Infections and the Cardiovascular System New Perspectives Emerging Infectious Diseases of the 21st Century

Series Editor: I. W. Fong Professor of Medicine, University of Toronto Head of Infectious Diseases, St. Michael’s Hospital

INFECTIONS AND THE CARDIOVASCULAR SYSTEM: New Perspectives Edited by I. W. Fong Infections and the Cardiovascular System New Perspectives

Edited by I. W. Fong Professor of Medicine, University of Toronto Head of Infectious Diseases, St. Michael's Hospital Toronto, Ontario, Canada

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Infectious agents have been recognized to involve the heart and vascular system for well over a century. Traditional concepts and teachings of their involvement in the pathogenesis of disease have been by a few established mechanisms. Bacterial and occasionally fungal microorganisms were known to invade and multiply on the of valves, vascular prostheses or shunts and aneurysm. Similarly viral, bacterial, mycobacterial, fungal, and parasitic pathogens could cause disease by invasion of the and muscles of the heart. Pathogenesis of some diseases of the endocardium, myocardium, and pericardium could involve indirect mechanisms with molecular mimicry inducing injury through an autoimmune process, such as in rheumatic heart disease and post viral . It was recognized by the mid-20th century that Treponema pallidum, the etiology of syphilis, could cause cardiovascular damage (aortitis and aortic aneurysm) by obliteration of the vasa vasorum supplying the root of the aorta by endarteritis obliterans, and by then the connection between streptococcal infection and rheumatic heart disease was clear. Since the last decade of the 20th century there has been renewed interest in the medical and public media on infectious diseases affecting the cardio- vascular and cerebrovascular systems, through the relationship with develop- ment or acceleration of atherosclerosis. Atherosclerosis has traditionally been considered the consequence of certain lifestyle (smoking, obesity, inactivity), hyperlipidemia, and hypertension or genetic diseases (diabetes mellitus, familial hypercholesterolemia, etc.). However, the concept that infections could play a role in the pathogenesis of atherosclerotic heart disease is not new, and was in vogue in the later part of the 19th century in Europe when the germ theory of many diseases was popular, especially after Koch proved that consumption was due to Mycobacteria tuberculosis. In the early part of the v vi Preface

20th century, Osler and Billings were advocates of the infectious theory of atherosclerotic . Interest in this theory waned soon after Anitschkow in St. Petersburg published his landmark studies of cholesterol- induced atherosclerosis in the rabbit model in 1913. However, we should learn from the lessons taught by the peptic ulcer and Helicobacter pylori saga in the pathogenesis of this common disease. It was just over two decades ago that the paradigm for peptic ulcer etiology was accepted as due to gastric acid hyper-secretion, with lifestyle factors such as stress playing a major precipitating factor. It should be remembered that around 1906, Billings speculated that some gastric and duodenal ulcers were caused by bacterial infection ofthe mucous membranes that rendered the cells prone to digestion by the gastric juices. He was concerned that long standing focal infection leading to chronic systemic disease was not appreciated. He wrote, “I think there can be no doubts that the insidious slow degenerative processes which occur in many patients who arrive at the meridian of life are due to slow intoxications from chronic focal infections variously located.” The main purpose of this book is to highlight and review these new perspec- tives of infections on the cardiovascular system.

ACKNOWLEDGMENTS

This book would not have been be possible without the collaboration of my colleagues in various studies, especially Dr. Brian Chiu and Dr. James Mahony. I am also grateful to Dr. Maria Kolia for her assistance in compiling various literature and data; to Dawn Bajhan, Debbie Reid and my wife (Cheryl) for their assiduous secretarial and administrative assistance.

I. W. FONG Contents

Section I

Traditional Infections Affecting the Cardiovascular System

Chapter 1

New Insights and Updates for Established Entities

1.1. Introduction 3 1.2. Infective 3 1.2.1. Advances in the Diagnosis of 5 1.2.2. Update on Prevention of Infective Endocarditis 7 1.2.3. Advances in the Treatment of Infective Endocarditis 10 1.3. Updates on Rheumatic and Rheumatic Carditis 12 1.3.1. Update on the Diagnosis of 13 1.3.2. Advances in the Pathogenesis of Rheumatic Fever and Carditis 13 1.3.3. Host Susceptibility to Rheumatic Fever and Carditis 15 1.3.4. Update of Rheumatic Fever Prophylaxis 15 1.3.5. Progress in 16 1.3.6. Causation of Myocarditis 17 1.3.7. Pathobiology of Myocarditis 18 1.3.8. Treatment of Myocarditis 20

vii viii Contents

1.4. Cardiac Device Infection—Updates 21 References 23

Chapter 2

Atherosclerosis and

2.1. Introduction 33 2.2. Pathology of Atherosclerosis 34 2.2.1. Inflammatory Response 35 2.2.2. Components of Atherosclerotic Lesion 36 2.3. Histological Classification of Atherosclerotic Lesions 39 2.4. Systemic Markers of Inflammation and Cardiovascular Disease 42 2.4.1. Fibrinogen 43 2.4.2. C-Reactive Protein 45 2.4.3. Leucocyte Count 46 2.4.4. Albumin 47 2.4.5. Serum Amyloid A Protein 48 2.4.6. Phospholipase- 49 2.4.7. 50 2.4.8. Adhesion Molecules 51 2.5. Conclusion 53 References 54

Chapter 3

Traditional Risk Factors and Newly Recognized Emerging Risk Factors for Cardiovascular Disease

3.1. Introduction 63 3.2. Hypercholesterolemia 63 3.3. Dyslipidemias 65 3.4. Smoking 67 3.5. Hypertension 68 3.6. Diabetes Mellitus 69 3.7. Obesity 70 3.8. Genetics 71 3.9. New Risk Factors for Atherosclerotic Cardiovascular Disease 73 3.9.1. Homocysteine 74 3.9.2. Left 76 3.9.3. Factors 76 3.9.4. Renal Impairment 77 Contents ix

3.10. Unresolved Issues 78 References 79

Chapter 4

Effect of Infection on Lipoproteins and the Coagulation System

4.1. Introduction 91 4.2. Lipoprotein and Atherosclerosis 91 4.2.1. Acute Phase Response 92 4.2.2. Alterations of Triglyceride and VLDL Metabolism 94 4.2.3. Cholesterol and LDL Alterations 95 4.2.4. Alteration of HDL Metabolism 96 4.3. Coagulation and Atherosclerosis 98 4.3.1. The Role of Plaque Rupture 99 4.3.2. Pathophysiology of Thrombus Formation on Atheroma 101 4.3.3. Infection and the Coagulation System 103 4.3.4. Links between Inflammation and Coagulation 104 4.3.5. Links between Inflammation, Thrombosis, and Atherosclerosis 106 References 107

Section II

Emerging Relationships of Infections and the Cardiovascular System

Chapter 5

Chlamydia pneumoniae and the Cardiovascular System

5.1. Microbiology of Chlamydia pneumoniae 121 5.2. Chlamydia Antigens 124 5.3. Epidemiology of Chlamydia pneumoniae Infections 124 5.4. Diagnosis of Chlamydia pneumoniae Infections 125 5.4.1. Serological Testing 125 5.4.2. Culture 126 5.4.3. Polymerase Chain Reaction (PCR) 129 5.4.4. Immunohistochemistry 129 5.5. Association of C. pneumoniae Infection and Vascular Disease 130 x Contents

5.5.1. Epidemiological Association 131 5.5.2. Pathological Evidence of Association 139 5.5.3. Culture of C. pneumoniae from Plaques 143 5.6. Evidence of Causality 144 5.6.1. Biological Mechanisms 144 5.6.2. Animal Models 146 5.6.3. Effect of Antimicrobials on Atherosclerosis in Animal Models 150 5.6.4. Clinical Trails 151 5.7. Future Directions 153 Addendum 155 References 156

Chapter 6

Periodontal Disease and the Cardiovascular System

6.1. Introduction 179 6.2. Periodontal Disease 179 6.2.1. Microbial Etiology 180 6.2.2. Pathobiology of Periodontal Disease 181 6.2.3. Risk Factors for Periodontal Disease 182 6.3. Periodontal Disease and Cardiovascular Disease and Atherosclerosis 183 6.3.1. Epidemiological Evidence 183 6.3.2. Pathological Evidence 189 6.4. Biological Mechanisms 189 6.4.1. Animal Models 192 6.4.2. Clinical Trials 193 6.5. Future Directions 194 References 195

Chapter 7

Cytomegalovirus and Herpes Simplex Virus in Cardiovascular Disease

7.1. Introduction 201 7.2. Microbiology 201 7.2.1. Cytomegalovirus 201 7.2.2. Herpes Simplex Virus 203 7.2.3. Epidemiology of Cytomegalovirus and Herpes Simplex Virus 204 Contents xi

7.3. Association of Cytomegalovirus and Cardiovascular Disease 204 7.3.1. Epidemiological Association of Cytomegalovirus in Native Coronary Heart Disease 205 7.3.2. Epidemiological Association of Cytomegalovirus in Cardiac Transplant 210 7.3.3. Epidemiological Association of Herpes Simplex Virus and Atherosclerotic Disease 210 7.4. Pathological Studies 210 7.5. Biological Mechanisms 220 7.5.1. Effect on Cholesterol and Lipoproteins 221 7.5.2. Viral Infection and the Coagulation Cascade 222 7.6. Animal Models 224 7.6.1. Animal Models of AllograftArteriosclerosis 224 7.7. Clinical Trials in Transplant Atherosclerosis 225 7.8. Conclusion and Future Directions 226 References 226

Chapter 8

Miscellaneous Infections and Atherosclerosis: Cardiovascular and Cerebrovascular Disease

8.1. Introduction 239 8.2. Helicobacter pylori and the Cardiovascular System 239 8.2.1. Microbiology and Epidemiology 239 8.2.2. Pathogenicity of Helicobacter pylori 240 8.2.3. Diagnosis of Helicobacter pylori Infection 241 8.3. Epidemiological Association of Helicobacter pylori and Cardiovascular Disease 241 8.3.1. Pathological Association of Helicobacter pylori and Atherosclerosis 242 8.3.2. Biological Mechanisms for Helicobacter pylori 245 8.3.3. Animal Model for Helicobacter pylori 247 8.3.4. Clinical Trials in Helicobacter pylori Infection and Cardiovascular Disease 247 8.4. Viruses (other than Herpes Viruses) Associated with Atherosclerotic Cardiovascular Disease 248 8.4.1. Coxsackie Virus 248 8.4.2. Influenza Virus 248 8.4.3. Virus 249 8.4.4. Human Immunodeficiency Virus (HIV) 250 xii Contents

8.5. Mycoplasma pneumoniae and Cardiovascular/ Cerebrovascular Disease 251 8.6. Pathogen Burden and Atherosclerotic Vascular Disease 251 8.6.1. Pathological Evidence of Multiple Organisms in Atheroma 253 8.6.2. Biological Mechanisms and Animal Model for Multiple Pathogens in Atherosclerosis 255 8.7. Conclusion and Future Directions 255 References 256

Index 267