One control group was infected with MCMV and given sham inoculations of CP (MCMV +/CP −). Three control groups of animals were also studied. In this study, apoE knockout mice were infected intraperitoneally with MCMV, followed by 2 intranasal doses of CP (MCMV +/CP +). The present investigation examines the hypothesis that infection of apoE knockout mice with multiple pathogens- namely, MCMV and CP-leads to a greater increase in lesion size than the increase that is seen with either pathogen alone. Using seroepidemiologic data, we found a strong association between pathogen burden and both the risk of CAD and the risk of adverse events occurring in patients with documented CAD. Our laboratory postulated that there is no single pathogen that contributes to atherogenesis but that risk of coronary artery disease (CAD) relates to the total number of a certain group of pathogens with which an individual is infected-that is, the aggregate pathogen burden. ĭifferent laboratories have implicated one or another pathogen as a causally relevant agent. A study of low-density lipoprotein receptor-deficient mice showed that, in this model, CP infection alone was not sufficient to induce atherosclerotic lesions rather, infection in combination with a high-cholesterol diet was necessary to enhance lesion size. Other animal models have been used to examine the potential causative role of CP infection in atherogenesis. Additional work in the apoE knockout mouse model demonstrated that infection of 8-weekold male mice with CP accelerated the development of atherosclerosis, as measured in the aortic arch. Recently published study results describe an increase in atherosclerotic lesion development in apoE knockout mice infected with murine CMV (MCMV) at 2 weeks of age. The apoE knockout mouse is a mouse strain that spontaneously develops atherosclerotic lesions when fed a normal chow diet. Additional studies with cholesterol-fed rabbits infected with CP demonstrated an acceleration in intimal thickening and an increase in plaque area. Earlier work with a normocholesterolemic rabbit model demonstrated a possible causative role of CP in atherogenesis. The development of animal models of atherosclerosis has made it possible to design controlled studies to examine definitively the issue of causality, at least in these animal models. Despite these studies, however, the complex nature of atherosclerosis in humans and the inability to observe the effects of infection unconfounded by multiple covariants makes it impossible to prove conclusively that pathogens are causally related to human atherogenesis. This evidence derives from seroepidemiologic studies, detection of pathogen in atherosclerotic plaques, and many mechanistic studies. Substantial evidence supports an association between atherosclerosis and infection with cytomegalovirus (CMV) or with Chlamydia pneumoniae (CP). Considerable attention has recently been focused on the possible role of infectious agents in atherogenesis.
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