Table Of ContentInfections 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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Preface
Infectious agents have been recognized to involve the heart and vascular
system for well over a century. Traditional concepts and teachings oftheir
involvement in the pathogenesis ofdisease have been by a few established
mechanisms. Bacterial andoccasionally fungal microorganisms were known
to invade and multiply on the endocardium ofvalves, vascularprostheses or
shunts and aneurysm. Similarly viral, bacterial, mycobacterial, fungal, and
parasitic pathogens could cause disease by invasion ofthe pericardium and
muscles of the heart. Pathogenesis of some diseases of the endocardium,
myocardium, and pericardium could involve indirect mechanisms with
molecular mimicry inducing injurythrough an autoimmune process, such as
in rheumatic heart disease andpost viral cardiomyopathy.
It wasrecognizedby themid-20thcentury that Treponemapallidum, the
etiology of syphilis, could cause cardiovascular damage (aortitis and aortic
aneurysm)by obliterationofthevasavasorum supplying therootofthe aorta
by endarteritis obliterans, and by then the connection between streptococcal
infection andrheumatic heart disease was clear.
Since the last decade ofthe 20th centurythere has beenrenewed 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
consideredthe consequence ofcertain 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 ofthe infectious theory of
atheroscleroticcardiovasculardisease. Interestinthis theory waned soonafter
Anitschkow in St. Petersburg published his landmark studies ofcholesterol-
induced atherosclerosis in the rabbit model in 1913.
However, we should learn from the lessons taught by the peptic ulcer
andHelicobacterpylori saga in the pathogenesis ofthis common disease. It
wasjust over two decades ago thatthe paradigm forpeptic ulcer etiologywas
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 speculatedthat some gastric andduodenal ulcerswere
causedbybacterialinfectionofthemucousmembranesthatrenderedthecells
prone todigestion bythe gastricjuices. Hewasconcernedthatlongstanding
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 whichoccurinmanypatients who arriveatthemeridianoflife are
due to slow intoxications from chronic focal infections variously located.”
The main purpose ofthis book is to highlight and review these newperspec-
tives ofinfections 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. IamalsogratefultoDr. MariaKolia forherassistance incompiling
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 Endocarditis 3
1.2.1. Advances in the Diagnosis ofInfective
Endocarditis 5
1.2.2. Update on Prevention ofInfective Endocarditis 7
1.2.3. Advances in theTreatment ofInfective
Endocarditis 10
1.3. Updates on Rheumatic FeverandRheumatic Carditis 12
1.3.1. Update on the Diagnosis ofRheumatic Fever 13
1.3.2. Advances inthePathogenesis ofRheumatic
Fever and Carditis 13
1.3.3. Host Susceptibility to Rheumatic Fever and Carditis 15
1.3.4. Update ofRheumatic Fever Prophylaxis 15
1.3.5. Progress in Myocarditis 16
1.3.6. Causation ofMyocarditis 17
1.3.7. Pathobiology of Myocarditis 18
1.3.8. Treatment ofMyocarditis 20
vii
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1.4. Cardiac Device Infection—Updates 21
References 23
Chapter 2
Atherosclerosis and Inflammation
2.1. Introduction 33
2.2. Pathology ofAtherosclerosis 34
2.2.1. Inflammatory Response 35
2.2.2. Components ofAtherosclerotic Lesion 36
2.3. Histological Classification of Atherosclerotic Lesions 39
2.4. Systemic Markers ofInflammation 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. Cytokines 50
2.4.8. Adhesion Molecules 51
2.5. Conclusion 53
References 54
Chapter 3
Traditional Risk Factors andNewly 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 Ventricular Hypertrophy 76
3.9.3. Coagulation Factors 76
3.9.4. Renal Impairment 77
Contents ix
3.10. UnresolvedIssues 78
References 79
Chapter 4
Effect of Infection on Lipoproteins and the Coagulation System
4.1. Introduction 91
4.2. Lipoprotein andAtherosclerosis 91
4.2.1. Acute PhaseResponse 92
4.2.2. Alterations of Triglyceride and VLDL Metabolism 94
4.2.3. Cholesterol and LDLAlterations 95
4.2.4. Alterationof HDL Metabolism 96
4.3. Coagulation andAtherosclerosis 98
4.3.1. The Role ofPlaqueRupture 99
4.3.2. Pathophysiology of Thrombus
Formation onAtheroma 101
4.3.3. Infection andthe Coagulation System 103
4.3.4. LinksbetweenInflammationandCoagulation 104
4.3.5. Links betweenInflammation,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 ofChlamydiapneumoniae 121
5.2. ChlamydiaAntigens 124
5.3. Epidemiology ofChlamydiapneumoniae Infections 124
5.4. Diagnosis ofChlamydiapneumoniae Infections 125
5.4.1. Serological Testing 125
5.4.2. Culture 126
5.4.3. Polymerase ChainReaction (PCR) 129
5.4.4. Immunohistochemistry 129
5.5. Association ofC. pneumoniae Infection and
Vascular Disease 130
x Contents
5.5.1. Epidemiological Association 131
5.5.2. Pathological Evidence ofAssociation 139
5.5.3. Culture ofC.pneumoniae fromPlaques 143
5.6. Evidence ofCausality 144
5.6.1. Biological Mechanisms 144
5.6.2. Animal Models 146
5.6.3. Effect ofAntimicrobials on Atherosclerosis in
Animal Models 150
5.6.4. ClinicalTrails 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 ofPeriodontal Disease 181
6.2.3. Risk Factors for Periodontal Disease 182
6.3. Periodontal Disease and CardiovascularDisease 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. ClinicalTrials 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 SimplexVirus 203
7.2.3. Epidemiology ofCytomegalovirus and
Herpes SimplexVirus 204
