Preface

Chapter 8 **Patient on ACS Pathway – Hypomagnesaemia a Contributory**

Ghulam Naroo, Tanveer Ahmed Yadgir, Bina Nasim and Omer Skaf

Suli Zhang, Jin Wang, Yunhui Du, Jianyu Shang, Li Wang, Jie Wang,

**Heart Diseases: Therapeutic Potentials and Challenges 163**

**Iodophenyl-Pentadecanoic Acid (123I-BMIPP) in Ischemic Heart**

Junichi Taki, Ichiro Matsunari, Hiroshi Wakabayashi, Anri Inaki and

Ke Wang, Kehua Bai, Tingting Lv, Xiao Li and Huirong Liu

Chapter 10 **Progenitor/Stem Cell Engineering for Treatment of Ischemic**

Yuliang Feng, Yigang Wang and Shi-Zheng Wu

Chapter 11 **Role of Fatty Acid Imaging with 123I- β-methyl-p-123I-**

**Factor to Myocardial Ischemia 133**

**Ischemia/Reperfusion Injury 143**

Chapter 9 **Cell Autophagy and Myocardial**

**VI** Contents

**Diseases 175**

Seigo Kinuya

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 global‐ ly each year. A staggering 82% of these deaths actually occur in the developing world. Such numbers are often difficult to comprehend. The gravity of the situation is enhanced when portrayed as the following: A coronary even occurs every 25 seconds and CHD kills one person every 34 seconds in the United States of America alone. 35 people under the age of 65 die prematurely in the United Kingdom 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 pathological mechanisms in‐ volved and development of targeted therapeutics; along with the implementation of lipid lowering therapy such as statins and new drug regimens including low molecular weight heparin and antiplatelet drugs such as glycoprotein IIb/IIIa receptor inhibitors. Recent ad‐ vances in acute surgical intervention have also improved mortality, especially with the ad‐ vent of drug eluting stents and minimally invasive coronary artery bypass grafting, along with improvements in cardioplegia and a systemic hypothermic environment.

The disease burden has a great financial impact on global healthcare systems and major eco‐ nomic 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 car‐ diovascular disease accounts for approximately 70% of the cost with 20% spent on pharma‐ cological agents. The total cost should include non-healthcare costs such as production losses in the workforce and informal care of people with the disease. Production loss is esti‐ mated to cost the UK economy £8.2 billion in 2006 (55% due to death and 45% due to ill‐ ness). 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 firstly introduces the heart and circulation and the development and anatomy of the coronary arteries before introducing the all encompassing umbrella of cardiovascular disease and the Pathobiology of ischemic heart disease (IHD). The epidemiological burden of Ischemic heart disease is described on a global scale; followed by risk factors, diagnostic modalities and treatment regimens for IHD. The next chapter describes the deleterious ef‐ fects of congenital heart diseases and the role of myocardial ischemia in these conditions, detailing the pathogenesis, diagnosis and treatment options before tacking strategies for prevention. Chapter three demonstrates the gender disparity in sudden cardiac death (SCD). SCD occurs predominantly in women often without previous symptoms or history of CVD. The mechanisms surrounding SCD are detailed followed by identification of those at risk and potential treatment strategies such as implantable cardioverter-defibrillators for high risk subjects. Chapter four reports on the significance of endothelial function and its

relationship to silent myocardial ischemia, especially in patients with concomitant diabetes mellitus. Damage to the endothelium is considered to be the initiation of the atherothrom‐ botic episode; be it chemically induced by reduction in nitric oxide, oxidative stress or in‐ flammation or by mechanical sheer stress and hemodynamic disruption. This is followed by the presentation of clinical findings in sixty patients with CHD and type II diabetes Mellitus compared to sixty eight patients with CHD but no evidence of diabetes. Using Holter ECG monitoring, echocardiography, vascular Doppler ultrasound, the vascular responses be‐ tween those with and those without diabetes were measured. Furthermore, cerebrovascular reactivity testing was also assessed. Patients with CHD and concomitant diabetes demon‐ strate reduced endothelium-dependent vasodilation compared to those CHD patients with‐ out CHD. As mentioned above, the economic cost of CHD is crippling healthcare budgets and contributes to loss of business revenue and national reduction in gross domestic prod‐ uct. Chapter five from experts at the Centers for Disease Control and Prevention, USA sur‐ veyed inpatient admissions between 2006-8. Some 41,546 claims were made for a primary diagnosis of acute myocardial infarction (46% ST segment elevation MI; STEMI). The associ‐ ated costs are highest in males than females and a geographical variation was observed. STEMI costs were higher than non-STEMI costs and costs were highest in those undergoing surgical revascularisation by primary coronary intervention or coronary artery bypass graft‐ ing. These data could be used to model more cost-effective AMI intervention programs. The next chapter details the biochemical tests available for the detection and diagnosis of cardiac ischemia. There are a plethora of candidate biomarkers however very few have made the transition to use in the clinical setting. Biomarkers up stream of the cardiac troponins may serve as sensitive tests, but at the cost of specificity thus reducing the overall diagnostic effi‐ ciency of the test. Malondialdehyde low-density lipoprotein, Myeloperoxidase, whole blood choline, and free fatty acids are described. The FDA cleared Ischemia Modified Albumin assay is described in detail including its clinical utility not only in acute chest pain but in those patients without acute coronary syndrome. Lastly, with the advent of sensitive cardiac troponin tests, the ischemia vs necrosis debate is challenged once again. Chapter seven dis‐ cusses the role of uric acid (the end product of purine metabolism) as a risk factor for the development of CVD. Similarly, the role of magnesium and the hypomagnesaemic state and its relationship in the development of clinical disorders such as diabetes, hypertension, athe‐ rosclerosis and acute coronary syndrome are discussed in the subsequent chapter. Chapter nine investigates the process of 'self-eating' or autophagy, detailing the intracellular signal‐ ling control mechanisms and its role in the maintenance of normal myocardial tissue and its cardioprotective effect during ischemia in the hypoxic myocardium. The understanding of autophagy may lead to possible therapeutic targets for IHD. The penultimate chapter is con‐ cerned with progenitor and stem cell engineering as a possible intervention to treat IHD. This is of great interest given recent advances in understanding progenitor cell biology but also poses many considerable challenges in transferring from laboratory based science into a clinical reality. The chapter reviews recent progress in progenitor and stem cell engineering, including cell sources, scaffold free tissue construct, myocardial tissue generation using de‐ cellularised native tissue, porous scaffolding and biosynthetic polymers. The final chapter of this text discuses the role of fatty acid imaging, in which fatty acid tracers labelled with the radioisotope of iodine, 123-I is used in single positron emission computer tomography (SPECT) imaging. An overview of myocardial fatty acid metabolism is given, along with de‐ scription of the iodine-labelled tracers and their myocardial tissue kinetics. This is followed by the clinical utility of the tracer in imaging post acute myocardial infarction, in those with

stable chronic coronary artery disease, risk stratification and the assessment of myocardial tissue viability and probably most importantly, prediction of functional recovery. Further‐ more, its role in chronic kidney disease is discussed in light of the high prevalence of CHD

**David C. Gaze**

Preface IX

Dept of Chemical Pathology Clinical Blood Sciences,

St George's Healthcare NHS Trust

London, United Kingdom

in this unique population.

stable chronic coronary artery disease, risk stratification and the assessment of myocardial tissue viability and probably most importantly, prediction of functional recovery. Further‐ more, its role in chronic kidney disease is discussed in light of the high prevalence of CHD in this unique population.

relationship to silent myocardial ischemia, especially in patients with concomitant diabetes mellitus. Damage to the endothelium is considered to be the initiation of the atherothrom‐ botic episode; be it chemically induced by reduction in nitric oxide, oxidative stress or in‐ flammation or by mechanical sheer stress and hemodynamic disruption. This is followed by the presentation of clinical findings in sixty patients with CHD and type II diabetes Mellitus compared to sixty eight patients with CHD but no evidence of diabetes. Using Holter ECG monitoring, echocardiography, vascular Doppler ultrasound, the vascular responses be‐ tween those with and those without diabetes were measured. Furthermore, cerebrovascular reactivity testing was also assessed. Patients with CHD and concomitant diabetes demon‐ strate reduced endothelium-dependent vasodilation compared to those CHD patients with‐ out CHD. As mentioned above, the economic cost of CHD is crippling healthcare budgets and contributes to loss of business revenue and national reduction in gross domestic prod‐ uct. Chapter five from experts at the Centers for Disease Control and Prevention, USA sur‐ veyed inpatient admissions between 2006-8. Some 41,546 claims were made for a primary diagnosis of acute myocardial infarction (46% ST segment elevation MI; STEMI). The associ‐ ated costs are highest in males than females and a geographical variation was observed. STEMI costs were higher than non-STEMI costs and costs were highest in those undergoing surgical revascularisation by primary coronary intervention or coronary artery bypass graft‐ ing. These data could be used to model more cost-effective AMI intervention programs. The next chapter details the biochemical tests available for the detection and diagnosis of cardiac ischemia. There are a plethora of candidate biomarkers however very few have made the transition to use in the clinical setting. Biomarkers up stream of the cardiac troponins may serve as sensitive tests, but at the cost of specificity thus reducing the overall diagnostic effi‐ ciency of the test. Malondialdehyde low-density lipoprotein, Myeloperoxidase, whole blood choline, and free fatty acids are described. The FDA cleared Ischemia Modified Albumin assay is described in detail including its clinical utility not only in acute chest pain but in those patients without acute coronary syndrome. Lastly, with the advent of sensitive cardiac troponin tests, the ischemia vs necrosis debate is challenged once again. Chapter seven dis‐ cusses the role of uric acid (the end product of purine metabolism) as a risk factor for the development of CVD. Similarly, the role of magnesium and the hypomagnesaemic state and its relationship in the development of clinical disorders such as diabetes, hypertension, athe‐ rosclerosis and acute coronary syndrome are discussed in the subsequent chapter. Chapter nine investigates the process of 'self-eating' or autophagy, detailing the intracellular signal‐ ling control mechanisms and its role in the maintenance of normal myocardial tissue and its cardioprotective effect during ischemia in the hypoxic myocardium. The understanding of autophagy may lead to possible therapeutic targets for IHD. The penultimate chapter is con‐ cerned with progenitor and stem cell engineering as a possible intervention to treat IHD. This is of great interest given recent advances in understanding progenitor cell biology but also poses many considerable challenges in transferring from laboratory based science into a clinical reality. The chapter reviews recent progress in progenitor and stem cell engineering, including cell sources, scaffold free tissue construct, myocardial tissue generation using de‐ cellularised native tissue, porous scaffolding and biosynthetic polymers. The final chapter of this text discuses the role of fatty acid imaging, in which fatty acid tracers labelled with the radioisotope of iodine, 123-I is used in single positron emission computer tomography (SPECT) imaging. An overview of myocardial fatty acid metabolism is given, along with de‐ scription of the iodine-labelled tracers and their myocardial tissue kinetics. This is followed by the clinical utility of the tracer in imaging post acute myocardial infarction, in those with

VIII Preface

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

**Chapter 1**

**Introduction to Ischemic Heart Disease**

Additional information is available at the end of the chapter

*"The heart has its reasons which reason knows not."* Blaise Pascal (1623-1662)

**1.1. Development and anatomy of the coronary arteries**

organ is held within the pericardial sac.

tricular and atrioventricular grooves.

as the intramural coronary system.

The heart is the vital organ that tirelessly pumps oxygenated blood from the lungs to the organs and peripheral tissues via the circulatory system. In return, deoxygenated blood is returned via the heart and the pulmonary circulation to the lungs to expel waste carbon dioxide (figure 1). The average human heart beats approximately 72 beats per minute totalling around 2.5 billion beats in a 66-year lifespan. The human heart weighs 250-300g in females and 300-350g in males. The heart is located in the mediastinum of the thorax, anterior to the vertebrae and posterior to the sternum. *Archosaurs* (crocodilians and birds) as well as *Mammalia* species show complete separation of the heart into two pumping units comprised of four distinct chambers. The myogenic musculature of the heart is supplied by the coronary arteries and the entire

As with any organ, the heart requires its own supply of blood for continued functioning. The supply of blood to the myocardium occurs via the coronary artery circuit (figure 2). Their name is derived from the Latin 'Corona', meaning crown as the main vessels encircle the interven‐

The arterial tree has two main compartments; firstly, the main arteries (table 1) and ramifica‐ tions on the surface of the myocardium, known as the extramural coronary system. Secondly, the branches of the surface vessels which penetrate deep into the myocardial tissues are known

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

© 2013 Gaze; 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.

David C. Gaze

**1. Introduction**

http://dx.doi.org/10.5772/55248

## **Introduction to Ischemic Heart Disease**

David C. Gaze

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55248

## **1. Introduction**

*"The heart has its reasons which reason knows not."* Blaise Pascal (1623-1662)

The heart is the vital organ that tirelessly pumps oxygenated blood from the lungs to the organs and peripheral tissues via the circulatory system. In return, deoxygenated blood is returned via the heart and the pulmonary circulation to the lungs to expel waste carbon dioxide (figure 1). The average human heart beats approximately 72 beats per minute totalling around 2.5 billion beats in a 66-year lifespan. The human heart weighs 250-300g in females and 300-350g in males. The heart is located in the mediastinum of the thorax, anterior to the vertebrae and posterior to the sternum. *Archosaurs* (crocodilians and birds) as well as *Mammalia* species show complete separation of the heart into two pumping units comprised of four distinct chambers. The myogenic musculature of the heart is supplied by the coronary arteries and the entire organ is held within the pericardial sac.

#### **1.1. Development and anatomy of the coronary arteries**

As with any organ, the heart requires its own supply of blood for continued functioning. The supply of blood to the myocardium occurs via the coronary artery circuit (figure 2). Their name is derived from the Latin 'Corona', meaning crown as the main vessels encircle the interven‐ tricular and atrioventricular grooves.

The arterial tree has two main compartments; firstly, the main arteries (table 1) and ramifica‐ tions on the surface of the myocardium, known as the extramural coronary system. Secondly, the branches of the surface vessels which penetrate deep into the myocardial tissues are known as the intramural coronary system.

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

The extramural coronary system is formed from two main arteries. The left coronary artery (LCA) and the right coronary artery (RCA). A third vessel exists in up to 50% of the population and is known as the conus artery. The diameters of the vessels are given in table 1. The intramural coronary system is a complex vascular network containing the main intramural branches which have region specific distribution patterns. The ventricular branches arise at right angles from the subepicardial arteries taking an endocardial route. An important component of the intramural system is the collateral or anastomotic arterial system. These vessels have a characteristic corkscrew appearance. They are present at birth and do not differ in distribution by age or gender. In the normal heart they are 20-350 μm in diameter.

**Figure 2.** Coronary artery anatomy. a) Left coronary artery and b) Right coronary artery. A, atrial branch; AM, acute marginal artery; AVCx, atrioventricular groove branch of circumflex; AVN, atrioventricular node artery; CB, conus branch; D, diagonal branch of LAD; LAC, left atrial circumflex; LAD, left anterior descending; LAO 30° left anterior obli‐ que projection; LAT, left lateral projection; LMS, left main stem; LV, left ventricular branches; MCx, main circumflex; PD, posterior descending; PLCx, posterior circumflex branch (obtuse marginal); RA, right atrial branch; RAO, 30o right an‐

Introduction to Ischemic Heart Disease http://dx.doi.org/10.5772/55248 3

terior oblique projection; RV, right ventricular branch; S, septal perforating arteries; SN, sinus node artery.

**Figure 1.** Anterior view of the human heart with blood vessels identified

The extramural coronary system is formed from two main arteries. The left coronary artery (LCA) and the right coronary artery (RCA). A third vessel exists in up to 50% of the population and is known as the conus artery. The diameters of the vessels are given in table 1. The intramural coronary system is a complex vascular network containing the main intramural branches which have region specific distribution patterns. The ventricular branches arise at right angles from the subepicardial arteries taking an endocardial route. An important component of the intramural system is the collateral or anastomotic arterial system. These vessels have a characteristic corkscrew appearance. They are present at birth and do not differ

2 Ischemic Heart Disease

in distribution by age or gender. In the normal heart they are 20-350 μm in diameter.

**Figure 1.** Anterior view of the human heart with blood vessels identified

**Figure 2.** Coronary artery anatomy. a) Left coronary artery and b) Right coronary artery. A, atrial branch; AM, acute marginal artery; AVCx, atrioventricular groove branch of circumflex; AVN, atrioventricular node artery; CB, conus branch; D, diagonal branch of LAD; LAC, left atrial circumflex; LAD, left anterior descending; LAO 30° left anterior obli‐ que projection; LAT, left lateral projection; LMS, left main stem; LV, left ventricular branches; MCx, main circumflex; PD, posterior descending; PLCx, posterior circumflex branch (obtuse marginal); RA, right atrial branch; RAO, 30o right an‐ terior oblique projection; RV, right ventricular branch; S, septal perforating arteries; SN, sinus node artery.


**Cardiovascular Disease**

Arteriosclerosis

Introduction to Ischemic Heart Disease http://dx.doi.org/10.5772/55248 5

Atherosclerosis

Stroke (Cerebrovascular accident)

Arterial embolus

Raynaud's phenomenon

**Diseases of the Heart Diseases of the Circulation**

Angina Pectoris Aortic aneurysm

Atrial flutter Aortic dissection

Wolff-Parkinson-White syndrome Hypertension

Premature ventricular complex Essential (primary) hypertension

Ventricular tachycardia Secondary hypertension Ventricaular fibrillation Malignant hypertension

Dilated Cardiomyopathy Transient ischemic attack

Congestive heart failure Acute arterial occlusion

Congenital heart disease Arteriovenous fistula

Ventricular septal defect Thoracic outlet syndrome

Atrial septal defect Vasculitis

Restrictive Cardiomyopathy Arterial disease

Unstable Angina Aortitis

Stable Angina

Arrhythmia

complete AV block)

Long QT syndrome

Cardiomyopathy

Hypertropic Cardiomyopathy

Patent ductus arteriosus

Premature atrial complex

Variant (Prinzmetal's) Angina

Heart block (first-degree and second-degree and

Paroxysmal supraventricular tachycardia

**Table 1.** The major coronary arteries.

The primitive embryonic heart is nourished via lacunar or intertrabeclar spaces, forming a netlike structure separating bundles of muscle fibres. Further evolutionary development results in endothelial budding. Originally this was thought to derive from the coronary sinus and aorta, forming superficial veins and arteries which penetrate into the myocardial tissue joining the lacunar spaces. It was then demonstrated in chick-quail chimaeras that the vessels were derived from the proepicardium structure common to the embryo and undergo a transition from epithelial to mesenchymal tissue. Mouse studies refute this, suggesting that the proepi‐ cardium gives rise to myocardial stroma and vascular smooth muscle but not coronary artery endothelial cells. Using clonal and histological analysis in the mouse, Red-Horse and collea‐ gues (Red-Horse et al. 2010) demonstrate that coronary arteries are formed by developmental reprogramming of venous cells, arising from angiogenic sprouts of the sinus venosus which returns blood to the embryonic heart. The understanding of angiogenesis in the myocardium may in future lead to more natural methods to stimulate vascular growth and engineering coronary bypass grafts rather than transplanting veins to revascularize damaged myocardium.

## **2. Cardiovascular disease**

A variety of diseases affect the primary functioning of the heart. Cardiovascular disease (CVD) is the collective name for diseases of the heart and blood vessels of the circulatory system. An atlas of types of cardiovascular diseases in the heart and in the circulation are given in table 2.

International efforts have been implemented to classify and code the different types of ischemic heart diseases. A number of notable indexing databases such as the International Classification of Diseases database, Disease Database eMedicine and MeSH databases have produced indexing codes. These are given in table 3.


**Vessel Median Diameter (range) in mm**

The primitive embryonic heart is nourished via lacunar or intertrabeclar spaces, forming a netlike structure separating bundles of muscle fibres. Further evolutionary development results in endothelial budding. Originally this was thought to derive from the coronary sinus and aorta, forming superficial veins and arteries which penetrate into the myocardial tissue joining the lacunar spaces. It was then demonstrated in chick-quail chimaeras that the vessels were derived from the proepicardium structure common to the embryo and undergo a transition from epithelial to mesenchymal tissue. Mouse studies refute this, suggesting that the proepi‐ cardium gives rise to myocardial stroma and vascular smooth muscle but not coronary artery endothelial cells. Using clonal and histological analysis in the mouse, Red-Horse and collea‐ gues (Red-Horse et al. 2010) demonstrate that coronary arteries are formed by developmental reprogramming of venous cells, arising from angiogenic sprouts of the sinus venosus which returns blood to the embryonic heart. The understanding of angiogenesis in the myocardium may in future lead to more natural methods to stimulate vascular growth and engineering coronary bypass grafts rather than transplanting veins to revascularize damaged myocardium.

A variety of diseases affect the primary functioning of the heart. Cardiovascular disease (CVD) is the collective name for diseases of the heart and blood vessels of the circulatory system. An atlas of types of cardiovascular diseases in the heart and in the circulation are given in table 2. International efforts have been implemented to classify and code the different types of ischemic heart diseases. A number of notable indexing databases such as the International Classification of Diseases database, Disease Database eMedicine and MeSH databases have produced

LEFT CORONARY ARTERY (LCA) 4 (2.5-5.5) Left anterior descending 3.6 (2-5) DG diagonal 2 (0.5-2.5) LCX circumflex 3 (1.5-5) LMG marginal 2.2 (1-3) RIGHT CORONARY ARTERY (RCA) 3.2 (1.5-5.5) RMG marginal 1.7 (1-2.5) PD posterior descending 2.1 (1-3) THIRD CORONARY ARTERY 'conus artery' 1.1 (0.7-2) Septal branches anterior from LCX 1 (0.5-2.5) Septal branches posterior from PD 0.7 (0.3-0.9) From ascending LAD 0.4 (0.3-0.7)

**Table 1.** The major coronary arteries.

4 Ischemic Heart Disease

**2. Cardiovascular disease**

indexing codes. These are given in table 3.


**Classification system Code**

410 Acute Myocardial infarction (AMI)

121 Acute Myocardial Infarction (AMI) 122 Subsequent Myocardial Infarction

Disease

413 Angina Pectoris

120 Angina Pectoris

Arteriosclerosis, IHD

Hypoxia refers to the physiological or pathological state in which oxygen supply is reduced despite adequate perfusion of the tissue. Anoxia is the absence of oxygen from the tissue, despite being adequately perfused. These are clearly distinguishable from ischemia where oxygen supply is restricted as a direct result of suboptimal tissue perfusion. Ischemic tissue also accumulates toxic metabolites due to the inadequate removal through the capillary and

The atherosclerotic process responsible for restriction of blood flow in the coronary arteries is a multifactorial process and is initiated by damage to the endothelium. Cholesterol rich low density lipoprotein (LDL) particles enter the intimal layer via the LDL receptor protein (Brown and Goldstein 1979), a mosaic cell surface protein that recognizes apolipoprotein B100 embedded in the LDL particle. It also recognizes apolipoprotein E found in chylomicrons and very low density lipoprotein remnants, or intermediate density lipoprotein. Macrophage cells accumulate oxidized lipid independently of the LDL receptor by endocytosis. This results in formation of juvenile raised fatty streaks within the endothelium. The macrophage release their lipid content and cytokines into the intima. Cytokines stimulate intimal thickening by

Med/1568 – Angina Pectoris

D017202 – Myocardial Ischemia

412 Old Myocardial Infarction

411 Other acute and subsequent forms of Ischemic Heart

Introduction to Ischemic Heart Disease http://dx.doi.org/10.5772/55248 7

414 Other forms of chronic ischemic heart disease

123 Certain current complications following AMI 124 Other acute ischemic heart diseases 125 Chronic ischemic heart disease

8695 - Ischemic or Ischaemic Heart disease, Myocardial Ischaemia, Steoncardia, Angina Pectoris, Coronary Artery

International Classification of Diseases (ICD-9)

International Classification of Diseases (ICD-10)

Medical Object Oriented Software Enterprises

**Table 3.** Classification codes of Ischemic Heart Disease

**3. Pathobiology of ischemic heart disease**

World Health Organisation, Geneva, Switzerland

World Health Organisation, Geneva, Switzerland

Diseases Database (DiseaseDB)

Medical Subject headings (MeSH) Unites States National Library of Medicine

Ltd London UK

eMedicine (WebMD) New York, USA

Bethesda, Maryland, USA

venous blood systems.

**Table 2.** Atlas of cardiovascular diseases of the heart and circulatory system.


**Table 3.** Classification codes of Ischemic Heart Disease

**Cardiovascular Disease**

**Diseases of the Heart Diseases of the Circulation**

Pulmonary stenosis Venous disease

Tricuspid atresia Varicose veins Truncus arteriosus Spider veins

Great vessel transposition Lymphedema

**Table 2.** Atlas of cardiovascular diseases of the heart and circulatory system.

Ebstein's abnormality of the tricuspid valve

Coronary artery disease Ischemic heart disease

6 Ischemic Heart Disease

Acute myocardial infarction

Cor pulmonale

Mitral stenosis

Aortic stenosis

Myocarditis

Pericarditis

Syncope

Myxoma

Heart valve disease

Mitral valve regurgitation

Mitral valve prolapse

Aortic regurgitation Tricuspid stenosis

Tricuspid regurgitation

Rheumatic disease

Sudden cardiac death

Cardiac tumours

Congential aortic stenosis Venous thrombosis Teratology of Fallot Deep vein thrombosis

## **3. Pathobiology of ischemic heart disease**

Hypoxia refers to the physiological or pathological state in which oxygen supply is reduced despite adequate perfusion of the tissue. Anoxia is the absence of oxygen from the tissue, despite being adequately perfused. These are clearly distinguishable from ischemia where oxygen supply is restricted as a direct result of suboptimal tissue perfusion. Ischemic tissue also accumulates toxic metabolites due to the inadequate removal through the capillary and venous blood systems.

The atherosclerotic process responsible for restriction of blood flow in the coronary arteries is a multifactorial process and is initiated by damage to the endothelium. Cholesterol rich low density lipoprotein (LDL) particles enter the intimal layer via the LDL receptor protein (Brown and Goldstein 1979), a mosaic cell surface protein that recognizes apolipoprotein B100 embedded in the LDL particle. It also recognizes apolipoprotein E found in chylomicrons and very low density lipoprotein remnants, or intermediate density lipoprotein. Macrophage cells accumulate oxidized lipid independently of the LDL receptor by endocytosis. This results in formation of juvenile raised fatty streaks within the endothelium. The macrophage release their lipid content and cytokines into the intima. Cytokines stimulate intimal thickening by smooth muscle cell proliferation, which then secrete collagen, causing fibrosis (figure 3). The lesion appears raised and yellow.

**4. Epidemiology of ischemic heart disease**

profound socio-economic impact.

burden than the acute events themselves.

developing word

According to the World Health Organisation, chronic diseases of which heart disease is the single largest contributing category; are responsible for 63% of all global deaths (United Nations High-Level Meeting on Noncommunicable Disease Prevention and Control 2012). Non communicable diseases kill 9 million people under the age of 60 every year which has a

Introduction to Ischemic Heart Disease http://dx.doi.org/10.5772/55248 9

The incidence of Ischemic heart disease (IHD) is higher than for any cancer or other non-CVD condition. Cardiovascular diseases (CVD) are the leading cause of death in the Western World and are dramatically increasing within developing countries. The Age-standardized estimate of mortality by cardiovascular diseases and diabetes per 100,000 people is given in figure 4. 17.1 million people die as a direct result of CVD per year and 82% of these deaths occur in the

It is predicted that by 2030 23 million people will die from a CVD. Data from the USA suggests that CVD was responsible for 34% of deaths in 2006 and over 151,000 Americans who died were <65 years old. The incidence of CVD is declining in the Western World even though rates of lifestyle associated risk factors such as obesity, smoking and type II diabetes mellitus are increasing. The decline is in part due to advances in therapeutic and invasive intervention. In creating better outcomes for those with acute cardiac conditions, patients develop heart failure which requires longer term treatment and monitoring and may in fact be a greater health

**Figure 4.** Age-standardized estimate of mortality by cardiovascular diseases and diabetes per 100,000 people. Source:

Global Health Observatory Data Repository, World Health Organisation.

**Figure 3.** Medium powered H&E histological micrograph of an intimal lesion (x200). FC, foam cell infiltrate; IC, intimal calcification; L, lumen; TI, tunica intima; TM, tunica media.

As the lesion develops, the medial layer of the vessel wall atrophies and the elastic lamina becomes disrupted. Collagen forms a fibrous cap over the lesion that appears hard and white (known as a fibrolipid plaque). The plaque contains macrophage laden with lipid (foam cells) as well as extracellular or 'free' lipid within the lesion. The endothelium is now in a fragile state. Ulceration of the cap occurs at weak points such as the shoulder region, near the endothelial lining. Rupture to the cap can cause turbulent blood flow in the lumen. The exposed lipid core causes aggregation of platelets and development of a thrombosis. This lesion grows due to further platelet aggregation and is responsible for narrowing of the lumen of the artery resulting in localized ischemia. Distal embolization of a piece of such thrombus may travel downstream and can completely occlude smaller arteries.

The symptomatic part of the continuum is known as the acute coronary syndrome (ACS) which is due to the rupture/erosion of the plaque. This produces, depending on the plaque size, vascular anatomy and presence of collateral vessels, a mismatch between the supply and demand for oxygen. A net reduction in supply compared to the demand results in ischemia. Tissue hypoxia proceeds resulting in inadequate blood/oxygen perfusion. If blood flow is not re-established, cardiac cell necrosis will occur. Post AMI survival results in remodelling processes in the myocardium and the development of cardiac failure.

## **4. Epidemiology of ischemic heart disease**

smooth muscle cell proliferation, which then secrete collagen, causing fibrosis (figure 3). The

**Figure 3.** Medium powered H&E histological micrograph of an intimal lesion (x200). FC, foam cell infiltrate; IC, intimal

As the lesion develops, the medial layer of the vessel wall atrophies and the elastic lamina becomes disrupted. Collagen forms a fibrous cap over the lesion that appears hard and white (known as a fibrolipid plaque). The plaque contains macrophage laden with lipid (foam cells) as well as extracellular or 'free' lipid within the lesion. The endothelium is now in a fragile state. Ulceration of the cap occurs at weak points such as the shoulder region, near the endothelial lining. Rupture to the cap can cause turbulent blood flow in the lumen. The exposed lipid core causes aggregation of platelets and development of a thrombosis. This lesion grows due to further platelet aggregation and is responsible for narrowing of the lumen of the artery resulting in localized ischemia. Distal embolization of a piece of such thrombus may travel

The symptomatic part of the continuum is known as the acute coronary syndrome (ACS) which is due to the rupture/erosion of the plaque. This produces, depending on the plaque size, vascular anatomy and presence of collateral vessels, a mismatch between the supply and demand for oxygen. A net reduction in supply compared to the demand results in ischemia. Tissue hypoxia proceeds resulting in inadequate blood/oxygen perfusion. If blood flow is not re-established, cardiac cell necrosis will occur. Post AMI survival results in remodelling

lesion appears raised and yellow.

8 Ischemic Heart Disease

calcification; L, lumen; TI, tunica intima; TM, tunica media.

downstream and can completely occlude smaller arteries.

processes in the myocardium and the development of cardiac failure.

According to the World Health Organisation, chronic diseases of which heart disease is the single largest contributing category; are responsible for 63% of all global deaths (United Nations High-Level Meeting on Noncommunicable Disease Prevention and Control 2012). Non communicable diseases kill 9 million people under the age of 60 every year which has a profound socio-economic impact.

The incidence of Ischemic heart disease (IHD) is higher than for any cancer or other non-CVD condition. Cardiovascular diseases (CVD) are the leading cause of death in the Western World and are dramatically increasing within developing countries. The Age-standardized estimate of mortality by cardiovascular diseases and diabetes per 100,000 people is given in figure 4. 17.1 million people die as a direct result of CVD per year and 82% of these deaths occur in the developing word

It is predicted that by 2030 23 million people will die from a CVD. Data from the USA suggests that CVD was responsible for 34% of deaths in 2006 and over 151,000 Americans who died were <65 years old. The incidence of CVD is declining in the Western World even though rates of lifestyle associated risk factors such as obesity, smoking and type II diabetes mellitus are increasing. The decline is in part due to advances in therapeutic and invasive intervention. In creating better outcomes for those with acute cardiac conditions, patients develop heart failure which requires longer term treatment and monitoring and may in fact be a greater health burden than the acute events themselves.

**Figure 4.** Age-standardized estimate of mortality by cardiovascular diseases and diabetes per 100,000 people. Source: Global Health Observatory Data Repository, World Health Organisation.

## **5. Risk factors**

There is no single causative risk factor for the development of IHD. A number of genetic and environmental risk factors have been established as causative in the development of the atherosclerotic lesion. Smoking and obesity cause 36% and 20% of IHD respectively. A large European meta-analysis of 197,473 participants reported an small association between job stress and the development of coronary artery disease (Kivimaki et al. 2012). There has been extensive research linking a sedentary lifestyle and a lack of exercise with a risk of IHD. The major risk factors for the development of IHD are given in table 4.

exertion. Patients benefit from cardiac stress testing, echocardiography. If indicated patients should receive coronary angiography to locate anatomically any stenosis with a view to revascularisation by stenting during percutaneous coronary intervention or coronary artery

Introduction to Ischemic Heart Disease http://dx.doi.org/10.5772/55248 11

In the primary care setting, patients may be suspected of having ischemic heart disease based on risk factor assessment and blood chemistry tests such as lipid profiling, inflammatory

Primarily the diagnosis of IHD occurs in the acute setting when patients present with symp‐ tomatic chest pain. Patients often present with a myriad of symptoms which confuse the clinical picture. Patients should receive immediate electrocardiography and pharmacological or surgical intervention in those who demonstrate ST-segment elevation in the context of STsegment myocardial infarction (STEMI). In suspected non-ST segment elevation myocardial infarction (NSTEMI) patients should undergo serial venepuncture for cardiac biomarkers, namely the cardiac troponins which are indicative of myocyte necrosis. Patients may undergo stress testing, whereby the stress response is induced by exercise or pharmacological agents allowing comparison of the coronary circulation at rest and under stress. Patients are moni‐ tored continuously whilst exercising on a treadmill, on a ergometer bicycle or following injection of agents such as adenosine, the adenosine A2A receptor Regadenoson or the betaagonist dobutamine. The agent of choice is dependent on drug interactions with medication

Cardiac ultrasound or echocardiography by two-dimensional, three-dimensional or Doppler ultrasound create images of the myocardium at work. Transthoracic echocardiogram (TTE) is the commonest form and the ultrasound transducer probe is placed non-invasively on the thorax. Transoesophageal echogram (TOE) is an alternative method where the transducer tip

Stable IHD patients can be adequately treated in the primary care setting with emphasis on both lifestyle and risk factor modifications to reduce the risk of a future adverse cardiac event. Modification of lifestyle risk factors such as smoking cessation and weight loss control have a direct impact on risk reduction. Further intervention such as treating hypertension, glycaemic control in diabetics and therapeutic intervention in hyperlipidaemia result in risk reduction. Furthermore, elective revascularisation of occluded coronary arteries may confer a reduction in mortality risk compared to conservative therapy. A meta-analysis of 13,121 patients in whom 6476 were randomised to revascularisation compared to medical treatment in the

is passed into the oesophagus, allowing imaging directly behind the heart.

bypass grafting (CABG) surgery.

**7. Diagnosis of ischemic heart disease**

markers and homocysteine concentration.

or concomitant disease states.

**8. Treatment of ischemic heart disease**


**Table 4.** Risk factors for the development of Ischaemic Heart Disease.

#### **6. Signs and symptoms of ischemic heart disease**

Ischemia may manifest in many forms. Most commonly, patients present with chest pain on exertion, in cold weather or in emotional situations. This discomfort is known as angina pectoris. Patients may present with acute chest pain at rest which typically radiates down the left arm and up the left side of the neck. Patients may experience nausea, vomiting, sweating and enhanced anxiety. Symptomatically, women present with less 'textbook' symptoms and often describe their condition as weakness, indigestion and fatigue (Kosuge et al. 2006). Up to 60% of AMI are referred to as silent without any observation of chest pain or other symptoms (Valensi et al. 2011).

Angina is diagnosed by evidence of deviation of the ST segment on the electrocardiogram, reduced uptake of thallium-201 during myocardial perfusion imaging or regional or global impairment of ventricular function. In patients with stable angina often have chest pain on exertion. Patients benefit from cardiac stress testing, echocardiography. If indicated patients should receive coronary angiography to locate anatomically any stenosis with a view to revascularisation by stenting during percutaneous coronary intervention or coronary artery bypass grafting (CABG) surgery.

## **7. Diagnosis of ischemic heart disease**

**5. Risk factors**

10 Ischemic Heart Disease

There is no single causative risk factor for the development of IHD. A number of genetic and environmental risk factors have been established as causative in the development of the atherosclerotic lesion. Smoking and obesity cause 36% and 20% of IHD respectively. A large European meta-analysis of 197,473 participants reported an small association between job stress and the development of coronary artery disease (Kivimaki et al. 2012). There has been extensive research linking a sedentary lifestyle and a lack of exercise with a risk of IHD. The

major risk factors for the development of IHD are given in table 4.

**Constant risk factors Modifiable risk factors**

Gender Hypertension

Earlobe crease (Frank's sign) Infection

**Table 4.** Risk factors for the development of Ischaemic Heart Disease.

(Valensi et al. 2011).

**6. Signs and symptoms of ischemic heart disease**

Age Hypercholesterolaemia/dyslipidaemia

Personal history of early IHD Tobacco and passive tobacco Smoking

Diabetes Mellitus type I Excessive alcohol consumption

Elevated homocysteine Diabetes Mellitus type II Elevated haemostatic factors Sedentary lifestyle Baldness & hair greying Low antioxidant levels

Family history of IHD Obesity (particularly central abdominal obesity)

Ischemia may manifest in many forms. Most commonly, patients present with chest pain on exertion, in cold weather or in emotional situations. This discomfort is known as angina pectoris. Patients may present with acute chest pain at rest which typically radiates down the left arm and up the left side of the neck. Patients may experience nausea, vomiting, sweating and enhanced anxiety. Symptomatically, women present with less 'textbook' symptoms and often describe their condition as weakness, indigestion and fatigue (Kosuge et al. 2006). Up to 60% of AMI are referred to as silent without any observation of chest pain or other symptoms

Angina is diagnosed by evidence of deviation of the ST segment on the electrocardiogram, reduced uptake of thallium-201 during myocardial perfusion imaging or regional or global impairment of ventricular function. In patients with stable angina often have chest pain on

Air pollution (CO, NO2, SO2) Combined oral contraceptive pill In the primary care setting, patients may be suspected of having ischemic heart disease based on risk factor assessment and blood chemistry tests such as lipid profiling, inflammatory markers and homocysteine concentration.

Primarily the diagnosis of IHD occurs in the acute setting when patients present with symp‐ tomatic chest pain. Patients often present with a myriad of symptoms which confuse the clinical picture. Patients should receive immediate electrocardiography and pharmacological or surgical intervention in those who demonstrate ST-segment elevation in the context of STsegment myocardial infarction (STEMI). In suspected non-ST segment elevation myocardial infarction (NSTEMI) patients should undergo serial venepuncture for cardiac biomarkers, namely the cardiac troponins which are indicative of myocyte necrosis. Patients may undergo stress testing, whereby the stress response is induced by exercise or pharmacological agents allowing comparison of the coronary circulation at rest and under stress. Patients are moni‐ tored continuously whilst exercising on a treadmill, on a ergometer bicycle or following injection of agents such as adenosine, the adenosine A2A receptor Regadenoson or the betaagonist dobutamine. The agent of choice is dependent on drug interactions with medication or concomitant disease states.

Cardiac ultrasound or echocardiography by two-dimensional, three-dimensional or Doppler ultrasound create images of the myocardium at work. Transthoracic echocardiogram (TTE) is the commonest form and the ultrasound transducer probe is placed non-invasively on the thorax. Transoesophageal echogram (TOE) is an alternative method where the transducer tip is passed into the oesophagus, allowing imaging directly behind the heart.

## **8. Treatment of ischemic heart disease**

Stable IHD patients can be adequately treated in the primary care setting with emphasis on both lifestyle and risk factor modifications to reduce the risk of a future adverse cardiac event. Modification of lifestyle risk factors such as smoking cessation and weight loss control have a direct impact on risk reduction. Further intervention such as treating hypertension, glycaemic control in diabetics and therapeutic intervention in hyperlipidaemia result in risk reduction. Furthermore, elective revascularisation of occluded coronary arteries may confer a reduction in mortality risk compared to conservative therapy. A meta-analysis of 13,121 patients in whom 6476 were randomised to revascularisation compared to medical treatment in the remainder demonstrated that bypass grafting and Percutaneous coronary intervention are superior to medical therapy alone with respect to 1-10 year mortality (Jeremias et al. 2009).

& Theorell, T. (2012). Job strain as a risk factor for coronary heart disease: a collabora‐

Introduction to Ischemic Heart Disease http://dx.doi.org/10.5772/55248 13

[4] Kosuge, M, Kimura, K, Ishikawa, T, Ebina, T, Hibi, K, Tsukahara, K, Kanna, M, Iwa‐ hashi, N, Okuda, J, Nozawa, N, Ozaki, H, Yano, H, Nakati, T, Kusama, I, & Ume‐ mura, S. (2006). Differences between men and women in terms of clinical features of

[5] Red-horse, K, Ueno, H, Weissman, I. L, & Krasnow, M. A. (2010). Coronary arteries form by developmental reprogramming of venous cells. *Nature* , 464, 549-553.

[6] United Nations High-Level Meeting on Noncommunicable Disease Prevention and

[7] Valensi, P, Lorgis, L, & Cottin, Y. (2011). Prevalence, incidence, predictive factors and prognosis of silent myocardial infarction: a review of the literature. *Arch.Cardio‐*

tive meta-analysis of individual participant data. *Lancet* , 380, 1491-1497.

ST-segment elevation acute myocardial infarction. *Circ.J.* , 70, 222-226.

Control. (2012).

*vasc.Dis.* , 104, 178-188.

Patients with symptomatic chest pain suggestive of an AMI and ST segment elevation should receive immediate revascularisation. Fibrinolytic therapy should be administered within 30 minutes and door-to-balloon PCI should occur in no more than 90 minutes from the onset of pain. For non ST segment elevation AMI patients, treatment with aspirin, glycoprotein IIb/IIIa inhibitor such as clopidogrel, low molecular weight heparin, glyceryl trinitrate and opioid therapy for persistent pain.

## **9. Conclusion**

Ischemic heart disease is the major contributing cause of death in the Western World and the incidence is increasing in developing countries. Successful advances in surgical and thera‐ peutic intervention are able to salvage myocardial tissue and increase prognosis if adminis‐ tered in the early phase following injury.

## **Author details**

David C. Gaze

Department of Chemical Pathology Clinical Blood Sciences, St. George's Healthcare NHS Trust, London, UK

## **References**


& Theorell, T. (2012). Job strain as a risk factor for coronary heart disease: a collabora‐ tive meta-analysis of individual participant data. *Lancet* , 380, 1491-1497.

remainder demonstrated that bypass grafting and Percutaneous coronary intervention are superior to medical therapy alone with respect to 1-10 year mortality (Jeremias et al. 2009).

Patients with symptomatic chest pain suggestive of an AMI and ST segment elevation should receive immediate revascularisation. Fibrinolytic therapy should be administered within 30 minutes and door-to-balloon PCI should occur in no more than 90 minutes from the onset of pain. For non ST segment elevation AMI patients, treatment with aspirin, glycoprotein IIb/IIIa inhibitor such as clopidogrel, low molecular weight heparin, glyceryl trinitrate and opioid

Ischemic heart disease is the major contributing cause of death in the Western World and the incidence is increasing in developing countries. Successful advances in surgical and thera‐ peutic intervention are able to salvage myocardial tissue and increase prognosis if adminis‐

Department of Chemical Pathology Clinical Blood Sciences, St. George's Healthcare NHS

[1] Brown, M. S, & Goldstein, J. L. (1979). Receptor-mediated endocytosis: insights from

[2] Jeremias, A, Kaul, S, Rosengart, T. K, Gruberg, L, & Brown, D. L. (2009). The impact of revascularization on mortality in patients with nonacute coronary artery disease.

[3] Kivimaki, M, Nyberg, S. T, Batty, G. D, Fransson, E. I, Heikkila, K, Alfredsson, L, Bjorner, J. B, Borritz, M, Burr, H, Casini, A, Clays, E, De Bacquer, D, Dragano, N, Fer‐ rie, J. E, Geuskens, G. A, Goldberg, M, Hamer, M, Hooftman, W. E, Houtman, I. L, Joensuu, M, Jokela, M, Kittel, F, Knutsson, A, Koskenvuo, M, Koskinen, A, Kouvo‐ nen, A, Kumari, M, Madsen, I. E, Marmot, M. G, Nielsen, M. L, Nordin, M, Oksanen, T, Pentti, J, Rugulies, R, Salo, P, Siegrist, J, Singh-manoux, A, Suominen, S. B, Vaana‐ nen, A, Vahtera, J, Virtanen, M, Westerholm, P. J, Westerlund, H, Zins, M, Steptoe, A,

the lipoprotein receptor system. *Proc.Natl.Acad.Sci.U.S.A* , 76, 3330-3337.

therapy for persistent pain.

tered in the early phase following injury.

*Am.J.Med.* , 122, 152-161.

**9. Conclusion**

12 Ischemic Heart Disease

**Author details**

Trust, London, UK

David C. Gaze

**References**


**Chapter 2**

**Myocardial Ischemia in**

Fabio Carmona, Karina M. Mata,

http://dx.doi.org/10.5772/53420

**1. Introduction**

**1.1. Concepts**

Marcela S. Oliveira and Simone G. Ramos

Additional information is available at the end of the chapter

cardial ischemia in this patient population [2].

reaches 12 to 14 per 1,000 live births [5].

Patients with congenital heart disease (CxHD) are surviving into adulthood, as well as living longer and growing older [1], due the major achievements in their diagnosis, medical man‐ agement, surgical repair, and postoperative treatment in the last three to four decades. An increasing numbers of patients with CxHD are encountered in our everyday practice. It is therefore timely and appropriate to start addressing the somewhat-neglected issue of myo‐

CxHD is, by definition, cardiovascular disease present at birth. It refers to anatomic defects and gross cardiac abnormalities due to an embryologic malformation in the structural development of the heart and major blood vessels, which is actually of functional significance [3]. Most CxHD occur due to gross structural developmental cardiovascular anomalies such as septal defects, stenosis or atresia of valves, hypoplasia or absence of one ventricle, or abnormal connections between great vessels and the heart. A few children are also born with arrhythmias (mainly conduction defects), and hypertrophic or dilated cardiomyopathy, although these are usually present later in childhood or adulthood. CxHD are the most common of all congenital malformations, with a reported incidence of 6 to 8 cases per 1,000 live births, and in an even higher percentage of foetuses [4]. In some studies this incidence

There is a great number of recognized heart defects occurring alone and in combination, ranging in severity from hemodynamically insignificant to extremely complex and life threatening conditions (Table 1). Although there may be genetic or environmental situations

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

© 2013 Carmona 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,

**Congenital Heart Disease: A Review**

## **Chapter 2**
