Infections and atherosclerosis: new clues from an old hypothesis?

The inability of "traditional" risk factors such as hypercholesterolemia, hypertension, and smoking to completely explain the incidence and trends in cardiovascular diseases has resulted in repeated calls for a search for "new risk factors" (1, 2). Recently, infections have been placed among these new putative risk factors (3-16). This commentary reviews the historical antecedents of the infectious hypothesis, which is actually one of the oldest etiologic theories of atherosclerosis. Because inflammation may mediate the putative atherogenic role of infections (8, 10, 13-15), the historical antecedents that have discussed a possible role of inflammation in atherogenesis are also briefly reviewed. This review demonstrates that inflammation and infection were considered as possibly atherogenic more than a century ago. However, these hypotheses were all but completely abandoned early in the present century, coinciding with a shift in paradigms in the pathogenetic theories of atherogenesis, i.e., with the development of the multifactorial model of causation of chronic ("non-infectious") diseases (17, 18). Striking resemblances are apparent between current research on the putative atherogenic role of infections and research on the topic that was conducted up to one century ago. The synthesis of past and current evidence reviewed here suggests the following hypotheses and clues for future studies: 1) that the study of a possible atherogenic role of infections should be extended to infectious agents other than the three that have been the focus of research in recent years (herpesvirus—mainly cytomegalovirus (CMV), Chlamydia pneumoniae, and Helicobacter pylori) (6, 7); 2) that the introduction of antibiotic therapies in the 1940s and 1950s may have contributed to the decline in coronary heart disease incidence and mortality ob-