© 2002 American Heart Association, Inc.
Editorials |
The Multiple Mechanisms by Which Infection May Contribute to Atherosclerosis Development and Course
From the Cardiovascular Research Institute, MedStar Research Institute, the Washington Hospital Center, Washington, DC.
Correspondence to Stephen E. Epstein, MD, Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, 110 Irving St, NW Suite 4B-1, Washington, DC 20010. E-mail stephen.epstein@medstar.net
Key Words: atherosclerosis • immune mechanisms • inflammation • pathogen burden
Among the initial studies suggesting that infection contributes causally to atherogenesis were investigations of human atherosclerotic tissue demonstrating the presence of pathogen in the diseased vessel wall and classical seroepidemiological studies in which associations were demonstrated between atherosclerosis and prior pathogen infection (evidenced by anti–pathogen antibodies). Appropriately, however, questions were raised relating to the biological meaning of such associations. A pathogen resident in an atherosclerotic vessel, for example, may be just an "innocent bystander," rather than a causally relevant agent; alternatively, atherosclerotic vessels might just be more vulnerable to infection. And although multiple seroepidemiological studies demonstrated associations between atherosclerosis and antibodies targeted to individual pathogens, other studies did not.1
In addition to these studies providing associative evidence linking infection to atherosclerosis, mechanistic investigations demonstrated important links (reviewed in Epstein et al2). For example, in vitro infection of cells of the vascular wall caused changes that could predispose to atherosclerosis: infection stimulates smooth muscle cell (SMC) proliferation; inhibits apoptosis; increases SMC migration; increases lipid accumulation; produces procoagulant effects; and increases expression of cytokines, chemokines, and cellular adhesion molecules. Infection also increases lesion development in animal models of atherosclerosis and of restenosis.
The nagging question persisted, however: Why, if infection were an important contributor to the development of atherosclerosis, was there such disparity among different epidemiological studies, and why were some individuals who had been infected with a candidate pathogen free of atherosclerosis, while others had extensive disease? Several tentative answers have been forthcoming, all pointing to the conclusion that if
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