotension*

Hemodynamic instability has been quoted as a risk factor for contrast-induced AKI. [6, 13, 15] This can be demonstrated in certain parameters like hypotension and placement of intraaortic balloon pump (IABP). [47] Gruberg and coworkers identified that use of IABP is linked to a 2 fold increase of developing contrast-induced AKI in patients receiving PCI. [48] In addition, anemia *per se* can also be treated in this regard as a factor that reduces tissue oxygenation and predisposes to CIN. [49]

warranted before we can conclude that NSAID is neutral or potentially promoting contrast-

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355

Other nephrotoxic agents such as cyclosporin, tacrolimus, platinum-based chemothera‐ peutic regimen can theoretically enhance the susceptibility of the kidney to the insult of contrast medium. [56] Likewise, few clinical data exists concerning this issue, but physi‐ cians and cardiologists are still advised to refrain from these drugs in patients preparing

Elevated high sensitivity CRP has recently been reported as a risk factor for contrast-in‐ duced AKI. [57] The mechanism is putatively related to higher inflammatory status and the cytokine effect, but this remains speculative. Some researchers also claimed that multiple myeloma elevates the risk of CIN, but this association is inconsistent among recent studies. [56, 58, 59] Multiple myeloma by itself might not increase the inherent risk, but patients with myeloma is frequently dehydrated, and such dehydration could underlie the basis of the

Procedure-related risk factors include the volume, the osmolality, and the route of contrast

Iodinated contrast media are structurally composed of carbon-based skeletons and iodide atoms, which render the molecules radiopaque. Contrast media are classified according to their osmolality into 3 types: high-osmolal (HOCM) (ex. diatrizoate), with an osmolality of ~2000 mOsm/kg; low-osmolal (LOCM)(ex. Iohexol, iopamidol, ioxaglate), with an osmolality of 600~800 mOsm/kg; and isosmolal (IOCM) (iodixanol), with an osmolality similar to se‐ rum. [2] When the contrast media were first introduced decades ago, only HOCM are avail‐ able for imaging purposes. LOCM/IOCM were later developed in 1980s and 1990s, in order to reduce the accompanied toxicity incurred by high osmolality. [8] Earlier meta-analysis be‐ fore 1990 demonstrated that the pooled OR for developing CIN decreased substantially after the introduction of LOCM. [60] High osmolality contrast medium is now an established risk factor for contrast-induced AKI. [2, 8, 14, 19] IOCM has been shown to possess the lowest risk for contrast -induced AKI in patients with CKD, but different IOCM agents do not seem to display clinically different effect. [61-64] A systemic review performed several years ago found that IOCM possess the lowest risk of contrast-induced AKI. [64] However, several clinical trials done in recent years yielded conflict results, with similar CIN rates between IOCM and LOCM agents. [65, 66] Despite these controversies, the American College of Car‐ diology (ACC) /American Heart Association (AHA) guidelines for the management of pa‐ tients with acute coronary syndrome (ACS) list IOCM as a class I recommendation. [67]

induced AKI at this time.

for coronary procedures.

*3.1.8. Miscellaneous*

heightened risk. [19]

medium administration.

**3.2. Procedure-related risk factors**

*3.2.1. Osmolality of contrast medium*

#### *3.1.5. Absolute intravascular volume depletion (dehydration)*

Dehydration is commonly cited as a risk factor for contrast-induced nephropathy. [35, 50, 51] However, few clinical trials actually prove this risk, possibly owing to the fact that dehy‐ dration status is difficult to demonstrate and quantify.

#### *3.1.6. Relative intravascular volume depletion*

Statuses such as congestive heart failure (CHF) also potentiate the development of con‐ trast-induced AKI, through mechanisms similar to dehydration and absolute intravascu‐ lar volume depletion. [2, 15] CHF is also a risk factor for AKI in critically ill patients. [2] Most clinical trials have shown than CHF (with a New York Heart Association [NYHA] grade 3-4) is associated with elevated risk of contrast-induced AKI (OR around 1.5-2.0). [13, 15, 35] There are also studies showing that AMI within 24 hours of PCI with a low left ventricular ejection fraction (LVEF) independently predicts occurrence of CIN, with a 80% higher risk. [6, 35]

#### *3.1.7. Drugs (Angiotensin-converting enzyme inhibitors [ACEI], angiotensin-receptor blockers [ARB], Non-steroidal anti-inflammatory agents [NSAID])*

ACEI and ARB, by virtue of their glomerular hemodynamic effect, have been implicated in predisposing patients to contrast-induced AKI. [42] However, minimal data exists regarding their actual role in the development of such renal injury. Currently, most available results are retrospective in nature, and case numbers are low. Umruddin and colleagues, in a small case control study, demonstrated that use of ACEI or ARB is associated with 2.5-3.0 fold higher risk of developing CIN after coronary angiography. [52] On the contrary, withdrawal of ACEI or ARB before coronary procedures does not seem to reduce the risk of contrastinduced AKI. [53]

NSAIDs are commonly prescribed for analgesic and anti-pyretic purposes, and are notori‐ ous for their adverse impact on cardiovascular outcomes after AMI. [54] Through the inter‐ ruption of intrarenal prostaglandin production, these drugs impede the hemodynamic regulation of kidney during nephrotoxic insults. Intuitively, they should contribute signifi‐ cantly to contrast-induced nephropathy, but there are very few clinical data currently. A Brazilian group identified no obvious increase in risk of CIN in patients taking NSAIDs be‐ fore they receive coronary procedures, but the case number was low. [55] Further study is warranted before we can conclude that NSAID is neutral or potentially promoting contrastinduced AKI at this time.

Other nephrotoxic agents such as cyclosporin, tacrolimus, platinum-based chemothera‐ peutic regimen can theoretically enhance the susceptibility of the kidney to the insult of contrast medium. [56] Likewise, few clinical data exists concerning this issue, but physi‐ cians and cardiologists are still advised to refrain from these drugs in patients preparing for coronary procedures.

#### *3.1.8. Miscellaneous*

*3.1.4. Arterial hypotension*

oxygenation and predisposes to CIN. [49]

*3.1.6. Relative intravascular volume depletion*

80% higher risk. [6, 35]

induced AKI. [53]

*3.1.5. Absolute intravascular volume depletion (dehydration)*

dration status is difficult to demonstrate and quantify.

*[ARB], Non-steroidal anti-inflammatory agents [NSAID])*

Hemodynamic instability has been quoted as a risk factor for contrast-induced AKI. [6, 13, 15] This can be demonstrated in certain parameters like hypotension and placement of intraaortic balloon pump (IABP). [47] Gruberg and coworkers identified that use of IABP is linked to a 2 fold increase of developing contrast-induced AKI in patients receiving PCI. [48] In addition, anemia *per se* can also be treated in this regard as a factor that reduces tissue

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

Dehydration is commonly cited as a risk factor for contrast-induced nephropathy. [35, 50, 51] However, few clinical trials actually prove this risk, possibly owing to the fact that dehy‐

Statuses such as congestive heart failure (CHF) also potentiate the development of con‐ trast-induced AKI, through mechanisms similar to dehydration and absolute intravascu‐ lar volume depletion. [2, 15] CHF is also a risk factor for AKI in critically ill patients. [2] Most clinical trials have shown than CHF (with a New York Heart Association [NYHA] grade 3-4) is associated with elevated risk of contrast-induced AKI (OR around 1.5-2.0). [13, 15, 35] There are also studies showing that AMI within 24 hours of PCI with a low left ventricular ejection fraction (LVEF) independently predicts occurrence of CIN, with a

*3.1.7. Drugs (Angiotensin-converting enzyme inhibitors [ACEI], angiotensin-receptor blockers*

ACEI and ARB, by virtue of their glomerular hemodynamic effect, have been implicated in predisposing patients to contrast-induced AKI. [42] However, minimal data exists regarding their actual role in the development of such renal injury. Currently, most available results are retrospective in nature, and case numbers are low. Umruddin and colleagues, in a small case control study, demonstrated that use of ACEI or ARB is associated with 2.5-3.0 fold higher risk of developing CIN after coronary angiography. [52] On the contrary, withdrawal of ACEI or ARB before coronary procedures does not seem to reduce the risk of contrast-

NSAIDs are commonly prescribed for analgesic and anti-pyretic purposes, and are notori‐ ous for their adverse impact on cardiovascular outcomes after AMI. [54] Through the inter‐ ruption of intrarenal prostaglandin production, these drugs impede the hemodynamic regulation of kidney during nephrotoxic insults. Intuitively, they should contribute signifi‐ cantly to contrast-induced nephropathy, but there are very few clinical data currently. A Brazilian group identified no obvious increase in risk of CIN in patients taking NSAIDs be‐ fore they receive coronary procedures, but the case number was low. [55] Further study is Elevated high sensitivity CRP has recently been reported as a risk factor for contrast-in‐ duced AKI. [57] The mechanism is putatively related to higher inflammatory status and the cytokine effect, but this remains speculative. Some researchers also claimed that multiple myeloma elevates the risk of CIN, but this association is inconsistent among recent studies. [56, 58, 59] Multiple myeloma by itself might not increase the inherent risk, but patients with myeloma is frequently dehydrated, and such dehydration could underlie the basis of the heightened risk. [19]

### **3.2. Procedure-related risk factors**

Procedure-related risk factors include the volume, the osmolality, and the route of contrast medium administration.

### *3.2.1. Osmolality of contrast medium*

Iodinated contrast media are structurally composed of carbon-based skeletons and iodide atoms, which render the molecules radiopaque. Contrast media are classified according to their osmolality into 3 types: high-osmolal (HOCM) (ex. diatrizoate), with an osmolality of ~2000 mOsm/kg; low-osmolal (LOCM)(ex. Iohexol, iopamidol, ioxaglate), with an osmolality of 600~800 mOsm/kg; and isosmolal (IOCM) (iodixanol), with an osmolality similar to se‐ rum. [2] When the contrast media were first introduced decades ago, only HOCM are avail‐ able for imaging purposes. LOCM/IOCM were later developed in 1980s and 1990s, in order to reduce the accompanied toxicity incurred by high osmolality. [8] Earlier meta-analysis be‐ fore 1990 demonstrated that the pooled OR for developing CIN decreased substantially after the introduction of LOCM. [60] High osmolality contrast medium is now an established risk factor for contrast-induced AKI. [2, 8, 14, 19] IOCM has been shown to possess the lowest risk for contrast -induced AKI in patients with CKD, but different IOCM agents do not seem to display clinically different effect. [61-64] A systemic review performed several years ago found that IOCM possess the lowest risk of contrast-induced AKI. [64] However, several clinical trials done in recent years yielded conflict results, with similar CIN rates between IOCM and LOCM agents. [65, 66] Despite these controversies, the American College of Car‐ diology (ACC) /American Heart Association (AHA) guidelines for the management of pa‐ tients with acute coronary syndrome (ACS) list IOCM as a class I recommendation. [67]

#### *3.2.2. Volume of contrast medium*

The volume of administered contrast medium can be another important factor regarding the risk of contrast-induced AKI. Multiple studies have identified that the mean contrast volume is an independent predictor of CIN. [5, 9, 15] Even small volumes of contrast medium (~30ml) might trigger renal injury in high-risk patients. [68] For every 100ml in‐ crease in the amount of contrast medium used, there is a concomitant 12% increase of the risk. [35] Several groups proposed that the volume of contrast administered should not exceed twice the number of a given patient's baseline eGFR value (in mililiter), while others found that adjustment of the contrast volume to one's body weight and sCr level could minimize the risk. [2, 69]

**4.1. Renal ischemia**

**4.2. Direct tubulotoxicity**

Animal studies showed that contrast medium intravascular injection can increase the activi‐ ty of a variety of vasoactive substances, including vasopressin, angiotensin II, dopamine-1, endothelin and adenosine, while decrease the activity of renal vasodilators such as nitric ox‐ ide and prostaglandins. [72, 73] Other mechanisms include high osmolality-related renal blood flow decrease, and the enhanced erythrocyte aggregation induced by contrast medi‐ um. [74, 75] This decrease in renal blood flow and GFR after exposure to contrast medium is frequently severer in dehydrated animals than euvolemic ones. [76] In particular, renal me‐ dulla is more susceptible to ischemic insult than renal cortex, and contrast medium has been

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The tubulotoxicity of contrast medium can be demonstrated in the pathological changes it induces, including epithelial vacuolization, cellular necrosis or apoptosis and interstitial in‐ flammation. [78] Contrast medium can additionally reduce antioxidant enzyme activity within the kidney of experimental animals, and free radical mediated cytotoxicity of the re‐ nal tubular cells has been detected in these models. [78] The higher osmolality of contrast medium can also contribute to its epithelial cell toxicity. The osmolar-driven solute diuresis with subsequent tubuloglomerular feedback activation can theoretically reduce GFR, and in‐ creased tubular hydrostatic pressures might cause compression of surrounding microvascu‐ latures, leading to a decrease in GFR. [42] In an in vitro cell model, apoptosis (presenting as DNA fragmentation) was found to increase in cells exposed to hyperosmolar contrast me‐ dia, with the degree of fragmentation proportional to the osmolality of contrast media. [79] Consequently, contrast medium possesses direct tubulotoxicity not only through the induc‐ tion of oxidative stress and cellular injury, but also through the hyperosmolality it carries. It would be interesting to speculate whether the available isosmotic contrast media can reduce the renal abnormality displayed by exposure to their high osmolar and low osmolar coun‐ terparts, but there seems to be no difference. [80] A plausible reason is that isosmolar con‐ trast medium still has increased viscosity and might cause more tubular cell vacuolization

Many research groups have strived to devise predictive models for patients with high risk of developing contrast-induced AKI. Mehran and colleagues developed a simple scoring method that integrates 8 baseline clinical variables to evaluate the risk of CIN after PCI. These variables include advanced age (defined as age > 75), hypotension, CHF, anemia, DM, CKD (defined as sCr > 1.5 mg/dL), use of IABP and procedural factors (volume of contrast medium), each with different score. [15] Risk categories are divided into low, moderate, high, and very high. They found that the incidence of contrast-induced AKI ranges from 7.5% in the low risk category, to 57.3% in the very high risk category. Bartholomew and

reported to cause shunting of blood flow to the cortex. [77]

and cessation of renal microcirculation. [81]

**5. Risk prediction and modeling**

#### *3.2.3. Route of contrast medium administration*

Circumstantial evidence has pointed out that intra-arterial injection of contrast medium car‐ ries a higher risk of contrast-induced AKI than intravenous use. [15, 70] However, no mech‐ anisms have been provided to explain this phenomenon. [2] Some speculative reasons are as follows: the dose used in intravenous enhancement for computed tomography (CT) is usual‐ ly lower than that for arteriography; patients who received contrast-enhanced CT are usual‐ ly less hemodynamically unstable than ones receiving intra-arterial studies; intra-arterial angiography may incidentally incur atheroembolism, which would not be expected to hap‐ pen in intravenous studies. [2, 19] There are also reports suggesting that patients who were at-risk for intra-arterial procedures might not be at-risk for intravenous studies. [3] Nonethe‐ less, based upon the available evidence, it is prudent to evaluate patients regarding the exact necessity, risk and benefit for intra-arterial or intravenous procedures. If both indications ex‐ ist with equal risk-benefit ratio, a choice of intravenous administration of contrast medium might be better.

## **4. Clinical course and pathophysiology of contrast-induced AKI**

The norm of contrast-induced nephropathy is that sCr begins to rise within 24 hours after contrast medium administration, peaks at 3-5 days, and returns to baseline level or near baseline within 1-3 weeks. [71] It has been shown that even transient rise of sCr can asso‐ ciate with longer hospital stay. [42] Most patients developing contrast-induced AKI do not require dialysis; however, they do have poorer short-term and long-term survival. [9, 48] Gruberg et al, in a large cohort of patients with CIN after coronary angiography, reported that only 0.4% require hemodialysis after AKI occurs, but those necessitating dialytic sup‐ port have particularly higher mortality (12-35%). [42, 48]

The pathophysiologic sequence of contrast-induced AKI includes a pre-existing impaired re‐ nal function, and the superimposed acute events consisting of vasoactive mediator-related vasoconstriction, triggered by iodinated contrast medium. [2] Besides, experimental studies also suggest that contrast-induced nephropathy can be a combination of both: renal ische‐ mia and the direct tubulotoxicity exerted by contrast medium. [42]

#### **4.1. Renal ischemia**

*3.2.2. Volume of contrast medium*

could minimize the risk. [2, 69]

might be better.

*3.2.3. Route of contrast medium administration*

The volume of administered contrast medium can be another important factor regarding the risk of contrast-induced AKI. Multiple studies have identified that the mean contrast volume is an independent predictor of CIN. [5, 9, 15] Even small volumes of contrast medium (~30ml) might trigger renal injury in high-risk patients. [68] For every 100ml in‐ crease in the amount of contrast medium used, there is a concomitant 12% increase of the risk. [35] Several groups proposed that the volume of contrast administered should not exceed twice the number of a given patient's baseline eGFR value (in mililiter), while others found that adjustment of the contrast volume to one's body weight and sCr level

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

Circumstantial evidence has pointed out that intra-arterial injection of contrast medium car‐ ries a higher risk of contrast-induced AKI than intravenous use. [15, 70] However, no mech‐ anisms have been provided to explain this phenomenon. [2] Some speculative reasons are as follows: the dose used in intravenous enhancement for computed tomography (CT) is usual‐ ly lower than that for arteriography; patients who received contrast-enhanced CT are usual‐ ly less hemodynamically unstable than ones receiving intra-arterial studies; intra-arterial angiography may incidentally incur atheroembolism, which would not be expected to hap‐ pen in intravenous studies. [2, 19] There are also reports suggesting that patients who were at-risk for intra-arterial procedures might not be at-risk for intravenous studies. [3] Nonethe‐ less, based upon the available evidence, it is prudent to evaluate patients regarding the exact necessity, risk and benefit for intra-arterial or intravenous procedures. If both indications ex‐ ist with equal risk-benefit ratio, a choice of intravenous administration of contrast medium

**4. Clinical course and pathophysiology of contrast-induced AKI**

port have particularly higher mortality (12-35%). [42, 48]

mia and the direct tubulotoxicity exerted by contrast medium. [42]

The norm of contrast-induced nephropathy is that sCr begins to rise within 24 hours after contrast medium administration, peaks at 3-5 days, and returns to baseline level or near baseline within 1-3 weeks. [71] It has been shown that even transient rise of sCr can asso‐ ciate with longer hospital stay. [42] Most patients developing contrast-induced AKI do not require dialysis; however, they do have poorer short-term and long-term survival. [9, 48] Gruberg et al, in a large cohort of patients with CIN after coronary angiography, reported that only 0.4% require hemodialysis after AKI occurs, but those necessitating dialytic sup‐

The pathophysiologic sequence of contrast-induced AKI includes a pre-existing impaired re‐ nal function, and the superimposed acute events consisting of vasoactive mediator-related vasoconstriction, triggered by iodinated contrast medium. [2] Besides, experimental studies also suggest that contrast-induced nephropathy can be a combination of both: renal ische‐ Animal studies showed that contrast medium intravascular injection can increase the activi‐ ty of a variety of vasoactive substances, including vasopressin, angiotensin II, dopamine-1, endothelin and adenosine, while decrease the activity of renal vasodilators such as nitric ox‐ ide and prostaglandins. [72, 73] Other mechanisms include high osmolality-related renal blood flow decrease, and the enhanced erythrocyte aggregation induced by contrast medi‐ um. [74, 75] This decrease in renal blood flow and GFR after exposure to contrast medium is frequently severer in dehydrated animals than euvolemic ones. [76] In particular, renal me‐ dulla is more susceptible to ischemic insult than renal cortex, and contrast medium has been reported to cause shunting of blood flow to the cortex. [77]

#### **4.2. Direct tubulotoxicity**

The tubulotoxicity of contrast medium can be demonstrated in the pathological changes it induces, including epithelial vacuolization, cellular necrosis or apoptosis and interstitial in‐ flammation. [78] Contrast medium can additionally reduce antioxidant enzyme activity within the kidney of experimental animals, and free radical mediated cytotoxicity of the re‐ nal tubular cells has been detected in these models. [78] The higher osmolality of contrast medium can also contribute to its epithelial cell toxicity. The osmolar-driven solute diuresis with subsequent tubuloglomerular feedback activation can theoretically reduce GFR, and in‐ creased tubular hydrostatic pressures might cause compression of surrounding microvascu‐ latures, leading to a decrease in GFR. [42] In an in vitro cell model, apoptosis (presenting as DNA fragmentation) was found to increase in cells exposed to hyperosmolar contrast me‐ dia, with the degree of fragmentation proportional to the osmolality of contrast media. [79] Consequently, contrast medium possesses direct tubulotoxicity not only through the induc‐ tion of oxidative stress and cellular injury, but also through the hyperosmolality it carries. It would be interesting to speculate whether the available isosmotic contrast media can reduce the renal abnormality displayed by exposure to their high osmolar and low osmolar coun‐ terparts, but there seems to be no difference. [80] A plausible reason is that isosmolar con‐ trast medium still has increased viscosity and might cause more tubular cell vacuolization and cessation of renal microcirculation. [81]

## **5. Risk prediction and modeling**

Many research groups have strived to devise predictive models for patients with high risk of developing contrast-induced AKI. Mehran and colleagues developed a simple scoring method that integrates 8 baseline clinical variables to evaluate the risk of CIN after PCI. These variables include advanced age (defined as age > 75), hypotension, CHF, anemia, DM, CKD (defined as sCr > 1.5 mg/dL), use of IABP and procedural factors (volume of contrast medium), each with different score. [15] Risk categories are divided into low, moderate, high, and very high. They found that the incidence of contrast-induced AKI ranges from 7.5% in the low risk category, to 57.3% in the very high risk category. Bartholomew and coworkers, in another large cohort of post-PCI CIN patients, derived a risk scoring scheme composed of DM, CHF, hypertension, peripheral vascular disease, IABP uses, CKD (defined as creatinine clearance < 60 ml/min), and procedural factors (urgent or emergency proce‐ dures, contrast volume ≧260ml). [13] Incidence of CIN ranged from 0.5% in the lowest risk category, to 43% in the highest risk category. These studies did prove that the risk factors identified previously are mutually additive, and the risk of contrast-induced AKI increases prominently as risk factors accumulate. However, none of the reported studies have been prospectively applied to different populations, and the utility in real-world is still in ques‐ tion. It is currently inappropriate to recommend the routine use of these models in risk strat‐ ification of specific population [2], but we should bear in mind that the more risk factors our patients possess, the higher risk he/she might develop AKI after receiving PCI.

**6.2. Volume expansion**

*6.2.1. Route of volume expansion*

sion purposes in clinical practice.

*6.2.2. Formula of hydration*

contrast-induced AKI.

tion cannot be perfomed for lack of ethical acceptability.

There is broad consensus that volume expansion (through isotonic saline hydration) is capa‐ ble of reducing the risk of contrast-induced nephropathy. The putative benefit of adequate volume expansion includes improving renal blood flow, inducing diuresis with dilution of contrast medium within renal tubules, suppression of the renin-angiotensin-aldosterone sys‐ tem, lowering the secretion of arginine vasopressin, and less reductions in the renal produc‐ tion of endogenous vasodilators (nitric oxide, prostaglandin). [82] However, firm evidence regarding the benefit of volume expansion is not available and not expected to exist, since randomized, double-blinded trials comparing hydration and a control group without hydra‐

Contrast-Induced Nephropathy in Coronary Angiography and Intervention

http://dx.doi.org/10.5772/54081

359

The route of volume expansion has been debated. Earlier expert group consensus suggested that intravenous hydration is more favorable than oral hydration [18], but clinical evidence seemed conflicting. Trivedi and coworkers prospectively evaluated the efficacy of unrestrict‐ ed oral fluids or intravenous normal saline for 24 hours (at a rate of 1ml/kg/hr, 12 hours be‐ fore and 12 hours after procedures) in a small group of elective PCI patients. [83] Contrastinduced AKI occurred significantly less frequently in the intravenous hydration group than the oral fluid group (3.7% vs. 34.6%). Dussol et al perfomed another study comparing intra‐ venous normal saline (at a rate of 15 ml/kg for 6 hours before procedure) to oral salt tablet (1g/10kg body weight for 2 days before procedure) in a moderately-sized cohort receiving various radiologic studies. [84] Oral salt supplement was found to be as effective as intrave‐ nous saline hydration for the prevention of contrast-induced AKI. However, the pre-proce‐ dural fasting policy routinely instituted in some groups might make oral salt tabley not feasible. Nonetheless, most groups currently use intravenous hydration for volume expan‐

Currently the most popular and effective solution for preventing CIN is isotonic saline (0.9%). Earlier studies comparing saline and other solutions including mannitol or mannitol with furosemide have demonstrated the superiority of saline infusion. [85, 86] The strategy of forced diuresis is also not favored by existing evidence. In the PRINCE study (Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation), Stevens and coworkers found no benefit from forced diuresis with intravenous crystalloid, furosemide, mannitol or lowdose dopamine therapy, compared with hydration alone in at-risk patients. [86] The lack of benefit of mannitol and furosemide might come from their renal untoward effects, including osmotic diuresis-related increase of renal oxygen consumption, vasoconstrictor effect of mannitol and diuretic-induced hypovolemia. [42] In addition, Mueller et al, in a large group of patients receiving PCI, compared the strategy of siotonic saline (0.9%) infusion to half-iso‐ tonic saline infusion (0.45%, + plus 5% glucose) starting one day before procedures. [87] Iso‐ tonic hydration is superior to half-isotonic hydration in the efficacy for prevention of

### **6. Strategies of prevention for contrast-induced AKI**

#### **6.1. Modification of risk factors**

Some of the patients' baseline comorbidities cannot be changed (eg. DM, CHF, etc.), but oth‐ ers are potentially modifiable to reduce the risk of developing CIN. First, the selection of the patients for PCI can be important. Patients with unstable hemodynamic status or circulatory collapse are at high-risk of developing contrast-induced AKI, and and the risk/benefit ratio needs to be carefully weighed for these patients. [42] The clinical need for PCI should be scrutinized, and the in-charge cardiologist or hospitalist should consider whether another procedure without the use of iodinated contrast media can act as a substitute. [59] Nonethe‐ less, in the setting of emergency procedures (like primary PCI), where the benefit of very early intervention outweighs the risk of waiting for the results of the blood test, it is still nec‐ essary to proceed without available sCr. [2] When possible, it is still desirable to obtain a pre-procedural blood sample for sCr, since the likelihood of impaired renal function preprocedurally can increase the subsequent risk of developing CIN and other adverse events. Second, patients with DM, HTN, CHF or potentially changing renal function should receive a pre-procedural baseline renal function testing (if they have not received one before), and if possible, a nephrology/radiology specialist consultation could be obtained. [2] Hyperglyce‐ mic status should be properly managed before procedure. Agents such as NSAIDs, diuretics (if feasible), and possibly ACEIs should be discontinued 1-2 days before administration of contrast media. [42] Finally, if PCI or diagnostic coronary angiography is warranted, the amount of contrast medium volume should be as little as possible, and the choice of contrast medium should be iso-osmolar or low osmolar agents, especially in patients with high risk. [2, 8, 14, 42] Repeated exposure should be delayed for 48 hours in patients at-risk of devel‐ oping contrast-induced AKI, and an even longer delay if patients are diabetic or have preexisting CKD. [42] Ideally, the interval between procedures should be 2 weeks, the expected recovery time for kidney after an acute insult, but frequently this is not possible, especially in patients with AMI and complicating courses. [19] In this situation, the interval should still be as long as clinically acceptable.

#### **6.2. Volume expansion**

coworkers, in another large cohort of post-PCI CIN patients, derived a risk scoring scheme composed of DM, CHF, hypertension, peripheral vascular disease, IABP uses, CKD (defined as creatinine clearance < 60 ml/min), and procedural factors (urgent or emergency proce‐ dures, contrast volume ≧260ml). [13] Incidence of CIN ranged from 0.5% in the lowest risk category, to 43% in the highest risk category. These studies did prove that the risk factors identified previously are mutually additive, and the risk of contrast-induced AKI increases prominently as risk factors accumulate. However, none of the reported studies have been prospectively applied to different populations, and the utility in real-world is still in ques‐ tion. It is currently inappropriate to recommend the routine use of these models in risk strat‐ ification of specific population [2], but we should bear in mind that the more risk factors our

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

Some of the patients' baseline comorbidities cannot be changed (eg. DM, CHF, etc.), but oth‐ ers are potentially modifiable to reduce the risk of developing CIN. First, the selection of the patients for PCI can be important. Patients with unstable hemodynamic status or circulatory collapse are at high-risk of developing contrast-induced AKI, and and the risk/benefit ratio needs to be carefully weighed for these patients. [42] The clinical need for PCI should be scrutinized, and the in-charge cardiologist or hospitalist should consider whether another procedure without the use of iodinated contrast media can act as a substitute. [59] Nonethe‐ less, in the setting of emergency procedures (like primary PCI), where the benefit of very early intervention outweighs the risk of waiting for the results of the blood test, it is still nec‐ essary to proceed without available sCr. [2] When possible, it is still desirable to obtain a pre-procedural blood sample for sCr, since the likelihood of impaired renal function preprocedurally can increase the subsequent risk of developing CIN and other adverse events. Second, patients with DM, HTN, CHF or potentially changing renal function should receive a pre-procedural baseline renal function testing (if they have not received one before), and if possible, a nephrology/radiology specialist consultation could be obtained. [2] Hyperglyce‐ mic status should be properly managed before procedure. Agents such as NSAIDs, diuretics (if feasible), and possibly ACEIs should be discontinued 1-2 days before administration of contrast media. [42] Finally, if PCI or diagnostic coronary angiography is warranted, the amount of contrast medium volume should be as little as possible, and the choice of contrast medium should be iso-osmolar or low osmolar agents, especially in patients with high risk. [2, 8, 14, 42] Repeated exposure should be delayed for 48 hours in patients at-risk of devel‐ oping contrast-induced AKI, and an even longer delay if patients are diabetic or have preexisting CKD. [42] Ideally, the interval between procedures should be 2 weeks, the expected recovery time for kidney after an acute insult, but frequently this is not possible, especially in patients with AMI and complicating courses. [19] In this situation, the interval should still

patients possess, the higher risk he/she might develop AKI after receiving PCI.

**6. Strategies of prevention for contrast-induced AKI**

**6.1. Modification of risk factors**

be as long as clinically acceptable.

There is broad consensus that volume expansion (through isotonic saline hydration) is capa‐ ble of reducing the risk of contrast-induced nephropathy. The putative benefit of adequate volume expansion includes improving renal blood flow, inducing diuresis with dilution of contrast medium within renal tubules, suppression of the renin-angiotensin-aldosterone sys‐ tem, lowering the secretion of arginine vasopressin, and less reductions in the renal produc‐ tion of endogenous vasodilators (nitric oxide, prostaglandin). [82] However, firm evidence regarding the benefit of volume expansion is not available and not expected to exist, since randomized, double-blinded trials comparing hydration and a control group without hydra‐ tion cannot be perfomed for lack of ethical acceptability.

#### *6.2.1. Route of volume expansion*

The route of volume expansion has been debated. Earlier expert group consensus suggested that intravenous hydration is more favorable than oral hydration [18], but clinical evidence seemed conflicting. Trivedi and coworkers prospectively evaluated the efficacy of unrestrict‐ ed oral fluids or intravenous normal saline for 24 hours (at a rate of 1ml/kg/hr, 12 hours be‐ fore and 12 hours after procedures) in a small group of elective PCI patients. [83] Contrastinduced AKI occurred significantly less frequently in the intravenous hydration group than the oral fluid group (3.7% vs. 34.6%). Dussol et al perfomed another study comparing intra‐ venous normal saline (at a rate of 15 ml/kg for 6 hours before procedure) to oral salt tablet (1g/10kg body weight for 2 days before procedure) in a moderately-sized cohort receiving various radiologic studies. [84] Oral salt supplement was found to be as effective as intrave‐ nous saline hydration for the prevention of contrast-induced AKI. However, the pre-proce‐ dural fasting policy routinely instituted in some groups might make oral salt tabley not feasible. Nonetheless, most groups currently use intravenous hydration for volume expan‐ sion purposes in clinical practice.

#### *6.2.2. Formula of hydration*

Currently the most popular and effective solution for preventing CIN is isotonic saline (0.9%). Earlier studies comparing saline and other solutions including mannitol or mannitol with furosemide have demonstrated the superiority of saline infusion. [85, 86] The strategy of forced diuresis is also not favored by existing evidence. In the PRINCE study (Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation), Stevens and coworkers found no benefit from forced diuresis with intravenous crystalloid, furosemide, mannitol or lowdose dopamine therapy, compared with hydration alone in at-risk patients. [86] The lack of benefit of mannitol and furosemide might come from their renal untoward effects, including osmotic diuresis-related increase of renal oxygen consumption, vasoconstrictor effect of mannitol and diuretic-induced hypovolemia. [42] In addition, Mueller et al, in a large group of patients receiving PCI, compared the strategy of siotonic saline (0.9%) infusion to half-iso‐ tonic saline infusion (0.45%, + plus 5% glucose) starting one day before procedures. [87] Iso‐ tonic hydration is superior to half-isotonic hydration in the efficacy for prevention of contrast-induced AKI.

The issue of sodium bicarbonate for preventing contrast-induced AKI is also controversial. It is suggested that sodium bicarbonate might result in urine alkalinization and reduce the generation of free radical through scavenging reactive oxygen species. [19] Bicarbonate can also increase urine flow, while on the contrary, the large amount of chloride from isotonic saline infusion may lead to constriction of the renal vasculature. [88] Merten and colleagues first performed a pilot study comparing sodium bicarbonate (154 mEq/L in dextrose 5% wa‐ ter at a rate of 3ml/kg/hour) started one hour before procedure and continued for six hours after (at a rate of 1ml/kg/hour), to infusion of sodium chloride at a similar rate. [89] The more favorable effect of sodium bicarbonate prophylaxis inspired multiple follow-up stud‐ ies focusing on similar issues, with more-or-less similar results. Several metanalysis con‐ cluded that sodium bicarbonate is more effective than sodium chloride in protecting against CIN, but the heterogeneity of included studies exist, with even publication bias in some studies. [88, 90] Besides, the lower risk of contrast-induced AKI does not seem to translate into lower mortality or less need for dialytic support. [91] The potential risk of al kalemia induced by sodium bicarbonate infusion in patients with CHF and electrolyte disturbance (hypocalcemia, hypokalemia) is another concern. Nonetheless, based upon existing evi‐ dence, sodium bicarbonate serves as an equal or even better choice for prevention of con‐ trast-induced AKI, compared with sodium chloride. [19]

More than 30 randomized controlled trials have been performed regarding the efficacy of NAC for preventing contrast-induced AKI, and most studies involve patients receiving PCI or diagnostic coronary angiography. The results are conflicting, with some display‐ ing lower incidence of CIN, while others demonstrating no significant benefit. [93-95] Some researchers proposed that higher dose NAC might be more effective than standard dose NAC [96], but we should remind ourselves that intravenous NAC at higher doses might be associated with significant side effects (hypotension, bronchospasm, etc.) Metaanalysis of existing studies also display conflicting results, depending on the studies in‐ cluded. [97-99] However, most studies are under-powered, and the beneficial effect of NAC is mostly deducted by earlier studies, with small size and lower quality. [19] Fur‐ thermore, there have been observations that NAC might lower sCr without affecting GFR, devoid of benefit to renal function. [100] In conclusion, the benefit of NAC in pre‐ venting contrast-induced AKI remains unproven, and the use of NAC should be careful‐

Contrast-Induced Nephropathy in Coronary Angiography and Intervention

http://dx.doi.org/10.5772/54081

361

Fenoldopam mesylate is a selective dopamine-1 receptor agonist that produces systemic and renal artery vasodilatation. [42] It is found to exhibit desirable renal effects includ‐ ing decrease in renal vascular resistance and increase in renal blood flow, GFR, with na‐ triuresis. Small-group studies have identified potential benefit of fenoldopam with normal saline in the amelioration of renal blood flow reduction caused by contrast me‐ dia, but this is not validated in a subsequent large, multicenter, double-blind random‐ ized placebo-controlled trial. [101] It is also found to perform inferiorly to NAC in several controlled trials. [102] Currently, the routine use of fenoldopam to protect against

Theophylline, through cyclic AMP generation, is found to relieve the renal vasoconstrictive reponse to contrast media injection potentially mediated by adenosine in animal models. [103] Multiple investigators have evaluated the competitive adenosine antagonists, theo‐ phylline and aminophylline as candidate agents for reducing the risk of CIN. A meta-analy‐ sis concluded that prophylactive theophylline use appears to protect against contrastinduced AKI, but the included trials are few, and publication bias is likely. [103] There are also studies suggesting the superiority of theophylline over NAC. [104] Further evaluation is needed in this regrad. Significant side effect resulting from use of theophylline is rarely

Ascorbic acid is a potent, water-soluble antioxidant capable of scavening reactive oxygen species that potentially introduces damage to vital macromolecules. Ascorbic acid has been shown to attenuate renal damage from various types of insult, including post-ischemic stress, cisplatin-related and aminoglycoside-related injury in animal models. [105] It also

observed during short-term use and if serum concentration being kept low.

ly weighed against the potential side effects listed above.

contrast-induced AKI could not be recommended.

*6.3.2. Fenoldopam*

*6.3.3. Theophylline*

*6.3.4. Ascorbic acid*

#### *6.2.3. Amount and rate of volume expansion*

There is currently no clear evidence for the optimal rate and duration of volume expansion. Correlation with patients' body weight seems reasonable, and expert consensus agrees that 1.0-1.5 ml/kg/hour of infusion is appropriate. [19] However, there are clinical trials compar‐ ing overnight hydration before elective procedures to bolus hydration immediately before the procedures, and continuous hydration seems to provide better protection. [92] It is rec‐ ommended now that intravenous hydration should start 12 hours before PCI or coronary angiography and continue for 12 hours after, at a rate provided above. [19]

#### **6.3. Pharmacological prophylaxis**

Other than intravenous hydration, pharmacologic prophylaxis for at-risk patients against CIN has been tested with multiple drugs, but currently no single agent is approved specifi‐ cally for this purpose. [19] Several candidate drugs have been attempted, with conflicting re‐ sults. We will briefly review these drugs in the following section.

#### *6.3.1. N-acetylcysteine (NAC)*

NAC has been the center of investigation during the last decade. It possesses antioxidant and potentially vasodilatory properties. [8] Usually NAC is given orally but intravenous formula is also available, and owing to its low price, the availability is also high. NAC has minimal side effects and is generally considered safe. The most common protocol of NAC is to give this agent orally 600mg twice a day for 24 hours on the day before and the day of procedure. [19]

More than 30 randomized controlled trials have been performed regarding the efficacy of NAC for preventing contrast-induced AKI, and most studies involve patients receiving PCI or diagnostic coronary angiography. The results are conflicting, with some display‐ ing lower incidence of CIN, while others demonstrating no significant benefit. [93-95] Some researchers proposed that higher dose NAC might be more effective than standard dose NAC [96], but we should remind ourselves that intravenous NAC at higher doses might be associated with significant side effects (hypotension, bronchospasm, etc.) Metaanalysis of existing studies also display conflicting results, depending on the studies in‐ cluded. [97-99] However, most studies are under-powered, and the beneficial effect of NAC is mostly deducted by earlier studies, with small size and lower quality. [19] Fur‐ thermore, there have been observations that NAC might lower sCr without affecting GFR, devoid of benefit to renal function. [100] In conclusion, the benefit of NAC in pre‐ venting contrast-induced AKI remains unproven, and the use of NAC should be careful‐ ly weighed against the potential side effects listed above.

#### *6.3.2. Fenoldopam*

The issue of sodium bicarbonate for preventing contrast-induced AKI is also controversial. It is suggested that sodium bicarbonate might result in urine alkalinization and reduce the generation of free radical through scavenging reactive oxygen species. [19] Bicarbonate can also increase urine flow, while on the contrary, the large amount of chloride from isotonic saline infusion may lead to constriction of the renal vasculature. [88] Merten and colleagues first performed a pilot study comparing sodium bicarbonate (154 mEq/L in dextrose 5% wa‐ ter at a rate of 3ml/kg/hour) started one hour before procedure and continued for six hours after (at a rate of 1ml/kg/hour), to infusion of sodium chloride at a similar rate. [89] The more favorable effect of sodium bicarbonate prophylaxis inspired multiple follow-up stud‐ ies focusing on similar issues, with more-or-less similar results. Several metanalysis con‐ cluded that sodium bicarbonate is more effective than sodium chloride in protecting against CIN, but the heterogeneity of included studies exist, with even publication bias in some studies. [88, 90] Besides, the lower risk of contrast-induced AKI does not seem to translate into lower mortality or less need for dialytic support. [91] The potential risk of al kalemia induced by sodium bicarbonate infusion in patients with CHF and electrolyte disturbance (hypocalcemia, hypokalemia) is another concern. Nonetheless, based upon existing evi‐ dence, sodium bicarbonate serves as an equal or even better choice for prevention of con‐

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

There is currently no clear evidence for the optimal rate and duration of volume expansion. Correlation with patients' body weight seems reasonable, and expert consensus agrees that 1.0-1.5 ml/kg/hour of infusion is appropriate. [19] However, there are clinical trials compar‐ ing overnight hydration before elective procedures to bolus hydration immediately before the procedures, and continuous hydration seems to provide better protection. [92] It is rec‐ ommended now that intravenous hydration should start 12 hours before PCI or coronary

Other than intravenous hydration, pharmacologic prophylaxis for at-risk patients against CIN has been tested with multiple drugs, but currently no single agent is approved specifi‐ cally for this purpose. [19] Several candidate drugs have been attempted, with conflicting re‐

NAC has been the center of investigation during the last decade. It possesses antioxidant and potentially vasodilatory properties. [8] Usually NAC is given orally but intravenous formula is also available, and owing to its low price, the availability is also high. NAC has minimal side effects and is generally considered safe. The most common protocol of NAC is to give this agent orally 600mg twice a day for 24 hours on the day before and

angiography and continue for 12 hours after, at a rate provided above. [19]

sults. We will briefly review these drugs in the following section.

trast-induced AKI, compared with sodium chloride. [19]

*6.2.3. Amount and rate of volume expansion*

**6.3. Pharmacological prophylaxis**

*6.3.1. N-acetylcysteine (NAC)*

the day of procedure. [19]

Fenoldopam mesylate is a selective dopamine-1 receptor agonist that produces systemic and renal artery vasodilatation. [42] It is found to exhibit desirable renal effects includ‐ ing decrease in renal vascular resistance and increase in renal blood flow, GFR, with na‐ triuresis. Small-group studies have identified potential benefit of fenoldopam with normal saline in the amelioration of renal blood flow reduction caused by contrast me‐ dia, but this is not validated in a subsequent large, multicenter, double-blind random‐ ized placebo-controlled trial. [101] It is also found to perform inferiorly to NAC in several controlled trials. [102] Currently, the routine use of fenoldopam to protect against contrast-induced AKI could not be recommended.

### *6.3.3. Theophylline*

Theophylline, through cyclic AMP generation, is found to relieve the renal vasoconstrictive reponse to contrast media injection potentially mediated by adenosine in animal models. [103] Multiple investigators have evaluated the competitive adenosine antagonists, theo‐ phylline and aminophylline as candidate agents for reducing the risk of CIN. A meta-analy‐ sis concluded that prophylactive theophylline use appears to protect against contrastinduced AKI, but the included trials are few, and publication bias is likely. [103] There are also studies suggesting the superiority of theophylline over NAC. [104] Further evaluation is needed in this regrad. Significant side effect resulting from use of theophylline is rarely observed during short-term use and if serum concentration being kept low.

#### *6.3.4. Ascorbic acid*

Ascorbic acid is a potent, water-soluble antioxidant capable of scavening reactive oxygen species that potentially introduces damage to vital macromolecules. Ascorbic acid has been shown to attenuate renal damage from various types of insult, including post-ischemic stress, cisplatin-related and aminoglycoside-related injury in animal models. [105] It also possesses extensive safety record as a harmless dietary supplement. Randomized controlled trials utilizing oral ascorbic acid as a prophylactive strategy for reducing CIN have been per‐ formed, and the results appear to be positive. [106] Boscheri et al, in a small cohort, failed to display benefit of ascorbid acid. [107] In this sense, definite conclusion also can not be made at this time, owing similarly to low case numbers and somewhat flawed study design.

**7. Conclusion**

contrast-induced AKI.

**Author details**

**References**

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

\*Address all correspondence to: austinr3@yahoo.com.tw

Quality and Outcomes 2011; 4:193-197.

College of Cardiology 2008; 51:1419-1428.

nal of Kidney Diseases 2002; 39:930-936.

tions 2003; 59:338-343.

Contrast-induced AKI, or contrast-induced nephropathy, is a growing issue in the contem‐ porary field of intervention cardiology and also in fields like diagnostic radiology. Although the definitions of contrast-induced AKI are still changing with the advancement of new bio‐ markers reflecting renal function and injury, the most popular and cost-effective method is still serum creatinine. As the understanding of the pathogenesis of CIN also progresses, more and more strategies for prevention of contrast-induced AKI are being developed and tested clinically. It will be vital for primary care physicians and cardiologists to carefully se‐ lect their patients as candidates of contrast medium containing procedures, knowledgeably stratify the risk, and implicate evidence-based prophylactic means to reduce the incidence of

Contrast-Induced Nephropathy in Coronary Angiography and Intervention

http://dx.doi.org/10.5772/54081

363

Division of Cardiology, Departments of Internal Medicine, National Taiwan University Hos‐

[1] Riley RF, Don CW, Powell W, Maynard C, Dean LS. Trends in Coronary Revascu‐ larization in the United States From 2001 to 2009. Circulation: Cardiovascular

[2] McCullough PA. Contrast-Induced Acute Kidney Injury. Journal of the American

[3] Weisbord SD, Mor MK, Resnick AL, Hartwig KC, Palevsky PM, Fine MJ. Inci‐ dence and Outcomes of Contrast-Induced AKI Following Computed Tomography.

[4] Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. American Jour‐

[5] Lindsay J, Apple S, Pinnow EE, et al. Percutaneous coronary intervention-associat‐ ed nephropathy foreshadows increased risk of late adverse events in patients with normal baseline serum creatinine. Catheterization and Cardiovascular Interven‐

Clinical Journal of the American Society of Nephrology 2008; 3:1274-1281.

pital and National Taiwan University College of Medicine, Taipei, Taiwan

#### *6.3.5. Statin*

Statin, also hydroxymethylglutaryl coenzymeA reductase (HMG-CoA) inhibitor, improves the lipid profiles of patients, and has reportedly pleiotropic effects on vasculature, including decreasing low-density lipoprotein (LDL), lipid peroxidation, improving inflammation, low‐ ering risk of cellular necrosis and elevated collagen content in human plaques. [108] Statin therapy significantly reduces cardiovascular mortality and morbidity in patients with hy‐ perlipidemia, and post-procedural statin also is shown to reduce cardiovascular events in patients receiving PCI. [109] Although the exact mechanism by which statin reduces iodinat‐ ed contrast media-induced AKI is still unclear, it is likely that one of the anti-oxidation, antiinflammatory, and anti-thrombotic effects can be the principle reason. [110] In a large group of PCI patients, statin use was found to reduce incidence of CIN (OR 0.87). [110] Patti et al further demonstrated that pre-procedural statin use not only prevents against contrast-in‐ duced AKI but also leads to a better long-term survival after 4 years of follow-up. [111] Sev‐ eral recent meta-analyses yielded conflicting results, and some researchers proposed that statin might be helpful mostly in patients with more advanced CKD. [112, 113] Thus, it re‐ mains unknown whether statins is beneficial for preventing contrast-induced AKI at present, and further clinical trials are awaited to determine the specific group of patients that acquire the most benefit from statin use.

#### *6.3.6. Iloprost*

Iloprost is a stable prostaglandin I2 (prostacyclin) analogue, which exerts renal vasodilatory effect and has been shown to protect animal kidneys against ischemic and toxic insults. [114] Development of contrast-induced AKI might partially originate from attenuation of the re‐ nal prostacylin response, and thus iloprost is theoretically beneficial for the prevention of CIN. Spargias and coworkers first conducted a pilot study on iloprost, with a regimen of 1-2 ng/kg/min infusion from 30-90 minutes before procedures and continuing until 4 hours after procedures, for prevention of CIN. [115] The result was promising. Subsequent larger con‐ firmatory trials yielded similarly positive findings. [116] However, these results were all produced by a single group, and other researchers have not been able to replicate their find‐ ings. The other drawbacks of iloprost are its tolerability issues. [116] Further studies are needed to affirm the role of iloprost in our armamentarium against contrast-induced AKI.

#### *6.3.7. Miscellaneous*

There is limited evidence regarding low-dose dopamine, calcium channel blockers, atrial na‐ triuretic peptides, L-arginine, endothelin antagonists in their roles in the prevention of con‐ trast-induced nephropathy. [19]

## **7. Conclusion**

possesses extensive safety record as a harmless dietary supplement. Randomized controlled trials utilizing oral ascorbic acid as a prophylactive strategy for reducing CIN have been per‐ formed, and the results appear to be positive. [106] Boscheri et al, in a small cohort, failed to display benefit of ascorbid acid. [107] In this sense, definite conclusion also can not be made at this time, owing similarly to low case numbers and somewhat flawed study design.

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

Statin, also hydroxymethylglutaryl coenzymeA reductase (HMG-CoA) inhibitor, improves the lipid profiles of patients, and has reportedly pleiotropic effects on vasculature, including decreasing low-density lipoprotein (LDL), lipid peroxidation, improving inflammation, low‐ ering risk of cellular necrosis and elevated collagen content in human plaques. [108] Statin therapy significantly reduces cardiovascular mortality and morbidity in patients with hy‐ perlipidemia, and post-procedural statin also is shown to reduce cardiovascular events in patients receiving PCI. [109] Although the exact mechanism by which statin reduces iodinat‐ ed contrast media-induced AKI is still unclear, it is likely that one of the anti-oxidation, antiinflammatory, and anti-thrombotic effects can be the principle reason. [110] In a large group of PCI patients, statin use was found to reduce incidence of CIN (OR 0.87). [110] Patti et al further demonstrated that pre-procedural statin use not only prevents against contrast-in‐ duced AKI but also leads to a better long-term survival after 4 years of follow-up. [111] Sev‐ eral recent meta-analyses yielded conflicting results, and some researchers proposed that statin might be helpful mostly in patients with more advanced CKD. [112, 113] Thus, it re‐ mains unknown whether statins is beneficial for preventing contrast-induced AKI at present, and further clinical trials are awaited to determine the specific group of patients

Iloprost is a stable prostaglandin I2 (prostacyclin) analogue, which exerts renal vasodilatory effect and has been shown to protect animal kidneys against ischemic and toxic insults. [114] Development of contrast-induced AKI might partially originate from attenuation of the re‐ nal prostacylin response, and thus iloprost is theoretically beneficial for the prevention of CIN. Spargias and coworkers first conducted a pilot study on iloprost, with a regimen of 1-2 ng/kg/min infusion from 30-90 minutes before procedures and continuing until 4 hours after procedures, for prevention of CIN. [115] The result was promising. Subsequent larger con‐ firmatory trials yielded similarly positive findings. [116] However, these results were all produced by a single group, and other researchers have not been able to replicate their find‐ ings. The other drawbacks of iloprost are its tolerability issues. [116] Further studies are needed to affirm the role of iloprost in our armamentarium against contrast-induced AKI.

There is limited evidence regarding low-dose dopamine, calcium channel blockers, atrial na‐ triuretic peptides, L-arginine, endothelin antagonists in their roles in the prevention of con‐

*6.3.5. Statin*

*6.3.6. Iloprost*

*6.3.7. Miscellaneous*

trast-induced nephropathy. [19]

that acquire the most benefit from statin use.

Contrast-induced AKI, or contrast-induced nephropathy, is a growing issue in the contem‐ porary field of intervention cardiology and also in fields like diagnostic radiology. Although the definitions of contrast-induced AKI are still changing with the advancement of new bio‐ markers reflecting renal function and injury, the most popular and cost-effective method is still serum creatinine. As the understanding of the pathogenesis of CIN also progresses, more and more strategies for prevention of contrast-induced AKI are being developed and tested clinically. It will be vital for primary care physicians and cardiologists to carefully se‐ lect their patients as candidates of contrast medium containing procedures, knowledgeably stratify the risk, and implicate evidence-based prophylactic means to reduce the incidence of contrast-induced AKI.

## **Author details**

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

\*Address all correspondence to: austinr3@yahoo.com.tw

Division of Cardiology, Departments of Internal Medicine, National Taiwan University Hos‐ pital and National Taiwan University College of Medicine, Taipei, Taiwan

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[88] Joannidis M, Schmid M, Wiedermann CJ. Prevention of contrast media-induced nephropathy by isotonic sodium bicarbonate: a meta-analysis. Wiener Klinische

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[90] Brar SS, Hiremath S, Dangas G, Mehran R, Brar SK, Leon MB. Sodium Bicarbon‐ ate for the Prevention of Contrast Induced-Acute Kidney Injury: A Systematic Re‐ view and Meta-analysis. Clinical Journal of the American Society of Nephrology

[91] Meier P, Ko D, Tamura A, Tamhane U, Gurm H. Sodium bicarbonate-based hy‐ dration prevents contrast-induced nephropathy: a meta-analysis. BMC Medicine

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[112] Zhou Y, Yuan WJ, Zhu N, Wang L. Short-term, high-dose statins in the preven‐ tion of contrast-induced nephropathy: a systematic review and meta-analysis. Clin

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**Chapter 18**

**Contrast-Induced Nephropathy:**

**Risk Factors, Clinical Implication,**

Additional information is available at the end of the chapter

effective preventive measures are necessary.

**2. Definition of CIN**

ternative cause [4].

http://dx.doi.org/10.5772/54036

**1. Introduction**

**Diagnostics Approach, Prevention**

Frantisek Kovar, Milos Knazeje and Marian Mokan

Contrast induced nephropathy (CIN) is an important and well‐known complication in pa‐ tients with chronic renal insufficiency undergoing both coronary angiography and coronary interventions. The estimated incidence of CN after coronary angiography was around 15%. In fact, CIN is the third leading cause of acute renal failure in hospitalized patients [1]. CIN is usually transient disorder, but in some cases may result in residual permanent renal dam‐ age, prolong hospital stay and increase medical cost [2]. Renal failure increases the risk of developing severe nonrenal complications that can lead to death. The mortality rate in sub‐ jects without renal failure was 7%, compared with 34% in patients with renal failure [3]. With the increasing number of patients undergoing percutaneous coronary intervention, it is expected that the burden of such iatrogenic complications will exponentially increase and

Contrast induced nephropathy is an important cause of nosocomial renal impairment. This deleterious effect of contrast agents on renal function is defined as an impairment of renal function with increase in serum creatinine level by more than 25% or 44umol/l occurring within 3 days after intravascular administration of contrast agents and in the absence of al‐

> © 2013 Kovar 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 18**

## **Contrast-Induced Nephropathy: Risk Factors, Clinical Implication, Diagnostics Approach, Prevention**

Frantisek Kovar, Milos Knazeje and Marian Mokan

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54036

## **1. Introduction**

Contrast induced nephropathy (CIN) is an important and well‐known complication in pa‐ tients with chronic renal insufficiency undergoing both coronary angiography and coronary interventions. The estimated incidence of CN after coronary angiography was around 15%. In fact, CIN is the third leading cause of acute renal failure in hospitalized patients [1]. CIN is usually transient disorder, but in some cases may result in residual permanent renal dam‐ age, prolong hospital stay and increase medical cost [2]. Renal failure increases the risk of developing severe nonrenal complications that can lead to death. The mortality rate in sub‐ jects without renal failure was 7%, compared with 34% in patients with renal failure [3]. With the increasing number of patients undergoing percutaneous coronary intervention, it is expected that the burden of such iatrogenic complications will exponentially increase and effective preventive measures are necessary.

## **2. Definition of CIN**

Contrast induced nephropathy is an important cause of nosocomial renal impairment. This deleterious effect of contrast agents on renal function is defined as an impairment of renal function with increase in serum creatinine level by more than 25% or 44umol/l occurring within 3 days after intravascular administration of contrast agents and in the absence of al‐ ternative cause [4].

© 2013 Kovar 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.

## **3. Incidence and clinical significance of CIN:**

The incidence of CIN in the general population has been estimated to be less than 2% [5]. However in high risk patients the incidence can increase to more than 50%. Pre-existing re‐ nal impairment and diabetes mellitus have been identified as the main conditions predis‐ posing to the development of CIN. Other risk factors include decreased effective blood volume, age > 75 years, heart failure, use of non-steroid anti-inflammatory drugs, diuretics, previous parenteral contrast medium administration within 72 hours and large volume of contrast medium [6].

peak increase between day 0 and day 3 (P for interaction <0.001). Peak increase of serum cre‐

All seven serious events deemed to be related to contrast medium occurred in the iohexol group; five patients in this group had acute renal failure related to the use of iohexol, and one patient had both acute renal failure and arrhythmia related to the use of

All seven serious events deemed to be related to contrast medium occurred in the iohexol group; five patients in this group had acute renal failure related to the use of iohexol, and one patient had both acute renal failure and arrhythmia related to the use of iohexol. Three

more than 0,5mg/dl more than 1,0mg/dl

**Peak increase of serum creatinine concentration**

Renal failure increases the risk of developing severe nonrenal complications that can lead to death. In analysis of 16 248 patients undergoing radiocontrast procedures, were identified 183 subjects who developed contrast media associated renal failure. These cases were matched for age and baseline serum creatinine level, with 174 paired subjects, who underwent similar contrast procedures but without developing renal failure. The mortality rate in subjects without renal failure was 7%, compared with 34% in patients with renal failure (odds ratio, 6,5; *P*<0,001). After adjusting for differences in co morbidity, renal failure was associated with an odds ratio of dying of 5,5. Subjects who died after developing renal failure had complicated clinical courses characterized by sepsis, bleeding, delirium, and respiratory failure; most of these complications developed after the onset of renal failure [3].

Renal failure increases the risk of developing severe nonrenal complications that can lead to death. In analysis of 16 248 patients undergoing radiocontrast procedures, were identified 183 subjects who developed contrast media associated renal failure. These cases were match‐ ed for age and baseline serum creatinine level, with 174 paired subjects, who underwent similar contrast procedures but without developing renal failure. The mortality rate in sub‐ jects without renal failure was 7%, compared with 34% in patients with renal failure (odds ratio, 6,5; *P*<0,001). After adjusting for differences in co morbidity, renal failure was associat‐ ed with an odds ratio of dying of 5,5. Subjects who died after developing renal failure had complicated clinical courses characterized by sepsis, bleeding, delirium, and respiratory fail‐

of these six patients recovered, two died, and one had persistent renal failure. [11].

Likelihood of death increases approximately 8.5-13.5 times in patients with CIN and need for hemodialysis comparing with CIN

Observation made by Gruber and coworkers confirmed that acute renal failure that requires dialysis after percutaneous coronary interventions is associated with very high in-hospital and 1-year mortality rates and a dramatic increase in hospital resource utilization. They compared clinical course in 51 consecutive patients who were not on dialysis on admission and developed acute renal failure that required in-hospital dialysis after coronary intervention and 7 690 patients who did not require dialysis after PCI. Patients who required dialysis were older, with a higher incidence of hypertension, diabetes, prior bypass surgery, chronic renal failure, and a significantly lower left ventricular ejection fraction. Despite similar angiographic success, these patients had a higher incidence of in-hospital mortality (27.5% vs. 1.0%, *P* < 0.0001), non–Q-wave myocardial infarction (45.7% vs. 14.6%, *P* < 0.0001), vascular and bleeding complications, and longer hospitalization. At 1-year follow-up, mortality (54.5% vs. 6.4%, *P* < 0.0001), myocardial infarction (4.5% vs. 1.6%, *P* = 0.006), and event-free survival (38.6% vs. 72.0%, *P* < 0.0001) were significantly

ure; most of these complications developed after the onset of renal failure [3].

for hemodialysis comparing with CIN patients but without hemodialysis [12, 13].

Similarly, analysis of 1 826 consecutive patients undergoing coronary intervention from aspect of the incidence, predictors, and mortality related to acute renal failure (ARF) and acute renal failure requiring dialysis (ARFD) after coronary intervention has shown that occurrence of ARFD after coronary intervention is rare (<1%) but is associated with high in-hospital lethality and poor long-term survival. Individual patient risk can be estimated from calculated CrCl, diabetic status, and expected contrast dose prior to a proposed coronary intervention [13]. The incidence of ARF and ARFD was 144,6/1,000 and 7,7/1,000 cases respectively.

Observation made by Gruber and coworkers confirmed that acute renal failure that requires dialysis after percutaneous coronary interventions is associated with very high in-hospital

Likelihood of death increases approximately 8.5-13.5 times in patients with CIN and need

iohexol. Three of these six patients recovered, two died, and one had persistent renal failure. [11].

worse in patients who required dialysis compared to patients who did not [12].

CIN is a significant cause of morbidity and mortality.

was 11.2 μmol per liter in the iodixanol group, as compared with 48.2 μmol per liter in the iohexol group (P=0.001). The effect of the base-line serum creatinine concentration was different in the two groups. Among patients who received iohexol, but not among those who received iodixanol, a higher base-line serum creatinine concentration was associated with a higher peak increase between day 0 and day 3 (P for interaction <0.001). Peak increase of serum creatinine level was higher in iohexanol group

Contrast-Induced Nephropathy: Risk Factors, Clinical Implication, Diagnostics Approach, Prevention

http://dx.doi.org/10.5772/54036

377

atinine level was higher in iohexanol group (Figure 1).

patients

Number of Iodixanol Iohexanol

2

Figure 1. Nephrotoxicity in iodixanol and iohexanol

CIN is a significant cause of morbidity and mortality.

**Figure 1.** Nephrotoxicity in iodixanol and iohexanol

patients but without hemodialysis [12, 13].

(Figure 1).

During the last two decades the number of computed tomographies has increased by 800% and between 1979 and 2002 the number of percutaneous cardiac interventions in the USA has risen by 390% [7]. As the number of susceptible patients exposed to parenteral iodinated contrast media expands, contrast-induced nephropathy represents an ever-growing clinical problem. Meanwhile, the main predisposing factors for CIN, namely diabetes mellitus and previous renal impairment are currently augmented. CIN represents the third most frequent cause of hospital acquired acute renal failure.

The first reported case of CIN was an acute renal failure following intravenous pyelography with 20 ml of Diodrast in patient with myelomatosis in 1954 year [8].

Renal failure following exposure to radiocontrast agents is usually nonoliguric. Creatinine rises within 48 hours, peaks 4 to 5 days after exposure and returns to baseline in 7 to 10 days. Complete recovery is expected in more than 75% of patients, who develop this compli‐ cation, but approximately 10% requires dialysis [9]. Introduction of low- and iso-osmolar contrast media has resulted in decreased frequency of contrast-induced nephropathy [10].

Effect and safety of iodixanol, a new generation iso-osmolar contrast medium, even when administered to high-risk patients was assessed in the Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media (NEPHRIC) study [11]. In this multicenter randomized study were enrolled patients with diabetes mellitus (type 1 or 2) and either a stable serum creatinine concentration (133 to 308 μmol per liter for men and 115 to 308 μmol per liter for women) as measured within three months before enroll‐ ment referred for coronary or aortofemoral angiography, had or a calculated creatinine clearance of no more than 60 ml per minute, according to the formula of Cockcroft and Gault. Study was designed to compare the renal effects of a nonionic, iso-osmolar, dimeric contrast medium, iodixanol (320 mg of iodine per milliliter; 290 mOsm per kilogram of wa‐ ter), with nonionic, low-osmolar, monomeric contrast medium iohexol (350 mg of iodine per milliliter; 780 mOsm per kilogram of water). Iodixanol induced a significantly smaller mean increase in the serum creatinine level than did iohexol. The peak increase in the serum crea‐ tinine concentration within three days after the administration of contrast medium was 11.2 μmol per liter in the iodixanol group, as compared with 48.2 μmol per liter in the iohexol group (P=0.001). The effect of the base-line serum creatinine concentration was different in the two groups. Among patients who received iohexol, but not among those who received iodixanol, a higher base-line serum creatinine concentration was associated with a higher

peak increase between day 0 and day 3 (P for interaction <0.001). Peak increase of serum cre‐ atinine level was higher in iohexanol group (Figure 1). was 11.2 μmol per liter in the iodixanol group, as compared with 48.2 μmol per liter in the iohexol group (P=0.001). The effect of the base-line serum creatinine concentration was different in the two groups. Among patients who received iohexol, but not among those who received iodixanol, a higher base-line serum creatinine concentration was associated with a higher peak increase between day 0 and day 3 (P for interaction <0.001). Peak increase of serum creatinine level was higher in iohexanol group

Figure 1. Nephrotoxicity in iodixanol and iohexanol **Figure 1.** Nephrotoxicity in iodixanol and iohexanol

(Figure 1).

**3. Incidence and clinical significance of CIN:**

cause of hospital acquired acute renal failure.

contrast medium [6].

The incidence of CIN in the general population has been estimated to be less than 2% [5]. However in high risk patients the incidence can increase to more than 50%. Pre-existing re‐ nal impairment and diabetes mellitus have been identified as the main conditions predis‐ posing to the development of CIN. Other risk factors include decreased effective blood volume, age > 75 years, heart failure, use of non-steroid anti-inflammatory drugs, diuretics, previous parenteral contrast medium administration within 72 hours and large volume of

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

During the last two decades the number of computed tomographies has increased by 800% and between 1979 and 2002 the number of percutaneous cardiac interventions in the USA has risen by 390% [7]. As the number of susceptible patients exposed to parenteral iodinated contrast media expands, contrast-induced nephropathy represents an ever-growing clinical problem. Meanwhile, the main predisposing factors for CIN, namely diabetes mellitus and previous renal impairment are currently augmented. CIN represents the third most frequent

The first reported case of CIN was an acute renal failure following intravenous pyelography

Renal failure following exposure to radiocontrast agents is usually nonoliguric. Creatinine rises within 48 hours, peaks 4 to 5 days after exposure and returns to baseline in 7 to 10 days. Complete recovery is expected in more than 75% of patients, who develop this compli‐ cation, but approximately 10% requires dialysis [9]. Introduction of low- and iso-osmolar contrast media has resulted in decreased frequency of contrast-induced nephropathy [10].

Effect and safety of iodixanol, a new generation iso-osmolar contrast medium, even when administered to high-risk patients was assessed in the Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media (NEPHRIC) study [11]. In this multicenter randomized study were enrolled patients with diabetes mellitus (type 1 or 2) and either a stable serum creatinine concentration (133 to 308 μmol per liter for men and 115 to 308 μmol per liter for women) as measured within three months before enroll‐ ment referred for coronary or aortofemoral angiography, had or a calculated creatinine clearance of no more than 60 ml per minute, according to the formula of Cockcroft and Gault. Study was designed to compare the renal effects of a nonionic, iso-osmolar, dimeric contrast medium, iodixanol (320 mg of iodine per milliliter; 290 mOsm per kilogram of wa‐ ter), with nonionic, low-osmolar, monomeric contrast medium iohexol (350 mg of iodine per milliliter; 780 mOsm per kilogram of water). Iodixanol induced a significantly smaller mean increase in the serum creatinine level than did iohexol. The peak increase in the serum crea‐ tinine concentration within three days after the administration of contrast medium was 11.2 μmol per liter in the iodixanol group, as compared with 48.2 μmol per liter in the iohexol group (P=0.001). The effect of the base-line serum creatinine concentration was different in the two groups. Among patients who received iohexol, but not among those who received iodixanol, a higher base-line serum creatinine concentration was associated with a higher

with 20 ml of Diodrast in patient with myelomatosis in 1954 year [8].

All seven serious events deemed to be related to contrast medium occurred in the iohexol group; five patients in this group had acute renal failure related to the use of iohexol, and one patient had both acute renal failure and arrhythmia related to the use of iohexol. Three of these six patients recovered, two died, and one had persistent renal failure. [11]. CIN is a significant cause of morbidity and mortality. All seven serious events deemed to be related to contrast medium occurred in the iohexol group; five patients in this group had acute renal failure related to the use of iohexol, and one patient had both acute renal failure and arrhythmia related to the use of iohexol. Three of these six patients recovered, two died, and one had persistent renal failure. [11].

Renal failure increases the risk of developing severe nonrenal complications that can lead to death. In analysis of 16 248 patients undergoing radiocontrast procedures, were identified 183 subjects who developed contrast media associated renal failure. These CIN is a significant cause of morbidity and mortality.

cases were matched for age and baseline serum creatinine level, with 174 paired subjects, who underwent similar contrast procedures but without developing renal failure. The mortality rate in subjects without renal failure was 7%, compared with 34% in patients with renal failure (odds ratio, 6,5; *P*<0,001). After adjusting for differences in co morbidity, renal failure was associated with an odds ratio of dying of 5,5. Subjects who died after developing renal failure had complicated clinical courses characterized by sepsis, bleeding, delirium, and respiratory failure; most of these complications developed after the onset of renal failure [3]. Likelihood of death increases approximately 8.5-13.5 times in patients with CIN and need for hemodialysis comparing with CIN patients but without hemodialysis [12, 13]. Observation made by Gruber and coworkers confirmed that acute renal failure that requires dialysis after percutaneous coronary interventions is associated with very high in-hospital and 1-year mortality rates and a dramatic increase in hospital resource utilization. They compared clinical course in 51 consecutive patients who were not on dialysis on admission and developed acute renal failure that required in-hospital dialysis after coronary intervention and 7 690 patients who did not require dialysis after PCI. Patients who required dialysis were older, with a higher incidence of hypertension, diabetes, prior bypass surgery, chronic Renal failure increases the risk of developing severe nonrenal complications that can lead to death. In analysis of 16 248 patients undergoing radiocontrast procedures, were identified 183 subjects who developed contrast media associated renal failure. These cases were match‐ ed for age and baseline serum creatinine level, with 174 paired subjects, who underwent similar contrast procedures but without developing renal failure. The mortality rate in sub‐ jects without renal failure was 7%, compared with 34% in patients with renal failure (odds ratio, 6,5; *P*<0,001). After adjusting for differences in co morbidity, renal failure was associat‐ ed with an odds ratio of dying of 5,5. Subjects who died after developing renal failure had complicated clinical courses characterized by sepsis, bleeding, delirium, and respiratory fail‐ ure; most of these complications developed after the onset of renal failure [3].

renal failure, and a significantly lower left ventricular ejection fraction. Despite similar angiographic success, these patients had a higher incidence of in-hospital mortality (27.5% vs. 1.0%, *P* < 0.0001), non–Q-wave myocardial infarction (45.7% vs. 14.6%, *P* < 0.0001), vascular and bleeding complications, and longer hospitalization. At 1-year follow-up, mortality (54.5% vs. 6.4%, *P* < Likelihood of death increases approximately 8.5-13.5 times in patients with CIN and need for hemodialysis comparing with CIN patients but without hemodialysis [12, 13].

0.0001), myocardial infarction (4.5% vs. 1.6%, *P* = 0.006), and event-free survival (38.6% vs. 72.0%, *P* < 0.0001) were significantly worse in patients who required dialysis compared to patients who did not [12]. Similarly, analysis of 1 826 consecutive patients undergoing coronary intervention from aspect of the incidence, predictors, and Observation made by Gruber and coworkers confirmed that acute renal failure that requires dialysis after percutaneous coronary interventions is associated with very high in-hospital

mortality related to acute renal failure (ARF) and acute renal failure requiring dialysis (ARFD) after coronary intervention has shown that occurrence of ARFD after coronary intervention is rare (<1%) but is associated with high in-hospital lethality and poor long-term survival. Individual patient risk can be estimated from calculated CrCl, diabetic status, and expected contrast dose prior to a proposed coronary intervention [13]. The incidence of ARF and ARFD was 144,6/1,000 and 7,7/1,000 cases respectively.

and 1-year mortality rates and a dramatic increase in hospital resource utilization. They compared clinical course in 51 consecutive patients who were not on dialysis on admission and developed acute renal failure that required in-hospital dialysis after coronary interven‐ tion and 7 690 patients who did not require dialysis after PCI. Patients who required dialysis were older, with a higher incidence of hypertension, diabetes, prior bypass surgery, chronic renal failure, and a significantly lower left ventricular ejection fraction. Despite similar an‐ giographic success, these patients had a higher incidence of in-hospital mortality (27.5% vs. 1.0%, *P* < 0.0001), non–Q-wave myocardial infarction (45.7% vs. 14.6%, *P* < 0.0001), vascular and bleeding complications, and longer hospitalization. At 1-year follow-up, mortality (54.5% vs. 6.4%, *P* < 0.0001), myocardial infarction (4.5% vs. 1.6%, *P* = 0.006), and event-free survival (38.6% vs. 72.0%, *P* < 0.0001) were significantly worse in patients who required dial‐ ysis compared to patients who did not [12].

(OR) = 0.83, 95% confidence interval (CI) 0.77 to 0.89, P <0.00001], diabetes (OR = 5.47, 95% CI 1.40 to 21.32, P = 0.01), and contrast dose (OR = 1.008, 95% CI 1.002 to 1.013, P = 0.01) to be independent predictors of ARFD. The in-hospital mortality for those who developed ARFD

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379

Moreover, development of CIN significantly prolongs hospitalization among survive pa‐ tients and is often associated with increased procedural complications rate (table 1) [2].

All modern contrast agents are based on iodine, because of its high atomic number and chem‐ ical versatility has proved to be an excellent agent for intravascular opacification. First report‐ ed parenteral application of an iodinated contrast agents was during an intravenous pyelography in 1919. Inorganic sodium iodide cause often toxic reactions. In 1929 was ex‐ plored an organic iodide preparation with one iodine atom per benzoic acid ring and in 1950s, more substituted tri-iodobenzoic acid derivates were developed (with three iodine atoms per

First generation contrast agents were ionic monomers containing a benzene ring with three iodine atoms, exhibiting high osmolarity in the range of 1500 to 1800 mOsm/kg (high osmo‐ lar contrast agents), roughly six times that of blood. This ratio-1,5 ionic compounds are sub‐ stituted ionic triiodobenzoic acid derivatives that contain three atoms of iodine for every two ions (substituted benzoic acid ring and accompanying cation). To have an iodine con‐ centration of 320 do 370 mg I/ml, as is required for coronary artery angiography, solution of these agents are extremely hypertonic with osmolarity more than 1500 mOsm/kg (Figure 2).

Ratio-3 lower-osmolarity contrast agents were introduced in 1980s. This contrast ages (ioxa‐ glate) was still ionic with dimeric structure that include six molecules iodine on the dimeric

ring). Specific side chains in position 1, 3 and 5 influence both solubility and toxicity.

was 35,7% and the 2-year survival was 18,8% [13].

**Figure 2.** Ionic monomer contrast agent (Diatrizoat)

ring (three atoms of iodine per one ion) (Figure 3).

**4. Contrast agents**

Similarly, analysis of 1 826 consecutive patients undergoing coronary intervention from as‐ pect of the incidence, predictors, and mortality related to acute renal failure (ARF) and acute renal failure requiring dialysis (ARFD) after coronary intervention has shown that occur‐ rence of ARFD after coronary intervention is rare (<1%) but is associated with high in-hospi‐ tal lethality and poor long-term survival. Individual patient risk can be estimated from calculated CrCl, diabetic status, and expected contrast dose prior to a proposed coronary in‐ tervention [13]. The incidence of ARF and ARFD was 144,6/1,000 and 7,7/1,000 cases respec‐ tively. The cutoff dose of contrast below which there was no ARFD was 100 ml. No patient with a CrCl > 47 ml/min developed ARFD. These thresholds were confirmed in the valida‐ tion set. Multivariate analysis found CrCl [odds ratio


**Table 1.** Procedural complications in patients both with and without CIN after coronary intervention

(OR) = 0.83, 95% confidence interval (CI) 0.77 to 0.89, P <0.00001], diabetes (OR = 5.47, 95% CI 1.40 to 21.32, P = 0.01), and contrast dose (OR = 1.008, 95% CI 1.002 to 1.013, P = 0.01) to be independent predictors of ARFD. The in-hospital mortality for those who developed ARFD was 35,7% and the 2-year survival was 18,8% [13].

Moreover, development of CIN significantly prolongs hospitalization among survive pa‐ tients and is often associated with increased procedural complications rate (table 1) [2].

## **4. Contrast agents**

and 1-year mortality rates and a dramatic increase in hospital resource utilization. They compared clinical course in 51 consecutive patients who were not on dialysis on admission and developed acute renal failure that required in-hospital dialysis after coronary interven‐ tion and 7 690 patients who did not require dialysis after PCI. Patients who required dialysis were older, with a higher incidence of hypertension, diabetes, prior bypass surgery, chronic renal failure, and a significantly lower left ventricular ejection fraction. Despite similar an‐ giographic success, these patients had a higher incidence of in-hospital mortality (27.5% vs. 1.0%, *P* < 0.0001), non–Q-wave myocardial infarction (45.7% vs. 14.6%, *P* < 0.0001), vascular and bleeding complications, and longer hospitalization. At 1-year follow-up, mortality (54.5% vs. 6.4%, *P* < 0.0001), myocardial infarction (4.5% vs. 1.6%, *P* = 0.006), and event-free survival (38.6% vs. 72.0%, *P* < 0.0001) were significantly worse in patients who required dial‐

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

Similarly, analysis of 1 826 consecutive patients undergoing coronary intervention from as‐ pect of the incidence, predictors, and mortality related to acute renal failure (ARF) and acute renal failure requiring dialysis (ARFD) after coronary intervention has shown that occur‐ rence of ARFD after coronary intervention is rare (<1%) but is associated with high in-hospi‐ tal lethality and poor long-term survival. Individual patient risk can be estimated from calculated CrCl, diabetic status, and expected contrast dose prior to a proposed coronary in‐ tervention [13]. The incidence of ARF and ARFD was 144,6/1,000 and 7,7/1,000 cases respec‐ tively. The cutoff dose of contrast below which there was no ARFD was 100 ml. No patient with a CrCl > 47 ml/min developed ARFD. These thresholds were confirmed in the valida‐

> CIN (n=254)

Procedural success 72,8 94,0 < 0,0001 Death 22,0 1,4 < 0,0001 Q-wave myocardial infarction 3,9 0,9 < 0,0001 Creatinine kinase elevation 16,9 6,1 < 0,0001 Shock 13,0 3,1 < 0,0001 Cardiac arrest 11,4 1,5 < 0,0001 Intraaortic balloon pump use 11,4 3,1 < 0,0001 Femoral bleeding 3,1 1,4 0,03 Stroke 1,2 0,03 0,05 Adult respiratory distress syndrome 9,4 0,7 < 0,0001 Gastrointestinal bleeding 4,3 1,2 < 0,0001

**Table 1.** Procedural complications in patients both with and without CIN after coronary intervention

**No CIN (n=7332) P-value**

ysis compared to patients who did not [12].

tion set. Multivariate analysis found CrCl [odds ratio

**Variable (%)**

CIN = contrast induced nephropathy

All modern contrast agents are based on iodine, because of its high atomic number and chem‐ ical versatility has proved to be an excellent agent for intravascular opacification. First report‐ ed parenteral application of an iodinated contrast agents was during an intravenous pyelography in 1919. Inorganic sodium iodide cause often toxic reactions. In 1929 was ex‐ plored an organic iodide preparation with one iodine atom per benzoic acid ring and in 1950s, more substituted tri-iodobenzoic acid derivates were developed (with three iodine atoms per ring). Specific side chains in position 1, 3 and 5 influence both solubility and toxicity.

First generation contrast agents were ionic monomers containing a benzene ring with three iodine atoms, exhibiting high osmolarity in the range of 1500 to 1800 mOsm/kg (high osmo‐ lar contrast agents), roughly six times that of blood. This ratio-1,5 ionic compounds are sub‐ stituted ionic triiodobenzoic acid derivatives that contain three atoms of iodine for every two ions (substituted benzoic acid ring and accompanying cation). To have an iodine con‐ centration of 320 do 370 mg I/ml, as is required for coronary artery angiography, solution of these agents are extremely hypertonic with osmolarity more than 1500 mOsm/kg (Figure 2).

**Figure 2.** Ionic monomer contrast agent (Diatrizoat)

Ratio-3 lower-osmolarity contrast agents were introduced in 1980s. This contrast ages (ioxa‐ glate) was still ionic with dimeric structure that include six molecules iodine on the dimeric ring (three atoms of iodine per one ion) (Figure 3).

(iodixanol). There are data suggesting a reduction of nephrotoxicity with this agent [11]. Nevertheless even third generation contrast agents have been implicated by some authors

Contrast-Induced Nephropathy: Risk Factors, Clinical Implication, Diagnostics Approach, Prevention

The osmolarity of a solution is proportional to the number of dissolved particles (ions, mole‐ cules). Thus, the osmolarity of contrast agent solution can be decreased by increasing the

**COMPOUND Iodine atoms Particles Ratio** Ionic monomers 3 2 1,5 Nonionic monomers 3 1 3,0 Ionic dimmers 6 2 3,0 Nonionic dimmers 6 1 6,0

(6:2) Ioxaglate <sup>320</sup> <sup>600</sup> 7,5

The exact pathogenesis of CIN is still unclear. Several injury pathways have been proposed.

**I/ml) Osmolarity (mOsm/kg) Viscosity (at**

Diatrizoate 370 2076 8,4 iothalmate 325 1797 2,8

Iopamidol 370 796 9,4 Iohexol 350 844 10,4 Ioversol 350 792 9,0 Ioxilan 350 695 8,1

Iodixanol 320 290 11,8

**37oC)**

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In table 3 are summarized properties of current available contrast agents.

for potential nephrotoxicity [14] (Figure 5).

**Table 2.** Osmolarity in the four categories of contrast media

High-osmolar ionic Ratio 1,5 (3:2)

Low-osmolar nonionic Ratio 3 (3:1)

Low-osmolar ionic dimmer Ratio 3

Iso-osmolar nonionic dimmer Ratio

**Table 3.** Properties of available contrast agents

**5. Patothophysiology of CIN:**

Important possible pathogenetic mechanisms of CIN involve:

6 (6:1)

**CLASS EXAMPLES IODINE (mg**

number of iodine atoms per dissolved particle (Table 2).

**Figure 3.** Ionic dimeric contrast agent (Ioxaglate)

The introduction of nonionic ratio-3 contrast agents was very important step in late 1980s. An iodine content of 320 to 370 mg I/ml can be achieved with an osmolarity of 600 to 700 mOsm/kg (between two and three times that of blood) (low osmolar contrast agents). Their viscosity is approximately 6 to 10 times that of water (Figure 4).

**Figure 4.** Nonionic monomer contrast agent (iopamidol)

**Figure 5.** Nonionic dimeric contrast agent (Iodixanol)

Third generation agents are dimmers almost iso-osmolar to plasma (iso-osmolar contrast agents) but with increased viscosity, which results in complicated injection through small vascular catheters. This iso-osmolar contrast agent is a ratio-6 nonionic dimeric compound (iodixanol). There are data suggesting a reduction of nephrotoxicity with this agent [11]. Nevertheless even third generation contrast agents have been implicated by some authors for potential nephrotoxicity [14] (Figure 5).

The osmolarity of a solution is proportional to the number of dissolved particles (ions, mole‐ cules). Thus, the osmolarity of contrast agent solution can be decreased by increasing the number of iodine atoms per dissolved particle (Table 2).


**Table 2.** Osmolarity in the four categories of contrast media

**Figure 3.** Ionic dimeric contrast agent (Ioxaglate)

**Figure 4.** Nonionic monomer contrast agent (iopamidol)

**Figure 5.** Nonionic dimeric contrast agent (Iodixanol)

viscosity is approximately 6 to 10 times that of water (Figure 4).

The introduction of nonionic ratio-3 contrast agents was very important step in late 1980s. An iodine content of 320 to 370 mg I/ml can be achieved with an osmolarity of 600 to 700 mOsm/kg (between two and three times that of blood) (low osmolar contrast agents). Their

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

Third generation agents are dimmers almost iso-osmolar to plasma (iso-osmolar contrast agents) but with increased viscosity, which results in complicated injection through small vascular catheters. This iso-osmolar contrast agent is a ratio-6 nonionic dimeric compound


In table 3 are summarized properties of current available contrast agents.

**Table 3.** Properties of available contrast agents

## **5. Patothophysiology of CIN:**

The exact pathogenesis of CIN is still unclear. Several injury pathways have been proposed. Important possible pathogenetic mechanisms of CIN involve:

**a.** a medullar hypoxia due to altered hemodynamics, which in the presence of impaired adaptive responses leads to tubular damage and

Available izo-osmolar contrast agents exhibit considerably higher viscosity and should im‐ pair renal medullar blood flow to a greater extent than low osmolar agents. This situation is indicated by a particularly reduced pO2 levels caused by iso osmolar contrast media in ex‐

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**Figure 7.** Medullar hypoxia induced by contrast media (ioxaglate, iopromide, and iotrolan in comparison to Ringer's

Reduction of pO2 is greater for iotrolan (iso-osmolar nonionic dimer) followed by ioxaglate (low-osmolar ionic dimer). Iopromide (low-osmolar monomer) had the least effect of the

Tubular viscosity will increase markedly toward distal sections of the kidney due to fluid reabsorbtion. When urine becomes very concentrated, tubular fluid viscosity will increase and tubular plugging may occur. Hydration attenuates fluid reabsorbtion in the collecting

Adverse effects of pronounced increases of viscosity on the kidney are schematically shown

perimental model (Figure 7) [20].

solution).

contrast media.

in figure 8 [19].

ducts and is therefore very beneficial [19].

**b.** a direct cytotoxic effect of the contrast agents on tubular cells.

Probably, a combination of various pathophysiologic mechanisms is involved. The contrast agent may have direct cytotoxic effects due to relatively high tissue osmolarity. The contrast medium induces renal vasoconstriction, leading to tubular injury or even necrosis.

It has been shown in experimental animal model that after parenteral administration of con‐ trast media they exhibit short-term renal vasodilatation, which is followed by prolonged vasoconstriction, resulting in a decrease in total renal blood flow and a reduction of glomer‐ ular filtration rate [15].

Elevated endothelia levels and other vasoconstrictor levels were detected in patients with CIN. Administration of radiocontrast agents in normal rats induces endothelia release [16]. Subsequent reperfusion injury may increase free radical formation and create oxidative stress. The contrast medium may precipitate with Tamm- Horsfall glycoprotein in distal tu‐ bule lumen and form casts [17].

Increased adenosine-induced renal vasoconstriction in combination with attenuated renal NO-dependent vasodilatation, may account for the predisposition of diabetic patients to CIN [18].

There is a relationship between osmolarity and viscosity in monomeric contrast media (Fig‐ ure 6) [19].

**Figure 6.** Osmolarity and viscosity for I-concentration of 300 mg/ml

Available izo-osmolar contrast agents exhibit considerably higher viscosity and should im‐ pair renal medullar blood flow to a greater extent than low osmolar agents. This situation is indicated by a particularly reduced pO2 levels caused by iso osmolar contrast media in ex‐ perimental model (Figure 7) [20].

**a.** a medullar hypoxia due to altered hemodynamics, which in the presence of impaired

Probably, a combination of various pathophysiologic mechanisms is involved. The contrast agent may have direct cytotoxic effects due to relatively high tissue osmolarity. The contrast

It has been shown in experimental animal model that after parenteral administration of con‐ trast media they exhibit short-term renal vasodilatation, which is followed by prolonged vasoconstriction, resulting in a decrease in total renal blood flow and a reduction of glomer‐

Elevated endothelia levels and other vasoconstrictor levels were detected in patients with CIN. Administration of radiocontrast agents in normal rats induces endothelia release [16]. Subsequent reperfusion injury may increase free radical formation and create oxidative stress. The contrast medium may precipitate with Tamm- Horsfall glycoprotein in distal tu‐

Increased adenosine-induced renal vasoconstriction in combination with attenuated renal NO-dependent vasodilatation, may account for the predisposition of diabetic patients to

There is a relationship between osmolarity and viscosity in monomeric contrast media (Fig‐

medium induces renal vasoconstriction, leading to tubular injury or even necrosis.

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

adaptive responses leads to tubular damage and

ular filtration rate [15].

CIN [18].

ure 6) [19].

bule lumen and form casts [17].

**Figure 6.** Osmolarity and viscosity for I-concentration of 300 mg/ml

**b.** a direct cytotoxic effect of the contrast agents on tubular cells.

**Figure 7.** Medullar hypoxia induced by contrast media (ioxaglate, iopromide, and iotrolan in comparison to Ringer's solution).

Reduction of pO2 is greater for iotrolan (iso-osmolar nonionic dimer) followed by ioxaglate (low-osmolar ionic dimer). Iopromide (low-osmolar monomer) had the least effect of the contrast media.

Tubular viscosity will increase markedly toward distal sections of the kidney due to fluid reabsorbtion. When urine becomes very concentrated, tubular fluid viscosity will increase and tubular plugging may occur. Hydration attenuates fluid reabsorbtion in the collecting ducts and is therefore very beneficial [19].

Adverse effects of pronounced increases of viscosity on the kidney are schematically shown in figure 8 [19].

**Figure 9.** Altered mitochondrial function in a proximal tubular cell line as determined by 3- (4,5-dimethylthiasol-2-

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The least influence was found by the low-osmolar agents, followed by theiso-osmolar con‐

Numerous studies have identified predisposing risk factors such as preexisting chronic kid‐ ney disease, particularly diabetic kidney disease, degree of renal dysfunction, volume deple‐ tion, co administration of nephrotoxic agents, high doses of radiocontrast, particularly ionic and high osmolar, repeated examinations at short intervals, as well as advanced cardiac fail‐

Multiple CIN risk factors, including both patient's factors and procedural factors are sum‐

yl)-2,5-diphenyltetrazolium bromide (MTT) reduction (24-hour treatment)

**6. Risks factors**

marized in table 4 and 5.

trast media (Iodixanol). The ionic substances showed the greatest effect.

ure [22, 23], perhaps also age, smoking, and hypercholesterolemia [23].

**Figure 8.** Flow chart of mechanisms linking fluid osmolarity to renal damage, GFR = glomerular filtration rate

As a consequence of contrast media administration, tubular cell damage can occur. Except for vacuolization, there was described pertubation of mitochondrial enzyme activity and mi‐ tochondrial membrane potential as a cause of alteration of proximal tubular functions (Fig‐ ure 9) [21].

Extend of mitochondrial enzyme activity impairment relies primarily on two features of the contrast media: ionicity and the molecular structure. Remarkably, low-osmolar (monomeric) contrast media had the least effect, followed by the iso-osmolar (dimeric, nonionic) agents. Ionic compounds revealed the most profound effects [21].

**Figure 9.** Altered mitochondrial function in a proximal tubular cell line as determined by 3- (4,5-dimethylthiasol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) reduction (24-hour treatment)

The least influence was found by the low-osmolar agents, followed by theiso-osmolar con‐ trast media (Iodixanol). The ionic substances showed the greatest effect.

### **6. Risks factors**

**Figure 8.** Flow chart of mechanisms linking fluid osmolarity to renal damage, GFR = glomerular filtration rate

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

ure 9) [21].

As a consequence of contrast media administration, tubular cell damage can occur. Except for vacuolization, there was described pertubation of mitochondrial enzyme activity and mi‐ tochondrial membrane potential as a cause of alteration of proximal tubular functions (Fig‐

Extend of mitochondrial enzyme activity impairment relies primarily on two features of the contrast media: ionicity and the molecular structure. Remarkably, low-osmolar (monomeric) contrast media had the least effect, followed by the iso-osmolar (dimeric, nonionic) agents.

Ionic compounds revealed the most profound effects [21].

Numerous studies have identified predisposing risk factors such as preexisting chronic kid‐ ney disease, particularly diabetic kidney disease, degree of renal dysfunction, volume deple‐ tion, co administration of nephrotoxic agents, high doses of radiocontrast, particularly ionic and high osmolar, repeated examinations at short intervals, as well as advanced cardiac fail‐ ure [22, 23], perhaps also age, smoking, and hypercholesterolemia [23].

Multiple CIN risk factors, including both patient's factors and procedural factors are sum‐ marized in table 4 and 5.


Most important predictor of CIN is baseline renal function (creatinine clearance < 60 ml/s). Presence of diabetes mellitus and the type and amount of contrast agents are strong risk fac‐

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Using these risk factors, there have been simple and reliable predictive scores for CIN devel‐

**Risk score Risk of CIN Risk of dialysis** ≤ 5 7,5% 0,04% 6-10 14,0% 0,12% 11-16 26,1% 1,09% ≥ 16 57,3% 12,6%

At present there is no specific therapy, which could reduce or reverse development of the CIN, once it is occurs. However, there is possibility of CIN prophylaxis. There are available published data on many different methods of prevention, but many of them failed in effi‐ ciency and quality of study design. The most important step in preventing CIN is to deter‐ mine whether a patient belongs to a risk group. If it is not so, there are not specific measures required. In the case of risk, it should be consider using another method of investigation

Hydration is the most important preventing tool consistently resulting in a decrease of CIN

In long-term study of 537 consecutive patients undergoing angiography (average dose of contrast agent 2ml/kg) there was not observed either clinical nor biochemical instance of acute renal failure, despite high risk profile of population. Prevalence of underlying clinical abnormalities was: prior stroke or myocardial infarction (58%), diabetes mellitus (33%), hy‐ pertension (46%), renal insufficiency (27%), liver disease (14%), proteinuria (14%), elevated uric acid level (13%). In 53% of patients two or more clinical abnormalities was detected. In 24%, there were two or more of the risk factors witch increased likelihood of renal failure. There was not restriction of fluids prior to angiography, infusing about 500 ml/hr during the

An important aspect is to ensure optimal volume repletion prior the procedure. It is recom‐ mended to parenterally administer of at least total 1 l of isotonic saline. Infusion usually be‐ gins at least 3 hours before and continues 6-8 hours after procedure. Initial infusion rate of

procedure and encouraging fluids following the examination [27].

tors as well ([24, 25].

oped (Table 6 and 7) [6, 26].

**Table 7.** Risk scores for CIN and outcomes

without need for contrast agent.

**7.1. Hydration**

incidence.

**7. Prevention of CIN**

**Table 4.** Patients factors associated with CIN


**Table 5.** Procedural factors associated with CIN


**Table 6.** Risk factor scores for a predictive score for CIN

Most important predictor of CIN is baseline renal function (creatinine clearance < 60 ml/s). Presence of diabetes mellitus and the type and amount of contrast agents are strong risk fac‐ tors as well ([24, 25].

Using these risk factors, there have been simple and reliable predictive scores for CIN devel‐ oped (Table 6 and 7) [6, 26].


**Table 7.** Risk scores for CIN and outcomes

## **7. Prevention of CIN**

Baseline creatinine level or creatinine clearance

Volume depletion, hypotension, hypovolemia

**Table 4.** Patients factors associated with CIN

Multiple contras media application within 72 hours

Estimated glomerular filtration rate < 60 ml/min/1,73m2

**Table 6.** Risk factor scores for a predictive score for CIN

**Risk factor Score**

2 for 40-60ml/min/1,73m2 4 for 20-40ml/min/1,73m2 6 for < 20ml/min/1,73m2

Hypotension (syst. BP < 80mmHg for 1 h requiring inotropic support 5 Intra aortic balloon pump (within 24h periprocedurally) 6 Congestive heart failure. NYHA class III/IV 5 Age "/> 75 years 4 Anemia ( hematocrit < 39% for mean and <36% for women) 3 Diabetes mellitus 3

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

Contrast media volume 1 for each 100 ml

Serum creatinine "/> 1,5 mg/ml 4

**Table 5.** Procedural factors associated with CIN

Diabetes mellitus Female gender

Anemia

Advanced age ("/> 70 year) Nephrotoxic medication

Acute coronary syndrome

Intra aortic balloon pump use Congestive heart failure Renal transplantant patient

Low cardiac output

Hypoalbuminemia Multiple myeloma

Contrast agents amount Osmolarity of contrast agents At present there is no specific therapy, which could reduce or reverse development of the CIN, once it is occurs. However, there is possibility of CIN prophylaxis. There are available published data on many different methods of prevention, but many of them failed in effi‐ ciency and quality of study design. The most important step in preventing CIN is to deter‐ mine whether a patient belongs to a risk group. If it is not so, there are not specific measures required. In the case of risk, it should be consider using another method of investigation without need for contrast agent.

### **7.1. Hydration**

Hydration is the most important preventing tool consistently resulting in a decrease of CIN incidence.

In long-term study of 537 consecutive patients undergoing angiography (average dose of contrast agent 2ml/kg) there was not observed either clinical nor biochemical instance of acute renal failure, despite high risk profile of population. Prevalence of underlying clinical abnormalities was: prior stroke or myocardial infarction (58%), diabetes mellitus (33%), hy‐ pertension (46%), renal insufficiency (27%), liver disease (14%), proteinuria (14%), elevated uric acid level (13%). In 53% of patients two or more clinical abnormalities was detected. In 24%, there were two or more of the risk factors witch increased likelihood of renal failure. There was not restriction of fluids prior to angiography, infusing about 500 ml/hr during the procedure and encouraging fluids following the examination [27].

An important aspect is to ensure optimal volume repletion prior the procedure. It is recom‐ mended to parenterally administer of at least total 1 l of isotonic saline. Infusion usually be‐ gins at least 3 hours before and continues 6-8 hours after procedure. Initial infusion rate of 100-150ml/hr are recommended with adjustment post procedure as clinically indicated [28].Caution should be applied in the patient with reduced left ventricular ejection fraction or congestive heart failure.

Prospective, randomized, controlled, open-label study was organized to compare the inci‐ dence of CIN with isotonic or half-isotonic hydration [29]. Patient scheduled for elective or emergency coronary angioplasty were randomly assigned to receive isotonic (0,9% saline) or half-isotonic (0,45% sodium chloride plus 5% glucose) hydration beginning the morning of the procedure for elective intervention or immediately before emergency intervention. CIN was defined as increase of serum creatinine at least 44umol/l within 48 hours. There were 15,7% diabetics, 25,6% women and 20,7% patients had chronic renal insufficiency, in this study population (Table 8),

**Figure 10.** Incidence of CIN, mortality and peripheral vascular complications

as independent risk factors for CIN (Table 9).

\* for an increase in baseline creatinine of 88 µmol/l

**Table 9.** Multivariate risk factor analysis for the development of CIN

of 1 ml/kg per hour for 6 hours after the procedure.

11.9%; 95% confidence interval [CI], 2.6%-21.2%; *P* = 0,02) Figure 11).

ment regimens.

**7.2. Bicarbonate**

Length of hospital stay was significantly increased in patients developing CIN in compari‐ son without nephropathy (8,1 vs. 4,7 days, p<0,001). However, it was similar in both treat‐

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In multivariate risk factors analysis, female sex and baseline creatinine level were revealed

**Risk factor P value Odds ratio (95% confident interval)**

In single-center, randomized controlled trial was compared infusion of sodium chloride vs. sodium bicarbonate as the hydration fluid to prevent renal failure in patients with stable re‐ nal insufficiency undergoing diagnostic or interventional procedures requiring radiographic contrast [30]. Patients received 154 mEq/L of either sodium chloride or sodium bicarbonate, as a bolus of 3 ml/kg per hour for 1 hour before iopamidol contrast, followed by an infusion

The primary outcome (development of contrast-induced nephropathy, defined by an in‐ crease in serum creatinine of 25% or more within 2 days after administration of the radio‐ graphic contrast) was observed in 1.7% (1 of 60) patients receiving sodium bicarbonate compared with 13.6% (8 of 59) in patients who received sodium chloride (mean difference,

Female sex 0,005 3,9 (1,5-10,1) Baseline creatinine <0,001 6,6 (3,2-13,8) \* Isotonic hydration 0,037 0,3 (0,1-0,9)


LVEF= left ventricular ejection fraction, MI=myocardial infarction

**Table 8.** Baseline clinical characteristics

CIN developed in 5 patients with isotonic infusion vs. 14 patients with half-isotonic infu‐ sion. Therefore, incidence of CIN was significantly reduced with isotonic (0,7%, 95% confi‐ dence interval, 0,1%-1,4%) vs. half-isotonic (2%, 95% CI, 1,0%-3,1%) hydration (p=0,04) (Figure 10).

**Figure 10.** Incidence of CIN, mortality and peripheral vascular complications

Length of hospital stay was significantly increased in patients developing CIN in compari‐ son without nephropathy (8,1 vs. 4,7 days, p<0,001). However, it was similar in both treat‐ ment regimens.

In multivariate risk factors analysis, female sex and baseline creatinine level were revealed as independent risk factors for CIN (Table 9).


\* for an increase in baseline creatinine of 88 µmol/l

**Table 9.** Multivariate risk factor analysis for the development of CIN

#### **7.2. Bicarbonate**

100-150ml/hr are recommended with adjustment post procedure as clinically indicated [28].Caution should be applied in the patient with reduced left ventricular ejection fraction

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

Prospective, randomized, controlled, open-label study was organized to compare the inci‐ dence of CIN with isotonic or half-isotonic hydration [29]. Patient scheduled for elective or emergency coronary angioplasty were randomly assigned to receive isotonic (0,9% saline) or half-isotonic (0,45% sodium chloride plus 5% glucose) hydration beginning the morning of the procedure for elective intervention or immediately before emergency intervention. CIN was defined as increase of serum creatinine at least 44umol/l within 48 hours. There were 15,7% diabetics, 25,6% women and 20,7% patients had chronic renal insufficiency, in this

**Characteristic Isotonic (n=685) Half-isotonic (n=698) P value** Age, year 64 (63-65) 64 (63-65) 0,71

Female sex 178 (26%) 176 (25%) 0,74

Chronic renal insufficiency 138 (20%) 148 (21%) 0,92

Diabetes mellitus 107 (16%) 110 (16%) 0,94

Arterial hypertension 445 (65%) 425 (61%) 0,12

Previous MI 327 (48%) 353 (51%) 0,29

Acute MI 54 (8%) 60 (9%) 0,63

Single vessel disease 244 (36%) 251 (36%) 0,90

3-vessel disease 252 (37%) 236 (34%) 0,25

LVEF ≥ 60% 287 (42%) 285 (41%) 0,70

LVEF 45-60% 292 (43%) 313 (45%) 0,39

LVEF 30-45% 88 (13%) 82 (12%) 0,54

LVEF < 30% 18 (3%) 17 (2%) 0,82

CIN developed in 5 patients with isotonic infusion vs. 14 patients with half-isotonic infu‐ sion. Therefore, incidence of CIN was significantly reduced with isotonic (0,7%, 95% confi‐ dence interval, 0,1%-1,4%) vs. half-isotonic (2%, 95% CI, 1,0%-3,1%) hydration (p=0,04)

LVEF= left ventricular ejection fraction, MI=myocardial infarction

**Table 8.** Baseline clinical characteristics

(Figure 10).

or congestive heart failure.

study population (Table 8),

In single-center, randomized controlled trial was compared infusion of sodium chloride vs. sodium bicarbonate as the hydration fluid to prevent renal failure in patients with stable re‐ nal insufficiency undergoing diagnostic or interventional procedures requiring radiographic contrast [30]. Patients received 154 mEq/L of either sodium chloride or sodium bicarbonate, as a bolus of 3 ml/kg per hour for 1 hour before iopamidol contrast, followed by an infusion of 1 ml/kg per hour for 6 hours after the procedure.

The primary outcome (development of contrast-induced nephropathy, defined by an in‐ crease in serum creatinine of 25% or more within 2 days after administration of the radio‐ graphic contrast) was observed in 1.7% (1 of 60) patients receiving sodium bicarbonate compared with 13.6% (8 of 59) in patients who received sodium chloride (mean difference, 11.9%; 95% confidence interval [CI], 2.6%-21.2%; *P* = 0,02) Figure 11).

Post hoc analysis revealed that the percentage change in glomerular filtration rate after con‐ trast was significantly improved in patients receiving sodium bicarbonate treatment (+8.5%) compared with those receiving sodium chloride (–0.1%) (mean difference, –8.6%; 95% CI,

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Blue heavy lines represent cases of contrast-induced renal failure. Dotted line indicates

Solomon R et al performed randomized comparison saline hydration and different types of diuretic strategies in patients scheduled for cardiac angiography who had serum creatinine concentrations exceeding 140 μmol/l or creatinine clearance rates below <1.0 ml/s [31].

All the patients received 0.45% saline intravenously at a rate of 1 ml /kg of body weight/1 hour beginning 12 hours before the angiography. This saline infusion was continued during the angiography (saline group) or was supplemented with 25 g of manitol, infused intrave‐ nously during the 60 minutes immediately before angiography (manitol group), or with 80 mg of furosemide, infused intravenously during the 30 minutes immediately before angiog‐ raphy (furosemide group). All the patients continued to receive 0.45 % saline intravenously at the same rate for 12 hours after angiography. A CIN was defined as an increase in the base-line serum creatinine concentration of at least ≥ 44 μmol per liter within 48 hours after

Study confirmed that hydration with 0.45 percent saline for 12 hours before and 12 hours after the administration of radiocontrast agents was the most effective means of preventing acute decreases in renal function in patients with chronic renal insufficiency with or without diabetes mellitus. Neither manitol nor furosemide offered any additional benefit when add‐

**Figure 13.** Effect of saline, manitol, and furosemide on the prevention of contrast-induced nephropathy

threshold for severe renal insufficiency (serum creatinine ≥221 μmol/L).

−17.0% to −0.2%; *P* = 0,02) (Figure 12) [30].

the injection of radiocontrast medium.

ed to this hydration protocol (Figure 13).

**Figure 11.** Prevention of CIN by bicarbonate

The absolute risk reduction of CIN, using sodium bicarbonate compared with sodium chlor‐ ide was 11.9%, resulting in a number needed to treat of 8.4 patients to prevent 1 case of renal failure.

When results were analyzed by another common definition of CIN (at least ≥44.2 μmol/l change in serum creatinine), 7 (11.9%) of 59 patients who were treated with sodium chloride developed contrast nephropathy vs. only 1 (1.7%) of 60 who received sodium bicarbonate (mean difference, 10.2%; 95% CI, 1.3%-19.1%; *P* =0,03).

**Figure 12.** Percentage change in estimated glomerular filtration rate in randomized patients following contrast

Post hoc analysis revealed that the percentage change in glomerular filtration rate after con‐ trast was significantly improved in patients receiving sodium bicarbonate treatment (+8.5%) compared with those receiving sodium chloride (–0.1%) (mean difference, –8.6%; 95% CI, −17.0% to −0.2%; *P* = 0,02) (Figure 12) [30].

Blue heavy lines represent cases of contrast-induced renal failure. Dotted line indicates threshold for severe renal insufficiency (serum creatinine ≥221 μmol/L).

Solomon R et al performed randomized comparison saline hydration and different types of diuretic strategies in patients scheduled for cardiac angiography who had serum creatinine concentrations exceeding 140 μmol/l or creatinine clearance rates below <1.0 ml/s [31].

(mean difference, 10.2%; 95% CI, 1.3%-19.1%; *P* =0,03).

**Figure 11.** Prevention of CIN by bicarbonate

failure.

CIN at 2 days (%)

**0,9% NaCl Bicarbonate**

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

The absolute risk reduction of CIN, using sodium bicarbonate compared with sodium chlor‐ ide was 11.9%, resulting in a number needed to treat of 8.4 patients to prevent 1 case of renal

When results were analyzed by another common definition of CIN (at least ≥44.2 μmol/l change in serum creatinine), 7 (11.9%) of 59 patients who were treated with sodium chloride developed contrast nephropathy vs. only 1 (1.7%) of 60 who received sodium bicarbonate

**Figure 12.** Percentage change in estimated glomerular filtration rate in randomized patients following contrast

P=0,02

All the patients received 0.45% saline intravenously at a rate of 1 ml /kg of body weight/1 hour beginning 12 hours before the angiography. This saline infusion was continued during the angiography (saline group) or was supplemented with 25 g of manitol, infused intrave‐ nously during the 60 minutes immediately before angiography (manitol group), or with 80 mg of furosemide, infused intravenously during the 30 minutes immediately before angiog‐ raphy (furosemide group). All the patients continued to receive 0.45 % saline intravenously at the same rate for 12 hours after angiography. A CIN was defined as an increase in the base-line serum creatinine concentration of at least ≥ 44 μmol per liter within 48 hours after the injection of radiocontrast medium.

Study confirmed that hydration with 0.45 percent saline for 12 hours before and 12 hours after the administration of radiocontrast agents was the most effective means of preventing acute decreases in renal function in patients with chronic renal insufficiency with or without diabetes mellitus. Neither manitol nor furosemide offered any additional benefit when add‐ ed to this hydration protocol (Figure 13).

**Figure 13.** Effect of saline, manitol, and furosemide on the prevention of contrast-induced nephropathy

It is necessary for optimal preprocedural management of patients at risk for CIN, carefully evaluate pharmacotherapy and withdrawn potentially nephrotoxic drugs, as clinically ap‐ propriate, (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, antirejection therapy) [2, 29, 31]. Angiotensin converting enzyme inhibitor therapy should continue with‐ out neither initiating nor changing dose until the patient safely past the risk period for CIN development [28]. In patient with diabetes mellitus, metformin should be withheld after procedure until it is clear that renal functions are without deterioration because risk of lac‐ tate acidosis [32].

However, in a subgroup of patients with peripheral vascular disease (PVD), ΔCr was −2,4 ± 2,3 in the Control group and 30,0 ± 12,0 μmol/l in the Dopamine group (p = 0,01). No signifi‐ cant difference occurred in ΔCr between Control and Dopamine in subgroups of patients

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Administration of contrast agent caused a small but significant increase in Cr blood level in high-risk patients. There is no advantage of dopamine over adequate hydration in patients

Fenoldopam mesylate is a dopamine A1 receptor agonist, augment renal plasma flow and preserves renal blood flow after iodinated contrast administration. It appeared promising in prevention of CIN in a pilot randomized placebo controlled double blind study in 45 pa‐ tients with chronic renal insufficiency who underwent angiography [36]. Patients were randomized to receive normal saline solution or saline solution with fenoldopan mesylate at

Renal plasma flow (primary endpoint) at 1 hour after angiography was 15,8% above baseline in fenoldopan group compared with 33,2% below baseline in the normal saline group (p<0,05). Incidence of CIN at 48 hour (secondary endpoint) was 41,0% in the normal saline group vs. 21% in the fenoldopam group (p=0,148). Renal plasma flow was significantly (p<0,001) re‐

Effect of fenoldopam mesylate was investigated in larger prospective randomized control‐ led CONTRAST study [37]. There were 315 patients with creatinine clearance less than 1.00 ml/s at 28 centers in the United States randomized to receive fenoldopam mesylate (0.05 μg/kg/min titrated to 0.10 μg/kg/min) (n = 157) or placebo (n = 158), starting 1 hour prior to angiography and continuing for 12 hours. Within 96 hours, the primary end point of con‐ trast-induced nephropathy had been reached in 33.6% of patients in the fenoldopam group vs. 30.1% of patients in the placebo group (relative risk [RR], 1.11; 95% confidence interval

**fenoldopam placebo**

P=0,54

duced in patients with CIN compared with patients without development of CIN [36].

with mild to moderate renal failure or DM undergoing coronary angiography [35].

0,1 ug/kg/min at lease 1hr before administration of contrast agent.

with preangiographic CRF or DM.

[CI], 0.79-1.57; *P* =.61) (Figure 15).

**0.00%**

**Figure 15.** Effect of fenoldopam on CIN prevention

**10.00%**

**20.00%**

**30.00%**

**40.00%**

**7.4. Fenoldopam**

#### **7.3. Dopamine**

Dopamine in low doses (0.5 to 2.5 μg/kg/min) stimulates dopaminergic receptors in the re‐ nal and mesenteric vasculature, resulting in selective vasodilatation. Low dose of dopamine increases renal plasma flow, glomerular filtration rate, and sodium excretion in subjects with normal renal function and with congestive heart failure [27, 33, 34].

Effect of low-dose dopamine in prevention of CIN was studied in prospective randomized trial in patients with chronic renal failure (CRF) (serum Cr <200 μmol/l) and/or diabetes mel‐ litus who underwent coronary angiography. All patients received intravenous hydration for 8 to 12 h before and 36 to 48 h after angiography with 0.45% saline/5% dextrose. In addition, the patients were randomly assigned to receive either 120 ml/day of 0.9% saline plus dopa‐ mine 2 μg/kg/min (Dopamine group), or saline alone (Control group) for 48 h [35].

There were 36 Dopamine-treated (30 diabetics and 6 with CRF) and 33 Control (28 diabetics and 5 with CRF) patients compared. Plasma creatinine (Cr) level increased in the Control group from 100,6 ± 5,2 before to 112,3 ± 8,0 μmol/liter within five days after angiography (p = 0,003), and in the Dopamine group from 100,3 ± 5,4 before to 117,5 ± 8,8 μmol/liter after angiography (p = 0,0001), respectively. There was no significant difference in the *change* of Cr level (ΔCr) between the two groups (Figure 14).

**Figure 14.** Effect low-dose dopamine on creatinine level in patients after angiography, AG=coronary angiography

However, in a subgroup of patients with peripheral vascular disease (PVD), ΔCr was −2,4 ± 2,3 in the Control group and 30,0 ± 12,0 μmol/l in the Dopamine group (p = 0,01). No signifi‐ cant difference occurred in ΔCr between Control and Dopamine in subgroups of patients with preangiographic CRF or DM.

Administration of contrast agent caused a small but significant increase in Cr blood level in high-risk patients. There is no advantage of dopamine over adequate hydration in patients with mild to moderate renal failure or DM undergoing coronary angiography [35].

#### **7.4. Fenoldopam**

It is necessary for optimal preprocedural management of patients at risk for CIN, carefully evaluate pharmacotherapy and withdrawn potentially nephrotoxic drugs, as clinically ap‐ propriate, (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, antirejection therapy) [2, 29, 31]. Angiotensin converting enzyme inhibitor therapy should continue with‐ out neither initiating nor changing dose until the patient safely past the risk period for CIN development [28]. In patient with diabetes mellitus, metformin should be withheld after procedure until it is clear that renal functions are without deterioration because risk of lac‐

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

Dopamine in low doses (0.5 to 2.5 μg/kg/min) stimulates dopaminergic receptors in the re‐ nal and mesenteric vasculature, resulting in selective vasodilatation. Low dose of dopamine increases renal plasma flow, glomerular filtration rate, and sodium excretion in subjects

Effect of low-dose dopamine in prevention of CIN was studied in prospective randomized trial in patients with chronic renal failure (CRF) (serum Cr <200 μmol/l) and/or diabetes mel‐ litus who underwent coronary angiography. All patients received intravenous hydration for 8 to 12 h before and 36 to 48 h after angiography with 0.45% saline/5% dextrose. In addition, the patients were randomly assigned to receive either 120 ml/day of 0.9% saline plus dopa‐

There were 36 Dopamine-treated (30 diabetics and 6 with CRF) and 33 Control (28 diabetics and 5 with CRF) patients compared. Plasma creatinine (Cr) level increased in the Control group from 100,6 ± 5,2 before to 112,3 ± 8,0 μmol/liter within five days after angiography (p = 0,003), and in the Dopamine group from 100,3 ± 5,4 before to 117,5 ± 8,8 μmol/liter after angiography (p = 0,0001), respectively. There was no significant difference in the *change* of

**Dopamine group Control group**

**Figure 14.** Effect low-dose dopamine on creatinine level in patients after angiography, AG=coronary angiography

**before AG after AG**

P=0,79

P=0,000 1

mine 2 μg/kg/min (Dopamine group), or saline alone (Control group) for 48 h [35].

with normal renal function and with congestive heart failure [27, 33, 34].

Cr level (ΔCr) between the two groups (Figure 14).

P=0,000 1

Creatinine (umol/l)

tate acidosis [32].

**7.3. Dopamine**

Fenoldopam mesylate is a dopamine A1 receptor agonist, augment renal plasma flow and preserves renal blood flow after iodinated contrast administration. It appeared promising in prevention of CIN in a pilot randomized placebo controlled double blind study in 45 pa‐ tients with chronic renal insufficiency who underwent angiography [36]. Patients were randomized to receive normal saline solution or saline solution with fenoldopan mesylate at 0,1 ug/kg/min at lease 1hr before administration of contrast agent.

Renal plasma flow (primary endpoint) at 1 hour after angiography was 15,8% above baseline in fenoldopan group compared with 33,2% below baseline in the normal saline group (p<0,05). Incidence of CIN at 48 hour (secondary endpoint) was 41,0% in the normal saline group vs. 21% in the fenoldopam group (p=0,148). Renal plasma flow was significantly (p<0,001) re‐ duced in patients with CIN compared with patients without development of CIN [36].

Effect of fenoldopam mesylate was investigated in larger prospective randomized control‐ led CONTRAST study [37]. There were 315 patients with creatinine clearance less than 1.00 ml/s at 28 centers in the United States randomized to receive fenoldopam mesylate (0.05 μg/kg/min titrated to 0.10 μg/kg/min) (n = 157) or placebo (n = 158), starting 1 hour prior to angiography and continuing for 12 hours. Within 96 hours, the primary end point of con‐ trast-induced nephropathy had been reached in 33.6% of patients in the fenoldopam group vs. 30.1% of patients in the placebo group (relative risk [RR], 1.11; 95% confidence interval [CI], 0.79-1.57; *P* =.61) (Figure 15).

**Figure 15.** Effect of fenoldopam on CIN prevention

The incidence of contrast-induced nephropathy was also similar in both groups when de‐ fined by an absolute increase in serum creatinine level. There were no significant interac‐ tions between treatment group and diabetic status, hypertension, baseline renal function, Nacetylcysteine use, or amount of hydration or contrast use.

antioxidant acetylcysteine (600 mg orally twice daily) and 0.45 percent saline intravenously, before and after administration of the contrast agent, or to receive placebo and saline [40].

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Ten of the 83 patients (12 percent) had an increase of creatinine level at least 44 μmol/l at 48 hours after administration of the contrast agent: 1 of the 41 patients in the acetylcysteine group (2 percent) and 9 of the 42 patients in the control group (21 percent; P=0.01; relative

**acetylcystein control**

In the acetylcysteine group, the mean serum creatinine concentration decreased significantly (P<0.001), from 220+/-118 to 186+/-112 μmol/l at 48 hours after the administration of the con‐ trast medium, whereas in the control group, the mean serum creatinine concentration in‐ creased nonsignificantly (P=0.18), from 212+/-114 to 226+/-133 μmol/l (P<0.001 for the

In prospective randomized RAPPIDE study, 80 patients with stable renal dysfunction un‐ dergoing coronary angiography and/or intervention were allocated to an administration of 150mg/kg acetylcystein in 500 ml saline over 30 min immediately before contrast followed by 50mg/kg acetylcystein in 500 ml saline over 4 hours or intravenously hydration (1ml/kg

Acute CIN occurred in 10 of the 80 patients (12,5%), 2 of the 41 (5%) in acetylcysteine group and in 8 of the 39 fluid-treated patients (21%), p=0,045, relative risk: 0,28; 95% confidence in‐

Prophylactic preventive double dose of N-acetylcystein was investigated in prospective randomized trial in population of 224 patients with chronic renal insufficiency (creatinine level ≥1.5mg/dl or eGFR< 1ml/s) undergoing intravascular administration of non-ionic, low-

P=0,01

risk, 0.1; 95 percent confidence interval, 0.02 to 0.9) (Figure 17).

0%

**Figure 17.** Effect of an acetylcystein on incidence of CIN

saline for 12hours pre and post-contrast) [41].

comparison between groups).

terval: 0,08 to 0,98 (Figure 18).

osmolarity contrast agent [42].

5%

10%

15%

20%

25%

#### **7.5. Acetylcystein**

N-acetylcysteine is a modified form of the amino acid cysteine, which is a nitrogen atom bound via an acetyl group (Figure 16). Molecular weight of N-acetylcysteine is 163,2. The main therapeutic indication is its use as an antidote for paracetamol overdose, as well as a mucolytic therapy.

The mechanism by which N-acetylcysteine may reduce the incidence of CIN remains un‐ clear so far. In its most important feature is considered a strong antioxidant effect, which can dispose of a wide range of oxygen radicals. Moreover, N-acetylcysteine is the precursor of the endogenous antioxidant glutathione. Reduce damage from oxygen radicals by N-acetyl‐ cysteine have been observed in myocardial infarction [38]. Similarly, N-acetylcysteine can preserve cell death in ischemia-reperfusion renal injury [39]. N-acetylcysteine increases the expression of NO synthase and also enhances the biological effect of nitric oxide itself by creating a compound S-nitrozotiole, which is also a strong and stable vasodilator. In this way, N-acetylcysteine reduces the renal vasoconstriction, and thereby improves blood flow to the kidneys.

N-Acetylcysteine is a free-radical scavenger and has been shown to be renoprotective in some studies [40]. There were performed a lot of randomized trials and meta-analysis with an acetylcysteine in prevention of CIN in high risk patients. Some contradictory results from these studies may be caused by different type or volume of used contrast agents as well as different dosage, timing and route of acetylcystein administration.

Tepel at al. prospectively assessed 83 patients with chronic renal insufficiency (serum creati‐ nine level 216+/-116 μmol/l, mean +/-SD) who were undergoing computed tomography with a nonionic, low-osmolarity contrast agent. Patients were randomly assigned either to receive the antioxidant acetylcysteine (600 mg orally twice daily) and 0.45 percent saline intravenously, before and after administration of the contrast agent, or to receive placebo and saline [40].

Ten of the 83 patients (12 percent) had an increase of creatinine level at least 44 μmol/l at 48 hours after administration of the contrast agent: 1 of the 41 patients in the acetylcysteine group (2 percent) and 9 of the 42 patients in the control group (21 percent; P=0.01; relative risk, 0.1; 95 percent confidence interval, 0.02 to 0.9) (Figure 17).

**Figure 17.** Effect of an acetylcystein on incidence of CIN

The incidence of contrast-induced nephropathy was also similar in both groups when de‐ fined by an absolute increase in serum creatinine level. There were no significant interac‐ tions between treatment group and diabetic status, hypertension, baseline renal function, N-

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

N-acetylcysteine is a modified form of the amino acid cysteine, which is a nitrogen atom bound via an acetyl group (Figure 16). Molecular weight of N-acetylcysteine is 163,2. The main therapeutic indication is its use as an antidote for paracetamol overdose, as well as a

The mechanism by which N-acetylcysteine may reduce the incidence of CIN remains un‐ clear so far. In its most important feature is considered a strong antioxidant effect, which can dispose of a wide range of oxygen radicals. Moreover, N-acetylcysteine is the precursor of the endogenous antioxidant glutathione. Reduce damage from oxygen radicals by N-acetyl‐ cysteine have been observed in myocardial infarction [38]. Similarly, N-acetylcysteine can preserve cell death in ischemia-reperfusion renal injury [39]. N-acetylcysteine increases the expression of NO synthase and also enhances the biological effect of nitric oxide itself by creating a compound S-nitrozotiole, which is also a strong and stable vasodilator. In this way, N-acetylcysteine reduces the renal vasoconstriction, and thereby improves blood flow

N-Acetylcysteine is a free-radical scavenger and has been shown to be renoprotective in some studies [40]. There were performed a lot of randomized trials and meta-analysis with an acetylcysteine in prevention of CIN in high risk patients. Some contradictory results from these studies may be caused by different type or volume of used contrast agents as well as

Tepel at al. prospectively assessed 83 patients with chronic renal insufficiency (serum creati‐ nine level 216+/-116 μmol/l, mean +/-SD) who were undergoing computed tomography with a nonionic, low-osmolarity contrast agent. Patients were randomly assigned either to receive the

different dosage, timing and route of acetylcystein administration.

acetylcysteine use, or amount of hydration or contrast use.

**7.5. Acetylcystein**

mucolytic therapy.

**Figure 16.** Formula N-acetyl cysteine.

to the kidneys.

In the acetylcysteine group, the mean serum creatinine concentration decreased significantly (P<0.001), from 220+/-118 to 186+/-112 μmol/l at 48 hours after the administration of the con‐ trast medium, whereas in the control group, the mean serum creatinine concentration in‐ creased nonsignificantly (P=0.18), from 212+/-114 to 226+/-133 μmol/l (P<0.001 for the comparison between groups).

In prospective randomized RAPPIDE study, 80 patients with stable renal dysfunction un‐ dergoing coronary angiography and/or intervention were allocated to an administration of 150mg/kg acetylcystein in 500 ml saline over 30 min immediately before contrast followed by 50mg/kg acetylcystein in 500 ml saline over 4 hours or intravenously hydration (1ml/kg saline for 12hours pre and post-contrast) [41].

Acute CIN occurred in 10 of the 80 patients (12,5%), 2 of the 41 (5%) in acetylcysteine group and in 8 of the 39 fluid-treated patients (21%), p=0,045, relative risk: 0,28; 95% confidence in‐ terval: 0,08 to 0,98 (Figure 18).

Prophylactic preventive double dose of N-acetylcystein was investigated in prospective randomized trial in population of 224 patients with chronic renal insufficiency (creatinine level ≥1.5mg/dl or eGFR< 1ml/s) undergoing intravascular administration of non-ionic, lowosmolarity contrast agent [42].

trast dose (mean value 101±23ml), no significant difference in renal function deterioration occurred between the 2 groups (3,6% in single dose group vs. 1,7% in double dose group, p=0,61). In the subgroup (n=109) with high (≥140ml) contrast dose (mean value 254±102ml), the event was significantly more frequent in the single dose group vs. double dose group

**No of trials included in**

Contrast-Induced Nephropathy: Risk Factors, Clinical Implication, Diagnostics Approach, Prevention

**meta analysis Relative risk (99% CI)**

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397

Effect of N-acetylcysteine was studied in several meta-analyses (Table 10) [43-51].

Birck 2003 7 0,435 (0,215-0,879) Isenbarger 2003 7 0,370 (0,160-0,840) Alonso 2004 12 0,550 (0,340-0,910) Bangshaw 2004 14 0,540 (0,320-0,910) Pannu 2004 15 0,650 (0,430-1,000)

Kshirsagar 2004 16 ND

Nallamothu 2004 20 0,730 (0,520-1,000) Liu 2005 9 0,430 (0,240-0,750) Duong 2005 14 0,570 (0,370-0,840)

**Table 10.** Meta-analyses of randomized prospective trials on effect of acetylcysteine for prevention of CIN

ministration of contrast medium, it did not reduce the incidence of CIN.

Although hemodialysis is an appropriate method in rapid elimination of the contrast agent, but in clinical trials it did not showed to be effective in the prevention of CIN [52, 53]. The probably reason is, that the potential kidney damage by contrast media occurs rapidly after its application. Although dialysis starts 1 hour before procedure or concurrently with ad‐

Hemofiltration has been shown to be effective in reducing CIN in high-risk patients with ad‐ vanced stage renal failure undergoing coronary intervention and is associated with im‐

In a prospective study were 114 consecutive patients with serum creatinine level > 176,8umol/l randomly assigned to groups [54]. One group consisted of patients who under‐ gone hemofiltration 4 to 6 hours before and 18 to 24 hours after coronary intervention, in the second patient group was given isotonic saline in the same time frame. A mean [±SD] serum creatinine level was 265,2±88,4 μmol/l in hemofiltration group and 274,0±88,.4 μmol/l in con‐

(18,9% vs. 5,4%, p=0,039, OR=0,24; CI=0,06-0,94) (Figure 19).

**First author Year of publication**

**7.6. Hemodialysis**

**7.7. Hemofiltration**

trol group (p=0,63).

proved in-hospital and long-term outcomes.

**Figure 18.** Incidence of CIN, RAPPIDE study results

Patients were randomly assigned to receive 0.45% saline intravenously and acetylcysteine at the standard dose (600mg orally twice daily; *n*=110) or at a double dose (1200mg orally twice daily; *n*=114) before and contrast agent administration.

**Figure 19.** Effect of single and double dose of N-acetylcystein on CIN incidence at 48h, CA=contrast agent

Increase of the creatinine level at least 44umol/l at 48h after the procedure occurred in 12/109 patients (11%) in the standard dose group and 4/114 patients (3.5%) in the double dose group (*P*=0.038; OR=0.29; 95% CI=0.09–0.94). In the subgroup (n=114) with low (<140ml) con‐ trast dose (mean value 101±23ml), no significant difference in renal function deterioration occurred between the 2 groups (3,6% in single dose group vs. 1,7% in double dose group, p=0,61). In the subgroup (n=109) with high (≥140ml) contrast dose (mean value 254±102ml), the event was significantly more frequent in the single dose group vs. double dose group (18,9% vs. 5,4%, p=0,039, OR=0,24; CI=0,06-0,94) (Figure 19).


Effect of N-acetylcysteine was studied in several meta-analyses (Table 10) [43-51].

**Table 10.** Meta-analyses of randomized prospective trials on effect of acetylcysteine for prevention of CIN

#### **7.6. Hemodialysis**

0%

**Figure 18.** Incidence of CIN, RAPPIDE study results

0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 20%

daily; *n*=114) before and contrast agent administration.

P=0,038

P=0,61

**acetylcystein control**

Patients were randomly assigned to receive 0.45% saline intravenously and acetylcysteine at the standard dose (600mg orally twice daily; *n*=110) or at a double dose (1200mg orally twice

**total low volume CA high volume CA**

P=0,039

**Single dose double dose**

Increase of the creatinine level at least 44umol/l at 48h after the procedure occurred in 12/109 patients (11%) in the standard dose group and 4/114 patients (3.5%) in the double dose group (*P*=0.038; OR=0.29; 95% CI=0.09–0.94). In the subgroup (n=114) with low (<140ml) con‐

**Figure 19.** Effect of single and double dose of N-acetylcystein on CIN incidence at 48h, CA=contrast agent

P=0,045

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

5%

10%

15%

20%

25%

Although hemodialysis is an appropriate method in rapid elimination of the contrast agent, but in clinical trials it did not showed to be effective in the prevention of CIN [52, 53]. The probably reason is, that the potential kidney damage by contrast media occurs rapidly after its application. Although dialysis starts 1 hour before procedure or concurrently with ad‐ ministration of contrast medium, it did not reduce the incidence of CIN.

#### **7.7. Hemofiltration**

Hemofiltration has been shown to be effective in reducing CIN in high-risk patients with ad‐ vanced stage renal failure undergoing coronary intervention and is associated with im‐ proved in-hospital and long-term outcomes.

In a prospective study were 114 consecutive patients with serum creatinine level > 176,8umol/l randomly assigned to groups [54]. One group consisted of patients who under‐ gone hemofiltration 4 to 6 hours before and 18 to 24 hours after coronary intervention, in the second patient group was given isotonic saline in the same time frame. A mean [±SD] serum creatinine level was 265,2±88,4 μmol/l in hemofiltration group and 274,0±88,.4 μmol/l in con‐ trol group (p=0,63).

Incidence of CIN in patients undergoing hemofiltration was much lower than that of only hydrated patients (5% vs. 50%, p<0,001). The rate of in-hospital events was 9 percent in the hemofiltration group and 52 percent in the control group (P<0.001). In-hospital mortality was 2 percent in the hemofiltration group and 14 percent in the control group (P=0.02), and the cumulative one-year mortality was 10 percent and 30 percent, respectively (P=0.01) (Fig‐ ure 20) [54].

Interpretation of the study results has some limitations. CIN was defined as more than 25% increase in serum creatinine, but hemofiltration itself remove creatinine from the blood, thus it is impossible to objectively evaluate true creatinine growth. Since the incidence of CIN in the control group far exceed the percentage incidence observed in other studies, it is likely that patients included in this study represent the specific, high risk group that is way the result cannot be simply applied to a wide population. Furthermore, hemofiltration is also an expensive elimination method, and thus cannot be generally recommended as a standard

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Practical recommendations for prevention of CIN are summarized in Table 12 (Schweiger

Withhold, if clinically appropriate, potentially nephrotoxic drugs including aminoglycoside antibiotics, anti-rejection

Administer a total of at least 1 l of isotonic saline beginning at least 3hrs before and continuing at least 6-8hr after

Consider holding appropriate medications until renal function returns to normal, i.e. metformin, nonsteroidal anti-

Schedule outpatient for early or delay procedure time to allow time to accomplish the hydration

measure for CIN prevention.

Low risk – eGFR "/> 60ml/min/1,73m2

High risk – eGFR < 60ml/min/1,73m2

Consider the following recommendation (No 2-No 5)

drugs and nonsteroidal anti-inflammatory drugs

154mEq/l @ 3ml/kg/hr starting 1hr before contrast 154mEq/l @ 1ml/kg/hr for 6hrs following contrast

**Table 12.** Recommendation for prevention of CIN

600mg orally q 12hrs "/> 4 doses beginning prior to contrast **Manage intravascular volume (avoid dehydration)**

Initiation infusion rate 100-150ml/hr adjusted post procedure as clinically indicated

eGFR = estimated glomerular filtration rate, S-Cr = serum creatinine level

Optimize hydration status

**Manage medications**

procedure

Sodium bicarbonate

Minimize volume

inflammatory drugs

**Radiographic contrast media**

Low- or iso-osmolar contrast agents **Postprocedure: discharge/follow-up** Obtain follow-up S-Cr 48 hrs post procedure

Administer N-acetylcysteine

MJ, 2006)

**Identify risk**

**Figure 20.** Influence of hemofiltration on incidence of CIN and both hospital and long-term outcome

Important post procedural complications were similar in both groups, except of pulmonary edema, renal replacement therapy (Table 11).


**Table 11.** Post procedural complications in both hemofiltration and control groups

Interpretation of the study results has some limitations. CIN was defined as more than 25% increase in serum creatinine, but hemofiltration itself remove creatinine from the blood, thus it is impossible to objectively evaluate true creatinine growth. Since the incidence of CIN in the control group far exceed the percentage incidence observed in other studies, it is likely that patients included in this study represent the specific, high risk group that is way the result cannot be simply applied to a wide population. Furthermore, hemofiltration is also an expensive elimination method, and thus cannot be generally recommended as a standard measure for CIN prevention.

Practical recommendations for prevention of CIN are summarized in Table 12 (Schweiger MJ, 2006)


**Table 12.** Recommendation for prevention of CIN

Incidence of CIN in patients undergoing hemofiltration was much lower than that of only hydrated patients (5% vs. 50%, p<0,001). The rate of in-hospital events was 9 percent in the hemofiltration group and 52 percent in the control group (P<0.001). In-hospital mortality was 2 percent in the hemofiltration group and 14 percent in the control group (P=0.02), and the cumulative one-year mortality was 10 percent and 30 percent, respectively (P=0.01) (Fig‐

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

**hemofiltration control**

<sup>p</sup>0,001 <sup>p</sup>0,001

**CIN MACE hospital**

Important post procedural complications were similar in both groups, except of pulmonary

Q MI 0 2(4%) 0,24 nonQ MI 1(2%) 1(2%) 1,00 Emergency CABG 0 0 1,00 Pulmonary edema 0 6(11%) 0,02 Hypotension or shock 1(2%) 3(5%) 0,36 Blood transfusion 1(2%) 3(5%) 0,36 Renal replacement the 2(3%) 14(25%) <0,001 All clinical events 5(9%) 29(52%) <0,001

**Figure 20.** Influence of hemofiltration on incidence of CIN and both hospital and long-term outcome

**Complication Hemofiltration group (n=58) Control group**

**Table 11.** Post procedural complications in both hemofiltration and control groups

**mortality**

P=0,02

**1y mortality**

**(n=56)**

**P value**

P=0,01

ure 20) [54].

0%

edema, renal replacement therapy (Table 11).

10%

20%

30%

40%

50%

60%

## **8. Contrast induced nephropathy among patients undergoing coronary angiography or percutaneous coronary intervention. Results from 12 months' consecutive cases analysis from University Hospital Martin, Slovakia**

orally hydrated (with the recommendation approximately 2000 ml of fluid on the examina‐ tion day), High risk patients were hydrated parenteral with saline at a dose of 0,5 to 1 ml /

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401

Contrast-induced nephropathy (CIN) was defined as an increase in baseline creatinine level of ≥ 25% (CIN25) or ≥ 44,2 micromol / l (CIN 0,5) or decrease baseline GFR of ≥ 25% within 24 to 48 hours after administration of contrast medium. Baseline glomerular filtration rate

Severe renal dysfunction (SRD) was defined as an acute renal failure requiring dialysis or a

Chronic kidney disease was determined according to the history with the presence of kid‐

The incidence of contrast-induced nephropathy was evaluated by Pearson Chi-square test. Quantitative parameters (age, BMI, sex, number of KL, SCr0, GFR0, left ventricular ejection fraction), were evaluated by the Mann-Whitney U - test and qualitative parameters (age

To assess correlation of the endpoints, we used the Spearmen correlation coefficient. Nu‐ merical values are expressed as median and quartile range or as a percentage of the total

There were excluded 19,2% patients with incomplete documentation of sampling creatinine values at 24 hours (SCr1) or at third to fifth day after contrast agent administration (SCr2) and patients in the chronic hemodialysis. In the final data analysis was then included 529

rise in baseline creatinine over 50% during 24 hours to 120 hours after the procedure.

(eGFR) was calculated according to the Cockcroft-Gault formula.

over 75 years, DM, chronic renal disease), by the Fisher's exact test.

amount. As statistically significant, we considered the value of p <0.05.

patients, whose basic clinical characteristics are listed in Table 13.

**Age "/> 75 years** 15,1% (80/529) **Diabetes mellitus (DM)** 30,3% (160/529) **Preexisting renal disease (CKD)** 14,6% (77/529) **DM + CKD** 6,6% (35/529) **PCI procedure** 62,38% (330/529)

DM = diabetes mellitus, CKD = chronic kidney disease, PCI = percutaneous coronary intervention

kg body weight per hour.

ney disease in nephrologic observation.

**8.4. Statistic methods**

**8.5. Results**

**Table 13.** Clinical characteristics

**8.3. Definitions**

#### **8.1. Objective**

The primary objective of this work was to evaluate the incidence of contrast-induced nephr‐ opathy in patients undergoing coronary angiography examination (KG) or percutaneous coronary intervention (PCI) and was hospitalized at the coronary care unit, I. Internal clinic, University hospital, Martin, Slovakia.

A secondary objective was to identify and assess the impact of major risk factors for devel‐ oping CIN. At the same time, we assessed the incidence of CIN according to the recom‐ mended definition, significance of serum creatinine at 24 hours, and at third to fifth day after administration of contrast medium and the use of scoring systems to estimate the risk of CIN development.

#### **8.2. Methods**

In the period from January 2008 to February 2009, we prospectively followed patients ad‐ mitted to the coronary care unit and department of invasive and interventional cardiology of I. Internal clinic, who underwent coronary angiography or coronary intervention. We studied basal serum creatinine level (SCr0), creatinine value at 16-24 hours after contrast ad‐ ministration (SCr1) and creatinine value at 3rd-5th day after contrast administration (SCr2), which was mostly obtained after hospitalization discharge during ambulatory collection and sent via mail by patients or their GPs. If there was a significant increase in creatinine level at 24 hours after invasive procedures, we recommend extending hospitalization in patients till normalization of values.

Patients without obtained SCr2 values and patients in chronic hemodialysis were excluded from the analysis.

Major risk factors for developing CIN (age, sex, diabetes mellitus, chronic kidney disease, type and amount of contrast medium administration) were monitored at the same time as well.

The invasive procedures contrast agent iopamidol (SCANLUX 370 ®) was used in all pa‐ tients. Iopamidol represents a non-ionic low-osmolar contrast agent with osmolarity 796 mOsm / kg. It is therefore hypertonic compared with blood plasma osmolarity which is ap‐ proximately 300 mOsm / kg. Its half-life after intravascular administration is approximately 2 hours with normal renal function. In patients with renal insufficiency there is prolonged elimination, depending on the degree of renal impairment and may takes several days.

In order to determine the risk of CIN, patients were divided into four groups according to the CIN risk score by Mehran. Patients at low and medium risk for the CIN developing were orally hydrated (with the recommendation approximately 2000 ml of fluid on the examina‐ tion day), High risk patients were hydrated parenteral with saline at a dose of 0,5 to 1 ml / kg body weight per hour.

#### **8.3. Definitions**

**8. Contrast induced nephropathy among patients undergoing coronary angiography or percutaneous coronary intervention. Results from 12 months' consecutive cases analysis from University Hospital Martin,**

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

The primary objective of this work was to evaluate the incidence of contrast-induced nephr‐ opathy in patients undergoing coronary angiography examination (KG) or percutaneous coronary intervention (PCI) and was hospitalized at the coronary care unit, I. Internal clinic,

A secondary objective was to identify and assess the impact of major risk factors for devel‐ oping CIN. At the same time, we assessed the incidence of CIN according to the recom‐ mended definition, significance of serum creatinine at 24 hours, and at third to fifth day after administration of contrast medium and the use of scoring systems to estimate the risk

In the period from January 2008 to February 2009, we prospectively followed patients ad‐ mitted to the coronary care unit and department of invasive and interventional cardiology of I. Internal clinic, who underwent coronary angiography or coronary intervention. We studied basal serum creatinine level (SCr0), creatinine value at 16-24 hours after contrast ad‐ ministration (SCr1) and creatinine value at 3rd-5th day after contrast administration (SCr2), which was mostly obtained after hospitalization discharge during ambulatory collection and sent via mail by patients or their GPs. If there was a significant increase in creatinine level at 24 hours after invasive procedures, we recommend extending hospitalization in patients till

Patients without obtained SCr2 values and patients in chronic hemodialysis were excluded

Major risk factors for developing CIN (age, sex, diabetes mellitus, chronic kidney disease, type and amount of contrast medium administration) were monitored at the same time as

The invasive procedures contrast agent iopamidol (SCANLUX 370 ®) was used in all pa‐ tients. Iopamidol represents a non-ionic low-osmolar contrast agent with osmolarity 796 mOsm / kg. It is therefore hypertonic compared with blood plasma osmolarity which is ap‐ proximately 300 mOsm / kg. Its half-life after intravascular administration is approximately 2 hours with normal renal function. In patients with renal insufficiency there is prolonged elimination, depending on the degree of renal impairment and may takes several days.

In order to determine the risk of CIN, patients were divided into four groups according to the CIN risk score by Mehran. Patients at low and medium risk for the CIN developing were

**Slovakia**

**8.1. Objective**

of CIN development.

normalization of values.

from the analysis.

well.

**8.2. Methods**

University hospital, Martin, Slovakia.

Contrast-induced nephropathy (CIN) was defined as an increase in baseline creatinine level of ≥ 25% (CIN25) or ≥ 44,2 micromol / l (CIN 0,5) or decrease baseline GFR of ≥ 25% within 24 to 48 hours after administration of contrast medium. Baseline glomerular filtration rate (eGFR) was calculated according to the Cockcroft-Gault formula.

Severe renal dysfunction (SRD) was defined as an acute renal failure requiring dialysis or a rise in baseline creatinine over 50% during 24 hours to 120 hours after the procedure.

Chronic kidney disease was determined according to the history with the presence of kid‐ ney disease in nephrologic observation.

#### **8.4. Statistic methods**

The incidence of contrast-induced nephropathy was evaluated by Pearson Chi-square test. Quantitative parameters (age, BMI, sex, number of KL, SCr0, GFR0, left ventricular ejection fraction), were evaluated by the Mann-Whitney U - test and qualitative parameters (age over 75 years, DM, chronic renal disease), by the Fisher's exact test.

To assess correlation of the endpoints, we used the Spearmen correlation coefficient. Nu‐ merical values are expressed as median and quartile range or as a percentage of the total amount. As statistically significant, we considered the value of p <0.05.

#### **8.5. Results**

There were excluded 19,2% patients with incomplete documentation of sampling creatinine values at 24 hours (SCr1) or at third to fifth day after contrast agent administration (SCr2) and patients in the chronic hemodialysis. In the final data analysis was then included 529 patients, whose basic clinical characteristics are listed in Table 13.


DM = diabetes mellitus, CKD = chronic kidney disease, PCI = percutaneous coronary intervention

**Table 13.** Clinical characteristics

CIN25 was observed in 3, 97% (21/529) patients and CIN 0,5 in 2,27% (12/529) patients. The decrease of eGFR ≥ 25% occurred in 2, 27% (12/529) patients. SRD occurred in 1, 51% (8/529) patients, dialysis was needed in 0,76% (4/529) patients. Severe hypotension requiring com‐ bined inotropic support was observed in 3 patients (0, 57%). There were 4 deaths from529 patients (0, 76%) as a consequence of the contrast induced nephropathy (2 men and 2 wom‐ en). Mortality rate of patients with CIN was 19% (4/21).Distribution of patients according to Mehranś risk score model is shown in Table 14.


EFLK Trial

Contrast-Induced Nephropathy: Risk Factors, Clinical Implication, Diagnostics Approach, Prevention

There was not observed correlation between the amount administered contrast agent and development of CIN (0.50), although patients with the development of CIN received signifi‐

> KL Trial

**Figure 22.** Amount of contrast agent administered in patients with CIN (kn) and without CIN (n)

**Figure 21.** Left ventricle ejection fraction (EFLK) (%) in patients with CIN (kn) and without CIN (n)

n kn

> n kn

KNTOT

KNTOT

http://dx.doi.org/10.5772/54036

403

cantly higher amount of contrast agent (Figure 22).

0

100

200

Measure

300

400

Measure

**Table 14.** Distribution of patients according risk score model (Mehran)

Patients with the development of CIN, compared with patients in whom CIN was not con‐ firmed, differed statistically significantly in age (p = 0.043), left ventricle systolic function (p <0.001), and the amount of administered contrast medium (p = 0.004). On the contrary statis‐ tically significant differences were not found in sex, BMI, the initial value of creatinine (SCr0), or the initial value calculated glomerular filtration rate (eGFR0). Both groups of pa‐ tients also differed significantly in the presence of chronic kidney disease (p <0.001) and in the combined appearance of diabetes and chronic kidney disease (p = 0.001). In contrast, both groups of patients did not differ significantly according of the risk age (over 75 years), or diabetes mellitus (Table 15, Figure 21).


CKD = chronic kidney disease, LVEF = left ventricle ejection fraction, BMI = body mass index, eGFR = estimated glomer‐ ular filtration rate, DM = diabetes mellitus

**Table 15.** Comparison of clinical parameters in patients with and without the occurrence of CIN

**Figure 21.** Left ventricle ejection fraction (EFLK) (%) in patients with CIN (kn) and without CIN (n)

CIN25 was observed in 3, 97% (21/529) patients and CIN 0,5 in 2,27% (12/529) patients. The decrease of eGFR ≥ 25% occurred in 2, 27% (12/529) patients. SRD occurred in 1, 51% (8/529) patients, dialysis was needed in 0,76% (4/529) patients. Severe hypotension requiring com‐ bined inotropic support was observed in 3 patients (0, 57%). There were 4 deaths from529 patients (0, 76%) as a consequence of the contrast induced nephropathy (2 men and 2 wom‐ en). Mortality rate of patients with CIN was 19% (4/21).Distribution of patients according to

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

**Score Number of pts CIN25 incidence** Low risk 77,5% (410/529) 2,44% (10/410) Medium risk 17,9% (95/529) 4,21% (4/95) High risk 3,59% (19/529) 21,05% (4/19) Very high risk 0,95% (5/529) 60% (3/5)

Patients with the development of CIN, compared with patients in whom CIN was not con‐ firmed, differed statistically significantly in age (p = 0.043), left ventricle systolic function (p <0.001), and the amount of administered contrast medium (p = 0.004). On the contrary statis‐ tically significant differences were not found in sex, BMI, the initial value of creatinine (SCr0), or the initial value calculated glomerular filtration rate (eGFR0). Both groups of pa‐ tients also differed significantly in the presence of chronic kidney disease (p <0.001) and in the combined appearance of diabetes and chronic kidney disease (p = 0.001). In contrast, both groups of patients did not differ significantly according of the risk age (over 75 years),

Parameter **with CIN without CIN P value**

Age (year) 62 71 0,043 Age > 75y (No of pts) 14,8% (75/508) 23,8% (5) 0,345 Sex (men/women)(No of pts) 63/37%(318/190) 62/38%(13/8) 1,00 BMI (kg/m2) 28,4 (25,8-31,2) 29,8 (27,7-34,0) 0,121 Diabetes mellitus (No of pts) 30% (152/508) 38,1% (8) 0,469 CKD (No of pts) 13,2% (67/508) 47,6% (10) < 0,001 Both DM and CKD (No of pts) 5,7% (29/508) 28,6% (6) 0,001 LVEF (%) 55 (50-60) 45 (40-50) < 0,001 Serum creatinine level (µmol/l) 100 (88-112) 105 (91-136) 0,129 eGFR (ml/min) 72,6 (60,6-90,0) 62,4 (45,6-91,2) 0,291

CKD = chronic kidney disease, LVEF = left ventricle ejection fraction, BMI = body mass index, eGFR = estimated glomer‐

**Table 15.** Comparison of clinical parameters in patients with and without the occurrence of CIN

**(n = 508) (n = 21)**

Mehranś risk score model is shown in Table 14.

**Table 14.** Distribution of patients according risk score model (Mehran)

or diabetes mellitus (Table 15, Figure 21).

ular filtration rate, DM = diabetes mellitus

There was not observed correlation between the amount administered contrast agent and development of CIN (0.50), although patients with the development of CIN received signifi‐ cantly higher amount of contrast agent (Figure 22).

**Figure 22.** Amount of contrast agent administered in patients with CIN (kn) and without CIN (n)

If the criterion value was chosen CIN25, diagnosis of CIN was determined by the value of delta SCr1 in 1,89% (10/519) and the delta SCr2 in 2,65% (14/515) of cases, together in the 3,97% (21/509) of cases. If the criterion value was determined CIN 0,5, CIN, diagnosis of CIN was established based on the value deltaSCr1 in 0,76% (4/524) and deltaSCr2 in 2,08% (11/517) of cases, together in 2,27% (12/516) of cases.

for adverse events - level 0 (deltaCr <25% <44 μmol / l), the highest (deltaCr> 25%> 44 μmol / l) - level 2 and intermediate (deltaCr> 25% <44 μmol / l) - level 1. Trend toward a worse clini‐ cal outcome is observed in patients at higher degrees of nephropathy. Multivariate analysis revealed stage 1 and 2 as an independent and significant indicator of 6-month MACE (major adverse cardiovascular events) compared with the degree 0. This scoring system reflects the fact that those patients who experienced an increase in CIN CIN25 or CIN0,5 are in fact two

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405

In our study, the overall incidence of CIN varied, according to the chosen definition of the baseline increase in serum creatinine, from 2,27% with the definition of CIN 0.5 to 3,97% us‐ ing the definition of CIN25. Using the definition of impairment eGFR of ≥ 25% compared to baseline, the overall incidence of CIN was 2,28%. Therefore, as the most-sensitive diagnostic

In most of the studies was the incidence of CIN based on an increase in creatinine levels at 24 hours after contrast agent administration. Management of patients with complete followup serum creatinine at 48 hours after contrast medium administration evaluated only Huber et al., while many others have failed to adequate monitoring of all patients enrolled, which bring potentially serious problem in interpreting their results. While our results suggest that CIN can be diagnosed according to the definition based on SCr1 value only in 25 - 47,6% cases and in 52,4 -75% of cases based on SCr2 value. Moreover, among patients developing severe renal dysfunction in the future (hemodialysis or death), 60% (3/5) had CIN diagnosed until just based on the SCr2 value. This raises the question of the need for routine clinical assessment of SCr2 (in the third to fifth day after contrast administration) in all patients at

The overall low incidence of CIN in our study can be attributed to several factors. There was present very high proportion of patients with low and moderate risk of developing CIN (77,5%, respectively. 17,96%). Moreover, before invasive procedure were patients hydrated both oral and parenteral way with saline. Hydration is widely recognized as the simplest and most effective preventive measure of CIN. In our series we noted paradoxical decrease in serum creatinine level after 16-24 hours following invasive procedure compared to base‐ line in 35,16% (186/529) patients, despite of administration of contrast agent. This finding demonstrates importance of standard saline hydration for patients prior to invasive proce‐ dures, as patients are admitted for coronary angiography or percutaneous coronary inter‐ vention often dehydrated. Another factor that can be attributed to a low incidence of CIN is the type and amount of contrast medium. In our study, non-ionic low-osmolar contrast me‐ dium iopamidol was used. This contrast agent has safety renal profile that is comparable

In our study was not confirmed a significant relationship between amount of used contrast agent and the incidence of CIN. However, dose of contrast medium was significantly higher in patients with development of CIN25, in comparison with dose used in patients who did

prognostic categories (nephropathy Level 1 and nephropathy Level 2) [57].

tool for CIN, was the determination of the CIN25 value.

with the safety profile of iso-osmolar contrast agent iodixanol.

not develop CIN25 (150 ml vs. 110 ml, p = 0,004).

risk [61, 62].

If the definition of CIN was used decrease in creatinine clearance, than diagnosis of CIN was determined by delta eGFR1 in 0.57% (3/524) of patients and delta eGFR2 in 1, 9% (10/517) of cases, together in 2,28% (12/515) of cases.

In a subset of patients with CIN, according of CIN25 definition, there were based on result of SCr1, diagnosed 47, 62% (10/21) and on SCr2 52,38% (11/21) patients. Using the definition CIN 0,5 there were based on result of SCr1 diagnosed 33,33% (4/12) and on SCr2 66,67% (8/12) patients. According of the reduction in eGFR as a definition of CIN, there were based on result of SCr1 diagnosed 25% (3/12) and on SCr2 75% (9/12) cases.

#### **8.6. Discussion**

The incidence of CIN depends on the study population and diagnostic criteria that define it and is reported in the range 4.4% -20%. While in the general population is low and ranges from 0,6 to 2,3% [55], significantly increases in patients with risk factors especially with documented cardiovascular disease and the acute coronary syndromes and may be as high as 57,3% [56]. In 250 patients with creatinine clearance <60 ml/min, the incidence of CIN ranged from 6,0% -21,6%. Similarly, using different definitions of CIN incidence was 4,4% -20% in diabetics and 2,8% -17,3% in 469 patients with elevated cardiac markers before PCI [57]. There are four currently used CIN definitions, but only two (CIN CIN25 and 0,5) allow more consistently predict the clinical course. In comparison to CIN25, the definition of CIN 0,5 provides greater differences between unselected group of patients and patients with high risk of CIN and is a stronger indicator of the unfavorable course.

A large variation in the incidence of CIN emphasizes the need for a uniform definition of CIN, which would allow proper comparison of results from different databases. The CIN25 and CIN 0,5 independently correlated with the clinical course. Patients with a seemingly small increase in creatinine level have adverse cardiovascular variables. The relationship be‐ tween increases in serum creatinine and glomerular filtration current is nonlinear. A small increase in creatinine level may represent significant deterioration in renal function, particu‐ larly at lower values of basal serum creatinine. Moreover, work dealing with a rise in serum creatinine showed that the peak levels are often not achieved until several days after expo‐ sure to contrast medium [58-60]. Because most of the patients are discharged after 24-48 hours after PCI, a small increase in creatinine may be a sign of further renal damage in the coming days. Besides of a consistent prognostic value, ideal definition of CIN should distin‐ guish between patients with moderate and high risk. Although the value of CIN25 and CIN 0,5 provide consistent prognostic value, CIN 0,5 clearly distinguishes between a whole pop‐ ulation and a subgroup of patients with chronic kidney disease at highest risk. In contrast, CIN25 has only low discriminatory value, but very high in patients with the lowest risk. Combining these two definitions, we can divide the patients into 3 groups: The lowest risk for adverse events - level 0 (deltaCr <25% <44 μmol / l), the highest (deltaCr> 25%> 44 μmol / l) - level 2 and intermediate (deltaCr> 25% <44 μmol / l) - level 1. Trend toward a worse clini‐ cal outcome is observed in patients at higher degrees of nephropathy. Multivariate analysis revealed stage 1 and 2 as an independent and significant indicator of 6-month MACE (major adverse cardiovascular events) compared with the degree 0. This scoring system reflects the fact that those patients who experienced an increase in CIN CIN25 or CIN0,5 are in fact two prognostic categories (nephropathy Level 1 and nephropathy Level 2) [57].

If the criterion value was chosen CIN25, diagnosis of CIN was determined by the value of delta SCr1 in 1,89% (10/519) and the delta SCr2 in 2,65% (14/515) of cases, together in the 3,97% (21/509) of cases. If the criterion value was determined CIN 0,5, CIN, diagnosis of CIN was established based on the value deltaSCr1 in 0,76% (4/524) and deltaSCr2 in 2,08%

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

If the definition of CIN was used decrease in creatinine clearance, than diagnosis of CIN was determined by delta eGFR1 in 0.57% (3/524) of patients and delta eGFR2 in 1, 9% (10/517) of

In a subset of patients with CIN, according of CIN25 definition, there were based on result of SCr1, diagnosed 47, 62% (10/21) and on SCr2 52,38% (11/21) patients. Using the definition CIN 0,5 there were based on result of SCr1 diagnosed 33,33% (4/12) and on SCr2 66,67% (8/12) patients. According of the reduction in eGFR as a definition of CIN, there were based

The incidence of CIN depends on the study population and diagnostic criteria that define it and is reported in the range 4.4% -20%. While in the general population is low and ranges from 0,6 to 2,3% [55], significantly increases in patients with risk factors especially with documented cardiovascular disease and the acute coronary syndromes and may be as high as 57,3% [56]. In 250 patients with creatinine clearance <60 ml/min, the incidence of CIN ranged from 6,0% -21,6%. Similarly, using different definitions of CIN incidence was 4,4% -20% in diabetics and 2,8% -17,3% in 469 patients with elevated cardiac markers before PCI [57]. There are four currently used CIN definitions, but only two (CIN CIN25 and 0,5) allow more consistently predict the clinical course. In comparison to CIN25, the definition of CIN 0,5 provides greater differences between unselected group of patients and patients with

A large variation in the incidence of CIN emphasizes the need for a uniform definition of CIN, which would allow proper comparison of results from different databases. The CIN25 and CIN 0,5 independently correlated with the clinical course. Patients with a seemingly small increase in creatinine level have adverse cardiovascular variables. The relationship be‐ tween increases in serum creatinine and glomerular filtration current is nonlinear. A small increase in creatinine level may represent significant deterioration in renal function, particu‐ larly at lower values of basal serum creatinine. Moreover, work dealing with a rise in serum creatinine showed that the peak levels are often not achieved until several days after expo‐ sure to contrast medium [58-60]. Because most of the patients are discharged after 24-48 hours after PCI, a small increase in creatinine may be a sign of further renal damage in the coming days. Besides of a consistent prognostic value, ideal definition of CIN should distin‐ guish between patients with moderate and high risk. Although the value of CIN25 and CIN 0,5 provide consistent prognostic value, CIN 0,5 clearly distinguishes between a whole pop‐ ulation and a subgroup of patients with chronic kidney disease at highest risk. In contrast, CIN25 has only low discriminatory value, but very high in patients with the lowest risk. Combining these two definitions, we can divide the patients into 3 groups: The lowest risk

(11/517) of cases, together in 2,27% (12/516) of cases.

on result of SCr1 diagnosed 25% (3/12) and on SCr2 75% (9/12) cases.

high risk of CIN and is a stronger indicator of the unfavorable course.

cases, together in 2,28% (12/515) of cases.

**8.6. Discussion**

In our study, the overall incidence of CIN varied, according to the chosen definition of the baseline increase in serum creatinine, from 2,27% with the definition of CIN 0.5 to 3,97% us‐ ing the definition of CIN25. Using the definition of impairment eGFR of ≥ 25% compared to baseline, the overall incidence of CIN was 2,28%. Therefore, as the most-sensitive diagnostic tool for CIN, was the determination of the CIN25 value.

In most of the studies was the incidence of CIN based on an increase in creatinine levels at 24 hours after contrast agent administration. Management of patients with complete followup serum creatinine at 48 hours after contrast medium administration evaluated only Huber et al., while many others have failed to adequate monitoring of all patients enrolled, which bring potentially serious problem in interpreting their results. While our results suggest that CIN can be diagnosed according to the definition based on SCr1 value only in 25 - 47,6% cases and in 52,4 -75% of cases based on SCr2 value. Moreover, among patients developing severe renal dysfunction in the future (hemodialysis or death), 60% (3/5) had CIN diagnosed until just based on the SCr2 value. This raises the question of the need for routine clinical assessment of SCr2 (in the third to fifth day after contrast administration) in all patients at risk [61, 62].

The overall low incidence of CIN in our study can be attributed to several factors. There was present very high proportion of patients with low and moderate risk of developing CIN (77,5%, respectively. 17,96%). Moreover, before invasive procedure were patients hydrated both oral and parenteral way with saline. Hydration is widely recognized as the simplest and most effective preventive measure of CIN. In our series we noted paradoxical decrease in serum creatinine level after 16-24 hours following invasive procedure compared to base‐ line in 35,16% (186/529) patients, despite of administration of contrast agent. This finding demonstrates importance of standard saline hydration for patients prior to invasive proce‐ dures, as patients are admitted for coronary angiography or percutaneous coronary inter‐ vention often dehydrated. Another factor that can be attributed to a low incidence of CIN is the type and amount of contrast medium. In our study, non-ionic low-osmolar contrast me‐ dium iopamidol was used. This contrast agent has safety renal profile that is comparable with the safety profile of iso-osmolar contrast agent iodixanol.

In our study was not confirmed a significant relationship between amount of used contrast agent and the incidence of CIN. However, dose of contrast medium was significantly higher in patients with development of CIN25, in comparison with dose used in patients who did not develop CIN25 (150 ml vs. 110 ml, p = 0,004).

This may explain the low prevalence of patients with age above 75 years (15,12%), diabetes mellitus (30,24%), with chronic kidney disease (14,56%) and also low doses of used contrast medium, the maximum dose was 350 ml.

**9. Conclusion**

CIN prevention.

**Author details**

**References**

at day 3 to 5 after invasive procedures.

Frantisek Kovar, Milos Knazeje and Marian Mokan

\*Address all correspondence to: fkovar8@gmail.com

I. Internal Clinic, University Hospital, Martin, Slovak Republic

spective study. Am J Med 1983; 74: 243–248

sensus report. Eur Radiol 1999; 9: 1602-1613

analysis. JAMA. 1996; 275: 1489-1494

Contrast induced nephropathy is common cause of renal functions impairment. Incidence of CIN in unselected patients undergoing angiographic procedures (coronary angiography, percutaneous coronary intervention) varies approximately 2-30%. Once occurs, CIN is asso‐ ciated with a significant increase in potentially serious morbidity and mortality. If possible, in patients at the highest risk for development of CIN, very useful is avoiding of contrast agent administration (or strongly limiting contrast volume of low or iso-osmolar contrast agents). To this high risk group are usually includes patients with diabetes mellitus, preex‐ isting renal insufficiency, hypotension (or incipient shock), congestive heart failure, anemia or at advanced age. This risky patients population requires appropriate both peri and post‐ procedural management. Most important measure is adequate hydration in order to avoid hypovolemia. Preferred type of solutions is parenteral isotonic saline or an isotonic sodium bicarbonate. Still limited evidence is for pharmacologic intervention (N-acetylcystein) in

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Since most cases of CIN, including patients with an unfavorable course in the future, were diagnosed on the basis of serum creatinine level at third to fifth day after administration of contrast medium, it is recommended for high-risk patients to assess serum creatinine level

[1] Hou SH, Bushinsky DA, Wish JB et al.: Hospital‐acquired renal insufficiency: a pro‐

[2] Rihal CS, Textor SC, Grill DE at al.: Incidence and prognostic importance of acute re‐ nal failure after percutaneous coronary intervention. Circulation 2002; 105: 2259-2264

[3] Levy EM, Viscoli CM, Horwitz RI: Effect of acute renal failure on mortality. A cohort

[4] Morcos SK, Thomsen HS, Web JAW: Contrast media safety committee of the Europe‐ an society of urogenital radiology. Contrast – media induced nephrotoxicity: a con‐

Generally, a safe dose of intravascular administrated iodinated contrast media is considered below 70 ml. The dose more than 5 ml / kg of patient weight is considered high risk [63, 64]. In patients with chronic kidney disease, dose of contrast medium for coronary angiography should be planned below 30 ml and if procedure will be followed by percutaneous coronary intervention than dose should be below 100 ml [64]. Even in our study, we confirmed that the dose of contrast medium into 70 ml can be considered relatively safe, because in this dose no CIN did occur in our study group.

Results of several studies suggested that the prevalence of CIN is more common in women than men in older age groups, mainly in the context of low eGFR in this group. These find‐ ings are supported by other studies that found a higher risk for developing of renal compli‐ cations after angiography in women than in men. However, previous findings were related to influencing factors such as age, which caused that women seemed to be a higher risk for developing CIN than men. In our group of patients had preexisting renal impairment 12,63% women and 16,61% men, which is one possible explanation for higher incidence of CIN in males.

Anemia seems also to be an independent risk factor for CIN. Several studies have shown that women more incline to anemia before angiography than men and have a trend to high‐ er risk of bleeding during periprocedural period [55]. The decrease in hematocrit of more than 6% doubles the risk of developing CIN, especially in women. Such a reduction in hem‐ atocrit can cause renal hypoperfusion, which potentiates renal damage caused by exposure to contrast media.

Patients with chronic kidney disease have a reduced vasodilatory response that is important factor in the development of CIN. At the same time, in these patients due to reduced glo‐ merular filtration extends elimination of contrast agent from circulation, thus potentiating its both cytotoxic and hemodynamic effect. Chronic kidney disease as a highly significant predictor of CIN was also confirmed by our study.

In our study, age was a marginally significant predictor of CIN and age over 75 years has not been demonstrated as important.

Advanced congestive heart failure and reduced left ventricle ejection fraction are character‐ ized by reduced cardiac output, increased neurohumoral vasoconstrictor activity and re‐ duced NO-dependent renal vasodilatation, which can lead to hypoperfusion of renal medulla [64]. Left ventricle systolic dysfunction was in our study recognized as highly sig‐ nificant predictor of CIN.

Diabetes mellitus was not an independent predictor, but in combination with chronic kid‐ ney disease has become a significant predictor of CIN development.

## **9. Conclusion**

This may explain the low prevalence of patients with age above 75 years (15,12%), diabetes mellitus (30,24%), with chronic kidney disease (14,56%) and also low doses of used contrast

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

Generally, a safe dose of intravascular administrated iodinated contrast media is considered below 70 ml. The dose more than 5 ml / kg of patient weight is considered high risk [63, 64]. In patients with chronic kidney disease, dose of contrast medium for coronary angiography should be planned below 30 ml and if procedure will be followed by percutaneous coronary intervention than dose should be below 100 ml [64]. Even in our study, we confirmed that the dose of contrast medium into 70 ml can be considered relatively safe, because in this

Results of several studies suggested that the prevalence of CIN is more common in women than men in older age groups, mainly in the context of low eGFR in this group. These find‐ ings are supported by other studies that found a higher risk for developing of renal compli‐ cations after angiography in women than in men. However, previous findings were related to influencing factors such as age, which caused that women seemed to be a higher risk for developing CIN than men. In our group of patients had preexisting renal impairment 12,63% women and 16,61% men, which is one possible explanation for higher incidence of

Anemia seems also to be an independent risk factor for CIN. Several studies have shown that women more incline to anemia before angiography than men and have a trend to high‐ er risk of bleeding during periprocedural period [55]. The decrease in hematocrit of more than 6% doubles the risk of developing CIN, especially in women. Such a reduction in hem‐ atocrit can cause renal hypoperfusion, which potentiates renal damage caused by exposure

Patients with chronic kidney disease have a reduced vasodilatory response that is important factor in the development of CIN. At the same time, in these patients due to reduced glo‐ merular filtration extends elimination of contrast agent from circulation, thus potentiating its both cytotoxic and hemodynamic effect. Chronic kidney disease as a highly significant

In our study, age was a marginally significant predictor of CIN and age over 75 years has

Advanced congestive heart failure and reduced left ventricle ejection fraction are character‐ ized by reduced cardiac output, increased neurohumoral vasoconstrictor activity and re‐ duced NO-dependent renal vasodilatation, which can lead to hypoperfusion of renal medulla [64]. Left ventricle systolic dysfunction was in our study recognized as highly sig‐

Diabetes mellitus was not an independent predictor, but in combination with chronic kid‐

ney disease has become a significant predictor of CIN development.

medium, the maximum dose was 350 ml.

dose no CIN did occur in our study group.

predictor of CIN was also confirmed by our study.

not been demonstrated as important.

nificant predictor of CIN.

CIN in males.

to contrast media.

Contrast induced nephropathy is common cause of renal functions impairment. Incidence of CIN in unselected patients undergoing angiographic procedures (coronary angiography, percutaneous coronary intervention) varies approximately 2-30%. Once occurs, CIN is asso‐ ciated with a significant increase in potentially serious morbidity and mortality. If possible, in patients at the highest risk for development of CIN, very useful is avoiding of contrast agent administration (or strongly limiting contrast volume of low or iso-osmolar contrast agents). To this high risk group are usually includes patients with diabetes mellitus, preex‐ isting renal insufficiency, hypotension (or incipient shock), congestive heart failure, anemia or at advanced age. This risky patients population requires appropriate both peri and post‐ procedural management. Most important measure is adequate hydration in order to avoid hypovolemia. Preferred type of solutions is parenteral isotonic saline or an isotonic sodium bicarbonate. Still limited evidence is for pharmacologic intervention (N-acetylcystein) in CIN prevention.

Since most cases of CIN, including patients with an unfavorable course in the future, were diagnosed on the basis of serum creatinine level at third to fifth day after administration of contrast medium, it is recommended for high-risk patients to assess serum creatinine level at day 3 to 5 after invasive procedures.

## **Author details**

Frantisek Kovar, Milos Knazeje and Marian Mokan

\*Address all correspondence to: fkovar8@gmail.com

I. Internal Clinic, University Hospital, Martin, Slovak Republic

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**Chapter 19**

**Myocardial Bridges in the ERA of**

Mohamed Bamoshmoosh and Paolo Marraccini

Cardiovascular (CV) and cerebrovascular (CBV) diseases are the leading causes of mor‐ tality in developed countries. In these countries CV risk factors like smoke, obesity, sed‐ entary life, dyslipidemias, hypertension and diabetes are well recognized and efforts have been efficaciously undertaken so that CV and CBV mortality in the second half of the last century has been significantly reduced. Cardiovascular and CBV diseases are al‐ so the leading cause of mortality in the developing world where in the last century we witnessed a rapid epidemiological as well as nutritional transition related mainly to in‐ creased urbanization and market globalization. Now the majority of CV and CBV mortal‐

Indeed the major responsible of CV as well as CBV diseases is the vascular atherosclerotic process. In particular the atherosclerotic calcified and non calcified plaques that cause coro‐ nary artery vessel lumen reduction are worldwide the leading cause of myocardial ischemia, which can lead to asymptomatic myocardial dysfunction, life threatening arrhythmias, angi‐

Besides the atherosclerotic coronary artery diseases there are also other non atherosclerotic coronary artery vessel lumen reductions, although their prevalence is less common. The non atherosclerotic coronary artery diseases are related to prolonged coronary artery spasm, hy‐

Congenital coronary artery anomalies are a heterogeneous group of diseases. In the majority of cases congenital coronary artery anomalies lack clinical significance and are merely epi‐ phenomena found accidentally during necropsies, while performing invasive or non inva‐ sive coronarography or during surgical interventions. However in some cases they may be

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

© 2013 Bamoshmoosh and Marraccini; 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,

pertrophic cardiomyopathy, vasculitis and congenital coronary anomalies.

Additional information is available at the end of the chapter

ity occurs in low and middle-income countries [1].

properly cited.

na, myocardial infarction and sudden death.

**Non-Invasive Angiography**

http://dx.doi.org/10.5772/54083

**1. Introduction**

**Chapter 19**

## **Myocardial Bridges in the ERA of Non-Invasive Angiography**

Mohamed Bamoshmoosh and Paolo Marraccini

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54083

## **1. Introduction**

Cardiovascular (CV) and cerebrovascular (CBV) diseases are the leading causes of mor‐ tality in developed countries. In these countries CV risk factors like smoke, obesity, sed‐ entary life, dyslipidemias, hypertension and diabetes are well recognized and efforts have been efficaciously undertaken so that CV and CBV mortality in the second half of the last century has been significantly reduced. Cardiovascular and CBV diseases are al‐ so the leading cause of mortality in the developing world where in the last century we witnessed a rapid epidemiological as well as nutritional transition related mainly to in‐ creased urbanization and market globalization. Now the majority of CV and CBV mortal‐ ity occurs in low and middle-income countries [1].

Indeed the major responsible of CV as well as CBV diseases is the vascular atherosclerotic process. In particular the atherosclerotic calcified and non calcified plaques that cause coro‐ nary artery vessel lumen reduction are worldwide the leading cause of myocardial ischemia, which can lead to asymptomatic myocardial dysfunction, life threatening arrhythmias, angi‐ na, myocardial infarction and sudden death.

Besides the atherosclerotic coronary artery diseases there are also other non atherosclerotic coronary artery vessel lumen reductions, although their prevalence is less common. The non atherosclerotic coronary artery diseases are related to prolonged coronary artery spasm, hy‐ pertrophic cardiomyopathy, vasculitis and congenital coronary anomalies.

Congenital coronary artery anomalies are a heterogeneous group of diseases. In the majority of cases congenital coronary artery anomalies lack clinical significance and are merely epi‐ phenomena found accidentally during necropsies, while performing invasive or non inva‐ sive coronarography or during surgical interventions. However in some cases they may be

properly cited.

responsible for chest discomfort, malignant arrhythmias, fatal or non fatal acute myocardial infarction, ventricular septum rupture, myocardial stunning, paroxysmal atrio-ventricular block, syncope and sudden death. In particular 19% of sudden deaths in young athletes are due to coronary artery anomalies [2].

The real incidence of this entity is unknown and varies according to the procedure used to study it. Myocardial bridges are rare in patients referred for cardiac surgery (0.2-0.3%) or ICA (0.4-4.9%) while they are very frequent during autopsy (5.4-85.7%) [5]. Such disparate autopsy prevalence rates may result from the selection and preparation of the hearts as well as variations in definitions of MBs and probably also to ethnicity [6]. On average MBs are present in about one third of adults [7]. Thus, MB should not be defined as a congenital cor‐ onary anomaly, but rather as a normal variant [3]. According to some Authors superficial MBs may not be exclusively congenital in origin, but may result from adulthood disease

Myocardial Bridges in the ERA of Non-Invasive Angiography

http://dx.doi.org/10.5772/54083

415

There are also myocardial loops that are thinner and derive from atrial myocardium, sur‐ round the vessel three quarters of the circumference, and return to atrial myocardium. Occa‐ sionally, a bridge may involve also a coronary vein. Both, myocardial loops and venous

The wide variation in frequency of MBs indicates that many MBs do not produce symptoms. Subjects may become symptomatic after the third decade of life unless MBs are associated with precipitating factors (i.e. high heart rate, myocardial contractility state, hypertrophic cardiomyopathy, decreased peripheral vascular resistance). Myocardial ischemia due to MB could be attributed to a combination of the following factors: increased heart rate compro‐ mising the diastolic filling, exercise-induced spasm, and systolic kinking which may cause

A milestone work in studying MBs is that of Ferreira *et al*. These Authors found a MB in 50 of the 90 hearts studied (55.6%) mainly on LAD. They distinguished MBs into two types. In the superficial type (75% of cases) the myocardial fibres cross the artery trans‐ versely towards the apex of the heart at an acute angle or perpendicularly. In the deep type (25% of cases) the myocardial fibres arise from the right ventricular apical trabecu‐ lae, surround the LAD with a muscle bundle that crosses the artery transversely, obli‐ quely, or helically before terminating in the interventricular septum. In the deep variant, no direct contact occurs between the MB and the adventitial wall of the tunnelled artery. In addition, adipose, neural, and loose connective tissues are interposed between the MB and the artery. The Authors speculated that the vessel may be more distorted and com‐

Some superficial MBs may be not completely covered by myocardial fibres, but by a thin layer of connective tissue, nerves and fatty tissue [7]. Obviously in these cases the systolic

Recently the use of multi-detector computed tomography (MDCT) made it possible to visu‐ alize in vivo the MBs. Konen *et al*. were moreover able to describe three types of MBs. Beside the superficial type (29% of cases) and deep type (41% of cases) described by Ferreira *et al*. the Authors characterized a third one called "right ventricular type" (29% of cases. In this type the descending coronary artery "disappears" and is visible only in the axial images where it has a course near the right ventricular wall. This type of MB seems to be more po‐

compression is light and may not be appreciated during angiographic studies.

tentially pathologic and more difficult to treat surgically [5].

processes that partially cover the artery with fibro-fatty connective tissue [7].

endothelium damage with platelet activation and thrombus formation [4, 7].

bridges appear to have no clinical relevance [7].

pressed in the deep type of MB [8].

In this chapter we will focus our attention on describing the second most common type of coronary congenital anomaly: the myocardial bridges (MBs). We will discuss the nature of MBs and how to diagnose them with particular attention to the use of cardiac computed to‐ mography (CCT).

## **2. Classifications**

In describing coronary anomalies Angelini et al. proposed that a condition should be consid‐ ered "normal when it is observed in > 1% of an unselected population; normal variant, an alternative, relatively unusual, morphological feature seen in > 1% of the same population; and anomaly, a morphological feature seen in < 1% of that population". These Authors per‐ formed their study using cine-angiograms [3]. The procedure used to define a normal from an abnormal coronary may be a bias. In fact coronary angiography is performed in sympto‐ matic patients while necropsies are usually done for medico-legal purposes especially for vi‐ olent non hospital based deaths whereas necropsy for hospital based deaths is decreasing. This bias explains why coronary anomalies of origination and course are rare during autop‐ sy (0.17% of the cases) while their incidence is higher in the population of patients referred for coronary angiography (0.6-1.3%).

Clinically coronary anomalies are evaluated with the same diagnostic tests used to study the atherosclerotic coronary artery diseases: electrocardiogram, exercise stress test, trans-thora‐ cic and trans-esophageal echocardiography, stress echocardiography, stress single photon emission computed tomography, myocardial perfusion imaging, magnetic resonance, frac‐ tional flow reserve, electron beam computed tomography, invasive coronary angiography (ICA) and non-invasive coronary angiography with CCT.

Myocardial bridges in humans are inborn coronary anomalies of intrinsic coronary arterial anatomy with an intramural course. Although it was Reyman in 1737 and then Black in 1805 who first described, as a curiosity during necropsy, the presence of a MB overlaying the left anterior descending coronary artery (LAD), the first detailed postmortem analysis of this anomaly was reported by Geiringer in 1951 [4].

In fact in humans coronary arteries and their main branches have an epicardial course run‐ ning over the cardiac musculature. In the presence of a MB a portion of one coronary artery or more dips into and underneath the heart muscle to come back out again in the majority of the cases. This condition is also known also as "intramuscular coronary artery", "tunnelled artery", "myocardial loop", "mural coronary artery", "intramural coronary artery", "myo‐ cardial bridging" or "coronary artery over bridging".

The real incidence of this entity is unknown and varies according to the procedure used to study it. Myocardial bridges are rare in patients referred for cardiac surgery (0.2-0.3%) or ICA (0.4-4.9%) while they are very frequent during autopsy (5.4-85.7%) [5]. Such disparate autopsy prevalence rates may result from the selection and preparation of the hearts as well as variations in definitions of MBs and probably also to ethnicity [6]. On average MBs are present in about one third of adults [7]. Thus, MB should not be defined as a congenital cor‐ onary anomaly, but rather as a normal variant [3]. According to some Authors superficial MBs may not be exclusively congenital in origin, but may result from adulthood disease processes that partially cover the artery with fibro-fatty connective tissue [7].

responsible for chest discomfort, malignant arrhythmias, fatal or non fatal acute myocardial infarction, ventricular septum rupture, myocardial stunning, paroxysmal atrio-ventricular block, syncope and sudden death. In particular 19% of sudden deaths in young athletes are

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

In this chapter we will focus our attention on describing the second most common type of coronary congenital anomaly: the myocardial bridges (MBs). We will discuss the nature of MBs and how to diagnose them with particular attention to the use of cardiac computed to‐

In describing coronary anomalies Angelini et al. proposed that a condition should be consid‐ ered "normal when it is observed in > 1% of an unselected population; normal variant, an alternative, relatively unusual, morphological feature seen in > 1% of the same population; and anomaly, a morphological feature seen in < 1% of that population". These Authors per‐ formed their study using cine-angiograms [3]. The procedure used to define a normal from an abnormal coronary may be a bias. In fact coronary angiography is performed in sympto‐ matic patients while necropsies are usually done for medico-legal purposes especially for vi‐ olent non hospital based deaths whereas necropsy for hospital based deaths is decreasing. This bias explains why coronary anomalies of origination and course are rare during autop‐ sy (0.17% of the cases) while their incidence is higher in the population of patients referred

Clinically coronary anomalies are evaluated with the same diagnostic tests used to study the atherosclerotic coronary artery diseases: electrocardiogram, exercise stress test, trans-thora‐ cic and trans-esophageal echocardiography, stress echocardiography, stress single photon emission computed tomography, myocardial perfusion imaging, magnetic resonance, frac‐ tional flow reserve, electron beam computed tomography, invasive coronary angiography

Myocardial bridges in humans are inborn coronary anomalies of intrinsic coronary arterial anatomy with an intramural course. Although it was Reyman in 1737 and then Black in 1805 who first described, as a curiosity during necropsy, the presence of a MB overlaying the left anterior descending coronary artery (LAD), the first detailed postmortem analysis of this

In fact in humans coronary arteries and their main branches have an epicardial course run‐ ning over the cardiac musculature. In the presence of a MB a portion of one coronary artery or more dips into and underneath the heart muscle to come back out again in the majority of the cases. This condition is also known also as "intramuscular coronary artery", "tunnelled artery", "myocardial loop", "mural coronary artery", "intramural coronary artery", "myo‐

due to coronary artery anomalies [2].

for coronary angiography (0.6-1.3%).

(ICA) and non-invasive coronary angiography with CCT.

anomaly was reported by Geiringer in 1951 [4].

cardial bridging" or "coronary artery over bridging".

mography (CCT).

**2. Classifications**

There are also myocardial loops that are thinner and derive from atrial myocardium, sur‐ round the vessel three quarters of the circumference, and return to atrial myocardium. Occa‐ sionally, a bridge may involve also a coronary vein. Both, myocardial loops and venous bridges appear to have no clinical relevance [7].

The wide variation in frequency of MBs indicates that many MBs do not produce symptoms. Subjects may become symptomatic after the third decade of life unless MBs are associated with precipitating factors (i.e. high heart rate, myocardial contractility state, hypertrophic cardiomyopathy, decreased peripheral vascular resistance). Myocardial ischemia due to MB could be attributed to a combination of the following factors: increased heart rate compro‐ mising the diastolic filling, exercise-induced spasm, and systolic kinking which may cause endothelium damage with platelet activation and thrombus formation [4, 7].

A milestone work in studying MBs is that of Ferreira *et al*. These Authors found a MB in 50 of the 90 hearts studied (55.6%) mainly on LAD. They distinguished MBs into two types. In the superficial type (75% of cases) the myocardial fibres cross the artery trans‐ versely towards the apex of the heart at an acute angle or perpendicularly. In the deep type (25% of cases) the myocardial fibres arise from the right ventricular apical trabecu‐ lae, surround the LAD with a muscle bundle that crosses the artery transversely, obli‐ quely, or helically before terminating in the interventricular septum. In the deep variant, no direct contact occurs between the MB and the adventitial wall of the tunnelled artery. In addition, adipose, neural, and loose connective tissues are interposed between the MB and the artery. The Authors speculated that the vessel may be more distorted and com‐ pressed in the deep type of MB [8].

Some superficial MBs may be not completely covered by myocardial fibres, but by a thin layer of connective tissue, nerves and fatty tissue [7]. Obviously in these cases the systolic compression is light and may not be appreciated during angiographic studies.

Recently the use of multi-detector computed tomography (MDCT) made it possible to visu‐ alize in vivo the MBs. Konen *et al*. were moreover able to describe three types of MBs. Beside the superficial type (29% of cases) and deep type (41% of cases) described by Ferreira *et al*. the Authors characterized a third one called "right ventricular type" (29% of cases. In this type the descending coronary artery "disappears" and is visible only in the axial images where it has a course near the right ventricular wall. This type of MB seems to be more po‐ tentially pathologic and more difficult to treat surgically [5].

Myocardial bridges can be classified also depending on the thickness, the length and the number (one or more) of MBs. Obviously MBs are also classified according to the coronary artery and the segment of the coronary artery involved. The majority of MBs are in the mid portion of LAD. However MBs have been found also over the proximal and distal parts of the LAD, the diagonal and marginal branches and over the posterior interventricular branch of the LAD. Bridging of the circumflex or the right coronary artery or one of their branches is not so common [9]. In the presence of two parallel LADs one of them frequently takes an intramural course [7].

arrhythmias, such as ventricular fibrillation. In fact many of the analyzed hearts with

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417

Recently several histopathologic studies clearly demonstrated that while the arterial inti‐ ma beneath the MB is significantly spared from atherosclerotic changes, the segments proximal to the MB are not interested by this atherosclerosis suppression. By scanning electron microscopy the endothelial cells in the tunnelled segment had a helical, spindleshaped orientation along the course of the segment as a sign of laminar flow and high shear. In the segments proximal to the MB the endothelium was flat, polygonal, and pol‐ ymorph, indicating low shear. Low shear stress facilitates adhesion and aggregation of platelets followed by subsequent thrombosis and is associated with a release of endothe‐ lial vasoactive agents such as endothelin-1, nitric oxide synthase and angiotensin-convert‐ ing enzyme which favour mass transfer of lipids into subentothelial space [13, 14]. Higher shear stress on the other side, results in lower levels of these vasoactive agents and in a suppression of lipid infiltration into subentothelial space. It has also been found that the intima beneath the bridged segment always consisted of contractile-type smooth muscle cells, while the segment proximal to the MB had synthetic-type smooth muscle cells. These types of cells usually proliferate and produce collagen fibrils and elastic fi‐ bres in the intima as atherosclerosis progresses. Moreover in the proximal segments to the MB the flow is turbulent accentuated by the retrograde blood flow caused by the "squeezing" of the MB during systole and a "sucking effect" of the proximal segment during the early phases of diastole. The increase of local wall tension and stretch in the segment proximal to MB may induce endothelial injury and plaque fissuring with subse‐ quent thrombus formation. All these complex hemodynamic alterations may explain the atherosclerotic plaque formation, mainly eccentric, at the entrance of the tunnelled seg‐ ment [4, 7, 9, 10, 14]. However, although the endothelium of MB is spared from athero‐ sclerotic lesions its function seems to be significantly impaired as estimated by the vasoactive response to achetylcoline and increased vasoconstriction [15]. These data sug‐ gest that MB itself may have a dysfunctional endothelium, a strong atherogenic factor that can cause myocardial ischemia, chest pain, life threatening arrhythmias, and sudden

The current gold standard technique for diagnosing MBs is coronary angiography. Port‐ man and Iwing in 1960 were the first to report the radiological appearance of transient stenosis in a segment of the LAD during systole in a 19 year old patient. The typical an‐ giographic finding of a MB is a systolic narrowing of an epicardial artery, known also as a "milking effect" phenomenon induced by systolic compression of the tunnelled seg‐ ment. Another angiographic finding is the presence of the "step down-step up" appear‐ ance, namely, a significant tortuosity of the segment beneath MB at the entrance (step-

MBs were from subjects who died of sudden death [12].

cardiac death [5].

**4. Angiographic findings**

down) and the exit (step-up) sites [4, 10] (Fig 1).

Although autopsy studies did not demonstrate any difference in the frequency of MBs by age or sex [8, 10] angiographic studies indicate that males have a higher incidence and lon‐ ger MBs probably owing to a higher musculature of the body in respect to females [9, 11].

A fairly large percentage of subjects with MBs may have concomitant atherosclerotic, mus‐ cular, or valvular heart diseases, which may independently affect the clinical outcome as well as the treatment strategy [4]. Typically, the MB patients are 5 to 10 years younger than those with symptomatic coronary disease. Typical angina is present in 55% to 70% of the cases, and atypical angina is often reported in association with rest angina. The co-presence of MBs with atherosclerotic coronary artery disease should be taken into account when it is not possible to detect a culprit lesion in symptomatic patients. Although MBs have excellent prognosis even in patients with ≥ 50% systolic compression, early diagnosis and treatment are important due to their possible complications [5].

Nowadays there is a debate concerning the evaluation of asymptomatic young athletes who have a low probability to have an atherosclerotic coronary artery disease. Some of these ath‐ letes however during or just after physical exertion or in circumstances non-associated with sports, during routine daily activities, while sedentary or even asleep may have an unex‐ pected death. In an autopsy-based registry comprising 1866 young athletes (19 ± 6 years) the cause of sudden death was in 56% of the cases due to CV disease. Of these the cause of sud‐ den death was attributable to hypertrophic cardiomyopathy in 36% of the cases and to coro‐ nary artery anomalies in 19% of the cases (119 cases of coronary artery anomalies of wrong sinus origin and 24 cases of MBs) [2].

### **3. Anatomic properties of myocardial bridges**

In a necropsy study Morales et al. found that hearts with MBs but with no evidence of other cardiac abnormalities had gross or microscopic alterations (or both), such as inter‐ stitial fibrosis, replacement fibrosis, contraction-band necrosis, or increased vascular den‐ sity, in areas of the myocardium supplied by the bridged LAD. According to the Authors, the histologic heterogeneity of these findings, with closely interspersed patches of normal myocardium, is related to the attenuation of blood flow due to the intramural course of the vessel. These blood flow alteration may induce chronic and/or acute transi‐ ent myocardial ischemia. The myocardial ischemia may be responsible of life threatening arrhythmias, such as ventricular fibrillation. In fact many of the analyzed hearts with MBs were from subjects who died of sudden death [12].

Recently several histopathologic studies clearly demonstrated that while the arterial inti‐ ma beneath the MB is significantly spared from atherosclerotic changes, the segments proximal to the MB are not interested by this atherosclerosis suppression. By scanning electron microscopy the endothelial cells in the tunnelled segment had a helical, spindleshaped orientation along the course of the segment as a sign of laminar flow and high shear. In the segments proximal to the MB the endothelium was flat, polygonal, and pol‐ ymorph, indicating low shear. Low shear stress facilitates adhesion and aggregation of platelets followed by subsequent thrombosis and is associated with a release of endothe‐ lial vasoactive agents such as endothelin-1, nitric oxide synthase and angiotensin-convert‐ ing enzyme which favour mass transfer of lipids into subentothelial space [13, 14]. Higher shear stress on the other side, results in lower levels of these vasoactive agents and in a suppression of lipid infiltration into subentothelial space. It has also been found that the intima beneath the bridged segment always consisted of contractile-type smooth muscle cells, while the segment proximal to the MB had synthetic-type smooth muscle cells. These types of cells usually proliferate and produce collagen fibrils and elastic fi‐ bres in the intima as atherosclerosis progresses. Moreover in the proximal segments to the MB the flow is turbulent accentuated by the retrograde blood flow caused by the "squeezing" of the MB during systole and a "sucking effect" of the proximal segment during the early phases of diastole. The increase of local wall tension and stretch in the segment proximal to MB may induce endothelial injury and plaque fissuring with subse‐ quent thrombus formation. All these complex hemodynamic alterations may explain the atherosclerotic plaque formation, mainly eccentric, at the entrance of the tunnelled seg‐ ment [4, 7, 9, 10, 14]. However, although the endothelium of MB is spared from athero‐ sclerotic lesions its function seems to be significantly impaired as estimated by the vasoactive response to achetylcoline and increased vasoconstriction [15]. These data sug‐ gest that MB itself may have a dysfunctional endothelium, a strong atherogenic factor that can cause myocardial ischemia, chest pain, life threatening arrhythmias, and sudden cardiac death [5].

## **4. Angiographic findings**

Myocardial bridges can be classified also depending on the thickness, the length and the number (one or more) of MBs. Obviously MBs are also classified according to the coronary artery and the segment of the coronary artery involved. The majority of MBs are in the mid portion of LAD. However MBs have been found also over the proximal and distal parts of the LAD, the diagonal and marginal branches and over the posterior interventricular branch of the LAD. Bridging of the circumflex or the right coronary artery or one of their branches is not so common [9]. In the presence of two parallel LADs one of them frequently takes an

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

Although autopsy studies did not demonstrate any difference in the frequency of MBs by age or sex [8, 10] angiographic studies indicate that males have a higher incidence and lon‐ ger MBs probably owing to a higher musculature of the body in respect to females [9, 11].

A fairly large percentage of subjects with MBs may have concomitant atherosclerotic, mus‐ cular, or valvular heart diseases, which may independently affect the clinical outcome as well as the treatment strategy [4]. Typically, the MB patients are 5 to 10 years younger than those with symptomatic coronary disease. Typical angina is present in 55% to 70% of the cases, and atypical angina is often reported in association with rest angina. The co-presence of MBs with atherosclerotic coronary artery disease should be taken into account when it is not possible to detect a culprit lesion in symptomatic patients. Although MBs have excellent prognosis even in patients with ≥ 50% systolic compression, early diagnosis and treatment

Nowadays there is a debate concerning the evaluation of asymptomatic young athletes who have a low probability to have an atherosclerotic coronary artery disease. Some of these ath‐ letes however during or just after physical exertion or in circumstances non-associated with sports, during routine daily activities, while sedentary or even asleep may have an unex‐ pected death. In an autopsy-based registry comprising 1866 young athletes (19 ± 6 years) the cause of sudden death was in 56% of the cases due to CV disease. Of these the cause of sud‐ den death was attributable to hypertrophic cardiomyopathy in 36% of the cases and to coro‐ nary artery anomalies in 19% of the cases (119 cases of coronary artery anomalies of wrong

In a necropsy study Morales et al. found that hearts with MBs but with no evidence of other cardiac abnormalities had gross or microscopic alterations (or both), such as inter‐ stitial fibrosis, replacement fibrosis, contraction-band necrosis, or increased vascular den‐ sity, in areas of the myocardium supplied by the bridged LAD. According to the Authors, the histologic heterogeneity of these findings, with closely interspersed patches of normal myocardium, is related to the attenuation of blood flow due to the intramural course of the vessel. These blood flow alteration may induce chronic and/or acute transi‐ ent myocardial ischemia. The myocardial ischemia may be responsible of life threatening

intramural course [7].

are important due to their possible complications [5].

**3. Anatomic properties of myocardial bridges**

sinus origin and 24 cases of MBs) [2].

The current gold standard technique for diagnosing MBs is coronary angiography. Port‐ man and Iwing in 1960 were the first to report the radiological appearance of transient stenosis in a segment of the LAD during systole in a 19 year old patient. The typical an‐ giographic finding of a MB is a systolic narrowing of an epicardial artery, known also as a "milking effect" phenomenon induced by systolic compression of the tunnelled seg‐ ment. Another angiographic finding is the presence of the "step down-step up" appear‐ ance, namely, a significant tortuosity of the segment beneath MB at the entrance (stepdown) and the exit (step-up) sites [4, 10] (Fig 1).

A limit of ICA is that it estimates coronary artery diameter as a percent by comparing it with the adjacent segment, which arbitrarily is considered normal. This visual procedure to esti‐ mate lesions has a high degree of intra and inter-observer variability. These limits have been reduced by improving the software (quantitative coronary angiography) and hardware (flat

Myocardial Bridges in the ERA of Non-Invasive Angiography

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419

**5. Intravascular ultrasound, intracoronary Doppler and intracoronary**

The performance of ICA increased with the introduction of important tools such as intravas‐ cular coronary ultrasound (IVUS), that for the first time visualized, in vivo, both vessel lu‐ men and walls, intracoronary Doppler-ultrasound and intracoronary pressure-wire. These tools increased our understanding of the morphological and functional features of MBs.

Although its anatomy and physiology are not fully understood the "half moon phenom‐ enon" is a characteristic and highly specific IVUS observation of MBs as it is only found in the tunnelled segments, but not in the proximal or distal segments of the vessel or in other arteries. The "half moon phenomenon" appears as an echolucent area surrounding the bridge segment. In the presence of a "half-moon phenomenon" the milking effect can be induced by intracoronary provocation tests, such as intracoronary nitroglycerin injec‐ tion, even if the bridge was previously angiographically undetectable [11]. Ultrasound pullback studies confirmed the histological findings of absence of atherosclerosis within the tunnelled segments, whereas there was a plaque in the segment proximal to the MB in about 90% of subjects. None of these proximal atherosclerotic lesions detected by IVUS has been seen on angiography confirming the known superiority of IVUS on an‐

In presence of MB the pullback of the intracoronary Doppler (0.0014 inch wire) reveals a characteristic flow pattern: "fingertip phenomenon" or "spike-and-dome pattern" which is present in most of the patients with MBs. This flow pattern described by Ge et al. [17] can be observed within and just proximal to the tunnelled segment and consists in a sharp accelera‐ tion of flow in early diastole followed by immediate marked deceleration and a mid to late diastolic pressure plateau. The Authors explain this flow pattern as an increase in the pres‐ sure gradient in the early diastole as a result of reduced distal coronary resistance while there is a delay in the relaxation of the myocardial fibres. The subsequent sharp deceleration in the coronary flow velocity results from the relaxation of the myocardial fibres and an in‐ crease in the vascular lumen. After the release of the compression, the lumen of the bridge segment remains unchanged in the second half of diastole and this corresponds to the pla‐ teau of the flow pattern at this phase. In deep myocardial bridges, rapid diastolic forward flow may be preceded by end-systolic flow inversion as a result of systolic squeezing of the bridge segment. In the subjects where the "fingertip phenomenon" is not present (13% of cases) this may be related to the fact that the bridging segment was not so severe to induce the hemodynamic disorders that lead to the "fingertip phenomenon" formation [17]. The

panel digital detectors) of angiographs.

giography in detecting atherosclerotic plaques [11].

**pressure**

**Figure 1.** Myocardial bridging on conventional coronary angiography in diastole and systole. Compression at the mid‐ dle of the left descending coronary artery occurs during systole with a clear step-down and step us phenomenon. Ar‐ rows indicate the beginning and the end of the tunnelled segment. The left descending coronary artery and the circumflex artery are free of atherosclerotic lesions.

The systolic compression is usually eccentric rather than concentric [11]. However, also the diastole is compromised. In fact measurements in patients with MB have shown a persistent diastolic diameter reduction enduring mid diastole. In a series of 42 patients a mean maximum systolic diameter reduction of 71% was found with a persistent reduc‐ tion of 35% during mid diastole, while 12% of patients showed a reduction of more than 50% in mid diastole [16]. Almost the same results were found by Bourassa et al. in a frame-by-frame analysis of cine-angiograms during a complete cardiac cycle. The Au‐ thors were able to demonstrate that 17 of 20 patients (85%) with a ≥ 75% milking effect of the LAD had an extension of the obstruction into diastole, which averaged 136 ms or 26% (range 4% to 50%) of diastole [4]. In borderline cases intracoronary nitroglycerine administration may uncover the systolic coronary compression. The milking effect is evaluated as grade I when the narrowing is less than 50%, grade II when it is between 50 and 75%, and grade III when it is greater than 75% [4].

The frequency of MBs reported in angiographic studies varies from 0.5 to 33%. This wide variation at angiography may in part be attributable to technologic advances in cine-angiog‐ raphy; to the orientation of the coronary artery and myocardial fibres; to the state of myocar‐ dial contractility; to the fact that small and thin bridges cause little compression badly detectable during angiography specially with no previous percentage of systolic narrowing specified for the designation of MB; if the study was retrospectively reviewed for the specif‐ ic purpose of assessing the frequency of MBs; to sample size and finally to different popula‐ tion selection and probably also to ethnicity. In patients with MBs chest pain is the common reason for angiography. At angiography the mid portion of the LAD is the most frequently affected vessel.

A limit of ICA is that it estimates coronary artery diameter as a percent by comparing it with the adjacent segment, which arbitrarily is considered normal. This visual procedure to esti‐ mate lesions has a high degree of intra and inter-observer variability. These limits have been reduced by improving the software (quantitative coronary angiography) and hardware (flat panel digital detectors) of angiographs.

## **5. Intravascular ultrasound, intracoronary Doppler and intracoronary pressure**

**Figure 1.** Myocardial bridging on conventional coronary angiography in diastole and systole. Compression at the mid‐ dle of the left descending coronary artery occurs during systole with a clear step-down and step us phenomenon. Ar‐ rows indicate the beginning and the end of the tunnelled segment. The left descending coronary artery and the

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

The systolic compression is usually eccentric rather than concentric [11]. However, also the diastole is compromised. In fact measurements in patients with MB have shown a persistent diastolic diameter reduction enduring mid diastole. In a series of 42 patients a mean maximum systolic diameter reduction of 71% was found with a persistent reduc‐ tion of 35% during mid diastole, while 12% of patients showed a reduction of more than 50% in mid diastole [16]. Almost the same results were found by Bourassa et al. in a frame-by-frame analysis of cine-angiograms during a complete cardiac cycle. The Au‐ thors were able to demonstrate that 17 of 20 patients (85%) with a ≥ 75% milking effect of the LAD had an extension of the obstruction into diastole, which averaged 136 ms or 26% (range 4% to 50%) of diastole [4]. In borderline cases intracoronary nitroglycerine administration may uncover the systolic coronary compression. The milking effect is evaluated as grade I when the narrowing is less than 50%, grade II when it is between

The frequency of MBs reported in angiographic studies varies from 0.5 to 33%. This wide variation at angiography may in part be attributable to technologic advances in cine-angiog‐ raphy; to the orientation of the coronary artery and myocardial fibres; to the state of myocar‐ dial contractility; to the fact that small and thin bridges cause little compression badly detectable during angiography specially with no previous percentage of systolic narrowing specified for the designation of MB; if the study was retrospectively reviewed for the specif‐ ic purpose of assessing the frequency of MBs; to sample size and finally to different popula‐ tion selection and probably also to ethnicity. In patients with MBs chest pain is the common reason for angiography. At angiography the mid portion of the LAD is the most frequently

circumflex artery are free of atherosclerotic lesions.

affected vessel.

50 and 75%, and grade III when it is greater than 75% [4].

The performance of ICA increased with the introduction of important tools such as intravas‐ cular coronary ultrasound (IVUS), that for the first time visualized, in vivo, both vessel lu‐ men and walls, intracoronary Doppler-ultrasound and intracoronary pressure-wire. These tools increased our understanding of the morphological and functional features of MBs.

Although its anatomy and physiology are not fully understood the "half moon phenom‐ enon" is a characteristic and highly specific IVUS observation of MBs as it is only found in the tunnelled segments, but not in the proximal or distal segments of the vessel or in other arteries. The "half moon phenomenon" appears as an echolucent area surrounding the bridge segment. In the presence of a "half-moon phenomenon" the milking effect can be induced by intracoronary provocation tests, such as intracoronary nitroglycerin injec‐ tion, even if the bridge was previously angiographically undetectable [11]. Ultrasound pullback studies confirmed the histological findings of absence of atherosclerosis within the tunnelled segments, whereas there was a plaque in the segment proximal to the MB in about 90% of subjects. None of these proximal atherosclerotic lesions detected by IVUS has been seen on angiography confirming the known superiority of IVUS on an‐ giography in detecting atherosclerotic plaques [11].

In presence of MB the pullback of the intracoronary Doppler (0.0014 inch wire) reveals a characteristic flow pattern: "fingertip phenomenon" or "spike-and-dome pattern" which is present in most of the patients with MBs. This flow pattern described by Ge et al. [17] can be observed within and just proximal to the tunnelled segment and consists in a sharp accelera‐ tion of flow in early diastole followed by immediate marked deceleration and a mid to late diastolic pressure plateau. The Authors explain this flow pattern as an increase in the pres‐ sure gradient in the early diastole as a result of reduced distal coronary resistance while there is a delay in the relaxation of the myocardial fibres. The subsequent sharp deceleration in the coronary flow velocity results from the relaxation of the myocardial fibres and an in‐ crease in the vascular lumen. After the release of the compression, the lumen of the bridge segment remains unchanged in the second half of diastole and this corresponds to the pla‐ teau of the flow pattern at this phase. In deep myocardial bridges, rapid diastolic forward flow may be preceded by end-systolic flow inversion as a result of systolic squeezing of the bridge segment. In the subjects where the "fingertip phenomenon" is not present (13% of cases) this may be related to the fact that the bridging segment was not so severe to induce the hemodynamic disorders that lead to the "fingertip phenomenon" formation [17]. The consequence of these phenomena is that in the segment proximal to the MB the pressure can become even higher than that in the aorta. At the entrance of the MB the high wall stress and disturbance in blood flow promote atherosclerosis [17]. Finally in subjects with MBs the coronary flow reserves, defined as the ratio of mean flow velocity achieved at peak hypere‐ mia obtained after intracoronary injection of papaverine or adenosine to mean resting flow velocity, is frequently reduced (2.0-2.6), values below 3.0, which is regarded as the lower normal limit [4].

proach to study the disease and its expected incremental information, combined with clini‐ cal judgment exceeds the expected negative consequences by a sufficiently wide margin)

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Cardiac computed tomography has however some important limits that must be consid‐ ered. Invasive coronary angiography is still superior over CCT because it has, for the mo‐ ment, a higher spatial (<0.16 mm vs approximately 0.4 mm of CCT) as well as temporal resolution (33 msec. vs 140 to 200 msec. of the recent cardiac computed systems or 83 msec. of the dual source system). Another limit of CCT present also with the currently available 64 channel systems is related to patient's heart rate which must be rhythmic and around or less than 60-64 beats per minute. Patients with atrial fibrillation or with a heart rate that can not be reduced to a rate of 60-64 beats per minute, for the moment, are not eligible to undergo this kind of examination. The introduction of new tools like the "ECG-tube current modula‐ tion" and the "step and shoot" procedures and the 128, 256, 320 and 640 channel or dual source scanners offers the possibility to study also patients with higher heart rates and with atrial fibrillation, making it possible to image the entire heart not only, as it is now, in a sin‐ gle breath hold, but in a single heartbeat [19]. Moreover less than or equal to 5% of patients have a un-valuable CCT scans due to motion artefacts, because the patient cannot follow breathing commands, involuntary motion of the diaphragm or because the patient is over‐

Particular attention must be also given to the dose of radiation delivered to patients. In the commonly used CCT systems the amount of radiation, expressed as units of millisieverts (equivalent to millijoules per kilogram of tissue), absorbed by patients during the test is 2-4 folds that of ICA [19]. However the introduction of improvements in CCT technologies de‐ creased significantly the radiation dose to equal almost that of traditional coronary angiog‐ raphy [21]. Finally it is worth noting that both ICA and CCT use non-ionic contrast medium to visualize coronary artery lumen. For this reason particular attention must be given in al‐

While studying MBs it is also important to consider that CCT analysis are mainly performed with images reconstructed during diastole (70-80% of the cardiac cycle) when there is the maximal vasodilatation and minimal motion artifacts. Conversely maximal lumen narrow‐ ing of MB is during the systolic phase (30-40% of cardiac cycle) where usually there are more motion artifacts. To better evaluate patient's MB it is therefore important to analyze the whole cardiac cycle, but good quality CCT images in both the diastolic and systolic

For the final interpretation of MBs conventional post-processing tools are used, namely: cross-sectional imaging, multiplanar reconstructions (MPR), curved MPR (cMPR), maxi‐

lergic patients and in patients with a pre-existing renal impairment [19].

**7. Myocardial bridges and cardiac computed tomography**

mum intensity projections (MIP) and three-dimension volume rendering (Fig 2).

phases are obtained only with the more recent CCT machines.

with a score of 9 out of 9 [20].

weigh or has respiratory problems.

## **6. Cardiac computed tomography**

The introduction of multidetector row systems in the field of cardiac computed tomography (CCT) has made imaging of the heart and in particular of epicardial coronary arteries feasi‐ ble. In the last two decades CCT has been used to study different group of subjects becom‐ ing in some cases the new "gold standard technique" instead of invasive coronary angiography (ICA), because of it's ability to visualize correctly coronary arteries and most interestingly to obtain this information non-invasively [18, 19, 20].

In particular CCT is widely used to study coronary artery anomalies. In fact ICA has some limits as it provides a few 2D view images of the coronary arteries and sometimes it fails to clearly visualize the relationship between the coronary vessels and the surrounding struc‐ tures. With ICA it is not always easy to selectively engage the anomalous coronary vessel, which may lead to the erroneous assumption that the coronary vessel is occluded. In addi‐ tion with this traditional 2D technique is more difficult to understand the course of the coro‐ nary vessels within the heart and discern the anterior versus the posterior direction of the anomalous vessels. On the other side CCT provides an unlimited number of 2D reformatted images as well as 3D images of the single vessel making it possible to have a 3D depiction of the whole heart [19].

The CCT information is very useful to the surgeon as it helps him to plan the surgery by seeing the exact course of the vessel and its relationship within the heart and with the other intra-thoracic organs and chest wall [19]. In addition, in case of extensive and deep MB there may be a technical challenge during coronary arterial bypass. The intra‐ muscular coronary artery may be difficult to localize and may require the use of intraoperative echocardiographic Doppler to explore the coronary artery to avoid, for example, accidental opening of the right ventricle during dissection of intramuscular LAD. It has also been suggested that a preoperative diagnosis of MBs on CCT may help in planning the surgery strategy allowing a key information for selecting the standard midsternotomy with or without cardiopulmonary bypass (coronary artery bypass graft or off-pump coronary bypass graft, respectively) or a minimally invasive approach through the small left anterior thoracotomy [5].

In the recent American Appropriate Use Criteria Task Force for CCT, the use of CCT in the "assessment of anomalies of coronary arterial and other thoracic arteriovenous vessels" was pointed to be most appropriate (i.e. the test is acceptable and considered a reasonable ap‐ proach to study the disease and its expected incremental information, combined with clini‐ cal judgment exceeds the expected negative consequences by a sufficiently wide margin) with a score of 9 out of 9 [20].

consequence of these phenomena is that in the segment proximal to the MB the pressure can become even higher than that in the aorta. At the entrance of the MB the high wall stress and disturbance in blood flow promote atherosclerosis [17]. Finally in subjects with MBs the coronary flow reserves, defined as the ratio of mean flow velocity achieved at peak hypere‐ mia obtained after intracoronary injection of papaverine or adenosine to mean resting flow velocity, is frequently reduced (2.0-2.6), values below 3.0, which is regarded as the lower

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

The introduction of multidetector row systems in the field of cardiac computed tomography (CCT) has made imaging of the heart and in particular of epicardial coronary arteries feasi‐ ble. In the last two decades CCT has been used to study different group of subjects becom‐ ing in some cases the new "gold standard technique" instead of invasive coronary angiography (ICA), because of it's ability to visualize correctly coronary arteries and most

In particular CCT is widely used to study coronary artery anomalies. In fact ICA has some limits as it provides a few 2D view images of the coronary arteries and sometimes it fails to clearly visualize the relationship between the coronary vessels and the surrounding struc‐ tures. With ICA it is not always easy to selectively engage the anomalous coronary vessel, which may lead to the erroneous assumption that the coronary vessel is occluded. In addi‐ tion with this traditional 2D technique is more difficult to understand the course of the coro‐ nary vessels within the heart and discern the anterior versus the posterior direction of the anomalous vessels. On the other side CCT provides an unlimited number of 2D reformatted images as well as 3D images of the single vessel making it possible to have a 3D depiction of

The CCT information is very useful to the surgeon as it helps him to plan the surgery by seeing the exact course of the vessel and its relationship within the heart and with the other intra-thoracic organs and chest wall [19]. In addition, in case of extensive and deep MB there may be a technical challenge during coronary arterial bypass. The intra‐ muscular coronary artery may be difficult to localize and may require the use of intraoperative echocardiographic Doppler to explore the coronary artery to avoid, for example, accidental opening of the right ventricle during dissection of intramuscular LAD. It has also been suggested that a preoperative diagnosis of MBs on CCT may help in planning the surgery strategy allowing a key information for selecting the standard midsternotomy with or without cardiopulmonary bypass (coronary artery bypass graft or off-pump coronary bypass graft, respectively) or a minimally invasive approach through

In the recent American Appropriate Use Criteria Task Force for CCT, the use of CCT in the "assessment of anomalies of coronary arterial and other thoracic arteriovenous vessels" was pointed to be most appropriate (i.e. the test is acceptable and considered a reasonable ap‐

interestingly to obtain this information non-invasively [18, 19, 20].

normal limit [4].

the whole heart [19].

the small left anterior thoracotomy [5].

**6. Cardiac computed tomography**

Cardiac computed tomography has however some important limits that must be consid‐ ered. Invasive coronary angiography is still superior over CCT because it has, for the mo‐ ment, a higher spatial (<0.16 mm vs approximately 0.4 mm of CCT) as well as temporal resolution (33 msec. vs 140 to 200 msec. of the recent cardiac computed systems or 83 msec. of the dual source system). Another limit of CCT present also with the currently available 64 channel systems is related to patient's heart rate which must be rhythmic and around or less than 60-64 beats per minute. Patients with atrial fibrillation or with a heart rate that can not be reduced to a rate of 60-64 beats per minute, for the moment, are not eligible to undergo this kind of examination. The introduction of new tools like the "ECG-tube current modula‐ tion" and the "step and shoot" procedures and the 128, 256, 320 and 640 channel or dual source scanners offers the possibility to study also patients with higher heart rates and with atrial fibrillation, making it possible to image the entire heart not only, as it is now, in a sin‐ gle breath hold, but in a single heartbeat [19]. Moreover less than or equal to 5% of patients have a un-valuable CCT scans due to motion artefacts, because the patient cannot follow breathing commands, involuntary motion of the diaphragm or because the patient is over‐ weigh or has respiratory problems.

Particular attention must be also given to the dose of radiation delivered to patients. In the commonly used CCT systems the amount of radiation, expressed as units of millisieverts (equivalent to millijoules per kilogram of tissue), absorbed by patients during the test is 2-4 folds that of ICA [19]. However the introduction of improvements in CCT technologies de‐ creased significantly the radiation dose to equal almost that of traditional coronary angiog‐ raphy [21]. Finally it is worth noting that both ICA and CCT use non-ionic contrast medium to visualize coronary artery lumen. For this reason particular attention must be given in al‐ lergic patients and in patients with a pre-existing renal impairment [19].

While studying MBs it is also important to consider that CCT analysis are mainly performed with images reconstructed during diastole (70-80% of the cardiac cycle) when there is the maximal vasodilatation and minimal motion artifacts. Conversely maximal lumen narrow‐ ing of MB is during the systolic phase (30-40% of cardiac cycle) where usually there are more motion artifacts. To better evaluate patient's MB it is therefore important to analyze the whole cardiac cycle, but good quality CCT images in both the diastolic and systolic phases are obtained only with the more recent CCT machines.

## **7. Myocardial bridges and cardiac computed tomography**

For the final interpretation of MBs conventional post-processing tools are used, namely: cross-sectional imaging, multiplanar reconstructions (MPR), curved MPR (cMPR), maxi‐ mum intensity projections (MIP) and three-dimension volume rendering (Fig 2).

strated that, in patients with culprit lesions in the LAD segment proximal to MB, the length and thickness of MBs were significantly greater, and the distance from the orifice of the left coronary artery to the entrance of MB was significantly shorter than those in patients with no culprit lesion in the LAD segment proximal to MB [24]. These results are similar to those of the autopsy studies that demonstrated that the anatomical proper‐ ties of MB muscle were closely associated with a shift of coronary intimal lesion more

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Since the introduction of CCT in the last decade of last century many papers have been pub‐

In particular many papers compared CCT to ICA. Recently a significant correlation was found between the within-MB diameters obtained with CCT and ICA during the systolic (1.3±0.3 mm vs. 1.2±0.5 mm: r= 0.394, P=0.028) and diastolic phases (1.4±0.4 mm vs. 1.6±0.6 mm: r= 0.524, P=0.001) [25]. However CCT is superior to ICA in diagnosing the presence of MB. Kim et al. found that while dynamic compression was present in 13.3% of the subjects (40/300) who underwent ICA, CCT revealed that 58% of the subjects (178/300) had myocar‐ dial bridging (partial encasement in 57 and full encasement in 117 subjects) [26]. Leschka et al. found that MB was revealed with CCT and ICA respectively in 26 and 12 of the 100 sub‐

When comparing CCT with IVUS, the sensitivity of detecting MB by CCT was found to be 93%, specificity 100%, positive predictive value and negative predictive value 100% and 91% respectively. A significant correlation was also observed between lumen diameters derived from CCT and IVUS (systolic phase: *r*=0.87, *P*<0.05; diastolic phase: *r*=0.92, *P*<0.05). Although minimal and maximal diameters of MB during systolic and diastolic phases derived from CCT were significantly smaller than those from IVUS (2.4±0.4 mm vs 2.6±0.5 mm, *P*<0.05) and (2.9±0.3 mm vs 3.3±0.3 mm, *P*<0.05) the narrowing percent derived from the two meth‐ ods was similar ((21.4±10.9% vs 17.4±7.6%, *P*>0.05). The Authors however note that CCT of‐ fers a safer, more comfortable and cost-effective examinations (in China the prices of IVUS

Usually in the CCT studies where MB is evaluated the coronary arteries are classified ac‐ cording to the American Heart Association classification system: right coronary artery: 1, proximal; 2, mid; 3, distal; 4a, posterior descending; 4b, posterolateral; left main coronary ar‐ tery: 5, LAD; 6, proximal; 7, mid; 8, distal; 9, first diagonal; 10, second diagonal; circumflex coronary artery: 11, proximal; 12, first marginal; 13, mid; 14, second marginal; 15, distal.

All studied performed the evaluation of MB mainly in the diastolic phase while a few stud‐ ies performed it in the systolic phase due to technical problems related to the increased mo‐ tion of the heart due to myocardial contraction in the systolic phase and to the limited

In the literature there is not a consensus in the definition of MB. Usually MB is defined as the existence of tissues exhibiting soft tissue density covering a part of the vessel, which had

proximally, an effect that may increase the risk of myocardial infarction [14].

lished showing the feasibility of CCT in evaluating patients with MB (Fig 3).

and MSCT are 1500 US \$ and 95 US \$ respectively [28].

temporal resolution of routinely available scanners [5, 22, 27, 29].

the same contrast enhancement as myocardial tissue [24].

jects studied [27].

The high temporal resolution obtained with the most recent scanners or dual source scanners enable the visualization of the vessel lumen during most of the cardiac cycle, and thus permit the observation of the milking effect in the 4-dimensional reconstruction [22]. Cardiac computed tomography helped to better evaluate the anatomical properties of MB. Several Authors using CCT confirmed what was already know from necropsies, CCA and IVUS studies that the tunnelled segments are spared from atherosclerotic changes [23]. However Zeina et al. found that the thickness and length of the bridge cor‐ related with the presence of stenosis in the LAD proximal to the MB suggesting that the MB may predispose to the development of atherosclerosis in the coronary artery seg‐ ment proximal to the bridge and that MB should be considered an anatomic risk factor in the evaluation of coronary artery disease patients [23]. Also Takamura et al. demon‐ strated that, in patients with culprit lesions in the LAD segment proximal to MB, the length and thickness of MBs were significantly greater, and the distance from the orifice of the left coronary artery to the entrance of MB was significantly shorter than those in patients with no culprit lesion in the LAD segment proximal to MB [24]. These results are similar to those of the autopsy studies that demonstrated that the anatomical proper‐ ties of MB muscle were closely associated with a shift of coronary intimal lesion more proximally, an effect that may increase the risk of myocardial infarction [14].

Since the introduction of CCT in the last decade of last century many papers have been pub‐ lished showing the feasibility of CCT in evaluating patients with MB (Fig 3).

In particular many papers compared CCT to ICA. Recently a significant correlation was found between the within-MB diameters obtained with CCT and ICA during the systolic (1.3±0.3 mm vs. 1.2±0.5 mm: r= 0.394, P=0.028) and diastolic phases (1.4±0.4 mm vs. 1.6±0.6 mm: r= 0.524, P=0.001) [25]. However CCT is superior to ICA in diagnosing the presence of MB. Kim et al. found that while dynamic compression was present in 13.3% of the subjects (40/300) who underwent ICA, CCT revealed that 58% of the subjects (178/300) had myocar‐ dial bridging (partial encasement in 57 and full encasement in 117 subjects) [26]. Leschka et al. found that MB was revealed with CCT and ICA respectively in 26 and 12 of the 100 sub‐ jects studied [27].

When comparing CCT with IVUS, the sensitivity of detecting MB by CCT was found to be 93%, specificity 100%, positive predictive value and negative predictive value 100% and 91% respectively. A significant correlation was also observed between lumen diameters derived from CCT and IVUS (systolic phase: *r*=0.87, *P*<0.05; diastolic phase: *r*=0.92, *P*<0.05). Although minimal and maximal diameters of MB during systolic and diastolic phases derived from CCT were significantly smaller than those from IVUS (2.4±0.4 mm vs 2.6±0.5 mm, *P*<0.05) and (2.9±0.3 mm vs 3.3±0.3 mm, *P*<0.05) the narrowing percent derived from the two meth‐ ods was similar ((21.4±10.9% vs 17.4±7.6%, *P*>0.05). The Authors however note that CCT of‐ fers a safer, more comfortable and cost-effective examinations (in China the prices of IVUS and MSCT are 1500 US \$ and 95 US \$ respectively [28].

Usually in the CCT studies where MB is evaluated the coronary arteries are classified ac‐ cording to the American Heart Association classification system: right coronary artery: 1, proximal; 2, mid; 3, distal; 4a, posterior descending; 4b, posterolateral; left main coronary ar‐ tery: 5, LAD; 6, proximal; 7, mid; 8, distal; 9, first diagonal; 10, second diagonal; circumflex coronary artery: 11, proximal; 12, first marginal; 13, mid; 14, second marginal; 15, distal.

**Figure 2.** Myocardial bridging at 64 multi-detector computed tomography. Volume rendering image of the heart (A). 3D image of the coronary tree (B). Multiplanar reconstructed image of the left descending coronary artery. The middle segment of the vessel is tunnelled by overlying myocardium (C). It is clearly evident the step up phenomenon.

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

The high temporal resolution obtained with the most recent scanners or dual source scanners enable the visualization of the vessel lumen during most of the cardiac cycle, and thus permit the observation of the milking effect in the 4-dimensional reconstruction [22]. Cardiac computed tomography helped to better evaluate the anatomical properties of MB. Several Authors using CCT confirmed what was already know from necropsies, CCA and IVUS studies that the tunnelled segments are spared from atherosclerotic changes [23]. However Zeina et al. found that the thickness and length of the bridge cor‐ related with the presence of stenosis in the LAD proximal to the MB suggesting that the MB may predispose to the development of atherosclerosis in the coronary artery seg‐ ment proximal to the bridge and that MB should be considered an anatomic risk factor in the evaluation of coronary artery disease patients [23]. Also Takamura et al. demon‐

All studied performed the evaluation of MB mainly in the diastolic phase while a few stud‐ ies performed it in the systolic phase due to technical problems related to the increased mo‐ tion of the heart due to myocardial contraction in the systolic phase and to the limited temporal resolution of routinely available scanners [5, 22, 27, 29].

In the literature there is not a consensus in the definition of MB. Usually MB is defined as the existence of tissues exhibiting soft tissue density covering a part of the vessel, which had the same contrast enhancement as myocardial tissue [24].

viation of the vessel into the myocardium. In the deep type the vessel dips as a U-shaped curve into the myocardium [30]. Another classification divided MB in complete or incom‐ plete. The complete types of MB were those where it was possible to demonstrate the con‐

Another definition of superficial and deep MB was given by Jodecy et al. These Authors de‐ fined the MB as "deep" when the vessel was surrounded entirely by myocardium in depth of a more than 2 mm, whereas it was defined as "superficial" when the vessel appeared ei‐ ther not entirely surrounded (but with a minimum of 75% of the circumference), or entirely

> **% of MB in LAD**

Kawaka et al. [34] 16 slices 148 (26) 91 20±8.6 (10.5-50.2) 1.8±0.7 (1.1-3.7) Kantraci et al. [35] 16 slices 626 (3.5) 100 17 (6-22) 2.5 (1.2-3.3) Ko et al. [36] 16 slices 401 (5.7) 91 15.7 (5-27) 3.2 (1.0-7.0) Canyigit et al. [31] 16 slices 280 (38.5) 81.6 15.8 (4-50.9) 1.7 (1-6.4) Chen et al. [37] 16 slices 276 (8.7) 76.7 24.6±11.8 (5.2-50.6) 3.7±1.9 (0.5-9.1) Takamura et al. [24] 16 slices 228 (18.8) 100 20.0 (2.4-54.7) 1.7 (0.4-9.7) Zeina et al. [23] 16/64 slices 300 (15.8) 87.5 19.5±5.7 (8-30) 2±0.6 (1-3.1) Konen et al. [5] 40/64 slices 118 (30.5) 72 23±9 (13-50) (0.1-6.2) Lubarsky et al. [38] 64 slices 245 (44) 100 28.7±16.5 NA Johansen et al. [32] 64 slices 152 (32) 69.4 NA NA Kim PJ et al. [26] 64 slices 300 (58) 100 29.1±15.5 1.4±1.0 Leschka et al. [27] 64 slices 100 (26) 98 24.3±10 (8-53) 2.6±0.8 (1.4-4.8) Koşar et al. [39] 64 slices 700 (37) NA NA NA Kim SY et al. [30] 64 slices 607 (6.4) 84.2 16.3±6.3 (6.9-30) 1.8±0.8 (0.5-3.9) Jeong et al. [25] 64 slices 120 (25) 47.4 20.5±6.8 (8-35) 2.3±1.2 (0.8-6.6) Jodocy et al. [29] 64 slices 221 (23) 91 14.9±6.5 (2.5-43.8) 2.6±1.6 (0.5-9.4) La Grutta et al. [40] 64 slices 254 (29) 93 NA NA Wrianta et al. [33] 64 slices 934 (16.3) 94 NA NA

Lu et al. [22] DSCT 53 (39.6) 57 23.2±9.5 3.5±1.0 Hwang et al. [42] DSCT 1275 (42) 100 21.0±11.6 3.0±1.4

MDCT: multidetector computed tomography; pts: patients; MB: myocardial bridges; LAD left anterior descending cor‐

**length mean (range)**

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425

506 (10.4) 96 23.4 (4.1-53.9) 2.6 (1-7.8)

**depth mean (range)**

tinuity of myocardium over the tunnelled segment [31].

surrounded by myocardium in less than 2 mm depth [29].

**number of pts (% of MB)**

**MDCT**

**Author [reference] type of**

Jacobs et al. [41] 64 slices-

DSCT

onary artery; NA : non available; DSCT: dual source computer tomography.

**Table 1.** Cardiac computed tomography papers where myocardial bridges were evaluated

**Figure 3.** Myocardial bridging at 64 multi-detector computed tomography. Volume rendering image of the heart (A). 3D image of the coronary tree (B). Multiplanar reconstructed image of intermediate branch which is tunnelled by overlying myocardium (C). While in D the vessel has an epicardial course in E and especially F the vessel is completely encompassed by the myocardium.

The length of MB is usually defined as the distance of the covering myocardial tissue from the entrance to the exit of the tunnelled artery, which is measured by curved MPR images (i.e. parallel to the course of the vessel) [24].

There are several definitions to describe the depth of MB. In the majority of the papers the depth is defined as the thickness of the deepest part from the surface of the covering myo‐ cardial tissue to the tunnelled artery, which is measured in an axial image (i.e. perpendicular to the course of the vessel) (Fig. 3) [24]. Myocardial bridges were divided into two types: su‐ perficial and deep. In the superficial type a myocardial band overlies the vessel with no de‐ viation of the vessel into the myocardium. In the deep type the vessel dips as a U-shaped curve into the myocardium [30]. Another classification divided MB in complete or incom‐ plete. The complete types of MB were those where it was possible to demonstrate the con‐ tinuity of myocardium over the tunnelled segment [31].

Another definition of superficial and deep MB was given by Jodecy et al. These Authors de‐ fined the MB as "deep" when the vessel was surrounded entirely by myocardium in depth of a more than 2 mm, whereas it was defined as "superficial" when the vessel appeared ei‐ ther not entirely surrounded (but with a minimum of 75% of the circumference), or entirely surrounded by myocardium in less than 2 mm depth [29].


MDCT: multidetector computed tomography; pts: patients; MB: myocardial bridges; LAD left anterior descending cor‐ onary artery; NA : non available; DSCT: dual source computer tomography.

**Table 1.** Cardiac computed tomography papers where myocardial bridges were evaluated

**Figure 3.** Myocardial bridging at 64 multi-detector computed tomography. Volume rendering image of the heart (A). 3D image of the coronary tree (B). Multiplanar reconstructed image of intermediate branch which is tunnelled by overlying myocardium (C). While in D the vessel has an epicardial course in E and especially F the vessel is completely

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

The length of MB is usually defined as the distance of the covering myocardial tissue from the entrance to the exit of the tunnelled artery, which is measured by curved MPR images

There are several definitions to describe the depth of MB. In the majority of the papers the depth is defined as the thickness of the deepest part from the surface of the covering myo‐ cardial tissue to the tunnelled artery, which is measured in an axial image (i.e. perpendicular to the course of the vessel) (Fig. 3) [24]. Myocardial bridges were divided into two types: su‐ perficial and deep. In the superficial type a myocardial band overlies the vessel with no de‐

encompassed by the myocardium.

(i.e. parallel to the course of the vessel) [24].

Arterial segments located in a deep gorge but covered only by a thin layer of muscle or fi‐ brous-fatty tissue were also considered by some Authors as MB because they also may be compressed during systole by the surrounding muscle [5]. According to other Authors the presence of myocardial bridging was defined as myocardium completely encompassing a section of coronary artery in at least one transverse image [32]. For Wirianta et al. MB was defined when at least half of the coronary artery was imbedded within the myocardium with a normal epicardial course of the proximal and distal portion [33].

(Italy), for their collaboration, Dr. Alessandro Mazzarisi for the technical support and Dr.

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427

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[2] Maron BJ, MD, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in

[3] Angelini P, Velasco JA, Flamm S. Coronary anomalies: incidence, pathophysiology,

[4] Bourassa MG, Butnaru A, Lespérance J, Tardif JC. Symptomatic myocardial bridges: overview of ischemic mechanisms and current diagnostic and treatment strategies. J

[5] Konen E, Goitein O, Sternik L, Eshet Y, Shemseh J, Di Segni E. The prevalence and anatomical patterns of intramuscular coronary arteries. J Am Coll Cardiol 2007; 49:

[6] Saidi H, Ongeti WK, Ogeng.o J. Morphology of human myocardial bridges and asso‐ ciation with coronary artery disease. African Health Sciences 2010; 10: 242-247

[7] Möhlenkamp S, Hort W, Ge J, Erbel R. Update on myocardial bridging. Circulation

[8] Ferreira Jr AG, Trotter SE, Konig Jr B, Decourt LV, Fox K, Olsen EGJ. Myocardial

[9] Loukas M, Von Kriegenbergh K, Gilkes M, Tubbs RS, Walker C, Malaiyand D, An‐ derson RH. Myocardial bridges: a review. Clinical Anatomy 2011; 24: 675-683

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young competitive athletes. Circulation 2009; 119: 1085-1092

and clinical relevance. Circulation 2002; 105: 2449-2454

Haifa Alsakkaf for the assistance with the manuscript.

Mohamed Bamoshmoosh1,2\* and Paolo Marraccini3

1 Fanfani Clinical Research Institute, Florence, Italy

3 CNR Institute of Clinical Physiology, Pisa, Italy

Lancet 2006; 367: 1747-57

Am Coll Cardiol 2003; 41: 351-9

2 University of Science and Technology, Sana'a, Yemen

\*Address all correspondence to: bamoshmoosh@hotmail.it

**Author details**

**References**

587-93

2002; 106: 2616-2622

The prevalence of MB according to CCT studies increased progressively with the introduc‐ tion of more modern scanners approaching values found in autopsy studies, which should be considered the ultimate gold standard method, rather than the results obtained in the ICA studies. This wide variation may be related to different reasons: differences between temporal and spatial resolution parameters of the scanners; different post processing techni‐ ques; different inclusion or exclusion of borderline cases; retrospective observation of arter‐ ies with the specific purpose to analyze MB; different population selection (i.e presence of symptomatic or asymptomatic patients, patients with hypertrophic cardiomyopathy); prob‐ ably also to ethnicity (Tab 1).

#### **8. Conclusion**

Myocardial bridges are normal variants of intrinsic coronary arterial anatomy with an intra‐ mural course that till 20 years ago were visualized during necropsies, surgery or conven‐ tional coronary angiography. Invasive coronary angiography alone or with the use of important tools such as intravascular coronary ultrasound, intracoronary Doppler-ultra‐ sound and intracoronary pressure-wire, is still considered the gold standard technique to study in vivo MBs. The introduction in the cardiac arena of CCT, that with very good accu‐ racy investigates coronary arteries, gave us a complementary and sometimes an alternative test to ICA and more interestingly provides this information non-invasively. In particular settings such as that of a coronary artery with MB, CCT seems to be even superior to ICA and to have results similar to autopsy which is the real gold standard technique to evaluate MBs. However to better understand the real usefulness of CCT in this particular field, fur‐ ther multi-centric interdisciplinary studies must be performed, to link the morphological with the clinical information especially in those patients who have MB and normal coronary arteries or coronary arteries with no culprit atherosclerotic lesions, but who may be at risk for cardiovascular morbidity or mortality.

#### **Acknowledgements**

We gratefully thank the radiology team of Fanfani Clinical Research Institute (Florence, Ita‐ ly) and in particular Dr. Fabio Fanfani, the Cardiopulmonary Radiological Research group of CNR Institute of Clinical Physiology of Pisa (Italy) and the Fondazione Monasterio of Pisa (Italy), for their collaboration, Dr. Alessandro Mazzarisi for the technical support and Dr. Haifa Alsakkaf for the assistance with the manuscript.

## **Author details**

Arterial segments located in a deep gorge but covered only by a thin layer of muscle or fi‐ brous-fatty tissue were also considered by some Authors as MB because they also may be compressed during systole by the surrounding muscle [5]. According to other Authors the presence of myocardial bridging was defined as myocardium completely encompassing a section of coronary artery in at least one transverse image [32]. For Wirianta et al. MB was defined when at least half of the coronary artery was imbedded within the myocardium

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

The prevalence of MB according to CCT studies increased progressively with the introduc‐ tion of more modern scanners approaching values found in autopsy studies, which should be considered the ultimate gold standard method, rather than the results obtained in the ICA studies. This wide variation may be related to different reasons: differences between temporal and spatial resolution parameters of the scanners; different post processing techni‐ ques; different inclusion or exclusion of borderline cases; retrospective observation of arter‐ ies with the specific purpose to analyze MB; different population selection (i.e presence of symptomatic or asymptomatic patients, patients with hypertrophic cardiomyopathy); prob‐

Myocardial bridges are normal variants of intrinsic coronary arterial anatomy with an intra‐ mural course that till 20 years ago were visualized during necropsies, surgery or conven‐ tional coronary angiography. Invasive coronary angiography alone or with the use of important tools such as intravascular coronary ultrasound, intracoronary Doppler-ultra‐ sound and intracoronary pressure-wire, is still considered the gold standard technique to study in vivo MBs. The introduction in the cardiac arena of CCT, that with very good accu‐ racy investigates coronary arteries, gave us a complementary and sometimes an alternative test to ICA and more interestingly provides this information non-invasively. In particular settings such as that of a coronary artery with MB, CCT seems to be even superior to ICA and to have results similar to autopsy which is the real gold standard technique to evaluate MBs. However to better understand the real usefulness of CCT in this particular field, fur‐ ther multi-centric interdisciplinary studies must be performed, to link the morphological with the clinical information especially in those patients who have MB and normal coronary arteries or coronary arteries with no culprit atherosclerotic lesions, but who may be at risk

We gratefully thank the radiology team of Fanfani Clinical Research Institute (Florence, Ita‐ ly) and in particular Dr. Fabio Fanfani, the Cardiopulmonary Radiological Research group of CNR Institute of Clinical Physiology of Pisa (Italy) and the Fondazione Monasterio of Pisa

with a normal epicardial course of the proximal and distal portion [33].

ably also to ethnicity (Tab 1).

for cardiovascular morbidity or mortality.

**Acknowledgements**

**8. Conclusion**

Mohamed Bamoshmoosh1,2\* and Paolo Marraccini3

\*Address all correspondence to: bamoshmoosh@hotmail.it

1 Fanfani Clinical Research Institute, Florence, Italy

2 University of Science and Technology, Sana'a, Yemen

3 CNR Institute of Clinical Physiology, Pisa, Italy

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[18] Bamoshmoosh M. When cardiac computed tomography becomes the gold standard technique to evaluate coronary artery disease patients. In: Baskot B (ed.) Coronary angiography. Advance in non invasive imaging approach for evaluation coronary ar‐

[19] Mark DB, Berman DS, Budoff MJ, Carr JJ, Gerber TC, Hecht HS, Hlatky MA, Hodg‐ son JM, Lauer MS, Miller JM, Morin RL, Mukherjee D, Poon M. Rubin GD, Schwartz RS. ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT 2010 Expert Consensus Document on Coronary Computed Tomographic Angiography. J Am Coll Cardiol 2010; 55:

[20] Taylor AJ, Cerqueira M, Hodgson JM, Mark D, Min J, O'Gara P, Rubin GD. ACCF/ SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for

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[32] Johansen C, Kirsch J, Araoz P, Williamson E. Detection of myocardial bridging by 64 row computed tomography angiography of the coronaries. J Comput Assist Tomogr 2008; 32: 448-451

**Chapter 20**

**Percutaneous. Recanalization of**

**Looking Back and Moving Forward**

Simona Giubilato, Salvatore Davide Tomasello and

Additional information is available at the end of the chapter

Alfredo Ruggero Galassi

http://dx.doi.org/10.5772/54079

in case of future acute events [7-9].

and reduced exposure to radiation.

**1. Introduction**

**Chronic Total Occlusion (CTO) Coronary Arteries:**

Chronic total occlusion (CTO) of coronary arteries is one of the most challenging PCI, usual‐ ly defined as more than three-month-old obstruction of a native coronary artery. This coro‐ nary lesion subset is a frequent finding in patients with coronary artery disease (CAD) as CTOs have been reported in approximately one-third of patients undergoing diagnostic cor‐ onary angiography. However only 7-15% of CTOs were treated with percutaneous coronary intervention (PCI) [1] (Figure 1). Perhaps for the fact that procedural success is hampered by the difficulties associated with crossing and/or dilating the occluded segment with guide‐ wires and recanalization devices and by a high incidence of restenosis and reocclusion.

Despite these obstacles, several studies have documented that successful PCI of CTOs leads to an improvement in anginal status, normalization of functional tests, improvement of left ventricular function and avoidance of coronary artery bypass graft surgery (CABG) [2-6]. Patients with untreated CTOs face a threefold increase in cardiac mortality or complications

Historically, a procedural success rate of 60-70% was achieved using anterograde ap‐ proach [6]. Nowadays, specifically trained operators are able to improve the rate of CTO recanalization thanks to several new techniques and dedicated device developments. In particular, the retrograde CTO PCI approach, that was first mastered by Japanese opera‐ tors, has evolved rapidly, resulting in higher success rates, shortened procedural time

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

© 2013 Giubilato 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,


## **Percutaneous. Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward**

Simona Giubilato, Salvatore Davide Tomasello and Alfredo Ruggero Galassi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54079

## **1. Introduction**

[32] Johansen C, Kirsch J, Araoz P, Williamson E. Detection of myocardial bridging by 64 row computed tomography angiography of the coronaries. J Comput Assist Tomogr

[33] Wirianta J, Mouden M, Ottervanger JP, Timmer JR, Juwana YB, de Boer MJ, Suryap‐ ranata H. Prevalence and predictors of bridging of coronary arteries in a large Indo‐ nesian population, as detected by 64-slice computed tomography scan. Neth Heart J

[34] Kawawaa Y, Ishikawa Y, Gomia T, Nagamotoa M, Terada H, Ishii T, Kohda E. Detec‐ tion of myocardial bridge and evaluation of its anatomical properties by coronary multislice spiral computed tomography. European Journal of Radiology 2007; 61:

[35] Kantarci M, Duran C, Durur I, Alper F, Onbas O, Gulbaran M, Okur A. Detection of myocardial bridging with ECG-Gated MDCT and multiplanar reconstruction. Amer‐

[36] Ko S-M, Choi J-S, Nam C-W, Hur S-H. Incidence and clinical significance of myocar‐ dial bridging with ECG-gated 16-row MDCT coronary angiography. Int J Cardiovasc

[37] Chen Y-D, Wu M-H, Sheu M-H, Chang Y-C. Myocardial bridging in Taiwan: depic‐ tion by multidetector computed tomography coronary angiography. J Formos Med

[38] Lubarsky L, Gupta MP, Hecht HS. Evaluation of myocardial bridging of the left ante‐ rior descending coronary artery by 64-Slice multidetector computed tomographic an‐

[39] Koşar P, Ergun E, Öztürk C, Koşar U. Anatomic variations and anomalies of the cor‐ onary arteries: 64-slice CT angiographic appearance. Diagn Interv Radiol 2009; 15:

[40] La Grutta L, Runza G, Galia M, Maffei E, Lo Re G, Grassedonio E, Tedeschi C, Cade‐ martiri F, Midiri M. Atherosclerotic pattern of coronary myocardial bridging as‐ sessed with CT coronary angiography. Int J Cardiovasc Imaging 2012; 28: 405-414

[41] Jacobs JE, Bod J, Kim DC, Hecht EM, Srichai MB. Myocardial bridging: evaluation us‐ ing single and dual-source multidetector cardiac computed tomographic angiogra‐

[42] Hwang JH, Ko SM, Roh HG, Song MG, Shin JK, Chee HK, Kim JS. Myocardial bridg‐ ing of the left anterior descending coronary artery: depiction rate and morphologic features by dual-source CT coronary angiography. Korean J Radiol 2010; 11: 514-521

Published online 06 June 2012. DOI 10.1007/s12471-012-0296-4

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

ican Journal of Radiology 2006; 186: S391-S394

giography. Am J Cardiol 2007; 100: 1081-1082

phy. J Comput Assist Tomogr 2008; 32: 242-246

Imaging 2008; 24: 445-452

Assoc 2009; 108: 469-474

2008; 32: 448-451

130-138

275–283

Chronic total occlusion (CTO) of coronary arteries is one of the most challenging PCI, usual‐ ly defined as more than three-month-old obstruction of a native coronary artery. This coro‐ nary lesion subset is a frequent finding in patients with coronary artery disease (CAD) as CTOs have been reported in approximately one-third of patients undergoing diagnostic cor‐ onary angiography. However only 7-15% of CTOs were treated with percutaneous coronary intervention (PCI) [1] (Figure 1). Perhaps for the fact that procedural success is hampered by the difficulties associated with crossing and/or dilating the occluded segment with guide‐ wires and recanalization devices and by a high incidence of restenosis and reocclusion.

Despite these obstacles, several studies have documented that successful PCI of CTOs leads to an improvement in anginal status, normalization of functional tests, improvement of left ventricular function and avoidance of coronary artery bypass graft surgery (CABG) [2-6]. Patients with untreated CTOs face a threefold increase in cardiac mortality or complications in case of future acute events [7-9].

Historically, a procedural success rate of 60-70% was achieved using anterograde ap‐ proach [6]. Nowadays, specifically trained operators are able to improve the rate of CTO recanalization thanks to several new techniques and dedicated device developments. In particular, the retrograde CTO PCI approach, that was first mastered by Japanese opera‐ tors, has evolved rapidly, resulting in higher success rates, shortened procedural time and reduced exposure to radiation.

© 2013 Giubilato 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.

It should keep in mind that reopening of a CTO needs to be carefully considered in the presence of symptoms or objective evidence of viability/ischaemia in the territory of the occluded artery.

**2. CTO anatomy and definitions**

classified as the two following phenomena:

progressive occlusion of a long standing concentric stenosis.

generally apart from the maximal narrowing area.

of plaque and sometimes several layers of additional thrombi).

A deeper understanding of CTO histopathology might offer insights into the development of new techniques and procedural strategies. The occluded part of the lumen in CTOs con‐ sists of two types of tissue: atheromatous plaque and old thrombus (Figure 2). The respec‐ tive amount of these items are largely dependent on CTO formation which may be grossly

Percutaneous Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward

http://dx.doi.org/10.5772/54079

433

**1.** The late organization and development of an acute occlusion due to a plaque rupture,

**2.** The progressive occlusion of a long term and high-degree stenosis (with a large amount

**Figure 2.** The two mechanisms of CTO formation: A) late evolution of an acute occlusion of an eccentric stenosis B)

The histopathology of CTOs was comprehensively described by Srivatsa and coll. in 1997 [10]. These lesions are characterized by a mix of luminal plaque, thrombin, fibrin, inflamma‐ tory cells and neovascular channels (Figure 3). The occlusive thrombus is mainly composed of collagen-rich extracellular matrix, intra and extracellular lipids, smooth muscle cells and mixed components, including a small quantity of cholesterol, dense collagen and calcium deposits. The core composition correlates with the CTO age. Older occlusions have higher concentration of fibrocalcific material (defined as "hard plaques"), while CTOs visible for less than one year have more cholesterol clefts and foam cells among less fibrous materials (defined as "soft plaque"). Typically CTOs may be classified as soft, hard or a mixture of both. Hard plaques are more prevalent with an increasing CTO age (> 1 year old) [11].

The aim of this chapter will be to provide a systematic overview of the current state-of-the art in percutaneous recanalization of CTO, to enhance the understanding of this complex procedure and, consequently, promote safe and effective PCI for patients who present with this lesion subset. Specifically, after a brief introduction about CTO anatomy and defini‐ tions, the chapter will be divided into five paragraphs that address the most important clini‐ cal and technical aspects of CTO PCI. In the first paragraph the complex clinical CTO decision-making process will be described. This crucial step consists in the evaluation of clinical indication, patient selection and revascularization strategies. In the second para‐ graph, specific tools for CTO recanalization will be illustrated focusing on improvements in guidewire and dedicate device technology, responsible for improved procedural success in PCI of CTO. A further paragraph will be dedicated to the stent choice for the treatment of CTO. In fact, there is overwhelming evidence in the literature that drug eluting stent (DES) rather than bare metal stent (BMS) reduce significantly the restenosis and reocclusion rates after recanalization of CTOs. The fourth paragraph, will deal with the description of all tech‐ niques to cross CTO by anterograde and retrograde techniques. In this paragraph, the atten‐ tion will be focused on common pitfalls and difficulties and related tips and tricks. Finally, the last paragraph will be focused on the strategies to prevent and treat the possible proce‐ dural complications including complications related to vascular access or to procedure such as coronary dissection, perforation or rupture and coronary thrombosis.

**Figure 1.** Diagnostic catheterization results stratified by treatment strategy. Adapted from Christofferson et al. [1]

## **2. CTO anatomy and definitions**

It should keep in mind that reopening of a CTO needs to be carefully considered in the presence of symptoms or objective evidence of viability/ischaemia in the territory of the

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

The aim of this chapter will be to provide a systematic overview of the current state-of-the art in percutaneous recanalization of CTO, to enhance the understanding of this complex procedure and, consequently, promote safe and effective PCI for patients who present with this lesion subset. Specifically, after a brief introduction about CTO anatomy and defini‐ tions, the chapter will be divided into five paragraphs that address the most important clini‐ cal and technical aspects of CTO PCI. In the first paragraph the complex clinical CTO decision-making process will be described. This crucial step consists in the evaluation of clinical indication, patient selection and revascularization strategies. In the second para‐ graph, specific tools for CTO recanalization will be illustrated focusing on improvements in guidewire and dedicate device technology, responsible for improved procedural success in PCI of CTO. A further paragraph will be dedicated to the stent choice for the treatment of CTO. In fact, there is overwhelming evidence in the literature that drug eluting stent (DES) rather than bare metal stent (BMS) reduce significantly the restenosis and reocclusion rates after recanalization of CTOs. The fourth paragraph, will deal with the description of all tech‐ niques to cross CTO by anterograde and retrograde techniques. In this paragraph, the atten‐ tion will be focused on common pitfalls and difficulties and related tips and tricks. Finally, the last paragraph will be focused on the strategies to prevent and treat the possible proce‐ dural complications including complications related to vascular access or to procedure such

as coronary dissection, perforation or rupture and coronary thrombosis.

**Figure 1.** Diagnostic catheterization results stratified by treatment strategy. Adapted from Christofferson et al. [1]

occluded artery.

A deeper understanding of CTO histopathology might offer insights into the development of new techniques and procedural strategies. The occluded part of the lumen in CTOs con‐ sists of two types of tissue: atheromatous plaque and old thrombus (Figure 2). The respec‐ tive amount of these items are largely dependent on CTO formation which may be grossly classified as the two following phenomena:


**Figure 2.** The two mechanisms of CTO formation: A) late evolution of an acute occlusion of an eccentric stenosis B) progressive occlusion of a long standing concentric stenosis.

The histopathology of CTOs was comprehensively described by Srivatsa and coll. in 1997 [10]. These lesions are characterized by a mix of luminal plaque, thrombin, fibrin, inflamma‐ tory cells and neovascular channels (Figure 3). The occlusive thrombus is mainly composed of collagen-rich extracellular matrix, intra and extracellular lipids, smooth muscle cells and mixed components, including a small quantity of cholesterol, dense collagen and calcium deposits. The core composition correlates with the CTO age. Older occlusions have higher concentration of fibrocalcific material (defined as "hard plaques"), while CTOs visible for less than one year have more cholesterol clefts and foam cells among less fibrous materials (defined as "soft plaque"). Typically CTOs may be classified as soft, hard or a mixture of both. Hard plaques are more prevalent with an increasing CTO age (> 1 year old) [11].

**Figure 4.** CTO microvessels. This image shows a healed total occlusion (arrowheads) with vascular channels (asterisks)

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435

The temporal criterion used to define a CTO has varied widely through the litterature, typically ranging from > 2 weeks [16] to > 3 months [17]. Furthermore, any definition of CTO must include different elements such as the degree of lumen narrowing, consider‐ ing if any antegrade blood flow is present. According to the consesus documents from the EuroCTO Club, lesions can be classified as CTOs, when there is TIMI 0 flow within the occluded segment and angiographic or clinical evidence or high likelihood of an oc‐

CTOs are characterized by significant atherosclerotic vessel narrowing with a lumen compromision that results in either complete interruption of antegrade blood flow as as‐ sessed by coronary TIMI flow (grade 0), also known as "true" total occlusion, or with minimal contrast penetration through the lesion without distal vessel opacification (TIMI grade 1 flow), frequently referred to as "functional" total occlusions. However, the iden‐ tification of TIMI 0 flow is not as straightforward as in recent post-MI occlusions, for which the TIMI classification was originally developed because antegrade contrast filling of the segment beyond the occlusion does not preclude TIMI 0 flow within the occluded segment. Indeed, particular conditions such as the presence of ipsilateral bridging collat‐ erals may give antegrade flow and the false impression of a functional incomplete occlu‐ sion but they are true CTO. Their presence should be differentiated from TIMI 0 flow within the occluded segment by careful assessment in different angiographic planes. Moreover, the presence of intraluminal channels certainly plays a role in crossing the oc‐ clusion; antegrade contrast filling of the segment beyond the occlusion flow, in the ab‐ sence of ipsilateral bridging collaterals and even when the occluded vessel segment

surrounded by a rich collagen matrix (yellow). Adapted from Hoye A [15].

clusion duration > 3 months [18].

**Figure 3.** CTO plaque components.

The intraluminal process of plaque and thrombus organization is often followed by the so called "negative remodeling". This event usually leads to an artery vessel shrinkage, which is mainly observed in CTOs older than 3 months. The negative remodelling process is con‐ nected to the replacement of soft plaque tissue with fibrous one, mainly in the middle sec‐ tion of the occlusion [12]. Another important CTO feature is the extensive process of "neovascularization" which increase with occlusion age. In CTOs that are less than one year old the new capillary formation is greater in the adventitia. In CTOs that are more than one year old there is a rich neovasculature network that often traverses the vessel wall (bridging collaterals) [13]. Neovascular process may usually lead to the formation of relatively large capillaries (from 100 to 500 μm) that are defined as "microchannels" (Figure 4). These ves‐ sels can frequently be found through the CTO's body and can partially recanalize the distal lumen [14]. Guidewires may use microchannels as a passage to reach the distal vessel, hence they may have an important therapeutic value. Microchannels might also communicate with vasa vasorum and facilitate an extra-luminal pathways of collaterals o the distal part of the occluded segment, giving the typical aspect of "caput medusae" that is usually a sign of an old and difficult lesion to cross. Moreover, CTOs usually present a higher concentration of fibrous tissue at the proximal and distal parts of the lesion. These areas create a "fibrous cap" which is the hardest part of the plaque that surrounds a softer core of organised throm‐ bus and lipids. Therefore, there are four components of CTO to take into consideration [15]: proximal cap, calcifications, microvessels and distal cap.

Percutaneous Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward http://dx.doi.org/10.5772/54079 435

**Figure 4.** CTO microvessels. This image shows a healed total occlusion (arrowheads) with vascular channels (asterisks) surrounded by a rich collagen matrix (yellow). Adapted from Hoye A [15].

The temporal criterion used to define a CTO has varied widely through the litterature, typically ranging from > 2 weeks [16] to > 3 months [17]. Furthermore, any definition of CTO must include different elements such as the degree of lumen narrowing, consider‐ ing if any antegrade blood flow is present. According to the consesus documents from the EuroCTO Club, lesions can be classified as CTOs, when there is TIMI 0 flow within the occluded segment and angiographic or clinical evidence or high likelihood of an oc‐ clusion duration > 3 months [18].

**Figure 3.** CTO plaque components.

proximal cap, calcifications, microvessels and distal cap.

The intraluminal process of plaque and thrombus organization is often followed by the so called "negative remodeling". This event usually leads to an artery vessel shrinkage, which is mainly observed in CTOs older than 3 months. The negative remodelling process is con‐ nected to the replacement of soft plaque tissue with fibrous one, mainly in the middle sec‐ tion of the occlusion [12]. Another important CTO feature is the extensive process of "neovascularization" which increase with occlusion age. In CTOs that are less than one year old the new capillary formation is greater in the adventitia. In CTOs that are more than one year old there is a rich neovasculature network that often traverses the vessel wall (bridging collaterals) [13]. Neovascular process may usually lead to the formation of relatively large capillaries (from 100 to 500 μm) that are defined as "microchannels" (Figure 4). These ves‐ sels can frequently be found through the CTO's body and can partially recanalize the distal lumen [14]. Guidewires may use microchannels as a passage to reach the distal vessel, hence they may have an important therapeutic value. Microchannels might also communicate with vasa vasorum and facilitate an extra-luminal pathways of collaterals o the distal part of the occluded segment, giving the typical aspect of "caput medusae" that is usually a sign of an old and difficult lesion to cross. Moreover, CTOs usually present a higher concentration of fibrous tissue at the proximal and distal parts of the lesion. These areas create a "fibrous cap" which is the hardest part of the plaque that surrounds a softer core of organised throm‐ bus and lipids. Therefore, there are four components of CTO to take into consideration [15]:

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

CTOs are characterized by significant atherosclerotic vessel narrowing with a lumen compromision that results in either complete interruption of antegrade blood flow as as‐ sessed by coronary TIMI flow (grade 0), also known as "true" total occlusion, or with minimal contrast penetration through the lesion without distal vessel opacification (TIMI grade 1 flow), frequently referred to as "functional" total occlusions. However, the iden‐ tification of TIMI 0 flow is not as straightforward as in recent post-MI occlusions, for which the TIMI classification was originally developed because antegrade contrast filling of the segment beyond the occlusion does not preclude TIMI 0 flow within the occluded segment. Indeed, particular conditions such as the presence of ipsilateral bridging collat‐ erals may give antegrade flow and the false impression of a functional incomplete occlu‐ sion but they are true CTO. Their presence should be differentiated from TIMI 0 flow within the occluded segment by careful assessment in different angiographic planes. Moreover, the presence of intraluminal channels certainly plays a role in crossing the oc‐ clusion; antegrade contrast filling of the segment beyond the occlusion flow, in the ab‐ sence of ipsilateral bridging collaterals and even when the occluded vessel segment shows no intraluminal contrast filling, indicates a functional and not a true CTO. Only meticulous filming and a vigorous contrast injection with a well engaged catheter allow us to conclude that TIMI flow is 0 within the occluded segment and the lesion should then be classified as a CTO [19]. In absence of serial angiograms, the duration of CTO is difficult to establish with certainty and it might be estimated from available clinical in‐ formation related to the timing of the event that caused the occlusion: acute MI or sud‐ den change in angina pattern with ECG changes consistent with the location of the occlusion.

peutic strategy might not be clinically appropriate but the decision to treat a CTO in an asymptomatic patient should be driven by a non-invasive functional imaging test, in order to clarify the amount of myocardial viability and severity/extension of myocardial ischemia. On the other hand symptomatic patients represent the greatest challenge for the clinical de‐

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**a.** When the CTO is the only culprit lesion in the coronary tree, and presence of viability/ ischemia by non invasive functional test has been shown, PCI is highly recommended especially if likelihood of success has been estimated >60%. Moreover, if PCI is unsuc‐ cessful, re-attempt might be performed 2-3 months later after first failure. Conversely, coronary artery bypass graft might be performed to guarantee a complete revasculari‐ zation, especially in case of a large myocardial ischemia or in case of refractory symp‐ toms. Underestimating the CTO clinical impact in a single vessel disease patient might be led to "catastrophic consequences". Indeed, although the CTO might be supplied by collateral circulation without ischemia at rest, acute donor vessel occlusion might cause

**b.** It is not rare to see patients with a CTO angiographically documented few years before and without other coronary vessel diseases, which start to be symptomatic for effort an‐ gina only many years after the angiographic documentation is shown. In these cases, symptoms and myocardial ischemia could be related to the disease progression in ves‐ sels different from CTO, progression of disease in the donor artery, or to a reduction of blood supply from collateral circulation due to coronary collateral vasospasm [20]. **c.** In case of multivessel disease, the presence of a CTO should not be a sufficient reason to deny percutanoeus revascularization in the absence of significant left main disease and when the other lesions are suitable for PCI. Indeed, if the decision to perform a PCI is taken, a staged approach should be a reasonable strategy in order to avoid excessively long procedures and the use of large amount of contrast media. In this case considera‐ tion of which artery to tackle first, should be based on its importance. When complete revascularization is to be achieved, it is suggested to start PCI at the CTO vessel. As in case of the failure attempt, patient might be fully revascularized by surgery. Inversion of collateral flow direction through the recanalised CTO may protect myocardium at risk during treatment of lesions in the collateral donor vessel. Conversely, in many pa‐ tients treatment at first of non occluded vessel may improve collateral visualization, sig‐ nificantly contributing to success of CTO recanalization. However, this strategy should be reserved to those patients in whom CTOs are likely to be successfully performed. **d.** Patient might also present two CTO vessels at the same time. In these cases if CTOs an‐ giographic characteristics are favourable and the patient does not present any clinical contraindications such as renal failure or other comorbidities, PCI may be performed on both CTOs during the same procedure, paying careful attention to the amount of con‐

cision making, because there are different scenarios which need to be considered:

a larger myocardial necrosis with a poor prognosis for the patients.

trast mean administered and to the duration of radiations exposure.

clinical, angiographic and technical features:

CTO decision-making process requires an individualized risk/benefit analysis, considering

Since the time of the occlusion cannot be known, CTOs are usually distinguished into three levels of certainty:


## **3. Decision-making process for patients affected by CTO**

The clinical presentation of CTOs can be quite variable ranging from patients with stable an‐ gina to patients with silent ischemia or heart failure of ischaemic origin, or those undergoing primary PCI due to acute occlusion in a different culprit vessel, in whom a CTO is discov‐ ered as an incidental finding.

Several factors are associated with CTO clinical presentation such as the presence of oth‐ er concomitant coronary lesions, the amount of CTOs related to myocardial viability, the severity and extension of CTO related to myocardial ischemia and finally the coronary artery involved.

Generally, asymptomatic patients, are more reliable to be left on medical therapy rather than being percutaneuosly revascularized, especially if these patients have one vessel disease or a previous PCI, which has been performed in another coronary vessel. Moreover, older pa‐ tients often exert low level of physical activity which might not lead to angina symptoms, underestimating the real burden of myocardium at risk. However, we know that this thera‐ peutic strategy might not be clinically appropriate but the decision to treat a CTO in an asymptomatic patient should be driven by a non-invasive functional imaging test, in order to clarify the amount of myocardial viability and severity/extension of myocardial ischemia.

shows no intraluminal contrast filling, indicates a functional and not a true CTO. Only meticulous filming and a vigorous contrast injection with a well engaged catheter allow us to conclude that TIMI flow is 0 within the occluded segment and the lesion should then be classified as a CTO [19]. In absence of serial angiograms, the duration of CTO is difficult to establish with certainty and it might be estimated from available clinical in‐ formation related to the timing of the event that caused the occlusion: acute MI or sud‐ den change in angina pattern with ECG changes consistent with the location of the

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

Since the time of the occlusion cannot be known, CTOs are usually distinguished into three

**a.** Certain (angiographically confirmed): the minority of cases where a previous angio‐ gram (for instance before a previous CABG operation, or after an acute myocardial in‐ farction) has confirmed the presence of TIMI 0 flow (3 months prior to the planned

**b.** Likely (clinically confirmed): an acute myocardial infarction in the territory of the occlud‐ ed artery distribution or acute coronary syndrome or deterioration of anginal threshold

**c.** Possible (undetermined): a CTO with TIMI 0 flow and angiographic anatomy sug‐ gestive of long-standing occlusion (collateral development, no contrast staining) with stable unchanged anginal symptoms in the last months or silent ischaemia or, in case of recent acute ischaemic episodes (acute myocardial infarction or unstable an‐ gina or worsening effort angina), with the presence of a culprit artery different from

The clinical presentation of CTOs can be quite variable ranging from patients with stable an‐ gina to patients with silent ischemia or heart failure of ischaemic origin, or those undergoing primary PCI due to acute occlusion in a different culprit vessel, in whom a CTO is discov‐

Several factors are associated with CTO clinical presentation such as the presence of oth‐ er concomitant coronary lesions, the amount of CTOs related to myocardial viability, the severity and extension of CTO related to myocardial ischemia and finally the coronary

Generally, asymptomatic patients, are more reliable to be left on medical therapy rather than being percutaneuosly revascularized, especially if these patients have one vessel disease or a previous PCI, which has been performed in another coronary vessel. Moreover, older pa‐ tients often exert low level of physical activity which might not lead to angina symptoms, underestimating the real burden of myocardium at risk. However, we know that this thera‐

without other possible culprit arteries ≥ 3 months before the current angiogram;

**3. Decision-making process for patients affected by CTO**

occlusion.

levels of certainty:

procedure);

the occluded vessel.

ered as an incidental finding.

artery involved.

On the other hand symptomatic patients represent the greatest challenge for the clinical de‐ cision making, because there are different scenarios which need to be considered:


CTO decision-making process requires an individualized risk/benefit analysis, considering clinical, angiographic and technical features:

**1.** clinical: patient's age, symptoms severity, associated co-morbidities (chronic obstructive pulmonary disease, diabetes mellitus, chronic renal insufficiency), left ventricular ejec‐ tion fraction, associate valve disease and overall functional status.

my and personal experience" and "with average recanalization success rate of >70% in experienced hands with contemporary techniques the presence of a CTO should not be suf‐

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The non invasive assessment of myocardial viability has proved clinically useful for distin‐ guishing hibernating myocardium from irreversibly injured myocardium in patients with chronic ischemic heart disease who exhibit marked regional and global left ventricular dys‐ function [25]. The accurate noninvasive determination of myocardial viability is critically important for clinical decision making [26]. It makes allowance for the selection of patients with CAD and resting left ventricular dysfunction who benefit from revascularization strat‐ egies. Patients with substantial zones of viability and asynergic myocardium should demon‐ strate better function and overall better outcomes after revascularization compare with

Thallium-201 is the imaging agent most frequently used with single photon emission tomog‐ raphy (SPECT) imaging for determination of myocardial viability. The reason is that the de‐ layed uptake of thallium-201 on rest-redistribution imaging is related to myocardial cellular integrity. Several groups have shown that approximately 70% of segments showing >50% or >60% thallium-201 uptake on 3- to 4 hour rest thallium-201 redistribution scintigrams will demonstrate improved systolic function after revascularization [27-28]. The greater the num‐ ber of viable segments detected preoperatively, the greater the improvement in LVEF post‐

Although, 99mTc-labeled perfusion agents, such as sestamibi and tetrofosmin, do not show any significant redistribution over time after being injected intravenously, several studies have shown comparable accuracy for viability detection between these agents and thalli‐ um-201 [29-30]. This is thought to be due to high extraction of these tracers in the region of low flow in which myocites are viable. These agents bind to the mitochondrial membrane

Positron emission tomography (PET) is considered to be the standard of reference for nonin‐ vasive detection of viability with nuclear cardiology techniques. A myocardial zone of asyn‐ ergy is determined to have preserved viability when there is a "mismatch" between perfusion and 18F-fluorodeoxyglucose (FDG) uptake. Patients with a "mismatch" pattern (low blood flow perfusion/high metabolic uptake) will often show improved regional and global left ventricular function after revascularization, whereas patients with a concordant reduction in perfusion and FDG uptake, referred to as a "match" pattern, have predomi‐ nantly scar and do not show any significant improvement in regional and global function

Allman et al performed a pooled analysis [32] consisted of 3088 patients in 24 studies report‐ ing viability by use of radionuclide imaging, PET or dobutamine echocardiography, and long-term survival after revascularization or medical therapy. In patients with predominant viability, follow-up on medical therapy was associated with very high risk, as demonstrated

and require an intact mitochondrial membrane potential for intracellular binding.

patients affected by a ventricular dysfunction related to large myocardial scar.

ficient reason to switch from PCI to surgery in multivessel disease".

**3.1. Non invasive detection of myocardial viability**

operatively.

after revascularization [31].


Regarding clinical features, a great concern is the patients' age. Indeed, in case of octogenari‐ ous patients, the operator should not expect any improvement of prognosis, and thus percuta‐ neous attempt of CTO is supposed to be undertaken, only in presence of severe ischemia or refractory symptoms. Another clinical feature to evaluate is the renal function. Parameter used to assess renal impairment is the serum level of creatinine, or the glomerular filtration rate as measured by Cockcroft-Gault formula [21]. However, the risk of contrast induced nephrop‐ athy does not relate only to renal impairment before the procedure, but also to left ventricular ejection fraction (LVEF) and the presence of associated comorbidities such as diabetes mellitus and older age. The LVEF assessment is also relevant to consider the opportunity in which the left ventricular assistance device might be used during the procedure, such as intra aortic bal‐ looning pumping (IABP). IABP displaces blood during diastole augmenting diastolic pres‐ sure. This augmented pressure wave carries blood flow up to the coronary arteries and can increase coronary blood flow across some coronary narrowing and, in some circumstances, even improving collateral flow to distal CTO coronary vessels. Immediately before systole, the deflation of the counter-pulsation balloon creates a negative space, reversing aortic flow and reducing ventricular after load and, hence, myocardial oxygen demand. Yoshitani, et al. dem‐ onstrated that IABP does not increase diastolic pressure distal to severe coronary stenosis, and thus, the major benefit of IABP in such patients with coronary artery disease is the reduction of myocardial oxygen demand [22]. The presence of left main stenosis might not represent a con‐ traindication for CTO PCI. Indeed, the percutaneous treatment for CTO at first, might protect the patient from procedural ischemia during left main PCI, in case of contraindications to sur‐ gery. Nevertheless, in these cases it is always recommended to use IABP if Euroscore is ≥ 6 [23].

In patients underwent previous surgical revascularization, CTO treatment is a dilemma and the choice between performing native vessel and graft recanalization is not always easy, es‐ pecially in case of old degenerated graft. Furthermore, even when the graft is not occluded but severely diseased at the level of the anastomosis PCI of the graft might be overtaken by recanalization of the native vessel if the occlusion is easy to approach. Moreover, it has been shown that myocardial ischemia might also occur in presence of a patent graft due to endo‐ thelial dysfunction [24]. Indeed, despite the presence of a patent and non-occlusive graft, re‐ gional myocardial blood perfusion might be still compromised, leading to ischemia.

A consensus document from EuroCTO Club [18] underlines that "PCI CTO should be at‐ tempted after careful review of clinical history, results of provocative tests, coronary anato‐ my and personal experience" and "with average recanalization success rate of >70% in experienced hands with contemporary techniques the presence of a CTO should not be suf‐ ficient reason to switch from PCI to surgery in multivessel disease".

### **3.1. Non invasive detection of myocardial viability**

**1.** clinical: patient's age, symptoms severity, associated co-morbidities (chronic obstructive pulmonary disease, diabetes mellitus, chronic renal insufficiency), left ventricular ejec‐

**2.** angiographycally: the extent and complexity of coronary disease (left main disease, bi‐ furcation lesion, ostial lesion, long lesion, severe calcification), often not recognized be‐

**3.** technical: to evaluate percentage of success of revascularization preventing complica‐ tions and considering restenosis rate on the basis of a total stent length required and

Regarding clinical features, a great concern is the patients' age. Indeed, in case of octogenari‐ ous patients, the operator should not expect any improvement of prognosis, and thus percuta‐ neous attempt of CTO is supposed to be undertaken, only in presence of severe ischemia or refractory symptoms. Another clinical feature to evaluate is the renal function. Parameter used to assess renal impairment is the serum level of creatinine, or the glomerular filtration rate as measured by Cockcroft-Gault formula [21]. However, the risk of contrast induced nephrop‐ athy does not relate only to renal impairment before the procedure, but also to left ventricular ejection fraction (LVEF) and the presence of associated comorbidities such as diabetes mellitus and older age. The LVEF assessment is also relevant to consider the opportunity in which the left ventricular assistance device might be used during the procedure, such as intra aortic bal‐ looning pumping (IABP). IABP displaces blood during diastole augmenting diastolic pres‐ sure. This augmented pressure wave carries blood flow up to the coronary arteries and can increase coronary blood flow across some coronary narrowing and, in some circumstances, even improving collateral flow to distal CTO coronary vessels. Immediately before systole, the deflation of the counter-pulsation balloon creates a negative space, reversing aortic flow and reducing ventricular after load and, hence, myocardial oxygen demand. Yoshitani, et al. dem‐ onstrated that IABP does not increase diastolic pressure distal to severe coronary stenosis, and thus, the major benefit of IABP in such patients with coronary artery disease is the reduction of myocardial oxygen demand [22]. The presence of left main stenosis might not represent a con‐ traindication for CTO PCI. Indeed, the percutaneous treatment for CTO at first, might protect the patient from procedural ischemia during left main PCI, in case of contraindications to sur‐ gery. Nevertheless, in these cases it is always recommended to use IABP if Euroscore is ≥ 6 [23].

In patients underwent previous surgical revascularization, CTO treatment is a dilemma and the choice between performing native vessel and graft recanalization is not always easy, es‐ pecially in case of old degenerated graft. Furthermore, even when the graft is not occluded but severely diseased at the level of the anastomosis PCI of the graft might be overtaken by recanalization of the native vessel if the occlusion is easy to approach. Moreover, it has been shown that myocardial ischemia might also occur in presence of a patent graft due to endo‐ thelial dysfunction [24]. Indeed, despite the presence of a patent and non-occlusive graft, re‐

A consensus document from EuroCTO Club [18] underlines that "PCI CTO should be at‐ tempted after careful review of clinical history, results of provocative tests, coronary anato‐

gional myocardial blood perfusion might be still compromised, leading to ischemia.

tion fraction, associate valve disease and overall functional status.

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

fore recanalization is performed.

vessel diameter size.

The non invasive assessment of myocardial viability has proved clinically useful for distin‐ guishing hibernating myocardium from irreversibly injured myocardium in patients with chronic ischemic heart disease who exhibit marked regional and global left ventricular dys‐ function [25]. The accurate noninvasive determination of myocardial viability is critically important for clinical decision making [26]. It makes allowance for the selection of patients with CAD and resting left ventricular dysfunction who benefit from revascularization strat‐ egies. Patients with substantial zones of viability and asynergic myocardium should demon‐ strate better function and overall better outcomes after revascularization compare with patients affected by a ventricular dysfunction related to large myocardial scar.

Thallium-201 is the imaging agent most frequently used with single photon emission tomog‐ raphy (SPECT) imaging for determination of myocardial viability. The reason is that the de‐ layed uptake of thallium-201 on rest-redistribution imaging is related to myocardial cellular integrity. Several groups have shown that approximately 70% of segments showing >50% or >60% thallium-201 uptake on 3- to 4 hour rest thallium-201 redistribution scintigrams will demonstrate improved systolic function after revascularization [27-28]. The greater the num‐ ber of viable segments detected preoperatively, the greater the improvement in LVEF post‐ operatively.

Although, 99mTc-labeled perfusion agents, such as sestamibi and tetrofosmin, do not show any significant redistribution over time after being injected intravenously, several studies have shown comparable accuracy for viability detection between these agents and thalli‐ um-201 [29-30]. This is thought to be due to high extraction of these tracers in the region of low flow in which myocites are viable. These agents bind to the mitochondrial membrane and require an intact mitochondrial membrane potential for intracellular binding.

Positron emission tomography (PET) is considered to be the standard of reference for nonin‐ vasive detection of viability with nuclear cardiology techniques. A myocardial zone of asyn‐ ergy is determined to have preserved viability when there is a "mismatch" between perfusion and 18F-fluorodeoxyglucose (FDG) uptake. Patients with a "mismatch" pattern (low blood flow perfusion/high metabolic uptake) will often show improved regional and global left ventricular function after revascularization, whereas patients with a concordant reduction in perfusion and FDG uptake, referred to as a "match" pattern, have predomi‐ nantly scar and do not show any significant improvement in regional and global function after revascularization [31].

Allman et al performed a pooled analysis [32] consisted of 3088 patients in 24 studies report‐ ing viability by use of radionuclide imaging, PET or dobutamine echocardiography, and long-term survival after revascularization or medical therapy. In patients with predominant viability, follow-up on medical therapy was associated with very high risk, as demonstrated by a 16% annual mortality rate. In similar patients, revascularization was associated with an 80% reduction in annual mortality rate [16% vs 3.2%, p<0.0001), as compared with medical therapy. Patients with the most severe LV dysfunction derived the greatest benefit from re‐ vascularization, that is the survival benefit associated with revascularization of patients with viable myocardium increased proportionately with worsening LVEF. The data suggested that the presence of viable myocardium as defined by noninvasive imaging in patients with heart failure, is a marker for very high natural history risk, and that risk appears to be signif‐ icantly reduced by revascularization.

tients with severely abnormal scans. Moreover, this study provides sufficient evidence that the absence or presence and type of collaterals do not influence prognosis but rather being equally distributed in all subsets of patients. It is also interesting to note that normal scans were rare among the CTO patients accounting for only 6% of all scans; indeed, despite the presence of well developed collaterals (either by Rentrop or Werner classifications) abnor‐ mal scans were shown in the majority of patients. As shown by Werner and colleagues even in patients with normal regional LV function, collaterals provide a normal coronary flow re‐ serve in less than 10% [44]. This study highlights how CTO patients need to be assessed ap‐ propriately by means of functional imaging testing before considering medical therapy instead of revascularization. Conversely, a functional nuclear stress imaging study would enable a tailored strategy of complete revascularization in those patients with multivessel disease and incomplete revascularization in which complete revascularization by PCI may

Percutaneous Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward

http://dx.doi.org/10.5772/54079

441

Although the concept of hibernating myocardium suggests that it is an adaptive steady state, potentially reversible with revascularization, several reports have suggested that pro‐ gressive structural and clinical deterioration may occur in this pathophysiologic setting, with more advanced structural changes being associated with less favourable improvement after revascularization [45]. Indeed, patients with more advanced abnormalities had less im‐ provement in regional and global function after revascularization suggesting that hiberna‐ tion is an incomplete adaptation to ischemia and that once identified, prompt revascularization should occur. Consistent with this concept are data from Beanlans et al [46] who reported that after identification of patients with ischemic cardiomyopathy who had significantly viable myocardium by PET imaging, a substantial delay in revasculariza‐ tion was associated with death during that delay and absence of post-revascularization LV functional improvement, as compared with patients undergoing more prompt revasculari‐ zation. These important studies have significant practical implications, suggesting that iden‐ tification of patients with substantial ischemia and viability are not only at long-term risk, but risk in the short term as well, and that optimal reversibility of LV dysfunction and im‐ provement in symptoms and outcome are dependent on prompt referral for revasculariza‐ tion. These important data might support the concept that viability information can assist in the selection of patients with CTO and regional left ventricular dysfunction for whom the most optimal potential outcome will come from PCI rather than medical treatment or surgi‐

Cardiac Magnetic Resonance Imaging (cMRI) has enormous potential thanks to its major at‐ tributes of high image quality and resolution combined with non-ionising radiation. It can provide high quality diagnostic information about cardiac and valvular function, coronary anatomy, coronary flow reserve, myocardial perfusion, myocardial viability, contractile re‐ serve and cardiac metabolism. It allows assessment of even subtotal wall motion disturban‐ ces resulting from the consistently high endocardial border definition, and the measurement of myocardial perfusion can be integrated into the same examination, with the high spatial resolution of the scans facilitating the determination of the transmural extent of a regional

be contraindicated, or difficult to achieve.

cal revascularization if not needed.

perfusion deficit.

#### **3.2. Impact of complete percutaneous revascularization**

Complete myocardial revascularization remains a desirable goal to obtain with PTCA or CABG [33]. However, incomplete revascularization with PCI of the culprit vessel may be the suitable strategy in selected patients [34]. This may occur, when the vessel, responsible of ischemia, can be identified, particularly when this vessel is a favourable lesion that serves a large non-infarct territory, in case of an acute coronary syndrome, left ventricular dysfunc‐ tion due to acute severe ischemia or pre-existing renal failure. Indeed, situations which in‐ volve complex anatomy such as CTOs may be more cumbersome to approach and a proper planning procedure rather than an hoc angioplasty may be also indicated in such patients. Hannan et al showed that incomplete revascularization with stenting is associated with an adverse impact on long-term mortality [35]. Even more important, this author showed that incompletely revascularized patients with total occlusions, particularly those with no other incompletely revascularized vessels experienced lower rates of subsequent PCI than other patients. Although, at first, it seems to be good news for these incompletely revascularized patients, the fact that they had higher long-term mortality than completely revascularized patients suggests that they might have benefited from more subsequent revascularization. Indeed, with the percutaneous approach the presence of a CTO remains the biggest and most important technical challenge to achieve complete revascularization. Furthermore, as the procedure of a CTO recanalization still remains time consuming, exposing the patient to high dose of ionizing radiation and contrast media, any percutaneous treatment in these subset of patients must be justified on the basis of a strict clinical indication, to improve pa‐ tients' symptoms and prognosis survival [6]. Taking all that into consideration, stress myo‐ cardial perfusion imaging is an effective means of identifying ischemic and viable myocardium and its vascular distribution in patients undergoing coronary revascularization [36-38]. Nuclear data have suggested that adverse events after incomplete revascularization occur more frequently in patients with perfusion defects [39-41], and that myocardial scin‐ tigraphy is able to provide incremental prognostic information after adjusting for clinical, angiographic and exercise variables [42]. Recently, we have shown that in patients with a CTO in a main coronary artery left untreated, patients with either a severe perfusion defect or ischemia and necrosis at stress myocardial scintigraphy have the worst prognosis in terms of hard events at 9 years follow-up as compared to patients with normal or near nor‐ mal myocardial scan or only either necrosis or ischemia [43]. In these patients the presence of another vessel incompletely revascularized beyond that of the CTO artery, did not seem to change the prognosis at follow-up as shown by the occurrence of hard events in those pa‐ tients with severely abnormal scans. Moreover, this study provides sufficient evidence that the absence or presence and type of collaterals do not influence prognosis but rather being equally distributed in all subsets of patients. It is also interesting to note that normal scans were rare among the CTO patients accounting for only 6% of all scans; indeed, despite the presence of well developed collaterals (either by Rentrop or Werner classifications) abnor‐ mal scans were shown in the majority of patients. As shown by Werner and colleagues even in patients with normal regional LV function, collaterals provide a normal coronary flow re‐ serve in less than 10% [44]. This study highlights how CTO patients need to be assessed ap‐ propriately by means of functional imaging testing before considering medical therapy instead of revascularization. Conversely, a functional nuclear stress imaging study would enable a tailored strategy of complete revascularization in those patients with multivessel disease and incomplete revascularization in which complete revascularization by PCI may be contraindicated, or difficult to achieve.

by a 16% annual mortality rate. In similar patients, revascularization was associated with an 80% reduction in annual mortality rate [16% vs 3.2%, p<0.0001), as compared with medical therapy. Patients with the most severe LV dysfunction derived the greatest benefit from re‐ vascularization, that is the survival benefit associated with revascularization of patients with viable myocardium increased proportionately with worsening LVEF. The data suggested that the presence of viable myocardium as defined by noninvasive imaging in patients with heart failure, is a marker for very high natural history risk, and that risk appears to be signif‐

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

Complete myocardial revascularization remains a desirable goal to obtain with PTCA or CABG [33]. However, incomplete revascularization with PCI of the culprit vessel may be the suitable strategy in selected patients [34]. This may occur, when the vessel, responsible of ischemia, can be identified, particularly when this vessel is a favourable lesion that serves a large non-infarct territory, in case of an acute coronary syndrome, left ventricular dysfunc‐ tion due to acute severe ischemia or pre-existing renal failure. Indeed, situations which in‐ volve complex anatomy such as CTOs may be more cumbersome to approach and a proper planning procedure rather than an hoc angioplasty may be also indicated in such patients. Hannan et al showed that incomplete revascularization with stenting is associated with an adverse impact on long-term mortality [35]. Even more important, this author showed that incompletely revascularized patients with total occlusions, particularly those with no other incompletely revascularized vessels experienced lower rates of subsequent PCI than other patients. Although, at first, it seems to be good news for these incompletely revascularized patients, the fact that they had higher long-term mortality than completely revascularized patients suggests that they might have benefited from more subsequent revascularization. Indeed, with the percutaneous approach the presence of a CTO remains the biggest and most important technical challenge to achieve complete revascularization. Furthermore, as the procedure of a CTO recanalization still remains time consuming, exposing the patient to high dose of ionizing radiation and contrast media, any percutaneous treatment in these subset of patients must be justified on the basis of a strict clinical indication, to improve pa‐ tients' symptoms and prognosis survival [6]. Taking all that into consideration, stress myo‐ cardial perfusion imaging is an effective means of identifying ischemic and viable myocardium and its vascular distribution in patients undergoing coronary revascularization [36-38]. Nuclear data have suggested that adverse events after incomplete revascularization occur more frequently in patients with perfusion defects [39-41], and that myocardial scin‐ tigraphy is able to provide incremental prognostic information after adjusting for clinical, angiographic and exercise variables [42]. Recently, we have shown that in patients with a CTO in a main coronary artery left untreated, patients with either a severe perfusion defect or ischemia and necrosis at stress myocardial scintigraphy have the worst prognosis in terms of hard events at 9 years follow-up as compared to patients with normal or near nor‐ mal myocardial scan or only either necrosis or ischemia [43]. In these patients the presence of another vessel incompletely revascularized beyond that of the CTO artery, did not seem to change the prognosis at follow-up as shown by the occurrence of hard events in those pa‐

icantly reduced by revascularization.

**3.2. Impact of complete percutaneous revascularization**

Although the concept of hibernating myocardium suggests that it is an adaptive steady state, potentially reversible with revascularization, several reports have suggested that pro‐ gressive structural and clinical deterioration may occur in this pathophysiologic setting, with more advanced structural changes being associated with less favourable improvement after revascularization [45]. Indeed, patients with more advanced abnormalities had less im‐ provement in regional and global function after revascularization suggesting that hiberna‐ tion is an incomplete adaptation to ischemia and that once identified, prompt revascularization should occur. Consistent with this concept are data from Beanlans et al [46] who reported that after identification of patients with ischemic cardiomyopathy who had significantly viable myocardium by PET imaging, a substantial delay in revasculariza‐ tion was associated with death during that delay and absence of post-revascularization LV functional improvement, as compared with patients undergoing more prompt revasculari‐ zation. These important studies have significant practical implications, suggesting that iden‐ tification of patients with substantial ischemia and viability are not only at long-term risk, but risk in the short term as well, and that optimal reversibility of LV dysfunction and im‐ provement in symptoms and outcome are dependent on prompt referral for revasculariza‐ tion. These important data might support the concept that viability information can assist in the selection of patients with CTO and regional left ventricular dysfunction for whom the most optimal potential outcome will come from PCI rather than medical treatment or surgi‐ cal revascularization if not needed.

Cardiac Magnetic Resonance Imaging (cMRI) has enormous potential thanks to its major at‐ tributes of high image quality and resolution combined with non-ionising radiation. It can provide high quality diagnostic information about cardiac and valvular function, coronary anatomy, coronary flow reserve, myocardial perfusion, myocardial viability, contractile re‐ serve and cardiac metabolism. It allows assessment of even subtotal wall motion disturban‐ ces resulting from the consistently high endocardial border definition, and the measurement of myocardial perfusion can be integrated into the same examination, with the high spatial resolution of the scans facilitating the determination of the transmural extent of a regional perfusion deficit.

Recently the technique of late enhancement with gadolinium contrast agent has been descri‐ bed, in which imaging of the heart is performed 15 minutes after an intravenous injection of gadolinium. The gadolinium concentrates in the necrotic (acute infarction) or scar tissue (chronic infarction) because of an increased partition coefficient and the infarcted area be‐ comes bright [47]. There is very close correlation between the volume of signal enhancement and infarct size in animal experiments of acute infarction. The technique has high resolution, and can define the transmural extent of necrosis and scar for the first time in vivo. Although the technique has been recently developed, it has obvious applications in defining whether infarction has actually occurred in borderline cases. The technique of late enhancement has also clinical application to the assessment of viability and it is an excellent technique for the detection and quantification of myocardial infarction as reported by many studies [48-49]. First pass perfusion is the most widely used cMRI-technique for the detection of reduced myocardial blood flow and yields superior results compared to SPECT [50].

**4. Tools for CTO recanalization**

drophilic coated and some not).

tips.

CTO wires.

pered wires.

**4.1. Micro-catheters and over the wire balloons**

There are four important features of CTO wires:

**1.** Polymer covers: these are plastic sleeves of flexible but solid material which are applied directly over the core or over spring coils covering the tip of the wire. Based on the presence or absence of a polymer, CTO wires are divided in two main categories: poly‐ mer jacket wires (by default also hydrophilic coated) and spring coil wires (some hy‐

Percutaneous Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward

http://dx.doi.org/10.5772/54079

443

**2.** Wire coatings: these affect lubricity and tracking and facilitate smooth movement. There are two types: hydrophilic and hydrophobic. Hydrophilic coatings attract water and are applied over polymer and stainless steel, including tip coils. They are thin and non-slippery when dry and become gelatinous when wet, reducing friction. They usual‐ ly cover the distal 30-35 cm of the wire. Hydrophobic coatings (Dow Corning Silicone) repel water. No wire flushing is required and they also reduce friction but not to the same extent as hydrophilic wires. These coatings usually cover the working area of wire, excluding the tip. There is an inverse relationship between lubricity and tactile feedback related to the presence or absence of coatings over coils and polymers at wire

**3.** Core materials and tapering: the majority of CTO wires have a stainless steel core. Mod‐ ern CTO wires have a transitionless parabolic core grind which provides excellent tor‐ que response and no prolapse points compared to conventional step tapering of non-

**4.** Tip stiffness: this ranges from 0.5 to 20 grams. Usually plastic jacket wires are in the low range of stiffness and spring coil wires cover the whole range. Tip tapering strongly af‐ fects penetration power as the force is applied over a smaller cross-sectional area in ta‐

Wires should be used with an over the wire (OTW) balloon or micro-catheter in order to ease torque in the tip response, preventing flexion, kinking, prolapse of the guide wire, and improv‐ ing penetration ability. They also allow one to modify and reshape the guide wire curve, and exchange one guide wire for another. Micro-catheters in comparison with OTW balloons may provide a better tip flexibility, improving wire manipulation due to their larger inner lumen and hydrophilic coating which reduces friction. They also have the advantage of a radiopaque marker at the "real catheter tip" which has a flat end. Both of these characteristics help to avoid advancing too far into the lesion, a mistake that occurs frequently with OTW balloons. Addi‐ tionally, most of the micro-catheters are braided which prevents shaft kinking, especially when crossing very tortuous vessels, a characteristic that OTW balloons lack. On the other hand mi‐ crocatheters are more expensive and do not offer dilating capacity. The choice between an OTW balloon catheter and a dedicated micro-catheter depends on the features and CTO com‐ plexity and on the operator's personal experience. Micro-catheters differ from each other re‐

The different noninvasive modalities available to assess myocardial viability interrogate dis‐ tinct pathophysiologic myocite and myocardial processes. The SPECT radionuclide tracers examine myocite cell membrane integrity, and dobutamine echocardiography assesses re‐ gional ventricular contractile reserve. PET images myocardial blood flow and metabolism, whereas magnetic resonance hyperenhancement imaging identifies scarred myocardium. Although no major differences have been identified among the modalities that would sug‐ gest differences in patient management, in a pooled analysis of studies reporting on rates of regional functional recovery, few years ago Bax et al. [38] reported that the radionuclide agents are more sensitive and that dobutamine echocardiography was more specific, with PET having slightly higher overall accuracy for predicting functional recovery [51].

However, in the presence of a CTO and a very low blood flow state due to the occluded ar‐ tery, which is supplied only by small collateral channels, dysfunctional but viable LV seg‐ ments may show a modest inotropic response to dobutamine because of the early occurrence of ischemia [52]. Indeed, asynergic but viable myocardium usually thickens un‐ der catecholamine stimulation [53]. However, this effect may be limited or even abolished in the presence of a very flow-limiting CTO, underestimating the amount of myocardial viabil‐ ity in these subsets of patients [54].

More recently contrast-enhanced MRI has shown to be comparable with a PET/SPECT imag‐ ing protocol for the prediction of regional and global functional improvement after revascu‐ larization [55]. However, in the presence of discrepant findings between the modalities, c-MRI is superior to PET/SPECT for predicting lack of recovery of segmental myocardial function after revascularization. One of the reason for this finding may be explained by dif‐ ferences in the way the two techniques assess myocardial viability [56]. Indeed, a relatively small volume of dysfunctional viable tissue may show increased 18F-FDG PET uptake, with PET indicating viability, whereas the coexistence amount of scar impedes functional recov‐ ery. Although some individual studies may suggest better prediction about functional re‐ covery by one test type over another, such data generally reflect differences in small regions or segments per patient and do not seem to affect long-term outcomes.

## **4. Tools for CTO recanalization**

Recently the technique of late enhancement with gadolinium contrast agent has been descri‐ bed, in which imaging of the heart is performed 15 minutes after an intravenous injection of gadolinium. The gadolinium concentrates in the necrotic (acute infarction) or scar tissue (chronic infarction) because of an increased partition coefficient and the infarcted area be‐ comes bright [47]. There is very close correlation between the volume of signal enhancement and infarct size in animal experiments of acute infarction. The technique has high resolution, and can define the transmural extent of necrosis and scar for the first time in vivo. Although the technique has been recently developed, it has obvious applications in defining whether infarction has actually occurred in borderline cases. The technique of late enhancement has also clinical application to the assessment of viability and it is an excellent technique for the detection and quantification of myocardial infarction as reported by many studies [48-49]. First pass perfusion is the most widely used cMRI-technique for the detection of reduced

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

The different noninvasive modalities available to assess myocardial viability interrogate dis‐ tinct pathophysiologic myocite and myocardial processes. The SPECT radionuclide tracers examine myocite cell membrane integrity, and dobutamine echocardiography assesses re‐ gional ventricular contractile reserve. PET images myocardial blood flow and metabolism, whereas magnetic resonance hyperenhancement imaging identifies scarred myocardium. Although no major differences have been identified among the modalities that would sug‐ gest differences in patient management, in a pooled analysis of studies reporting on rates of regional functional recovery, few years ago Bax et al. [38] reported that the radionuclide agents are more sensitive and that dobutamine echocardiography was more specific, with

myocardial blood flow and yields superior results compared to SPECT [50].

PET having slightly higher overall accuracy for predicting functional recovery [51].

ity in these subsets of patients [54].

However, in the presence of a CTO and a very low blood flow state due to the occluded ar‐ tery, which is supplied only by small collateral channels, dysfunctional but viable LV seg‐ ments may show a modest inotropic response to dobutamine because of the early occurrence of ischemia [52]. Indeed, asynergic but viable myocardium usually thickens un‐ der catecholamine stimulation [53]. However, this effect may be limited or even abolished in the presence of a very flow-limiting CTO, underestimating the amount of myocardial viabil‐

More recently contrast-enhanced MRI has shown to be comparable with a PET/SPECT imag‐ ing protocol for the prediction of regional and global functional improvement after revascu‐ larization [55]. However, in the presence of discrepant findings between the modalities, c-MRI is superior to PET/SPECT for predicting lack of recovery of segmental myocardial function after revascularization. One of the reason for this finding may be explained by dif‐ ferences in the way the two techniques assess myocardial viability [56]. Indeed, a relatively small volume of dysfunctional viable tissue may show increased 18F-FDG PET uptake, with PET indicating viability, whereas the coexistence amount of scar impedes functional recov‐ ery. Although some individual studies may suggest better prediction about functional re‐ covery by one test type over another, such data generally reflect differences in small regions

or segments per patient and do not seem to affect long-term outcomes.

There are four important features of CTO wires:


#### **4.1. Micro-catheters and over the wire balloons**

Wires should be used with an over the wire (OTW) balloon or micro-catheter in order to ease torque in the tip response, preventing flexion, kinking, prolapse of the guide wire, and improv‐ ing penetration ability. They also allow one to modify and reshape the guide wire curve, and exchange one guide wire for another. Micro-catheters in comparison with OTW balloons may provide a better tip flexibility, improving wire manipulation due to their larger inner lumen and hydrophilic coating which reduces friction. They also have the advantage of a radiopaque marker at the "real catheter tip" which has a flat end. Both of these characteristics help to avoid advancing too far into the lesion, a mistake that occurs frequently with OTW balloons. Addi‐ tionally, most of the micro-catheters are braided which prevents shaft kinking, especially when crossing very tortuous vessels, a characteristic that OTW balloons lack. On the other hand mi‐ crocatheters are more expensive and do not offer dilating capacity. The choice between an OTW balloon catheter and a dedicated micro-catheter depends on the features and CTO com‐ plexity and on the operator's personal experience. Micro-catheters differ from each other re‐ garding construction characteristics, as well as flexibility, pushability, and trackability properties. One of the micro-catheters most generally used is the Finecross which is braided, hydrophilic coated and has a tapered body. It is available in 130cm and 150cm lengths, for the antegrade and retrograde approaches respectively.

vice was associated with lower time of procedure, time of fluoroscopy, and contrast load administration as compared with conventional techniques [58]. In the prospective multicen‐ ter CRAFT registry that enrolled 80 patients where the device was used as a first treatment

Percutaneous Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward

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445

*BridgePoint system.* The BridgePoint technologies consists of three devices that can be used alone, or in concert with other wires/devices for rapid and safe CTO crossing and provision‐ al luminal re-entry. The Crossboss catheter is an OTW stainless steel catheter with a round‐ ed tip that can negotiate CTOs by using rapid bi-directional rotation. If the Crossboss, or conventional wires and devices, gain subintimal/subadventitial position, the flat Stingray balloon (with an exit port oriented toward the lumen) and Stingray guide wire can be utiliz‐ ed for dedicated lumen re-entry and distal vessel access. The FAST-CTOs pivotal trial enrol‐ led 147 patients with wire-refractory CTOs. Technical success was 77%, 30 day MACE < 5%, and average procedure time was 105 minutes [60]. Recently, the preliminary European expe‐ rience (42 patients) with this system was reported and the success rate was 67% without any

The selection of the access route is dependent on the individual patient situation (e.g., severe peripheral vascular disease, which may mandate a radial approach) as well as on the opera‐ tor's preference. Guiding catheter size is limited from the radial approach, but the radial ar‐ tery can be easily used for contralateral injection (5 or 6 Fr diagnostic catheters). Most experts use the femoral approach (90% in Europe) and it has not been shown that either ac‐ cess is preferable except for about 10% of the cases in which even experienced radial opera‐

Good passive support with coaxial alignment into the coronary artery for active support is crucial. Passive support is stronger with larger guiding catheters (7 and 8 Fr) while 6 Fr cath‐ eters offer the best balance between active and passive support. For the left coronary system extra backup–type catheters (Voda left, extra backup, geometric left, left support) are pref‐ erable, although some operators still prefer Amplatz type or even Judkins type catheters, the latter needing more manipulation to achieve optimal position and back up in complex cases (Figure 5). For the right coronary artery 6F and 7F catheters can be used with left Amplatz 0.75-2 shapes, hockey stick shapes for gentle superior origins of the RCA, Judkins shape for slightly inferior origins and internal mammary artery type guiding catheters for upward ori‐ gins (Figure 6). One word of caution is that there is a higher risk of vessel injury at the osti‐ um and first bend of the right coronary artery especially with an Amplats left that has a tendency to jump into the artery, and with all kinds of 8 Fr catheters. In case of ostial dissec‐ tion, a soft-tipped wire must be selected and steered carefully past the dissection that needs to be fixed before continuing the procedure. Often the guide catheter has to be changed to

choice success rate was 76% [59].

**5. The key of success of CTO PCI**

avoid an orientation towards the dissection.

tors select the femoral route.

safety issues [61].

The Tornus (Asahi Intecc Co., Nagoya, Japan) crossing micro-catheter has been developed to penetrate severe and hard lesions with greater flexibility and torquability with a rotational burrowing advancement manually manoeuvred by controlled counter-clockwise rotation.

The Corsair (Asahi Intecc Co., Nagoya, Japan) is a septal dilator catheter used for the retro‐ grade approach. This is a micro-catheter which is dedicated for selective engagement of the collateral channel. It consists of a tapered tip and screw head structure, which reinforces tor‐ que transmission for the guide wire and creates better back-up support for CTO penetration. The Corsair provides superior tip flexibility which enables smooth approaches to narrow tortuous vessels, such as septal channels. Unlike other general micro-catheters, the Corsair possesses a soft tip with tungsten powder mix and a 0.8 mm platinum marker coil 5 mm from the tip, which makes it easy to identify the distal tip under fluoroscopy.

The Venture™ Catheter (Velocimed, Minneapolis, Minnesota, USA) is an over the wire, low profile support catheter, 6F compatible, flexible, torqueable with a radiopaque atraumatic tip. It has been recently designed to help direct the wire where there are difficult angles, providing strong support especially in occlusive lesions. It is also available as a rapid ex‐ change device.

The Twin pass (Vascular Solutions, Inc Minneapolis, Minnesota, USA) is a dual access lu‐ men rapid exchange micro-catheter (rapid exchange and over the wire) which helps the guide wire placement and exchange after reopening the occlusion and gaining access to dif‐ ferent main branches.

The Crusade (Kaneka Corporation, Japan) micro-catheter has the similar design and applica‐ tion of the Twin pass.

#### **4.2. Dedicated devices in clinical use**

Many dedicated devices to open CTOs were developed in the past, but most disappeared because they did not prove superior to conventional CTO procedure equipment. The follow‐ ing dedicated devices are currently in clinical use:

*Crosser.* The Crosser CTO recanalization system (Flow-Cardia Inc, CA, USA) is comprised of a generator, transducer, foot switch, and a disposable catheter. Through the generator the catheter tip vibrates at a rate of 21,000 cycles/sec. This vibration provides mechanical impact and cavitational effects, which aid in the recanalization of the occluded artery. The catheter is monorail, hydrophilic, and can be advanced over a standard 0.014 inch guide wire. It is 1.1 mm in diameter, which makes it compatible with 6 Fr guiding catheters, and has a blunt tip. In a small single centre experience comprising 28 patients (30 lesions) technical success was obtained in 63% of the occlusions with minor complications [57]. In a single center reg‐ istry of 45 patients with relative complex CTOs success rate was 84% but the use of the de‐ vice was associated with lower time of procedure, time of fluoroscopy, and contrast load administration as compared with conventional techniques [58]. In the prospective multicen‐ ter CRAFT registry that enrolled 80 patients where the device was used as a first treatment choice success rate was 76% [59].

*BridgePoint system.* The BridgePoint technologies consists of three devices that can be used alone, or in concert with other wires/devices for rapid and safe CTO crossing and provision‐ al luminal re-entry. The Crossboss catheter is an OTW stainless steel catheter with a round‐ ed tip that can negotiate CTOs by using rapid bi-directional rotation. If the Crossboss, or conventional wires and devices, gain subintimal/subadventitial position, the flat Stingray balloon (with an exit port oriented toward the lumen) and Stingray guide wire can be utiliz‐ ed for dedicated lumen re-entry and distal vessel access. The FAST-CTOs pivotal trial enrol‐ led 147 patients with wire-refractory CTOs. Technical success was 77%, 30 day MACE < 5%, and average procedure time was 105 minutes [60]. Recently, the preliminary European expe‐ rience (42 patients) with this system was reported and the success rate was 67% without any safety issues [61].

## **5. The key of success of CTO PCI**

garding construction characteristics, as well as flexibility, pushability, and trackability properties. One of the micro-catheters most generally used is the Finecross which is braided, hydrophilic coated and has a tapered body. It is available in 130cm and 150cm lengths, for the

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

The Tornus (Asahi Intecc Co., Nagoya, Japan) crossing micro-catheter has been developed to penetrate severe and hard lesions with greater flexibility and torquability with a rotational burrowing advancement manually manoeuvred by controlled counter-clockwise rotation.

The Corsair (Asahi Intecc Co., Nagoya, Japan) is a septal dilator catheter used for the retro‐ grade approach. This is a micro-catheter which is dedicated for selective engagement of the collateral channel. It consists of a tapered tip and screw head structure, which reinforces tor‐ que transmission for the guide wire and creates better back-up support for CTO penetration. The Corsair provides superior tip flexibility which enables smooth approaches to narrow tortuous vessels, such as septal channels. Unlike other general micro-catheters, the Corsair possesses a soft tip with tungsten powder mix and a 0.8 mm platinum marker coil 5 mm

The Venture™ Catheter (Velocimed, Minneapolis, Minnesota, USA) is an over the wire, low profile support catheter, 6F compatible, flexible, torqueable with a radiopaque atraumatic tip. It has been recently designed to help direct the wire where there are difficult angles, providing strong support especially in occlusive lesions. It is also available as a rapid ex‐

The Twin pass (Vascular Solutions, Inc Minneapolis, Minnesota, USA) is a dual access lu‐ men rapid exchange micro-catheter (rapid exchange and over the wire) which helps the guide wire placement and exchange after reopening the occlusion and gaining access to dif‐

The Crusade (Kaneka Corporation, Japan) micro-catheter has the similar design and applica‐

Many dedicated devices to open CTOs were developed in the past, but most disappeared because they did not prove superior to conventional CTO procedure equipment. The follow‐

*Crosser.* The Crosser CTO recanalization system (Flow-Cardia Inc, CA, USA) is comprised of a generator, transducer, foot switch, and a disposable catheter. Through the generator the catheter tip vibrates at a rate of 21,000 cycles/sec. This vibration provides mechanical impact and cavitational effects, which aid in the recanalization of the occluded artery. The catheter is monorail, hydrophilic, and can be advanced over a standard 0.014 inch guide wire. It is 1.1 mm in diameter, which makes it compatible with 6 Fr guiding catheters, and has a blunt tip. In a small single centre experience comprising 28 patients (30 lesions) technical success was obtained in 63% of the occlusions with minor complications [57]. In a single center reg‐ istry of 45 patients with relative complex CTOs success rate was 84% but the use of the de‐

from the tip, which makes it easy to identify the distal tip under fluoroscopy.

antegrade and retrograde approaches respectively.

change device.

ferent main branches.

tion of the Twin pass.

**4.2. Dedicated devices in clinical use**

ing dedicated devices are currently in clinical use:

The selection of the access route is dependent on the individual patient situation (e.g., severe peripheral vascular disease, which may mandate a radial approach) as well as on the opera‐ tor's preference. Guiding catheter size is limited from the radial approach, but the radial ar‐ tery can be easily used for contralateral injection (5 or 6 Fr diagnostic catheters). Most experts use the femoral approach (90% in Europe) and it has not been shown that either ac‐ cess is preferable except for about 10% of the cases in which even experienced radial opera‐ tors select the femoral route.

Good passive support with coaxial alignment into the coronary artery for active support is crucial. Passive support is stronger with larger guiding catheters (7 and 8 Fr) while 6 Fr cath‐ eters offer the best balance between active and passive support. For the left coronary system extra backup–type catheters (Voda left, extra backup, geometric left, left support) are pref‐ erable, although some operators still prefer Amplatz type or even Judkins type catheters, the latter needing more manipulation to achieve optimal position and back up in complex cases (Figure 5). For the right coronary artery 6F and 7F catheters can be used with left Amplatz 0.75-2 shapes, hockey stick shapes for gentle superior origins of the RCA, Judkins shape for slightly inferior origins and internal mammary artery type guiding catheters for upward ori‐ gins (Figure 6). One word of caution is that there is a higher risk of vessel injury at the osti‐ um and first bend of the right coronary artery especially with an Amplats left that has a tendency to jump into the artery, and with all kinds of 8 Fr catheters. In case of ostial dissec‐ tion, a soft-tipped wire must be selected and steered carefully past the dissection that needs to be fixed before continuing the procedure. Often the guide catheter has to be changed to avoid an orientation towards the dissection.

When the distal vessel is mainly filled by retrograde collaterals, or there are bridging collat‐ erals originating near the occlusion that are likely to have their flow impaired after wirecatheter advancement, contralateral injection is necessary from the beginning of the procedure. The contralateral approach can also be achieved by puncturing the same groin with a 4 to 6 Fr catheter, which may allow the procedure to be better tolerated. The opera‐ tors of the EuroCTO Club have used contralateral injection in 62% of cases of their personal

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447

A floppy wire is often the best initial choice to negotiate the segment proximal to the occlu‐ sion and advance an OTW balloon or microcatheter up to the proximal stump and then ex‐

Until recently, the standard way of selecting a guide wire was to use a gradual step-up ap‐ proach, which consists of tackling the lesion with a medium-tipped guide wire (3-6 gr) and then exchanging it for a stiffer one (9-12 gr). Using this approach, a reasonable choice is to start with a Medium or a Miracle 3 first (Asahi Intecc Co., Nagoya, Japan), then switching to

The introduction of very soft tapered polymeric wires such as the Fielder XT dramatically changed this practice. Soft tapered polymeric wires became the standard to start CTO proce‐ dures; in about 40% of the cases this wire will cross the occlusion taking advantage of invisi‐ ble tiny channels [62]. The current trend is a sharp step up to very stiff tapered spring coil tapered hydrophilic wires such as Confianza pro 12 gr and PROGRESS 200T to overcome any hard calcified or fibrotic segments of the occlusion and quickly return to soft polymer/ hydrophilic wires to continue long segment tracking and complete crossing of the CTO. This strategy significantly reduces procedural time and material consumption. With contempo‐ rary CTO techniques soft polymer wires are of increasing use followed by spring coil stiff

but hydrophilic wires while bare spring coil wires became of secondary importance.

The shaping of a CTO guide wire tip is very important. Usually, a small 40-50° curve, 1.0-2.0 mm from the tip of the wire is needed to penetrate the proximal fibrous cap. In hard spring coil wires a gentler secondary 15-20° curve, 3.0-4.0 mm proximal to the distal tip is necessary to navigate into the CTO body, to orient the tip and to cross the distal fibrous cap especially

There are three fundamental elements of wire handling: rotating, pushing and pulling. After entering the proximal cap, one should very gently push while simultaneously keep applying torque, until the wire slides into the body of the occlusion. The wire should be rotated clock‐ wise and counter clockwise, but not more than 360° in the same direction, in order to keep good tip control. Uncontrolled wire spinning may result in large dissections that might make difficult to find the distal true lumen or lead to complications such as wire exit and

If resistance is strong, pushing (advancement of the OTW catheter close to the tip of the wire to increase stiffness and pushability) may open a false lumen and should be avoided. Apply‐

series (range 33-78%) [62].

stiffer wires.

change it to a stiffer dedicated wire.

in vessels bigger than 3.5 mm.

**5.1. Single wire techniques**

perforation or wire entrapment.

**Figure 5.** Guiding catheter selection for left coronary artery; A) normal left main; B) short left main.

**Figure 6.** Guiding catheter selection for right coronary artery; A) normal origin; B) Shephered's crook origin; C) low origin with horizontal course.

When the distal vessel is mainly filled by retrograde collaterals, or there are bridging collat‐ erals originating near the occlusion that are likely to have their flow impaired after wirecatheter advancement, contralateral injection is necessary from the beginning of the procedure. The contralateral approach can also be achieved by puncturing the same groin with a 4 to 6 Fr catheter, which may allow the procedure to be better tolerated. The opera‐ tors of the EuroCTO Club have used contralateral injection in 62% of cases of their personal series (range 33-78%) [62].

A floppy wire is often the best initial choice to negotiate the segment proximal to the occlu‐ sion and advance an OTW balloon or microcatheter up to the proximal stump and then ex‐ change it to a stiffer dedicated wire.

Until recently, the standard way of selecting a guide wire was to use a gradual step-up ap‐ proach, which consists of tackling the lesion with a medium-tipped guide wire (3-6 gr) and then exchanging it for a stiffer one (9-12 gr). Using this approach, a reasonable choice is to start with a Medium or a Miracle 3 first (Asahi Intecc Co., Nagoya, Japan), then switching to stiffer wires.

The introduction of very soft tapered polymeric wires such as the Fielder XT dramatically changed this practice. Soft tapered polymeric wires became the standard to start CTO proce‐ dures; in about 40% of the cases this wire will cross the occlusion taking advantage of invisi‐ ble tiny channels [62]. The current trend is a sharp step up to very stiff tapered spring coil tapered hydrophilic wires such as Confianza pro 12 gr and PROGRESS 200T to overcome any hard calcified or fibrotic segments of the occlusion and quickly return to soft polymer/ hydrophilic wires to continue long segment tracking and complete crossing of the CTO. This strategy significantly reduces procedural time and material consumption. With contempo‐ rary CTO techniques soft polymer wires are of increasing use followed by spring coil stiff but hydrophilic wires while bare spring coil wires became of secondary importance.

The shaping of a CTO guide wire tip is very important. Usually, a small 40-50° curve, 1.0-2.0 mm from the tip of the wire is needed to penetrate the proximal fibrous cap. In hard spring coil wires a gentler secondary 15-20° curve, 3.0-4.0 mm proximal to the distal tip is necessary to navigate into the CTO body, to orient the tip and to cross the distal fibrous cap especially in vessels bigger than 3.5 mm.

#### **5.1. Single wire techniques**

**Figure 5.** Guiding catheter selection for left coronary artery; A) normal left main; B) short left main.

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

**Figure 6.** Guiding catheter selection for right coronary artery; A) normal origin; B) Shephered's crook origin; C) low

origin with horizontal course.

There are three fundamental elements of wire handling: rotating, pushing and pulling. After entering the proximal cap, one should very gently push while simultaneously keep applying torque, until the wire slides into the body of the occlusion. The wire should be rotated clock‐ wise and counter clockwise, but not more than 360° in the same direction, in order to keep good tip control. Uncontrolled wire spinning may result in large dissections that might make difficult to find the distal true lumen or lead to complications such as wire exit and perforation or wire entrapment.

If resistance is strong, pushing (advancement of the OTW catheter close to the tip of the wire to increase stiffness and pushability) may open a false lumen and should be avoided. Apply‐ ing rotation in combination with appropriate wire selection is the right choice as it will mini‐ mize resistance at the tip.

More recently, Carlino [66] proposed the "Microchannel technique". The idea came from histological CTO data demonstrating that most occlusions have intra-luminal micro-chan‐ nels with size between 100-500 μm that run within and parallel to the occluded vessel [67-68]. According to this technique after central puncture of the proximal cap with a very stiff spring coil wire for a length no longer than 1-2 mm and advancement of a OTW balloon or a micro-catheter, contrast is injected aiming to enlarge and connect these micro-channels creating a communication between the proximal and distal true lumens favoring guide wire crossing through the occlusion. This technique is mostly proposed for straight CTO seg‐

Percutaneous Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward

http://dx.doi.org/10.5772/54079

449

Galassi further refined the STAR proposing the "Mini-STAR" technique using the very soft Fielder polymeric guide wires. The Fielder FC and XT (tapered) can track intra-occlusion channels navigating though the occlusion. In cases of channel interruption or presence of harder tissue by forcing the wire when supported by a micro-catheter a J-tip shape is auto‐ matically created within the occlusion. This J tip is smaller compared to the one purposely created with stiffer polymeric guide wires during the STAR technique allowing "mini subintimal tracking" with the creation of much smaller subintimal spaces. This technique was successful as a rescue in 97.6% of cases during the same procedure after failure to recanalise

with conventional techniques, and during a second attempt in 84.6% of the cases [69].

The retrograde techniques have a long standing history. In the late 80s Hartzler intro‐ duced the retrograde dilatation of native artery stenosis proximal to a distal SVG anasto‐ mosis. In the early 90s retrograde wire crossing of CTOs via saphenous vein graft (SVG) grafts were attempted. In late 90s the invention of the bilateral approach led to the mark‐ er wire technique where the retrograde wire was used as a roadmap for the antegrade wire. In the early 2000s initial attempts to break the distal cap with balloons were at‐ tempted and in 2005 Katoh pioneered the field introducing the Controlled Antegrade and Retrograde subintimal Tracking (CART) technique [70] establishing the modern era of retrograde CTO recanalisation. Beyond the concept of retrograde dilatation within the occlusion to facilitate antegrade wire crossing, the novelties introduced in this procedure was the retrograde balloon dilatation. Indeed, the principle of this technique is retro‐ grade penetration and dilatation of the occlusion, most often close to the distal cap, thus creating a large target (subintimal space) facilitating antegrade wire crossing. In the re‐ verse CART, the principle is the same as the CART technique with the difference that the subintimal space is created with antegrade balloon dilatations facilitating the crossing of the occlusion with the retrograde wire. Currently, this is the dominant technique in the retrograde CTO approach [71]. IVUS guidance for the connection of the antegrade and retrograde subintimal spaces [72], led by Japanese operators, significantly contribut‐ ed to our understanding of these techniques, but did not receive widespread adoption due to its inherent complexity and cost. More recently, a variety of modifications to these cornerstone techniques have been introduced such as subintimal space stabilization with stents (stent CART technique after septal overdilatation and retrograde stenting and

ments with a concave proximal cap that will facilitate central puncture.

**5.4. Retrograde approach**

Wires, especially stiff ones, have the tendency to follow the outer part of the vessel curve which in tortuous occlusions can easily lead to vessel exit and perforation. It is important to direct the wire tip towards the inner part of vessel bends. Calcification or occluded stents are often good markers of the vessel course. Bridging collaterals should be carefully recog‐ nised and avoided as modern wires, especially polymer ones, can easily track these vessels and lead to major complications if perforated or dilated.

#### **5.2. Parallel-wire technique**

The parallel-wire technique was first described by Reifart in 1995 and was further devel‐ oped by Katoh [63]. It is a cornerstone technique in CTO PCI that every operator should be familiar with. When the first wire enter the false lumen, it is left in place, and a second wire (typically stiffer and often tapered with different tip bend) supported by an OTW catheter, is passed parallel to the first wire aiming for the distal true lumen. The initial wire serves as a marker, occludes the wrong pathway and can potentially modify the anatomy by changing vessel geometry and smoothening sharp curves.

If the second wire also fails to enter the distal true lumen and follows a different incorrect pathway, often on the opposite wall, the first wire is withdrawn and steered in the direction of the true lumen using the second wire as a marker; the so-called "see saw" technique. Oc‐ casionally, three or more wires are used. As in single wire techniques it is of paramount im‐ portance not to over-rotate and push either of the wires, in order to avoid creation of large dissection and subintimal spaces as well as to avoid wire twisting. Often re-puncturing the proximal cup or navigating through the occlusion with a difference of fraction of a millime‐ tre is critical for success.

#### **5.3. Techniques with sub-intimal tracking**

The STAR technique (sub-intimal tracking and re-entry) was introduced by Colombo [64] who demonstrated that the technique was feasible and safe. This method involves fashion‐ ing a large "umbrella-handle" shaped bend at the tip of a hydrophilic wire once the wire is within the dissection flap. Force is then applied to this tip and evenly distributed over a large surface area, along the length of the umbrella-handle, to break through the sub-endo‐ thelial layer thereby creating a communication between the false lumen and the true lumen. Carlino [65] introduced the modified STAR technique (guided-STAR technique), by inject‐ ing contrast into the subintimal space in an effort to simplify the original technique and make it more widely applicable. Once in a dissection plane pure contrast is gently injected from via an OTW balloon or a micro-catheter drawing a roadmap of the occluded segment. The injection might cause a coronary dissection whether tubular (a linear morphology con‐ sistent with the vessel outline) or storm cloud (small side branch or bridging collaterals dis‐ section with diffuse contrast extravasation into the adventitia). Sometimes a communication between the false and true lumen can be created.

More recently, Carlino [66] proposed the "Microchannel technique". The idea came from histological CTO data demonstrating that most occlusions have intra-luminal micro-chan‐ nels with size between 100-500 μm that run within and parallel to the occluded vessel [67-68]. According to this technique after central puncture of the proximal cap with a very stiff spring coil wire for a length no longer than 1-2 mm and advancement of a OTW balloon or a micro-catheter, contrast is injected aiming to enlarge and connect these micro-channels creating a communication between the proximal and distal true lumens favoring guide wire crossing through the occlusion. This technique is mostly proposed for straight CTO seg‐ ments with a concave proximal cap that will facilitate central puncture.

Galassi further refined the STAR proposing the "Mini-STAR" technique using the very soft Fielder polymeric guide wires. The Fielder FC and XT (tapered) can track intra-occlusion channels navigating though the occlusion. In cases of channel interruption or presence of harder tissue by forcing the wire when supported by a micro-catheter a J-tip shape is auto‐ matically created within the occlusion. This J tip is smaller compared to the one purposely created with stiffer polymeric guide wires during the STAR technique allowing "mini subintimal tracking" with the creation of much smaller subintimal spaces. This technique was successful as a rescue in 97.6% of cases during the same procedure after failure to recanalise with conventional techniques, and during a second attempt in 84.6% of the cases [69].

#### **5.4. Retrograde approach**

ing rotation in combination with appropriate wire selection is the right choice as it will mini‐

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

Wires, especially stiff ones, have the tendency to follow the outer part of the vessel curve which in tortuous occlusions can easily lead to vessel exit and perforation. It is important to direct the wire tip towards the inner part of vessel bends. Calcification or occluded stents are often good markers of the vessel course. Bridging collaterals should be carefully recog‐ nised and avoided as modern wires, especially polymer ones, can easily track these vessels

The parallel-wire technique was first described by Reifart in 1995 and was further devel‐ oped by Katoh [63]. It is a cornerstone technique in CTO PCI that every operator should be familiar with. When the first wire enter the false lumen, it is left in place, and a second wire (typically stiffer and often tapered with different tip bend) supported by an OTW catheter, is passed parallel to the first wire aiming for the distal true lumen. The initial wire serves as a marker, occludes the wrong pathway and can potentially modify the anatomy by changing

If the second wire also fails to enter the distal true lumen and follows a different incorrect pathway, often on the opposite wall, the first wire is withdrawn and steered in the direction of the true lumen using the second wire as a marker; the so-called "see saw" technique. Oc‐ casionally, three or more wires are used. As in single wire techniques it is of paramount im‐ portance not to over-rotate and push either of the wires, in order to avoid creation of large dissection and subintimal spaces as well as to avoid wire twisting. Often re-puncturing the proximal cup or navigating through the occlusion with a difference of fraction of a millime‐

The STAR technique (sub-intimal tracking and re-entry) was introduced by Colombo [64] who demonstrated that the technique was feasible and safe. This method involves fashion‐ ing a large "umbrella-handle" shaped bend at the tip of a hydrophilic wire once the wire is within the dissection flap. Force is then applied to this tip and evenly distributed over a large surface area, along the length of the umbrella-handle, to break through the sub-endo‐ thelial layer thereby creating a communication between the false lumen and the true lumen. Carlino [65] introduced the modified STAR technique (guided-STAR technique), by inject‐ ing contrast into the subintimal space in an effort to simplify the original technique and make it more widely applicable. Once in a dissection plane pure contrast is gently injected from via an OTW balloon or a micro-catheter drawing a roadmap of the occluded segment. The injection might cause a coronary dissection whether tubular (a linear morphology con‐ sistent with the vessel outline) or storm cloud (small side branch or bridging collaterals dis‐ section with diffuse contrast extravasation into the adventitia). Sometimes a communication

mize resistance at the tip.

**5.2. Parallel-wire technique**

tre is critical for success.

and lead to major complications if perforated or dilated.

vessel geometry and smoothening sharp curves.

**5.3. Techniques with sub-intimal tracking**

between the false and true lumen can be created.

The retrograde techniques have a long standing history. In the late 80s Hartzler intro‐ duced the retrograde dilatation of native artery stenosis proximal to a distal SVG anasto‐ mosis. In the early 90s retrograde wire crossing of CTOs via saphenous vein graft (SVG) grafts were attempted. In late 90s the invention of the bilateral approach led to the mark‐ er wire technique where the retrograde wire was used as a roadmap for the antegrade wire. In the early 2000s initial attempts to break the distal cap with balloons were at‐ tempted and in 2005 Katoh pioneered the field introducing the Controlled Antegrade and Retrograde subintimal Tracking (CART) technique [70] establishing the modern era of retrograde CTO recanalisation. Beyond the concept of retrograde dilatation within the occlusion to facilitate antegrade wire crossing, the novelties introduced in this procedure was the retrograde balloon dilatation. Indeed, the principle of this technique is retro‐ grade penetration and dilatation of the occlusion, most often close to the distal cap, thus creating a large target (subintimal space) facilitating antegrade wire crossing. In the re‐ verse CART, the principle is the same as the CART technique with the difference that the subintimal space is created with antegrade balloon dilatations facilitating the crossing of the occlusion with the retrograde wire. Currently, this is the dominant technique in the retrograde CTO approach [71]. IVUS guidance for the connection of the antegrade and retrograde subintimal spaces [72], led by Japanese operators, significantly contribut‐ ed to our understanding of these techniques, but did not receive widespread adoption due to its inherent complexity and cost. More recently, a variety of modifications to these cornerstone techniques have been introduced such as subintimal space stabilization with stents (stent CART technique after septal overdilatation and retrograde stenting and the stent reverse-CART technique) introduced by Sianos [73]. The retrograde wire cross‐ ing technique (crossing of the occlusion purely retrograde without the need for creation of subintimal spaces), which accounts for almost 30% of successes, as well as the marker wire technique should also be kept in mind as simpler retrograde techniques which can always prove helpful [74].

**6.1. Paclitaxel-eluting stents (PES) for CTOs**

51%) and reocclusion (2% vs 23%).

as observed in non occlusive lesions.

9% and a single reocclusion (3%).

**6.2. Sirolimus eluting stents (SES) for CTOs - Registries**

Werner et al. [82] evaluated the efficacy of PES in 48 consecutive patients with CTOs com‐ pared with a matched group of 48 patients previously treated with BMS. Patients matching was performed on the basis of a history of diabetes mellitus, prior MI, diameter and number of stents implanted, lesion location and left ventricular function. The PES-treated group had significantly fewer adverse events relating to the reduced need for repeat revascularization; the advantage of PES over BMS was also significant both in diabetic and non-diabetic pa‐ tients. Angiographic follow-up demonstrated the efficacy of the PES with a significantly smaller late lumen loss in the PES-treated group and significantly less restenosis (8% vs

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Two additional registries studied the role of PES in CTOs: among 65 patients with CTOs in the international WISDOM Registry, treatment with the PES resulted in freedom from MACE and repeat intervention at 1 year in 93.3% and 98.3% of patients [83], respectively; in the European TRUE Registry, among 183 with CTO treated with PES, 7-months rates of restenosis and target vessel revascularization were 17.0% and 16.9% respectively [84].

Several observational studies examining clinical outcomes among patients treated with DES following successful CTO recanalization demonstrated the notion that unlike BMS, DES may achieve similar reductions in the need for repeat target vessel revascularization (TVR),

The first data on the effectiveness of SES usage for CTOs came from the Rapamycin Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry, a prospective sin‐ gle centre study set-up with the aim of evaluating the safety and efficacy of SES in a ''real world'' scenario [85]. In this registry SES was the device of first choice for every PCI per‐ formed at the Thoraxcenter irrespective of patient or lesion characteristics. Among 56 pa‐ tients treated with SES following successful CTO revascularization during the first months, the 1-year survival free of major adverse cardiac events (MACE) defined as the composite of death, acute myocardial infarction or TVR was 96.4% compared with 82.1% among an his‐ torical control group of 28 patients receiving bare metal stents (p < 0.05). Six-month follow up angiography performed in 33 patients treated with SES showed a remarkable suppres‐ sion of neointimal proliferation, with in-stent late loss of 0.13±0.46, a binary restenosis rate of

More recently, the RESEARCH investigators have reported the 3-year clinical and angio‐ graphic follow-up of patients with CTO in a consecutive series of 147 patients [86], with comparison between BMS (n = 71) and SES (n = 76). The cumulative event-free survival of MACE was 81.7% in BMS group and 84.2% in SES group (p = 0.7). The authors concluded that, despite clinical benefit after 1 year, the use of SES was no longer associated with signifi‐ cantly lower rates of TVR and MACE in patients with CTOs after 3 years of follow-up com‐ pared with BMS. The issue of long term outcome after successful CTO revascularization and

DES implantation will surely continue to deserve attention in the future.

#### **6. The stent choice for CTO treatment**

Several randomized studies have compared balloon angioplasty with stent implantation for the treatment of CTOs (Figure 7). Although these trials have shown diverse results regard‐ ing entry criteria, antithrombotic regimen and trial design, their findings are remarkably concordant. The restenosis rate was reduced from 70% in the balloon treated groups to 30% in the stent groups, with a corresponding reduction in the need for revascularization and with no increased risk of stent thrombosis. Also the rate of reocclusion was significantly re‐ duce by stent implantation. The introduction of DES has determined a significant reduction in restenosis and re-occlusion as compared to BMS.

**Figure 7.** Restenosis after percutaneous recanalizzation of CTO: an overview of POBA versus stent implantation randomized trial

It is advisable to use DES with a very low late lumen loss are in CTOs, as these lesions have a large plaque load and the compression of these plaques within the adventital space pro‐ motes intimal proliferation and therefore high restenosis and re-occlusion rates as previous‐ ly demonstrated with BMS [75-81].

### **6.1. Paclitaxel-eluting stents (PES) for CTOs**

the stent reverse-CART technique) introduced by Sianos [73]. The retrograde wire cross‐ ing technique (crossing of the occlusion purely retrograde without the need for creation of subintimal spaces), which accounts for almost 30% of successes, as well as the marker wire technique should also be kept in mind as simpler retrograde techniques which can

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

Several randomized studies have compared balloon angioplasty with stent implantation for the treatment of CTOs (Figure 7). Although these trials have shown diverse results regard‐ ing entry criteria, antithrombotic regimen and trial design, their findings are remarkably concordant. The restenosis rate was reduced from 70% in the balloon treated groups to 30% in the stent groups, with a corresponding reduction in the need for revascularization and with no increased risk of stent thrombosis. Also the rate of reocclusion was significantly re‐ duce by stent implantation. The introduction of DES has determined a significant reduction

**Figure 7.** Restenosis after percutaneous recanalizzation of CTO: an overview of POBA versus stent implantation

It is advisable to use DES with a very low late lumen loss are in CTOs, as these lesions have a large plaque load and the compression of these plaques within the adventital space pro‐ motes intimal proliferation and therefore high restenosis and re-occlusion rates as previous‐

always prove helpful [74].

randomized trial

ly demonstrated with BMS [75-81].

**6. The stent choice for CTO treatment**

in restenosis and re-occlusion as compared to BMS.

Werner et al. [82] evaluated the efficacy of PES in 48 consecutive patients with CTOs com‐ pared with a matched group of 48 patients previously treated with BMS. Patients matching was performed on the basis of a history of diabetes mellitus, prior MI, diameter and number of stents implanted, lesion location and left ventricular function. The PES-treated group had significantly fewer adverse events relating to the reduced need for repeat revascularization; the advantage of PES over BMS was also significant both in diabetic and non-diabetic pa‐ tients. Angiographic follow-up demonstrated the efficacy of the PES with a significantly smaller late lumen loss in the PES-treated group and significantly less restenosis (8% vs 51%) and reocclusion (2% vs 23%).

Two additional registries studied the role of PES in CTOs: among 65 patients with CTOs in the international WISDOM Registry, treatment with the PES resulted in freedom from MACE and repeat intervention at 1 year in 93.3% and 98.3% of patients [83], respectively; in the European TRUE Registry, among 183 with CTO treated with PES, 7-months rates of restenosis and target vessel revascularization were 17.0% and 16.9% respectively [84].

#### **6.2. Sirolimus eluting stents (SES) for CTOs - Registries**

Several observational studies examining clinical outcomes among patients treated with DES following successful CTO recanalization demonstrated the notion that unlike BMS, DES may achieve similar reductions in the need for repeat target vessel revascularization (TVR), as observed in non occlusive lesions.

The first data on the effectiveness of SES usage for CTOs came from the Rapamycin Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry, a prospective sin‐ gle centre study set-up with the aim of evaluating the safety and efficacy of SES in a ''real world'' scenario [85]. In this registry SES was the device of first choice for every PCI per‐ formed at the Thoraxcenter irrespective of patient or lesion characteristics. Among 56 pa‐ tients treated with SES following successful CTO revascularization during the first months, the 1-year survival free of major adverse cardiac events (MACE) defined as the composite of death, acute myocardial infarction or TVR was 96.4% compared with 82.1% among an his‐ torical control group of 28 patients receiving bare metal stents (p < 0.05). Six-month follow up angiography performed in 33 patients treated with SES showed a remarkable suppres‐ sion of neointimal proliferation, with in-stent late loss of 0.13±0.46, a binary restenosis rate of 9% and a single reocclusion (3%).

More recently, the RESEARCH investigators have reported the 3-year clinical and angio‐ graphic follow-up of patients with CTO in a consecutive series of 147 patients [86], with comparison between BMS (n = 71) and SES (n = 76). The cumulative event-free survival of MACE was 81.7% in BMS group and 84.2% in SES group (p = 0.7). The authors concluded that, despite clinical benefit after 1 year, the use of SES was no longer associated with signifi‐ cantly lower rates of TVR and MACE in patients with CTOs after 3 years of follow-up com‐ pared with BMS. The issue of long term outcome after successful CTO revascularization and DES implantation will surely continue to deserve attention in the future.

Ge et al. provided other insights into the angiographic and clinical impact of implantation of SES in the re-opened CTOs [87]. The results of a group comprised of 122 patients treated with SES were compared with a historical control group of 259 patients treated for the same kind of lesions during an antecedent 2-year period. Coronary enzyme release during the procedures was insignificantly different despite considerably longer stented segments in the SES treated group. At 6-month follow-up, the cumulative rate of MACE was 16.4% in the SES group and 35.1% in the BMS group (p<0.001), whereas the incidence of restenosis was 9.2% and 33.3% (P<0.001) in SES vs BMS, respectively. The need for revascularization in the SES group was significantly lower, both for target lesion revascularization (TLR) (7.4 vs. 26.3%, P<0.001) and TVR (9.0 vs. 29.0%, P<0.001). No differences were observed between the groups in the occurrence of death, myocardial infarction, or stent thrombosis in the 6-month observation period.

spective trial, which esamining the safety and efficacy of SES in CTOs PCI. In this study, the 6-months binary restenosis rates were 9.5% in-stent, 12.4% in-segment, and 22.6% in-"work‐ ing lenght" representing the entire treatment segment. Rates of 1-year target lesion revascu‐ larization, MI and target vessel failure were 9.8%, 1.0% and 10.9%, respectively. Stent

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More recently, Galassi et al. have published the results of SECTOR (Sirolimus-Eluting Stent in Complex Coronary Chronic Total Occlusion Revascularization) Registry designed to as‐ sess angiographic and clinical outcomes after sirolimus-eluting stent (SES) implantation in the setting of a "real world" series of complex CTOs [91]. In this registry, the 9-12 months angiographic follow-up performed in 85.5% of lesions showed a binary restenosis rate of 16.8%. Moreover, at 2-year clinical follow-up, the rates of target lesion revascularization,

The PRISON II [92] has been the first randomized trial performed to compare DES and BMS. PRISON II addressed a primary end point of angiographic binary restenosis at six months and secondary end points of MACE, target vessel failure (TVF), in-stent and in-segment mean luminal diameter (MLD), late lumen loss, late-loss index, and percent diameter steno‐ sis at six months. A total of 200 patients were randomized to a bare BX Velocity stent or to the SES. In-stent restenosis results were 7% for the SES patient cohort vs. 36% for the pa‐ tients in the bare metal control arm of the study (p <0.001). The SES also achieved statistical significance in key clinical endpoints such as target lesion revascularization (4% vs. 19%; p=0.001); TVF (8% vs 24%; p= 0.003) and MACE (4% vs 20%; p<0.001). In-stent late loss in the SES patient cohort was 0.05 mm and 1.09 mm in the control (p=0.0001). Such strong evidence from a well-conducted randomized study has provided clear evidence of efficacy of the SES

Long term results of PRISON II were recently published [93]. At 5-year follow-up, event rates still favoured the SES arm over the BMS arm. In fact, SES group had significantly lower rates of target lesion revascularisation (12% vs. 30%, p=0.001), target vessel revascularisation (17% vs. 34%, p=0.009) and MACE (12% vs. 36%, p<0.001). There were no significant differ‐ ences in death and myocardial infarction. On the other hand, there is a trend to a higher

The CORACTO study [94] was performed to evaluate the sirolimus-coated CURA stent in 95 patients with a CTO of > 3 months duration. Patients were randomized to treatment with either the CURA stent or BMS implantation; the primary end-point was late loss and reste‐ nosis at 6 months. Follow-up angiography demonstrated significant differences between the two groups in favour of CURA stents. The mean late loss was 1.46 mm in those treated with BMS vs 0.41 mm in the CURA stent group (p<0.001). The suppression of neointimal prolifer‐ ation was associated with less restenosis, reocclusion, and need for TVR. No patient died or

non-Q wave MI, and total MACE were of 11.1%, 2%, and 13.1%, respectively.

**6.3. Sirolimus eluting stents for CTOs - Randomized trials**

and follow up is awaited to evaluate the long term outcomes.

stent thrombosis rate in the SES group (8% vs. 3%, p=0,21).

suffered a stent thrombosis or myocardial infarction.

thrombosis occurred in two patients (1.0%) [90].

The e-CYPHER was a registry designed to capture postmarketing surveillance data on the use of SES. Between April 2002 and September 2005, data on 15,157 patients treated with SES at 279 centers from 41 countries were entered into the registry. From the total amount of patients enrolled in the registry, 6-month follow-up data were available for 10,962 patients. A sub-analysis [88] assessed the outcomes of CTO, defined as an occlusion lasting > 3 months. A total of 415 patients were identified, representing 2.9% of the total population. When their results were compared with those ones seen for the rest of the patients enrolled in the registry, there was no difference regarding death, myocardial infarction, TLR, or MACE. Investigators concluded that the event rates were similar for patients with CTO treated with the SES and patients treated for other lesion types, with a low rate of TLR (2.9%) and MACE (6.5%) in the CTO group at 6-month follow-up.

The Sirolimus-eluting Stent in Chronic Total Occlusion (SICTO) study was a multicentre, prospective, non-randomized study of coronary stenting with SES in patients with CTOs [89]. A total amount of 25 patients was treated with the SES stent after successful balloon angioplasty and IVUS examination. At 6-month angiographic and IVUS follow-up, the use of the SES stent was associated with improvements both in reference vessel diameter and minimum lumen diameter. In addition, the rate of in-stent late loss was -0.1 ± 0.3 mm and percent stent plaque volume was 13.1 ± 18.4%. The number of events at 6 months was also very low, with no deaths, myocardial infarction, stent thrombosis, or target lesion revascula‐ rization. There were 2 cases of target vessel revascularization (8%).

As a part of a multicentre Asian registry evaluating DES, Nakamura et al. investigated clini‐ cal and angiographic outcomes in 60 patients who received SES and 120 patients who re‐ ceived BMS [83]. After 6 months, the SES group still had significantly lower restenosis and reocclusion rates (2% and 0%, respectively) than did the BMS group (32% and 6%, respec‐ tively). Afterwards the loss was significantly smaller in the SES group than in the BMS group. Moreover, the SES group had fewer cardiac events, including target lesion revascula‐ rization (2% vs 23%, p < 0.001), than the BMS group did. At 1 year, treatment with SES was associated with sustained reductions in hierarchical MACE and TLR.

The ACROSS/TOSCA 4 (Approaches to Chronic Occlusions with Sirolimus-Eluting Stents/ Total Occlusion Study of Coronary Arteries 4) study was amulticenter, non randomized pro‐

spective trial, which esamining the safety and efficacy of SES in CTOs PCI. In this study, the 6-months binary restenosis rates were 9.5% in-stent, 12.4% in-segment, and 22.6% in-"work‐ ing lenght" representing the entire treatment segment. Rates of 1-year target lesion revascu‐ larization, MI and target vessel failure were 9.8%, 1.0% and 10.9%, respectively. Stent thrombosis occurred in two patients (1.0%) [90].

More recently, Galassi et al. have published the results of SECTOR (Sirolimus-Eluting Stent in Complex Coronary Chronic Total Occlusion Revascularization) Registry designed to as‐ sess angiographic and clinical outcomes after sirolimus-eluting stent (SES) implantation in the setting of a "real world" series of complex CTOs [91]. In this registry, the 9-12 months angiographic follow-up performed in 85.5% of lesions showed a binary restenosis rate of 16.8%. Moreover, at 2-year clinical follow-up, the rates of target lesion revascularization, non-Q wave MI, and total MACE were of 11.1%, 2%, and 13.1%, respectively.

### **6.3. Sirolimus eluting stents for CTOs - Randomized trials**

Ge et al. provided other insights into the angiographic and clinical impact of implantation of SES in the re-opened CTOs [87]. The results of a group comprised of 122 patients treated with SES were compared with a historical control group of 259 patients treated for the same kind of lesions during an antecedent 2-year period. Coronary enzyme release during the procedures was insignificantly different despite considerably longer stented segments in the SES treated group. At 6-month follow-up, the cumulative rate of MACE was 16.4% in the SES group and 35.1% in the BMS group (p<0.001), whereas the incidence of restenosis was 9.2% and 33.3% (P<0.001) in SES vs BMS, respectively. The need for revascularization in the SES group was significantly lower, both for target lesion revascularization (TLR) (7.4 vs. 26.3%, P<0.001) and TVR (9.0 vs. 29.0%, P<0.001). No differences were observed between the groups in the occurrence of death, myocardial infarction, or stent thrombosis in the 6-month

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

The e-CYPHER was a registry designed to capture postmarketing surveillance data on the use of SES. Between April 2002 and September 2005, data on 15,157 patients treated with SES at 279 centers from 41 countries were entered into the registry. From the total amount of patients enrolled in the registry, 6-month follow-up data were available for 10,962 patients. A sub-analysis [88] assessed the outcomes of CTO, defined as an occlusion lasting > 3 months. A total of 415 patients were identified, representing 2.9% of the total population. When their results were compared with those ones seen for the rest of the patients enrolled in the registry, there was no difference regarding death, myocardial infarction, TLR, or MACE. Investigators concluded that the event rates were similar for patients with CTO treated with the SES and patients treated for other lesion types, with a low rate of TLR

The Sirolimus-eluting Stent in Chronic Total Occlusion (SICTO) study was a multicentre, prospective, non-randomized study of coronary stenting with SES in patients with CTOs [89]. A total amount of 25 patients was treated with the SES stent after successful balloon angioplasty and IVUS examination. At 6-month angiographic and IVUS follow-up, the use of the SES stent was associated with improvements both in reference vessel diameter and minimum lumen diameter. In addition, the rate of in-stent late loss was -0.1 ± 0.3 mm and percent stent plaque volume was 13.1 ± 18.4%. The number of events at 6 months was also very low, with no deaths, myocardial infarction, stent thrombosis, or target lesion revascula‐

As a part of a multicentre Asian registry evaluating DES, Nakamura et al. investigated clini‐ cal and angiographic outcomes in 60 patients who received SES and 120 patients who re‐ ceived BMS [83]. After 6 months, the SES group still had significantly lower restenosis and reocclusion rates (2% and 0%, respectively) than did the BMS group (32% and 6%, respec‐ tively). Afterwards the loss was significantly smaller in the SES group than in the BMS group. Moreover, the SES group had fewer cardiac events, including target lesion revascula‐ rization (2% vs 23%, p < 0.001), than the BMS group did. At 1 year, treatment with SES was

The ACROSS/TOSCA 4 (Approaches to Chronic Occlusions with Sirolimus-Eluting Stents/ Total Occlusion Study of Coronary Arteries 4) study was amulticenter, non randomized pro‐

(2.9%) and MACE (6.5%) in the CTO group at 6-month follow-up.

rization. There were 2 cases of target vessel revascularization (8%).

associated with sustained reductions in hierarchical MACE and TLR.

observation period.

The PRISON II [92] has been the first randomized trial performed to compare DES and BMS. PRISON II addressed a primary end point of angiographic binary restenosis at six months and secondary end points of MACE, target vessel failure (TVF), in-stent and in-segment mean luminal diameter (MLD), late lumen loss, late-loss index, and percent diameter steno‐ sis at six months. A total of 200 patients were randomized to a bare BX Velocity stent or to the SES. In-stent restenosis results were 7% for the SES patient cohort vs. 36% for the pa‐ tients in the bare metal control arm of the study (p <0.001). The SES also achieved statistical significance in key clinical endpoints such as target lesion revascularization (4% vs. 19%; p=0.001); TVF (8% vs 24%; p= 0.003) and MACE (4% vs 20%; p<0.001). In-stent late loss in the SES patient cohort was 0.05 mm and 1.09 mm in the control (p=0.0001). Such strong evidence from a well-conducted randomized study has provided clear evidence of efficacy of the SES and follow up is awaited to evaluate the long term outcomes.

Long term results of PRISON II were recently published [93]. At 5-year follow-up, event rates still favoured the SES arm over the BMS arm. In fact, SES group had significantly lower rates of target lesion revascularisation (12% vs. 30%, p=0.001), target vessel revascularisation (17% vs. 34%, p=0.009) and MACE (12% vs. 36%, p<0.001). There were no significant differ‐ ences in death and myocardial infarction. On the other hand, there is a trend to a higher stent thrombosis rate in the SES group (8% vs. 3%, p=0,21).

The CORACTO study [94] was performed to evaluate the sirolimus-coated CURA stent in 95 patients with a CTO of > 3 months duration. Patients were randomized to treatment with either the CURA stent or BMS implantation; the primary end-point was late loss and reste‐ nosis at 6 months. Follow-up angiography demonstrated significant differences between the two groups in favour of CURA stents. The mean late loss was 1.46 mm in those treated with BMS vs 0.41 mm in the CURA stent group (p<0.001). The suppression of neointimal prolifer‐ ation was associated with less restenosis, reocclusion, and need for TVR. No patient died or suffered a stent thrombosis or myocardial infarction.

#### **6.4. Comparative DES trials in CTOs revascularization**

The clinical outcomes of both SES and PES for the treatment of CTO were further analyzed in the registry data from Rotterdam [95]. A cohort of 76 patients was treated with SES; sub‐ sequently, in the first quarter of 2003, all patients were treated with PES, including 57 treat‐ ed for a CTO. These patients were compared with a similar group of patients (n=26] treated with BMS in the 6-month period preceding April 2002. At 400 days, the cumulative survivalfree of target vessel revascularization was 80.8% in the BMS group versus 97.4% and 96.4% in the SES and PES groups respectively (p=0.01). The authors concluded that the use of both the SES and PES in the treatment of CTOs reduces the need for repeat revascularization compared to BMS.

proved stent expansion in its entire length and resulted in better outcomes with less need for TVR [101-103]. Consequently, post-dilatation has been widely, although not universally, used. With the advent of DES and much lower rates of TVR, there has been renewed controversy re‐ garding the need for adjunctive balloon post-dilatation to optimize outcomes. However DES thrombosis, which might be related to procedural variables, such as minimal stent area (MSA) and stent expansion following stent deployment, makes a come back the role of post-dilata‐ tion. Indeed, the frequency of stent thrombosis following DES implantation is relatively low [104-105], but the clinical sequeale of stent thrombosis are catastrophic and include death in about 45% of patients and non-fatal myocardial infarction in most of the survivors [106].

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Similarly to stent thrombosis, maximizing MSA appears important in reducing the risk of TVR. This should be theoretically even more important in case of long standing CTO where severe and diffuse disease in presence of extensive calcification might prevent adequate

The inability to achieve optimum stent deployment is not due to undersizing the stent deliv‐ ery balloon, but rather due to an inability of the stent delivery balloon to expand fully the stent to nominal size. With postdilatation using noncompliant balloons, the frequency of

Lesions with heavy calcification or large plaque burden, such as CTO lesion, are likely to have increased resistance to dilatation. In such situations, inadequate stent expansion may be evident from the contour of the deployment balloon or the angiographic appearance of the stent post stent deployment. However, inadequate stent expansion is usually not detect‐ able by angiographic assessment. In situations where there is likely to be increased resist‐ ance to dilatation, postdilatation with noncompliant balloons at high pressure appears to be

Theoretically, in an attempt to minimize stent thrombosis and TVR, post-dilatation with non-compliant balloons should be performed by IVUS guidance. Unfortunately, it is not practical and probably not cost-effective to perform IVUS and post-dilatation to all patients undergoing DES implantation. Moreover after DES implantation in long CTO lesion with multiple stents overlapping is recommended to perform post-dilatation with non compliant balloon in order to improve MSA and thus to obtained a good angiographic outcome.

Post-dilatation can improve significantly MSA within the limits of reference vessel size even if it is still likely not to affect non-uniformity expansion. An uniform stent expansion may be achieved with either adequate pre-dilatation or by the use of rotational atherectomy in calci‐ fied lesions to allow the simmetricity expansion of the lesion by the balloon and stent.

The PCI CTO procedural complications can be classified as follows: vascular access related and procedure related. Despite the development of new devices and techniques, complica‐ tions still occasionally occur today. This is highlighted by the complications reducing with

stent expansion [107].

a good strategy.

**7. Complications of CTO PCI**

achieving optimum stent deployment doubles [108].

Another report by Jang et al. involved 107 patients with CTO who received SES, and 29 patients with CTO who received PES [96]. At 6-month angiographic follow up, the reste‐ nosis rate was significantly higher in the PES group (28.6% vs. 9.4%; p = 0.02). Similarly, the late loss was significantly higher in the PES group (0.8 mm vs. 0.4 mm; p = 0.025). At one-year follow up, the MACE-free survival rate was significantly higher in the SES group (95.8% vs. 85.8%; p = 0.049).

Recently, a randomized study evaluating SES and PES has been performed by De Lezo et al [97]. No significant differences were reported between SES and PES in the rates of restenosis (7.4% versus 19%, respectively) and TLR (3.3% versus 7.0%). However, the PES group was found to have a significantly higher late loss and neointimal area on intravascular ultrasound. At 15 months, death and myocardial infarction rates were comparable between the two stents.

A prospective analysis of 1149 patients with 1183 CTOs (396 SES, 526 PES, 177 ZES, 64 EPC capture, 43 EES) in five high volume Asian centers after successful recanalization of CTO was recently performed [98]. The study endpoints were 30 days and 9 months MACE, 9 months angiographic restenosis and TLR. In this series patients treated with SES showed lesser rate of restenosis compared with other drug-eluting stents.

PRISON III ongoing trial will address whether or not SES are superior to other drug-eluting stents in total coronary occlusions. Indeed this prospective, randomized trial, SES implanta‐ tion will be compared with zotarolimus-eluting stent implantation for the treatment of total coronary occlusions. A total of 300 patients will be followed for up to 5 years with angio‐ graphic follow-up at 8 months. The primary end point will be in-segment late luminal loss at 8 months angiographic follow-up [99].

A new randomised ongoing trial, the Non-Acute Coronary occlusion treated by EveroLi‐ mus-Eluting Stent (CIBELES) trial, aims to compare everolimus-eluting stent and sirolimuseluting stent in treating CTOs, in terms of angiographic efficacy [100].

#### **6.5. Optimization of stent deployment**

The introduction of stent delivery systems, which used semi-compliant balloons to deploy stents at higher pressures, initially resulted in less use of balloon post-dilatation. However, it was soon recognized that adjunctive balloon post-dilatation following deployment of BMS im‐ proved stent expansion in its entire length and resulted in better outcomes with less need for TVR [101-103]. Consequently, post-dilatation has been widely, although not universally, used. With the advent of DES and much lower rates of TVR, there has been renewed controversy re‐ garding the need for adjunctive balloon post-dilatation to optimize outcomes. However DES thrombosis, which might be related to procedural variables, such as minimal stent area (MSA) and stent expansion following stent deployment, makes a come back the role of post-dilata‐ tion. Indeed, the frequency of stent thrombosis following DES implantation is relatively low [104-105], but the clinical sequeale of stent thrombosis are catastrophic and include death in about 45% of patients and non-fatal myocardial infarction in most of the survivors [106].

Similarly to stent thrombosis, maximizing MSA appears important in reducing the risk of TVR. This should be theoretically even more important in case of long standing CTO where severe and diffuse disease in presence of extensive calcification might prevent adequate stent expansion [107].

The inability to achieve optimum stent deployment is not due to undersizing the stent deliv‐ ery balloon, but rather due to an inability of the stent delivery balloon to expand fully the stent to nominal size. With postdilatation using noncompliant balloons, the frequency of achieving optimum stent deployment doubles [108].

Lesions with heavy calcification or large plaque burden, such as CTO lesion, are likely to have increased resistance to dilatation. In such situations, inadequate stent expansion may be evident from the contour of the deployment balloon or the angiographic appearance of the stent post stent deployment. However, inadequate stent expansion is usually not detect‐ able by angiographic assessment. In situations where there is likely to be increased resist‐ ance to dilatation, postdilatation with noncompliant balloons at high pressure appears to be a good strategy.

Theoretically, in an attempt to minimize stent thrombosis and TVR, post-dilatation with non-compliant balloons should be performed by IVUS guidance. Unfortunately, it is not practical and probably not cost-effective to perform IVUS and post-dilatation to all patients undergoing DES implantation. Moreover after DES implantation in long CTO lesion with multiple stents overlapping is recommended to perform post-dilatation with non compliant balloon in order to improve MSA and thus to obtained a good angiographic outcome.

Post-dilatation can improve significantly MSA within the limits of reference vessel size even if it is still likely not to affect non-uniformity expansion. An uniform stent expansion may be achieved with either adequate pre-dilatation or by the use of rotational atherectomy in calci‐ fied lesions to allow the simmetricity expansion of the lesion by the balloon and stent.

## **7. Complications of CTO PCI**

**6.4. Comparative DES trials in CTOs revascularization**

compared to BMS.

group (95.8% vs. 85.8%; p = 0.049).

at 8 months angiographic follow-up [99].

**6.5. Optimization of stent deployment**

The clinical outcomes of both SES and PES for the treatment of CTO were further analyzed in the registry data from Rotterdam [95]. A cohort of 76 patients was treated with SES; sub‐ sequently, in the first quarter of 2003, all patients were treated with PES, including 57 treat‐ ed for a CTO. These patients were compared with a similar group of patients (n=26] treated with BMS in the 6-month period preceding April 2002. At 400 days, the cumulative survivalfree of target vessel revascularization was 80.8% in the BMS group versus 97.4% and 96.4% in the SES and PES groups respectively (p=0.01). The authors concluded that the use of both the SES and PES in the treatment of CTOs reduces the need for repeat revascularization

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

Another report by Jang et al. involved 107 patients with CTO who received SES, and 29 patients with CTO who received PES [96]. At 6-month angiographic follow up, the reste‐ nosis rate was significantly higher in the PES group (28.6% vs. 9.4%; p = 0.02). Similarly, the late loss was significantly higher in the PES group (0.8 mm vs. 0.4 mm; p = 0.025). At one-year follow up, the MACE-free survival rate was significantly higher in the SES

Recently, a randomized study evaluating SES and PES has been performed by De Lezo et al [97]. No significant differences were reported between SES and PES in the rates of restenosis (7.4% versus 19%, respectively) and TLR (3.3% versus 7.0%). However, the PES group was found to have a significantly higher late loss and neointimal area on intravascular ultrasound. At 15 months, death and myocardial infarction rates were comparable between the two stents.

A prospective analysis of 1149 patients with 1183 CTOs (396 SES, 526 PES, 177 ZES, 64 EPC capture, 43 EES) in five high volume Asian centers after successful recanalization of CTO was recently performed [98]. The study endpoints were 30 days and 9 months MACE, 9 months angiographic restenosis and TLR. In this series patients treated with SES showed

PRISON III ongoing trial will address whether or not SES are superior to other drug-eluting stents in total coronary occlusions. Indeed this prospective, randomized trial, SES implanta‐ tion will be compared with zotarolimus-eluting stent implantation for the treatment of total coronary occlusions. A total of 300 patients will be followed for up to 5 years with angio‐ graphic follow-up at 8 months. The primary end point will be in-segment late luminal loss

A new randomised ongoing trial, the Non-Acute Coronary occlusion treated by EveroLi‐ mus-Eluting Stent (CIBELES) trial, aims to compare everolimus-eluting stent and sirolimus-

The introduction of stent delivery systems, which used semi-compliant balloons to deploy stents at higher pressures, initially resulted in less use of balloon post-dilatation. However, it was soon recognized that adjunctive balloon post-dilatation following deployment of BMS im‐

lesser rate of restenosis compared with other drug-eluting stents.

eluting stent in treating CTOs, in terms of angiographic efficacy [100].

The PCI CTO procedural complications can be classified as follows: vascular access related and procedure related. Despite the development of new devices and techniques, complica‐ tions still occasionally occur today. This is highlighted by the complications reducing with improved learning curve. Therefore, the operator's experience is essential in order to quickly recognise and handle all sorts of complications.

Femoral pseudoaneurysm and artero-venuos fistulae might occur in case of low puncture (more than 2 cm below the inguinal ligament). Diagnosis is based on clinical grounds (the presence of hard and pulsatile mass in the case of pseudoaneurysm and the presence of con‐ tinuous murmur in case of an artero-venous fistulae) and confirmed by Doppler examina‐ tion. In most cases pseudoaneurysm can be closed successfully with femoral compression guided by echocardiography followed by bed rest for 12-24 hours after discontinuation of

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457

Dissection can be caused by the wire or the sheath at the access site and can extend retro‐ gradely upward in to the vascular system; this occurs more frequently in older and hyper‐

Complications directly related to CTO procedure might be summarized in: *coronary perfora‐ tion or rupture, coronary ostium dissection, coronary thrombosis and entrapment of device into a le‐ sion*. Among these complications, coronary perforation is associated with different adverse cardiac event such as myocardial infarction and cardiac tamponade. Although coronary per‐ foration accounts for 10% of total referrals for emergent cardiac surgery, it is most common‐ ly managed in the catheterization laboratory with different approach. Several large PCI series shows an incidence of coronary perforation below 1% [110-113], and the presence of a

During PCI, coronary perforation is one of the most undesirable complications because it is occasionally life-threatening by causing cardiac tamponade or acute myocardial infarction [110-113]; it represents a disruption of the vessel wall through the intima, media and adven‐ titia. Coronary perforations risk factors during standard PCI can be classified as *patient relat‐ ed, angiographic related and device and/or procedure related*. In term of *patient-related* risk several studies found that older age and female gender are associated with an increased incidence

*Angiographic related* risk factors are represented by heavy calcification and innaccurate as‐ sessment of vessel diameter size. Indeed, these lesions require often the use of multiple bal‐ loon dilatations coupled with relatively high inflation pressure, before and/or after stent implantation, in order to achieve full stent expansion. These might cause vessel wall perfo‐ ration, especially when are used compliant or semi-compliant balloon. In a study of Tobis et al. the use of a high balloon to vessel ratio (1.2:1) with a mean inflation pressure of 15 atm determined an incidence of vessel rupture and major dissection of approximately 3-4% of the cases [116]. In the same study, the use of a smaller balloons, in a different subgroup, but with higher mean inflation pressure (16 atm) was associated with reduction of coronary per‐ foration rate (0.7%) [116]. For these reasons, we suggest to use small diameter size balloon

tensinve patients with marked aortic tortuosity and may cause limb ischemia.

CTO does not seem to increase significantly this value [114].

antithrombotic medication.

**7.3. Coronary perforation**

of coronary perforation [107, 108, 115].

when performing PCI in CTO lesion.

**7.2. Complications procedure related**

#### **7.1. Complications vascular access related**

Access site complications are common during intravascular procedure and include hemato‐ mas of any size, pseudoaneurysm, and artero-venuos fistulae [109]. Despite of the need of large size sheath and double coronary cannulation, both femoral vascular access are general‐ ly recommended during CTO PCI. Some operators prefer to place two sheaths in the same femoral artery, in order to reduce patient discomfort (Figure 8) however, this approach re‐ strict the use up to smaller size sheaths and might limit the use of closure device after proce‐ dure thus increasing the occurrence of rare complication such as acute limb ischemia.

**Figure 8.** Two 6 French sheath in a femoral artery

Such complications are more frequent in older, female, overweight or previously anticougu‐ lated patients, and can be prevent by careful puncture, compression technique and 6-12 hours bed rest after procedure. Small hematomas are common (2-15%) and usually produce only mild discomfort for a few days. Large hematomas (>10 cm) are less frequent (1-2%) and might require prolonged rest and a delay in hospital discharge; the complete resolution, thus may take in 3-4 weeks. Diagnosis can be based on clinical features (no femoral mur‐ mur) and confirmed by a Doppler study performed with standard echocardiography equip‐ ment. Occasionally, large hematomas become infected, and in this case is important to surgically drain the cavity by purulent materials. This may take 2-3 months to heal.

Uncontrolled bleeding (either evident or into retroperitoneal space) with severe haemodi‐ namic compromise require aggressive fluid blood replacement, ruling out bleeding from an‐ other origin. In these cases vascular surgery might resolve the complications.

Femoral pseudoaneurysm and artero-venuos fistulae might occur in case of low puncture (more than 2 cm below the inguinal ligament). Diagnosis is based on clinical grounds (the presence of hard and pulsatile mass in the case of pseudoaneurysm and the presence of con‐ tinuous murmur in case of an artero-venous fistulae) and confirmed by Doppler examina‐ tion. In most cases pseudoaneurysm can be closed successfully with femoral compression guided by echocardiography followed by bed rest for 12-24 hours after discontinuation of antithrombotic medication.

Dissection can be caused by the wire or the sheath at the access site and can extend retro‐ gradely upward in to the vascular system; this occurs more frequently in older and hyper‐ tensinve patients with marked aortic tortuosity and may cause limb ischemia.

#### **7.2. Complications procedure related**

improved learning curve. Therefore, the operator's experience is essential in order to quickly

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

Access site complications are common during intravascular procedure and include hemato‐ mas of any size, pseudoaneurysm, and artero-venuos fistulae [109]. Despite of the need of large size sheath and double coronary cannulation, both femoral vascular access are general‐ ly recommended during CTO PCI. Some operators prefer to place two sheaths in the same femoral artery, in order to reduce patient discomfort (Figure 8) however, this approach re‐ strict the use up to smaller size sheaths and might limit the use of closure device after proce‐ dure thus increasing the occurrence of rare complication such as acute limb ischemia.

Such complications are more frequent in older, female, overweight or previously anticougu‐ lated patients, and can be prevent by careful puncture, compression technique and 6-12 hours bed rest after procedure. Small hematomas are common (2-15%) and usually produce only mild discomfort for a few days. Large hematomas (>10 cm) are less frequent (1-2%) and might require prolonged rest and a delay in hospital discharge; the complete resolution, thus may take in 3-4 weeks. Diagnosis can be based on clinical features (no femoral mur‐ mur) and confirmed by a Doppler study performed with standard echocardiography equip‐ ment. Occasionally, large hematomas become infected, and in this case is important to

Uncontrolled bleeding (either evident or into retroperitoneal space) with severe haemodi‐ namic compromise require aggressive fluid blood replacement, ruling out bleeding from an‐

surgically drain the cavity by purulent materials. This may take 2-3 months to heal.

other origin. In these cases vascular surgery might resolve the complications.

recognise and handle all sorts of complications.

**7.1. Complications vascular access related**

**Figure 8.** Two 6 French sheath in a femoral artery

Complications directly related to CTO procedure might be summarized in: *coronary perfora‐ tion or rupture, coronary ostium dissection, coronary thrombosis and entrapment of device into a le‐ sion*. Among these complications, coronary perforation is associated with different adverse cardiac event such as myocardial infarction and cardiac tamponade. Although coronary per‐ foration accounts for 10% of total referrals for emergent cardiac surgery, it is most common‐ ly managed in the catheterization laboratory with different approach. Several large PCI series shows an incidence of coronary perforation below 1% [110-113], and the presence of a CTO does not seem to increase significantly this value [114].

#### **7.3. Coronary perforation**

During PCI, coronary perforation is one of the most undesirable complications because it is occasionally life-threatening by causing cardiac tamponade or acute myocardial infarction [110-113]; it represents a disruption of the vessel wall through the intima, media and adven‐ titia. Coronary perforations risk factors during standard PCI can be classified as *patient relat‐ ed, angiographic related and device and/or procedure related*. In term of *patient-related* risk several studies found that older age and female gender are associated with an increased incidence of coronary perforation [107, 108, 115].

*Angiographic related* risk factors are represented by heavy calcification and innaccurate as‐ sessment of vessel diameter size. Indeed, these lesions require often the use of multiple bal‐ loon dilatations coupled with relatively high inflation pressure, before and/or after stent implantation, in order to achieve full stent expansion. These might cause vessel wall perfo‐ ration, especially when are used compliant or semi-compliant balloon. In a study of Tobis et al. the use of a high balloon to vessel ratio (1.2:1) with a mean inflation pressure of 15 atm determined an incidence of vessel rupture and major dissection of approximately 3-4% of the cases [116]. In the same study, the use of a smaller balloons, in a different subgroup, but with higher mean inflation pressure (16 atm) was associated with reduction of coronary per‐ foration rate (0.7%) [116]. For these reasons, we suggest to use small diameter size balloon when performing PCI in CTO lesion.

*Among device and/or procedure related* complications several authors have shown that the use of *atheroblative debulking devices (laser, rotational atherectomy, directional coronary atherectomy)* might be associated with coronary perforation [112-113]. Other devices such us cutting bal‐ loon, IVUS probe, extraction catheters and embolic protection device might also enhance the likelihood of coronary perforation, as well as stiffer and/or hydrophilic wires that are rou‐ tinely used for CTO recanalization. During the procedure is important to follow the path of the guide wire in multiple orthogonal projection, in order to recognize promptly site of ves‐ sel wall apart or segment of sub-intimal tracking.

In case of *type I perforation*, the retrieval of guidewire is sufficient to cope with the com‐ plication. In other cases a prolonged (3-5 minutes) proximal balloon inflation or stent im‐ plantation might help to solve the problem. However, a careful observation for 15-30 minutes with repeated injection of contrast mean is highly recommended. If the extrava‐ sation enlarges during time, intravenous administration of protamine sulfate is advised in order to neutralizing the anticoagulant effect, as patients performing CTO PCI are treated by unfractioned heparin alone. Generally re-administration of protamine sulfate is given intravenously over a 3–5 min time period for obtaining a ACT target less than 150 seconds as reported [112-115]. Moreover, it is to remember that protamine sulfate ad‐ ministration is safe in case of BMS implantation [117] but it might cause, albeit rarely,

Percutaneous Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward

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459

In *type II perforation*, proximal balloon inflation and reversal of anticoagulation with prota‐ mine sulfate are the first actions to take. Echocardiographic assessment should be performed without delay; early diastolic right ventricular collapse and late diastolic right atrial collapse are early signs of cardiac tamponade and precede the haemodinamic instability. If these signs are observed urgent pericardiocentesis should be recommended and this is an action to be taken immediately after recognition of the perforation and before clinical symptoms develop. A placement of coronary perfusion catheter (CPC) balloon might be indicated, if after 5-10 minutes of proximal balloon inflation the seal of perforation does not occur. The passive CPC balloon has been initially developed to allow demands of the myocardium at risk, for prolonged inflation in patients with rigid artery stenosis [119] and later modified to seal coronary perforation. Several types of this device have the same principle design which consist of side-holes in the shaft of the catheter proximal and distal to the balloon, allowing passive blood perfusion during balloon inflation, depending on the aortic perfusion pres‐ sure. Perfusion catheters provide a blood flow of 40-60 ml/minutes to the region at risk [119]. Nevertheless, a significant number of patients do not tolerate prolonged inflation peri‐ ods, either because of obstruction of a side branch or due to inadequate flow relative to the demands of the myocardium at risk. Therefore the CPC balloon devices might be used in preparation of emergent cardiac surgery [120], reducing pericardial blood blush and Q wave myocardial infarction occurrence. Emergent cardiac surgery is reserved for patients in

The onset of *type III perforation* is usually dramatically: an immediate aggressive treat‐ ment strategy is needed, including adequate volume resuscitation, administration of cate‐ cholamines and urgent pericardiocentesis. Obviously, a proximal balloon inflation and heparin reversal is also needed immediately; and after the stabilization of patient clinical status a placement of covered stent (in case of epicardial coronary rupture) or synthetic microsphere embolization (in case of distal perforation) might seal the perforation [111-115]. In case of perforation resolution is advisable a careful post-procedure echocar‐ diograms monitoring, before pericardial catheter removal and at discharge. The figure 9 reports a practical algorithm for the management of coronary perforation adapted by

stent thrombosis with potential fatal consequences, in case of DES use [118].

whom hemostasis is not achieved with these measures.

Dippel and colleagues [121] (Figure 9)

Perforation due to stiff wires are divided in two categories: perforation of the false lumen while advancing the stiff wire into it, and perforation in distal small branch after crossing CTO lesion. Generally the first type of perforation do not require a specific treatment be‐ cause it disappears after dilatation on another false lumen. Conversely in distal small branch perforation a careful observation through multiple contrast injection are needed to confirm the risk related to perforation. Indeed, these might lead to early or late cardiac tamponade. Thus, is recommended at the end of procedure, even if in successful cases, to perform at least two orthogonal cine angiograms to exclude the presence of it.

Ellis et al., on the basis of prospectively recorded data of a total of 12.900 PCI procedure from 11 US sites during a 2-year period [110], were able to drawn a coronary perforation classification related to the angiographic appearance of blood extravasation during the pro‐ cedure in four types:


In addition this study evaluated its proposal classification system as a tool to predict out‐ come and as the basis management as follow:


Myocardial infarction and the majority of emergent CABG and cardiac tamponade were entirely limited of type III perforation [113]. Coronary perforation is associated with a significant mortality risk; its management and treatment need to be initiated very quick‐ ly. The strategy of treatment is determinate by angiographic characteristics and clinical circumstances [115].

In case of *type I perforation*, the retrieval of guidewire is sufficient to cope with the com‐ plication. In other cases a prolonged (3-5 minutes) proximal balloon inflation or stent im‐ plantation might help to solve the problem. However, a careful observation for 15-30 minutes with repeated injection of contrast mean is highly recommended. If the extrava‐ sation enlarges during time, intravenous administration of protamine sulfate is advised in order to neutralizing the anticoagulant effect, as patients performing CTO PCI are treated by unfractioned heparin alone. Generally re-administration of protamine sulfate is given intravenously over a 3–5 min time period for obtaining a ACT target less than 150 seconds as reported [112-115]. Moreover, it is to remember that protamine sulfate ad‐ ministration is safe in case of BMS implantation [117] but it might cause, albeit rarely, stent thrombosis with potential fatal consequences, in case of DES use [118].

*Among device and/or procedure related* complications several authors have shown that the use of *atheroblative debulking devices (laser, rotational atherectomy, directional coronary atherectomy)* might be associated with coronary perforation [112-113]. Other devices such us cutting bal‐ loon, IVUS probe, extraction catheters and embolic protection device might also enhance the likelihood of coronary perforation, as well as stiffer and/or hydrophilic wires that are rou‐ tinely used for CTO recanalization. During the procedure is important to follow the path of the guide wire in multiple orthogonal projection, in order to recognize promptly site of ves‐

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

Perforation due to stiff wires are divided in two categories: perforation of the false lumen while advancing the stiff wire into it, and perforation in distal small branch after crossing CTO lesion. Generally the first type of perforation do not require a specific treatment be‐ cause it disappears after dilatation on another false lumen. Conversely in distal small branch perforation a careful observation through multiple contrast injection are needed to confirm the risk related to perforation. Indeed, these might lead to early or late cardiac tamponade. Thus, is recommended at the end of procedure, even if in successful cases, to perform at

Ellis et al., on the basis of prospectively recorded data of a total of 12.900 PCI procedure from 11 US sites during a 2-year period [110], were able to drawn a coronary perforation classification related to the angiographic appearance of blood extravasation during the pro‐

**•** Type IV (cavity spilling) perforation into anatomic cavity chamber, coronary sinus, etc.

In addition this study evaluated its proposal classification system as a tool to predict out‐

**•** Type I: fully contained perforation rarely result in tamponade or in myocardial ischemia **•** Type II: limited extravasation perforation have high treatment success rate when man‐ aged with prolonged balloon inflation, and commonly have a low occurrence of persistent contrast extravasation, consequently resulting in a low incidence of adverse sequelae

**•** Type III: brisk extravasation perforation are associated with rapid development of hemo‐ dynamic compromise and life-threatening complication, include cardiac tamponade and

Myocardial infarction and the majority of emergent CABG and cardiac tamponade were entirely limited of type III perforation [113]. Coronary perforation is associated with a significant mortality risk; its management and treatment need to be initiated very quick‐ ly. The strategy of treatment is determinate by angiographic characteristics and clinical

sel wall apart or segment of sub-intimal tracking.

cedure in four types:

circumstances [115].

least two orthogonal cine angiograms to exclude the presence of it.

**•** Type I, perforation with extaluminal crater without extravasation

the need for emergent bypass surgery with high rate of mortality

**•** Type III, extravasation through frank (≥ 1mm) perforation

come and as the basis management as follow:

**•** Type II, pericardial or myocardial blush without contrast jet extravasation

In *type II perforation*, proximal balloon inflation and reversal of anticoagulation with prota‐ mine sulfate are the first actions to take. Echocardiographic assessment should be performed without delay; early diastolic right ventricular collapse and late diastolic right atrial collapse are early signs of cardiac tamponade and precede the haemodinamic instability. If these signs are observed urgent pericardiocentesis should be recommended and this is an action to be taken immediately after recognition of the perforation and before clinical symptoms develop. A placement of coronary perfusion catheter (CPC) balloon might be indicated, if after 5-10 minutes of proximal balloon inflation the seal of perforation does not occur. The passive CPC balloon has been initially developed to allow demands of the myocardium at risk, for prolonged inflation in patients with rigid artery stenosis [119] and later modified to seal coronary perforation. Several types of this device have the same principle design which consist of side-holes in the shaft of the catheter proximal and distal to the balloon, allowing passive blood perfusion during balloon inflation, depending on the aortic perfusion pres‐ sure. Perfusion catheters provide a blood flow of 40-60 ml/minutes to the region at risk [119]. Nevertheless, a significant number of patients do not tolerate prolonged inflation peri‐ ods, either because of obstruction of a side branch or due to inadequate flow relative to the demands of the myocardium at risk. Therefore the CPC balloon devices might be used in preparation of emergent cardiac surgery [120], reducing pericardial blood blush and Q wave myocardial infarction occurrence. Emergent cardiac surgery is reserved for patients in whom hemostasis is not achieved with these measures.

The onset of *type III perforation* is usually dramatically: an immediate aggressive treat‐ ment strategy is needed, including adequate volume resuscitation, administration of cate‐ cholamines and urgent pericardiocentesis. Obviously, a proximal balloon inflation and heparin reversal is also needed immediately; and after the stabilization of patient clinical status a placement of covered stent (in case of epicardial coronary rupture) or synthetic microsphere embolization (in case of distal perforation) might seal the perforation [111-115]. In case of perforation resolution is advisable a careful post-procedure echocar‐ diograms monitoring, before pericardial catheter removal and at discharge. The figure 9 reports a practical algorithm for the management of coronary perforation adapted by Dippel and colleagues [121] (Figure 9)

**7.6. Entrapment of device inside a lesion**

**Author details**

**References**

1987;9:763-8.

*Heart J* 1990;120:270-4.

*Circulation* 1992;85:106-15.

tal coronary occlusion. *Am Heart J* 2005;149:129-37.

collaterals, as solution to this complication is only surgery.

Simona Giubilato, Salvatore Davide Tomasello and Alfredo Ruggero Galassi

cular Interventional Unit, Cannizzaro Hospital, University of Catania, Italy

clusion on treatment strategy. Am J Cardiol 2005; 95, 1088-1091.

Department of Medical Sciences and Pediatrics, Catheterization Laboratory and Cardiovas‐

[1] Christofferson RD, Lehmann KG, Martin GV et al. Effect of chronic total coronary oc‐

[2] Melchior JP, Doriot PA, Chatelain P, Meier B, Urban P, Finci L, Rutishauser W. Im‐ provement of left ventricular contraction and relaxation synchronism after recanali‐ zation of chronic total coronary occlusion by angioplasty. *J Am Coll Cardiol*

[3] Warren RJ, Black AJ, Valentine PA, Manolas EG, Hunt D. Coronary angioplasty for chronic total occlusion reduces the need for subsequent coronary bypass surgery. *Am*

[4] Ivanhoe RJ, Weintraub WS, Douglas JS, Jr., Lembo NJ, Furman M, Gershony G, Co‐ hen CL, King SB, 3rd. Percutaneous transluminal coronary angioplasty of chronic to‐ tal occlusions. Primary success, restenosis, and long-term clinical follow-up.

[5] Werner GS, Surber R, Kuethe F, Emig U, Schwarz G, Bahrmann P, Figulla HR. Collat‐ erals and the recovery of left ventricular function after recanalization of a chronic to‐

[6] Suero JA, Marso SP, Jones PG, Laster SB, Huber KC, Giorgi LV, Johnson WL, Ruther‐ ford BD. Procedural outcomes and long-term survival among patients undergoing

Entrapment of device such as microcatheter or standard balloon might occur after CTO wire crossing especially in highly calcified and tortuous vessel. Several dedicated devices such as Tornus catheter, Corsair and Gopher might rarely stuck into the vessel in severe calcified le‐ sions. Such an evenience might be approached by the see saw technique with stiff wires; in‐ deed, the use of another stiff wire might find the way of a new dissection plane at the blocking site, breaking the calcium load which grapped the device. During retrograde ap‐ proach, in case of very tortuous collaterals it is also possible entrapment of guide wire with‐ in the coronary artery. In these cases attention should be paid not to twist the wire into

Percutaneous Recanalization of Chronic Total Occlusion (CTO) Coronary Arteries: Looking Back and Moving Forward

http://dx.doi.org/10.5772/54079

461

**Figure 9.** Algorithm of coronary perforation management in relation to angiographic type; adapted by Dippel et. al

#### **7.4. Coronary ostium dissection**

The need of high back-up force in CTO PCI, make the choice of guiding catheter very impor‐ tant. Several high back-up guiding catheters, such as Amplatz, could injure the coronary os‐ tium, causing flow limiting tubular dissection. Indeed, "maladroit" manipulation of guiding catheter or its deep intubation might also cause ostium dissection. This event happens fre‐ quently in the right coronary artery in case of proximal vessel disease. Thereafter in these case is recommended to stabilized the ostium and the proximal part of the vessel with stent implantation prior to beginning CTO PCI. Particular attention might give at the cannulation of donor vessel in case of retrograde approach. Indeed a dissection in the donor vessel might cause severe peri-procedural events.

#### **7.5. Coronary thrombosis**

The use of complex technique, such as retrograde approach and the use of multiple guide wire and device might added the risk of coronary thrombosis. Thus, after administration of initial bolus of 80-100 Units/Kg is recommended checking the ACT every 30 minutes main‐ taining the ACT >300 seconds (>350 second in case of retrograde approach). Indeed, careful observation in an angiogram might help to recognize early phase of coronary thrombosis. If a thrombus is observed, is advisable to abort the procedure, take away the double cannula‐ tion and resolve the situation with use of aspiration device and Gp IIb/IIIa inhibitors admin‐ istration. Distal embolization resulting in slow-flow phemonenon is very frequent after CTO balloon dilatation; in these cases intracoronary administration of vasodilatator such as ade‐ nosine of nitroprusside could improve coronary flow significantly.

#### **7.6. Entrapment of device inside a lesion**

Entrapment of device such as microcatheter or standard balloon might occur after CTO wire crossing especially in highly calcified and tortuous vessel. Several dedicated devices such as Tornus catheter, Corsair and Gopher might rarely stuck into the vessel in severe calcified le‐ sions. Such an evenience might be approached by the see saw technique with stiff wires; in‐ deed, the use of another stiff wire might find the way of a new dissection plane at the blocking site, breaking the calcium load which grapped the device. During retrograde ap‐ proach, in case of very tortuous collaterals it is also possible entrapment of guide wire with‐ in the coronary artery. In these cases attention should be paid not to twist the wire into collaterals, as solution to this complication is only surgery.

## **Author details**

Simona Giubilato, Salvatore Davide Tomasello and Alfredo Ruggero Galassi

Department of Medical Sciences and Pediatrics, Catheterization Laboratory and Cardiovas‐ cular Interventional Unit, Cannizzaro Hospital, University of Catania, Italy

## **References**

**Figure 9.** Algorithm of coronary perforation management in relation to angiographic type; adapted by Dippel et. al

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

The need of high back-up force in CTO PCI, make the choice of guiding catheter very impor‐ tant. Several high back-up guiding catheters, such as Amplatz, could injure the coronary os‐ tium, causing flow limiting tubular dissection. Indeed, "maladroit" manipulation of guiding catheter or its deep intubation might also cause ostium dissection. This event happens fre‐ quently in the right coronary artery in case of proximal vessel disease. Thereafter in these case is recommended to stabilized the ostium and the proximal part of the vessel with stent implantation prior to beginning CTO PCI. Particular attention might give at the cannulation of donor vessel in case of retrograde approach. Indeed a dissection in the donor vessel might

The use of complex technique, such as retrograde approach and the use of multiple guide wire and device might added the risk of coronary thrombosis. Thus, after administration of initial bolus of 80-100 Units/Kg is recommended checking the ACT every 30 minutes main‐ taining the ACT >300 seconds (>350 second in case of retrograde approach). Indeed, careful observation in an angiogram might help to recognize early phase of coronary thrombosis. If a thrombus is observed, is advisable to abort the procedure, take away the double cannula‐ tion and resolve the situation with use of aspiration device and Gp IIb/IIIa inhibitors admin‐ istration. Distal embolization resulting in slow-flow phemonenon is very frequent after CTO balloon dilatation; in these cases intracoronary administration of vasodilatator such as ade‐

nosine of nitroprusside could improve coronary flow significantly.

**7.4. Coronary ostium dissection**

cause severe peri-procedural events.

**7.5. Coronary thrombosis**


percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience. *J Am Coll Cardiol* 2001;38:409-14.

[16] Werner GS, Emig U, Mutschke O et al. Regression of collateral function after recanal‐ ization of chronic total coronary occlusion: a serial assessment by intracoronary pres‐

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[17] Zidar FJ, Kaplan BM, O'Neill WW et al. Prospective, randomized trial of prolonged intracoronary urokinase infusion for chronic total occlusions in native coronary arter‐

[18] Di Mario C, Werner S, Sianos G et al. – European perspective in the recanalisation of Chronic Total Occlusion (CTO): consensus document from the EuroCTO club. Euro‐

[19] Srivatsa S, Holmes D. The histopathology of angiographic chronic total coronary ar‐ tery occlusion and changes in neovascular pattern and intimal plaque composition associated with progressive occlusion duration. J Invasive Cardiol 1997; 9, 294-301.

[20] Pupita G, Maseri A, Galassi AR, et al. Myocardial ischemia caused by distal coronary

[21] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.

[22] Yoshitani H, Akasaka T, Kaji S et al. Effects of IABP on coronary pressure in patients

[23] Briguori C, Airoldi F, Chieffo A, et al. Elective versus provisional intraaortic balloon pumping in unprotected left main stenting. Am Heart J 2006; 152: 565-72.

[24] Noguchi T, Miyazaki S, Morii I, Daikoku S, Goto Y, Nonogi H. Percutaneous translu‐ minal coronary angioplasty of chronic total occlusions. determinants of primary suc‐ cess and long-term clinical outcome. Cathet Cardiovasc Interv 2000; 49:258–264

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## *Edited by Branislav G. Baskot*

The mortality from ischemic heart disease has decreased in recent years. The better understanding of risk factors associated with development of coronary artery disease has significantly contributed to this decline. Improvements in medical and interventional therapy have reduced the complications associated with acute myocardial infarction as well as revascularization. After the introduction of imaging modalities, the noninvasive characterization of regional function, perfusion and metabolism allowed for more sophisticated tissue characterization to identify reversible dysfunction with high diagnostic and prognostic accuracy. We now can legitimately claim that computed tomography angiography (CTA) of the coronary arteries is available. In the evaluation of patients with suspected coronary artery disease, many guidelines today consider CTA an alternative to stress testing. However the nuclear technique most frequently used by cardiologists is myocardial perfusion imaging (MPI). The combination of a nuclear camera with CTA allows for the attainment of coronary anatomic, cardiac function and MPI from one piece of equipment. Assessing cardiac viability is now fairly routine with these enhancements to cardiac imaging. Traditional coronary angiography presents a variety of limitations related to image acquisition, content, interpretation, and patient safety. Barriers to such improvements include the paucity of clinical outcomes studies related to new imaging technology, the need for physician and staff member training, and the costs associated with acquiring and effectively using these advances in coronary angiography. This issue is full of important information that every cardiologist needs to now.

> ISBN 978-953-51-1043-9 ISBN 978-953-51-7116-4

What Should We Know About Prevented, Diagnostic,

and Interventional Therapy in Coronary Artery Disease

What Should We Know

About Prevented, Diagnostic,

and Interventional Therapy in

Coronary Artery Disease

*Edited by Branislav G. Baskot*

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