Insights Into the Role of Infection in Atherogenesis and in Plaque Rupture

T he potential contribution of infection to the induction and progression of atherosclerosis has been characterized by profound controversy, continuing to the present time.Controversy also surrounds the concept that infection can precipitate plaque rupture, an event complicating the course of atherosclerosis and clinically characterized by acute myocardial infarction and death.The purpose of this article is (1) to review what we believe are the most compelling data that either are compatible with or refute the concept that infection plays a role in atherogenesis or plaque rupture; (2) to present the mechanisms that may contribute to such effects; and (3) to discuss the impact on the infection/atherosclerosis paradigm of the recent negative therapeutic trials examining the effects of macrolide antibiotics on cardiovascular end points in patients with coronary artery disease (CAD). Evidence Suggesting That Pathogens Contribute to AtherogenesisAlthough anecdotal information existed for many years suggesting that acute infection can trigger an acute myocardial infarction, 1,2 it was the groundbreaking work by Minick and Fabricant and their coworkers 3,4 in the1970s that began the serious scientific exploration of the relation between infection and atherosclerosis.These investigators demonstrated thatMarek's disease virus, an avian herpesvirus, caused atherosclerotic-like lesions in multiple arteries of chickens and that infection of smooth muscle cells (SMCs) with the virus in vitro caused cholesterol accumulation.Evidence was subsequently published extending the infection/atherosclerosis paradigm to humans.Thus, pathogens were found to reside in human atherosclerotic vessels, [5][6][7][8] and seroepidemiological studies demonstrated an association between pathogen-specific antibodies and atherosclerosis.Such associations were found with multiple pathogens, including cytomegalovirus (CMV), herpes simplex virus (HSV) types 1 and 2, Chlamydia pneumonia, Helicobacter pylori, and hepatitis A virus, as well as periodontal pathogens.9 -16 However, other studies failed to show such associations, 17,18 leading to discussions of the limitations of seroepidemiological studies in evaluating a causal role between infection and atherogenesis.19,20 Adding to the skepticism surrounding the infection/atherosclerosis paradigm, all of the evidence derived from human studies through the late 1990s showing that pathogens reside in atherosclerotic lesions and that anti-pathogen antibodies are associated with atherosclerosis was appropriately considered purely observational and could not be considered as demonstrating a causal role of infection in atherosclerosis.Short of the type of study demonstrating that H pylori causes stomach ulcers (in which the investigator actually ingested H pylori and developed an ulcer 21 ), the only way to prove that pathogens/hosts have the molecular interactive programs that are capable of actually causing atherosclerosis is by demonstrating, in animal studies, that infection does in fact lead to atherosclerosis.Whether such results, even if reproducibly demonstrated, apply to humans would still be problematic.However, it might be argued that the combination of consistent causal studies in animals and compelling mechanistic data could tip the scales.Following is an analysis of such studies.It is obviously up to the reader to determine which way the scales are tipped.Despite publication of the results by Fabricant and coworkers in the 1970s, a large hiatus followed until their results were confirmed and expanded.Beginning in the late 1990s, however, additional animal studies were performed indicating that pathogens do have the capacity to induce atherosclerosis.Thus, acute infection with CMV in rats caused injury to endothelial cells lining the aorta, 22 and acute infection of old (Ͼ24 months) apolipoprotein E (apoE) knockout mice with influenza A virus promoted the development of inflammation, SMC proliferation, and fibrin deposition in atherosclerotic plaques; of interest, 1 of the 10 mice infected exhibited a subocclusive platelet and fibrin-rich thrombus.23 Most importantly from a proof-of-concept perspective, chronic infection of apoE knockout mice (which spontaneously develop atherosclerotic lesions) with such pathogens as CMV or C pneumonia actually increased atherosclerotic lesion size.24 -27 Mechanisms by Which Pathogens Can Contribute to Atherogenesis Direct Effects on Cells of the Vessel WallPathogens can either directly infect cells of the vessel wall, where they could persist in a latent state, replicate at a low