Chlamydia pneumoniae and coronary heart diseaseBMJ 1997; 314 doi: https://doi.org/10.1136/bmj.314.7097.1778 (Published 21 June 1997) Cite this as: BMJ 1997;314:1778
Coincidence, association, or causation?
Established cardiovascular risk factors such as cigarette smoking, diabetes mellitus, hypertension, and hypercholesterolaemia do not fully explain the temporal and geographical variations in the prevalence of coronary heart disease over the past century. Clinical data and animal models suggest that common chronic infections (including cytomegalovirus, herpesviruses, Helicobacter pylori, and dental sepsis) may also contribute to the pathogenesis of atherosclerosis.1 However, the evidence that these infections can directly cause atherosclerosis is inconclusive.
Much stronger evidence now exists linking Chlamydia pneumoniae, an obligate intracellular pathogen, with coronary heart disease. This organism is a common cause of respiratory tract infections, which are usually subclinical and self limiting. Since C pneumoniae is difficult to culture, confirmation of infection often requires identifying systemic antibody responses. About half of the population is seropositive to C pneumoniae by the age of 50 years, suggesting that reinfection is common.2
Several recent studies have shown an association between antibodies to C pneumoniae and coronary heart disease.3 4 5 6 In 1988 investigators in Finland showed that patients with acute myocardial infarction and known chronic coronary heart disease had significantly elevated antibody titres against C pneumoniae compared with healthy controls.3 These researchers also showed prospectively that patients in the Helsinki heart study who had elevated IgA titres against C pneumoniae, or the presence of immune complexes containing C pneumoniae antigen, were twice as likely to suffer a cardiac event within the following six months (odds ratio 2.3, 95% confidence interval 1.3 to 5.2).4 This increased risk was independent of age, hypertension, and smoking status. Other workers have corroborated the association between titre and prevalence of coronary heart disease.5 6
Such seroepidemiological studies can be criticised with regards to the selection of control patients; the titres of antibodies to C pneumoniae empirically chosen to indicate seropositivity; and the uncertainty as to whether an elevated antibody titre indicates active infection with C pneumoniae, past infection, or is just a reflection of antigenic cross reactivity.
Examination of plaques from coronary7 8 and other arteries9 (using both immunohistochemical and polymerase chain reaction techniques) has provided more direct evidence of possible involvement of C pneumoniae in atherosclerotic disease. In one study of coronary artery specimens at necropsy the organism was identified within macrophages, which make up the lipid rich core of plaques, and in smooth muscle cells, but not in normal tissue adjacent to the sclerotic lesions nor in control normal arteries.7 In another investigation C pneumoniae was detected in 71 of 90 (79%) coronary atherectomy specimens from patients with angina but in only one of 24 (4%) samples from patients without atherosclerosis.8
How C pneumoniae enters atheromatous plagues and whether its presence reflects pathogenetic involvement in atherogenesis are not known. Macrophages may ingest particles of C pneumoniae in the lungs or elsewhere before migrating to the atheromatous lesion. C pneumoniae may simply reside in such macrophages without causing harmful effects, such that the association of the organism's presence and atherosclerosis is purely coincidental.
Alternatively, C pneumoniae is a plausible candidate for triggering and perpetuating inflammatory changes that contribute to the development of atherosclerosis. Chronic infection of macrophages with injury to blood vessels may be analogous to the pathogenesis of trachoma. In this case the closely related organism, Chlamydia trachomatis, causes scarring of the eye and blindness many years after the original infection, which is characterised by conjunctival infiltration with macrophages and lymphocytes.10 Infection with C pneumoniae might induce a chronic immune activation, mediated by cytokines, that contributes to direct, chronic endothelial cell damage or stimulates the synthesis of acute phase reactants such as fibrinogen11 and C reactive protein.12 Chronic infection might also increase expression of monocyte derived procoagulants such as tissue factor13 and thereby increase the risk of local or distant thrombosis.
The biological properties of C pneumoniae make it a potential culprit for initiating or modulating plaque formation. Like peptic ulceration related to infection with Helicobacter pylori, atherosclerosis may be a chronic inflammatory condition with a treatable infective cause. Preliminary evidence suggests that elevated antibody titres to C pneumoniae may be an independent predictor of outcome in men who have had a myocardial infarction. Furthermore, data suggest that in such patients antibiotic treatment reduces serum and monocyte activation markers14 and is associated with a reduced likelihood of further cardiovascular events.15
Laboratory, seroepidemiological, and pathological evidence is accumulating for an association between C pneumoniae and coronary heart disease, but whether the organism is directly causal remains unclear. Establishing that such a widespread infection contributes substantially to the development of coronary heart disease will require further investigation; infection with C pneumoniae could turn out to be an important risk factor in certain individuals and to have complex interactions with conventional atherogenic risk factors. Large, prospective eradication trials with antichlamydial antibiotics, currently being designed, will help to finally clarify what role C pneumoniae plays in coronary artery disease.