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Special Communication |

Chlamydia pneumoniae as an Emerging Risk Factor in Cardiovascular Disease

Murat V. Kalayoglu, MD, PhD; Peter Libby, MD; Gerald I. Byrne, PhD
JAMA. 2002;288(21):2724-2731. doi:10.1001/jama.288.21.2724.
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Recent appreciation of atherosclerosis as a chronic, inflammatory disease has rekindled efforts to examine the role that infectious agents may play in atherogenesis. In particular, much interest has focused on infection with Chlamydia pneumoniae. The possibility that a prokaryote contributes to atherogenesis has high clinical interest, as C pneumoniae infection may be a treatable risk factor. To review the evidence implicating C pneumoniae in the pathogenesis of atherosclerosis, we searched MEDLINE for articles published between January 1966 and October 2002 on the association of C pneumoniae and atherosclerosis. We also used online resources, texts, meeting abstracts, and expert opinion. We included 5 types of studies (epidemiological, pathology based, animal model, cell biology, and human antibiotic treatment trials) and extracted diagnostic, pathophysiologic, and therapeutic information from the selected literature; consensus was reached on interpretation discrepancies. Chlamydia pneumoniae is associated with atherosclerosis by epidemiological and pathology-based studies. Animal model and cell biology studies suggest that the pathogen can modulate atheroma biology, including lipid- and inflammatory-related processes. Although some preliminary antibiotic treatment trials in patients with coronary artery disease indicated a reduction in recurrent coronary events, larger studies have not shown benefits in individuals with stable coronary artery disease. It is unlikely that C pneumoniae infection is necessary to initiate atherosclerosis. Furthermore, conventional antibiotic therapy may not eradicate the organism or reduce mortality in individuals with atherosclerotic vascular disease. Nevertheless, the current body of evidence establishes this pathogen as a plausible, potentially modifiable risk factor in cardiovascular disease.

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Figure 1. Life Cycle of Chlamydia pneumoniae
Graphic Jump Location
Chlamydial elementary bodies adhere to the host cell and are endocytosed (1). The pathogen prevents phagosome-lysosome fusion, differentiates into the reticulate body (2), and begins replicating within the inclusion (3). Replicating reticulate bodies may redifferentiate back into elementary bodies (4a and 5) and lyse the host cell to begin a new round of infection (6). In addition, under conditions of immune stress such as the presence of IFN-γ, the pathogen may adopt a noninfectious, nonreplicating persistent form (4b); when the stress is removed, the pathogen can redifferentiate into infectious elementary bodies to begin a new cycle of infection. IFN indicates interferon.
Figure 2. Mechanisms by Which Chlamydia pneumoniae May Promote Atherosclerosis
Graphic Jump Location
Circulating monocytes infected with C pneumoniae adhere to and migrate through the endothelium, undergo cytolysis, release infectious elementary bodies, and establish chronic infection within the intima. Chlamydia pneumoniae in the persistent form, contained within a subgroup of host cells (not shown), reenter the productive life cycle, lyse the cells, and are released as infectious elementary bodies within the intima. Elementary bodies are capable of infecting and replicating within all atheroma cell types, including resident macrophages, smooth muscle cells, and endothelial cells. Chlamydia pneumoniae modulates cell biology to trigger inflammatory cascades, release matrix metalloproteinases and procoagulant factors, recruit specific T-cell responses, alter cellular lipid metabolism, promote smooth muscle cell proliferation, induce endothelial leukocyte adhesion molecule expression, and impair arterial relaxation. VCAM indicates vascular cell adhesion molecule; ICAM, intercellular adhesion molecule; E-selectin, endothelium selectin; IL, interleukin; LDL, low-density lipoprotein; oxLDL, oxidized LDL; cHsp60, chlamydial heat shock protein 60 kd; cLPS, chlamydial lipopolysaccharide; MIP, macrophage inflammatory protein; MCP, monocyte chemoattractant protein; TNF, tumor necrosis factor; IFN, interferon; and FGF, fibroblast growth factor.



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