Review
Role of acute infection in triggering acute coronary syndromes

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Summary

Acute coronary syndromes are a leading cause of morbidity and mortality worldwide. The mechanisms underlying the triggering of these events are diverse and include increased coronary and systemic inflammatory activity, dominant prothrombotic conditions, increased biomechanical stress on coronary arteries, variations in the coronary arterial tone, disturbed haemodynamic homoeostasis, and altered myocardial metabolic balance. There is experimental evidence that acute infections can promote the development of acute coronary syndromes, and clinical data strongly support a role for acute infections in triggering these events. In our Review, we summarise the pathogenesis of coronary artery disease and present the evidence linking acute infections with the development of acute coronary syndromes. Greater awareness of this association is likely to encourage research into ways of protecting patients who are at high risk.

Introduction

Coronary artery disease is the leading cause of death worldwide.1 Acute coronary syndromes, which include unstable angina and acute myocardial infarction, are the most feared complication of coronary artery disease. We2, 3, 4, 5 and others6, 7, 8 have shown that acute infections are associated with, and appear to have a role in causing, the development of acute coronary syndromes. In our Review, we provide an overview of the pathophysiology of coronary artery disease and acute coronary syndromes and review the in-vitro, animal, and human studies that clarify the role of acute infection in triggering these syndromes. The putative roles of Chlamydophila pneumoniae, cardiotropic viruses (eg, coxsackie), and chronic infections (including periodontal disease) in these conditions are beyond the scope of this Review.

Section snippets

Atherosclerosis: an inflammatory disease

Atherosclerosis is an inflammatory condition that begins with endothelial injury. A variety of stimuli including raised concentration of cholesterol in blood, exposure to tobacco, diabetes mellitus, hypertension, or rheological stress alter endothelial function, increasing permeability to low-density lipoproteins and allowing the migration of leucocytes (particularly monocytes and lymphocytes) into the arterial intima.9, 10, 11, 12 Within the arterial wall, low-density lipoproteins are

Acute coronary syndrome

Slowly growing atherosclerotic plaques cause progressive coronary obstruction that eventually can lead to effort angina. Most acute coronary syndromes, however, arise from thrombotic complications at the site of lesions that were not necessarily haemodynamically significant (ie, those causing less than 50% stenosis of a coronary artery).14 The surface of these lesions becomes disrupted, exposing underlying thrombogenic elements (collagen, phospholipids, tissue factor, and platelet-adhesive

Triggering by acute infections

Inflammation has a central role in triggering acute coronary syndromes.25 The development of acute coronary syndromes is preceded by high concentrations of inflammatory markers in the blood, such as C-reactive protein, neutrophil myeloperoxidase, procalcitonin, and white blood cells.26, 27, 28, 29 When compared with patients with stable coronary artery disease, patients with acute coronary syndromes have higher inflammatory activity across the entire coronary bed and, aside from the culprit

Clinical studies

Strong evidence supports an association between acute coronary syndromes and acute respiratory infections (table 1). Both acute respiratory infections and acute coronary syndromes vary with the seasons, peaking in the winter.76, 77 Acute respiratory symptoms shortly precede up to a third of acute coronary syndromes.8, 62, 63, 65, 69, 75, 78 Large and well-designed retrospective studies consistently find a two-fold to three-fold increase in the risk for acute coronary syndromes within 1–2 weeks

The argument of causality

Differentiating causal relations from those based on bias, chance, or confounding is often challenging and elusive. Sir Austin Bradford Hill, in 1965,111 summarised nine guiding principles that provide a framework for this process (strength of association, temporal relation, consistency, coherence, analogy, biological plausibility, biological gradient, experimental evidence, and specificity). On the basis of these principles we argue that there is a causal relation between acute respiratory

Future directions

We have reviewed the evidence that acute infections, especially respiratory infections, trigger acute coronary syndromes. This association is supported by pathophysiological observations, and epidemiological and clinical findings. Because a large proportion of acute respiratory infections such as influenza and pneumonia tend to happen in patients at higher risk for coronary disease, this association deserves attention by the medical community.

Future investigations should characterise the

Search strategy and selection criteria

In addition to reviewing our own files on specific infections, infecting organisms, inflammation, and acute coronary syndromes, we searched published work, with no language restrictions, within Ovid/Medline, PubMed, and the Cochrane database (date limits were from 1950 to Dec 5, 2009). The search terms used, singly and in combination, were “atherosclerosis”, “coronary heart disease”, “coronary disease”, “acute coronary syndrome”, “myocardial infarction”, “angina”, “cardiovascular death”,

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