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## **Meet the editor**

After undergraduate and postgraduate study in the North of England and London respectively, David Gaze works as a Research Biochemist in Clinical Blood Sciences at St George's Hospital and Medical School, London. His area of research interest is the development and clinical utility of cardiovascular biomarkers for assessment of patients with cardiovascular disease and cardi-

orenal disease. He has authored and co authored over 115 peer reviewed original papers, editorials and reviews, 145 conference proceedings and has authored two book chapters and a textbook on cardiac troponin. He has delivered over 25 invited international presentations. He received two NACB distinguished abstracts awards (2006/2008) and a diploma for oral presentation from the 17th IFCC–FESCC European Congress of Clinical Chemistry and Laboratory Medicine. He is a member of the American Association of Clinical Biochemistry, Association for Biochemistry, Institute of Biomedical Sciences, Fellow of the Royal Society of Medicine and a member of the Pathological Society of Great Britain.

Contents

**Preface IX** 

**Part 1 Epidemiology and Pathophysiology of Coronary Artery Disease 1** 

Chapter 3 **Coronary Flow: From Pathophysiology** 

Chapter 1 **Epidemiology of Coronary Artery Disease 3** 

Chapter 2 **Gender Differences in Coronary Artery Disease 31**  Ryotaro Wake and Minoru Yoshiyama

**to Clinical Noninvasive Evaluation 43** 

Chapter 4 **Coronary Microvascular Dysfunction in CAD:** 

Chapter 5 **Coronary Artery Disease and Pregnancy 81** 

**Part 2 Coronary Artery Disease Diagnostics 101** 

Chapter 6 **Cardiovascular Biomarkers for the Detection of Cardiovascular Disease 103** 

Chapter 7 **Do We Need Another Look at Serum Uric Acid** 

Siniša Car and Vladimir Trkulja

**in Cardiovascular Disease? Serum Uric Acid as** 

Chapter 8 **Stress Testing and Its Role in Coronary Artery Disease 147**  Rajkumar K. Sugumaran and Indu G. Poornima

David C. Gaze

John F. Beltrame, Rachel Dreyer and Rosanna Tavella

Francesco Bartolomucci, Francesco Cipriani and Giovanni Deluca

**Consequences and Potential Therapeutic Applications 65** 

Titia P.E. Ruys, Mark R. Johnson and Jolien W. Roos-Hesselink

**a Predictor of Outcomes in Acute Myocardial Infarction 123** 

Alan N. Beneze, Jeffrey M. Gold and Betsy B. Dokken

### Contents

#### **Preface XI**


	- **Part 2 Coronary Artery Disease Diagnostics 101**
	- **Part 3 Treatment Regimens for Coronary Artery Disease 183**

### Preface

Cardiovascular disease is ranked as the leading cause of death world wide. According to the World Heart Federation, cardiovascular disease is responsible for 17.1 million deaths globally each year. Surprisingly, 82% of these deaths occur in the developing world. Such numbers are often difficult to comprehend. The gravity of the situation is enhanced when portrayed as the following: Heart disease kills one person every 34 seconds in the USA alone. 35 people under the age of 65 die prematurely in the UK every day due to cardiovascular disease (12,500 deaths per annum). Although the leading killer, the incidence of cardiovascular disease has declined in recent years due to a better understanding of the pathology, implementation of lipid lowering therapy new drug regimens including low molecular weight heparin and antiplatelet drugs such as glycoprotein IIb/IIIa receptor inhibitors and acute surgical intervention.

The disease burden has a great financial impact on global healthcare systems and major economic consequences for world economies. Cardiovascular disease cost the UK healthcare system £14.4 billion (€16.7 billion; \$22.8 billion) in 2006. Hospital care for patients with cardiovascular disease accounts for approximately 70% of the cost with 20% spent on pharmacological agents. The total cost should include nonhealthcare costs such as production losses in the workforce and informal care of people with the disease. Production loss is estimated to cost the UK economy £8.2 billion in 2006 (55% due to death and 45% due to illness). Informal care cost the UK economy £8.0 billion in 2006. Overall cardiovascular disease is estimated to cost the UK economy £30.7 billion per annum.

This text aims to deliver the current understanding of coronary artery disease and is split into three main sections:

1. *Epidemiology and pathophysiology of coronary artery disease* where the spectrum of the disease will be described in relation to geographical location. Data from the industrialised countries on rates of myocardial infarction and angina are discussed in particular with reference to the wider healthcare and socioeconomic status. In the second chapter gender differences in rates and type of cardiovascular diseases are discussed. Often women view cardiovascular disease as a lower disease category than breast or cervical cancer. The differences in atherosclerotic pathology between men and women are discussed as well as the different approaches to diagnostic regimens, treatment and mortality. Coronary blood flow is discussed with reference to the turbulence caused by atherosclerotic lesions and the clinical importance of Doppler Echocardiography in the evaluation of ischemic myocardium. In clinical practice, many patients present with angina and reduced coronary flow reserve despite normal coronary angiography of the large epicardial arteries. In this situation the vessels that limit flow to myocardium are the more distal epicardial prearterioles and intramyocardial arterioles typically too small to be visualized by conventional coronary angiography. Coronary microvascular dysfunction is poorly understood and difficult to manage. In addition, the presence of coronary microvascular dysfunction can be a confounding factor in the management of cardiac patients and is discussed in detail. The final chapter in this section deals with coronary artery disease during pregnancy. The incidence of pregnancy related acute coronary syndrome is 6 per 100,000 deliveries. One of the most important risk factors is maternal age. Pregnancy is a hypercoagulable state and has a major impact on hemodynamics. The presence of reduced left ventricular function increases the chance of an adverse maternal and fetal outcome. The underlying cause of an acute coronary syndrome may be different from outside pregnancy. The aetiology, pathophysiology and associated mortality as well as treatment options are discussed.

Preface XI

published in 2010 proposes that Exercise ECG should not be used to diagnose or exclude angina for people without known coronary artery disease Historically exercise electrocardiography in the diagnosis of coronary artery disease has been questioned. However, the greater the ST segment changes on exercise electrocardiography, the greater the post-exercise probability of coronary artery disease. The chapter demonstrates the different impact the exercise electrocardiography has on subsequent management, depending on the method

3. *Treatment regimens for coronary artery disease* The discovery of statins over 30 years ago comprised a revolution in the management of dyslipidaemia. Statins target hepatocytes and inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that converts HMG-CoA into mevalonic acid, a cholesterol precursor. They directly inhibit cholesterol synthesis. Statins exert several beneficial effects on patients with coronary artery disease, whether managed conservatively or undergoing surgical or percutaneous treatment. This chapter discusses the effects of optimal statin therapy in primary and secondary prevention, in particular clinical settings such as; acute coronary syndrome, and in patients undergoing percutaneous coronary intervention or coronary artery bypass surgery. The second chapter in this section looks at the effectiveness and efficiency of drug eluting stents. With the use of data from stent registries in Europe and clinical trails in the field, this chapter discusses the benefit of drug eluting over bare metal stents with respect to restenosis rates, cardiac morbidity and mortality and provides an economic basis for their use. The third chapter tackles the impact of incomplete revascularisation on survival in systematic offpump coronary artery bypass grafting surgery. It remains unclear whether the decreased number of grafts seen in off-pump versus on-pump bypass grafting is owing to patient selection. Incomplete revascularisation can derive from a surgical strategy of target vessel revascularisation in high-risk patients, where the impact of surgery is minimised to reduce perioperative mortality and morbidity, aiming to achieve the best feasible safe revascularisation. Revascularisation of diabetic patients is discussed in detail in the next chapter with the aid of case studies for illustration. Diabetes mellitus constitutes an independent predictor of early stent thrombosis, both in bare metal and drug eluting stents. Current guidelines favor coronary artery bypass graft surgery over percutaneous coronary intervention in most diabetic patients with multi-vessel disease; however, substantial variability exists in the current medical practice suggesting a lack of clinical consensus. The penultimate chapter of this section discusses diastolic heart failure following cardiac surgery; defining the clinical spectrum, the pathophysiology of diastole and contributing factors. The authors describe in detail methods to assess diastolic function. The final chapter discusses the role of spinal cord stimulation for the management of angina from coronary artery disease. Despite the recent advances in managing angina pectoris, many patients suffer from intractable pain. For those patients who have already failed optimal medical and surgical therapy, very few,

employed to analyse the data.

2. *Coronary artery disease diagnostics.* The first chapter of this section deals with the laboratory based biomarkers used to detect coronary artery disease. The challenge has been the identification of a cardiospecific biomarker. The cardiovascular biomarkers essentially fall into three categories. Those that identify patients at risk atherosclerosis; those associated with plaque destabilisation and those which indicate rupture of the plaque, necrosis and cardiac insufficiency. The use of serum uric acid as a predictive biomarker in myocardial infarction is discussed in the second chapter. A plethora of non-clinical, clinical and epidemiological studies have accumulated over the decades that aimed to elucidate molecular and cellular mechanisms of uric acid and its role as a diagnostic and prognostic aid or importantly, as a therapeutic target. This stems from its antioxidant potential. The role of serum uric acid on the cardiovascular system with respect to hypertension, stroke, renal failure, heart failure and coronary heart disease are discussed. Being able to identify patients with coronary artery disease early will help lower hospital costs and decrease mortality and morbidity. Stress testing has emerged as the sole non-invasive method for risk stratifying patients. Apart from highlighting the advantages and disadvantages of various stress testing modalities, the chapter reviews which patients should undergo stress testing based on appropriateness criteria; managed separately based on their risk factors and identifying those who may be at increased risk of acute myocardial infarction or death. The final chapter of this section discusses the role of exercise electrocardiography in patients with stable chest pain. A UK National Institute for Health and Clinical Excellence (NICE) guideline on the diagnosis of discomfort of suspected cardiac origin published in 2010 proposes that Exercise ECG should not be used to diagnose or exclude angina for people without known coronary artery disease Historically exercise electrocardiography in the diagnosis of coronary artery disease has been questioned. However, the greater the ST segment changes on exercise electrocardiography, the greater the post-exercise probability of coronary artery disease. The chapter demonstrates the different impact the exercise electrocardiography has on subsequent management, depending on the method employed to analyse the data.

X Preface

options are discussed.

different approaches to diagnostic regimens, treatment and mortality. Coronary blood flow is discussed with reference to the turbulence caused by atherosclerotic lesions and the clinical importance of Doppler Echocardiography in the evaluation of ischemic myocardium. In clinical practice, many patients present with angina and reduced coronary flow reserve despite normal coronary angiography of the large epicardial arteries. In this situation the vessels that limit flow to myocardium are the more distal epicardial prearterioles and intramyocardial arterioles typically too small to be visualized by conventional coronary angiography. Coronary microvascular dysfunction is poorly understood and difficult to manage. In addition, the presence of coronary microvascular dysfunction can be a confounding factor in the management of cardiac patients and is discussed in detail. The final chapter in this section deals with coronary artery disease during pregnancy. The incidence of pregnancy related acute coronary syndrome is 6 per 100,000 deliveries. One of the most important risk factors is maternal age. Pregnancy is a hypercoagulable state and has a major impact on hemodynamics. The presence of reduced left ventricular function increases the chance of an adverse maternal and fetal outcome. The underlying cause of an acute coronary syndrome may be different from outside pregnancy. The aetiology, pathophysiology and associated mortality as well as treatment

2. *Coronary artery disease diagnostics.* The first chapter of this section deals with the laboratory based biomarkers used to detect coronary artery disease. The challenge has been the identification of a cardiospecific biomarker. The cardiovascular biomarkers essentially fall into three categories. Those that identify patients at risk atherosclerosis; those associated with plaque destabilisation and those which indicate rupture of the plaque, necrosis and cardiac insufficiency. The use of serum uric acid as a predictive biomarker in myocardial infarction is discussed in the second chapter. A plethora of non-clinical, clinical and epidemiological studies have accumulated over the decades that aimed to elucidate molecular and cellular mechanisms of uric acid and its role as a diagnostic and prognostic aid or importantly, as a therapeutic target. This stems from its antioxidant potential. The role of serum uric acid on the cardiovascular system with respect to hypertension, stroke, renal failure, heart failure and coronary heart disease are discussed. Being able to identify patients with coronary artery disease early will help lower hospital costs and decrease mortality and morbidity. Stress testing has emerged as the sole non-invasive method for risk stratifying patients. Apart from highlighting the advantages and disadvantages of various stress testing modalities, the chapter reviews which patients should undergo stress testing based on appropriateness criteria; managed separately based on their risk factors and identifying those who may be at increased risk of acute myocardial infarction or death. The final chapter of this section discusses the role of exercise electrocardiography in patients with stable chest pain. A UK National Institute for Health and Clinical Excellence (NICE) guideline on the diagnosis of discomfort of suspected cardiac origin 3. *Treatment regimens for coronary artery disease* The discovery of statins over 30 years ago comprised a revolution in the management of dyslipidaemia. Statins target hepatocytes and inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that converts HMG-CoA into mevalonic acid, a cholesterol precursor. They directly inhibit cholesterol synthesis. Statins exert several beneficial effects on patients with coronary artery disease, whether managed conservatively or undergoing surgical or percutaneous treatment. This chapter discusses the effects of optimal statin therapy in primary and secondary prevention, in particular clinical settings such as; acute coronary syndrome, and in patients undergoing percutaneous coronary intervention or coronary artery bypass surgery. The second chapter in this section looks at the effectiveness and efficiency of drug eluting stents. With the use of data from stent registries in Europe and clinical trails in the field, this chapter discusses the benefit of drug eluting over bare metal stents with respect to restenosis rates, cardiac morbidity and mortality and provides an economic basis for their use. The third chapter tackles the impact of incomplete revascularisation on survival in systematic offpump coronary artery bypass grafting surgery. It remains unclear whether the decreased number of grafts seen in off-pump versus on-pump bypass grafting is owing to patient selection. Incomplete revascularisation can derive from a surgical strategy of target vessel revascularisation in high-risk patients, where the impact of surgery is minimised to reduce perioperative mortality and morbidity, aiming to achieve the best feasible safe revascularisation. Revascularisation of diabetic patients is discussed in detail in the next chapter with the aid of case studies for illustration. Diabetes mellitus constitutes an independent predictor of early stent thrombosis, both in bare metal and drug eluting stents. Current guidelines favor coronary artery bypass graft surgery over percutaneous coronary intervention in most diabetic patients with multi-vessel disease; however, substantial variability exists in the current medical practice suggesting a lack of clinical consensus. The penultimate chapter of this section discusses diastolic heart failure following cardiac surgery; defining the clinical spectrum, the pathophysiology of diastole and contributing factors. The authors describe in detail methods to assess diastolic function. The final chapter discusses the role of spinal cord stimulation for the management of angina from coronary artery disease. Despite the recent advances in managing angina pectoris, many patients suffer from intractable pain. For those patients who have already failed optimal medical and surgical therapy, very few, if any, therapeutic options are available. Spinal cord stimulation may play a unique role in managing such refractory anginal pain. This chapter details, the mechanisms of spinal cord stimulation, methodology employed as well as clinical outcomes.

#### **Acknowledgements**

I would like to acknowledge the tremendous efforts of the contributing authors to these chapters. The tireless work they have provided gives insight into the world of the basic and clinical sciences. It is their drive to continue to investigate and share their findings that drives forward science. In essence, through their work, we hope to provide help and treatment for the millions of people affected by coronary artery disease around the globe. I would also like to thank Mr Vedran Greblo of InTECH publishers for keeping the production of this book active and to for steering me to complete the editorial review by the appropriate deadlines. Lastly I have to say thank you to the true unsung heroes. The patients and their families who agree to participate in research programs; the benefits of which may not necessarily help themselves but could help their fellow humans in the future. It is these people who deserve the most credit.

> **David C. Gaze**  Dept of Chemical Pathology Clinical Blood Sciences, St George's Healthcare NHS Trust, London, UK

XII Preface

credit.

outcomes.

**Acknowledgements** 

if any, therapeutic options are available. Spinal cord stimulation may play a unique role in managing such refractory anginal pain. This chapter details, the mechanisms of spinal cord stimulation, methodology employed as well as clinical

I would like to acknowledge the tremendous efforts of the contributing authors to these chapters. The tireless work they have provided gives insight into the world of the basic and clinical sciences. It is their drive to continue to investigate and share their findings that drives forward science. In essence, through their work, we hope to provide help and treatment for the millions of people affected by coronary artery disease around the globe. I would also like to thank Mr Vedran Greblo of InTECH publishers for keeping the production of this book active and to for steering me to complete the editorial review by the appropriate deadlines. Lastly I have to say thank you to the true unsung heroes. The patients and their families who agree to participate in research programs; the benefits of which may not necessarily help themselves but could help their fellow humans in the future. It is these people who deserve the most

**David C. Gaze** 

UK

Dept of Chemical Pathology Clinical Blood Sciences,

St George's Healthcare NHS Trust, London,

**Part 1** 

**Epidemiology and Pathophysiology** 

**of Coronary Artery Disease** 

## **Part 1**

### **Epidemiology and Pathophysiology of Coronary Artery Disease**

**1** 

*Australia* 

**Epidemiology of Coronary Artery Disease** 

*Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital,* 

Epidemiology involves the study of the frequency, distribution, and impact of diseases within a community in order to address potential prevention or treatment of these conditions. Accordingly, evaluating the epidemiology of coronary artery disease (CAD) constitutes a particularly wide spectrum that cannot be comprehensively covered in a solitary book chapter. Consequently this first section will provide an introductory broad overview of CAD including pathophysiological concepts, clinical manifestations, geographic variations and its impact on patient health. After defining the broader context of this large

The coronary circulation consists of coronary arteries, the microcirculation and the coronary veins. Its function is to supply oxygen and nutrients to the myocardium and remove carbon dioxide and waste products. The importance of this function is exemplified by the fact that a 50% or more reduction in this blood supply to the myocardium is incompatible with life. Thus, not surprisingly, dysfunction of the coronary circulation may result in significant

Although beyond the scope of this chapter, it should be noted that disturbances of the coronary circulation may involve dysfunction within the microcirculation as well as the coronary arteries. Thus the all-encompassing term 'coronary heart disease' includes both CAD and microvascular dysfunction. The later may mimic the clinical manifestations of CAD and indeed may co-exist with CAD. However, defining the epidemiology of microvascular dysfunction is especially difficult since specialised investigations are required to confirm its

In contrast, CAD is more readily identifiable and the most common underlying pathophysiological process is coronary atherosclerotic disease. This may be identified by imaging techniques such as coronary angiography, or unequivocally at post-mortem autopsy. Accordingly, detailing the epidemiology of CAD is more readily achievable and

Coronary atherosclerotic disease involves the epicardial coronary arteries and may manifest as an acute or chronic coronary syndrome. Acute coronary syndromes (ACS) typically arise

presence, as it may occur in the absence of associated structural microvascular disease.

**1. Introduction**

field, the specific scope of chapter will be outlined.

**1.1 Defining coronary artery disease** 

morbidity and mortality.

the focus of this chapter.

**1.2 Atherosclerotic coronary syndromes** 

John F. Beltrame, Rachel Dreyer and Rosanna Tavella

### **Epidemiology of Coronary Artery Disease**

John F. Beltrame, Rachel Dreyer and Rosanna Tavella *Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Australia* 

#### **1. Introduction**

Epidemiology involves the study of the frequency, distribution, and impact of diseases within a community in order to address potential prevention or treatment of these conditions. Accordingly, evaluating the epidemiology of coronary artery disease (CAD) constitutes a particularly wide spectrum that cannot be comprehensively covered in a solitary book chapter. Consequently this first section will provide an introductory broad overview of CAD including pathophysiological concepts, clinical manifestations, geographic variations and its impact on patient health. After defining the broader context of this large field, the specific scope of chapter will be outlined.

#### **1.1 Defining coronary artery disease**

The coronary circulation consists of coronary arteries, the microcirculation and the coronary veins. Its function is to supply oxygen and nutrients to the myocardium and remove carbon dioxide and waste products. The importance of this function is exemplified by the fact that a 50% or more reduction in this blood supply to the myocardium is incompatible with life. Thus, not surprisingly, dysfunction of the coronary circulation may result in significant morbidity and mortality.

Although beyond the scope of this chapter, it should be noted that disturbances of the coronary circulation may involve dysfunction within the microcirculation as well as the coronary arteries. Thus the all-encompassing term 'coronary heart disease' includes both CAD and microvascular dysfunction. The later may mimic the clinical manifestations of CAD and indeed may co-exist with CAD. However, defining the epidemiology of microvascular dysfunction is especially difficult since specialised investigations are required to confirm its presence, as it may occur in the absence of associated structural microvascular disease.

In contrast, CAD is more readily identifiable and the most common underlying pathophysiological process is coronary atherosclerotic disease. This may be identified by imaging techniques such as coronary angiography, or unequivocally at post-mortem autopsy. Accordingly, detailing the epidemiology of CAD is more readily achievable and the focus of this chapter.

#### **1.2 Atherosclerotic coronary syndromes**

Coronary atherosclerotic disease involves the epicardial coronary arteries and may manifest as an acute or chronic coronary syndrome. Acute coronary syndromes (ACS) typically arise

Epidemiology of Coronary Artery Disease 5

 Haemorrhagic Stroke Hypertensive Heart Disease

Atherothrombotic Stroke

Atherothrombotic Stroke

Epidemiology not only involves monitoring diseases within the community but also their impact on health. Thus the focus should not only be on the disease manifestations of CAD (such as acute and chronic coronary syndromes) but also the patient's perception of the impact of these disorders on their health. The term '*health status*' (see Figure 1) is used to define the patient's perception (rather than the clinician's perception) of the disease process on their lifestyle. This incorporates the symptoms experienced (e.g. angina), the functional limitation from the symptom (eg reduced exercise tolerance) and quality of life (i.e. the

Rumsfeld, Circulation 2002, 106:5-7. (Rumsfeld, 2002). Copyright gained from Wolters Kluwer Health

 Rheumatic Heart Disease Nutritional Cardiomyopathy  Sub-Saharan Africa Rural South America Rural Southern Asia

Urban Southern Asia

China

 Urban India Latin America Former USSR

 Western Europe North America Australia, New Zealand

**Transition Stage** %**Deaths**\* **Cardiovascular Conditions Countries** 

CAD

CAD
