Review articleChronic infection in the aetiology of atherosclerosis—focus on Chlamydia pneumoniae☆
Introduction
Atherosclerosis and related diseases, in particular myocardial infarction (MI) and coronary heart disease (CHD) are a major cause of morbidity and mortality worldwide. Differences in the prevalence of conventional cardiovascular risk factors (such as smoking, hypertension and dyslipidaemia) do not account fully for temporal and geographical variations in the prevalence or severity of CHD [1], [2]. Consequently, there is intense research interest focused on seeking other atherogenic risk factors.
The potential role of common infectious agents in the pathogenesis and progression of atherosclerosis has been studied increasingly over the last decade. The evidence for Chlamydia pneumoniae as a potential causative agent is strongest, and is based on findings of numerous sero-epidemiological studies, examination of atheromatous plaque specimens, in-vitro animal models and recently, pilot anti-chlamydial antibiotic intervention trials. This review aims to discuss the evidence implicating C. pneumoniae as an aetiological agent in atherogenesis—highlighting both current knowledge and possible further lines of investigation.
The widely accepted ‘response to injury’ hypothesis of atherosclerosis proposes that an initial insult to the arterial wall triggers atherogenesis and plaque formation [3]. It is also recognised that ‘plaque activity’ and the function of the cellular components can be a more important determinant the clinical manifestations of atherosclerosis than is the degree of stenosis of arterial lesions [4]. Although many factors may initiate atherogenesis, the process ultimately involves an inflammatory state in which macrophages and T lymphocytes play a major role [5]. Antigen within the plaque may trigger/perpetrate the immunological activity and therefore the atherogenic inflammation. Suggested antigenic stimuli include modified LDL-cholesterol [6], but also components of intracellular pathogens such as cytomegalovirus (CMV) and C. pneumoniae.
Section snippets
Candidate infective agents and atherogenesis
In the 1970s, animal experiments showed that avian herpesvirus infection resulted in intense fibro-lipid deposition within major arterial walls of affected birds; these lesions closely resembled atherosclerosis [7]. Vaccination before exposure to the virus prevented formation of such lesions [8]. Herpes simplex virus has not generally been associated with human cardiovascular disease in epidemiological studies [9], but CMV, another common herpesvirus, has been linked to some forms of vascular
Sero-epidemiology
In 1988, Saikku and co-workers, provided the first evidence suggesting a role of C. pneumoniae [25] in CHD. Elevated antibodies to C. pneumoniae and immune complexes containing C. pneumoniae antigen were detected in patients with acute MI and chronic CHD. The investigators postulated that acute MI might be linked to an exacerbation of chronic C. pneumoniae infection. More recently, Danesh et al. [14] reviewed 18 published sero-epidemiological studies (involving about 2700 cases). They showed
C. pneumoniae and CHD: a current perspective
Over the last decade, about 70–80 published studies (conducted in 18 different countries) have shown a positive association between C. pneumoniae and CHD (Table 1). The research—both clinically-orientated and laboratory-based—has now intensified. The focus now is on establishing whether C. pneumoniae plays a causative role in the pathogenesis of atherosclerosis (and CHD), and whether anti-chlamydial antibiotics have a protective benefit against secondary cardiovascular events.
A clear mechanism
Conclusions
A significant pathogenetic role of C. pneumoniae in atherosclerosis and CHD is plausible, but unproven. Investigators in different institutions studying patients at various stages of CHD, have consistently identified a link between positive anti-C. pneumoniae antibody serology (or the presence of C. pneumoniae DNA/protein) and atherosclerotic disease. Reports of infection-induced atherosclerosis in animal models in addition to ‘live’ intact C. pneumoniae organisms being isolated from human
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Modification of ‘The John French Memorial Lecture’, delivered at the British Atherosclerosis Society Meeting, Oxford, UK, on 2nd April 1998.