Is inflammation the critical factor linking vulnerable coronary plaques to clinicalcoronary disease

Amajor emerging insight is the role of inflammation at all stages of the evolution and progression of atherosclerosis (1– 4). Atherosclerosis develops as a response of the vessel wall to chronic multifactorial injury, including the effects of hyperlipidemia, hypertension, cigarette smoke (and possibly other environmental toxins), diabetes mellitus, and other risk factors. Inflammation is the local response to injury with associated secondary systemic manifestations. The inflammatory response is accomplished by multiple interactions between blood cells and plasma constituents and the vessel wall, with the process controlled by a number of chemical mediators (1– 4). A key element in atherogenesis is the activation of a selective inflammatory pathway involving the interaction of monocytes and T lymphocytes with altered endothelium and the accumulation of activated macrophages and T lymphocytes in the intima mediated by monocyte chemoattractant protein-1 and other chemokines (1–5). Secretion of cytokines, such as platelet-derived growth factor, leads to accumulation and proliferation of vascular smooth muscle cells that secrete collagen, elastin, and glycosaminoglycans (1,2). Lipids, particularly oxidized low-density lipoprotein, accumulate in the macrophages and smooth muscle cells, thereby forming foam cells, and also in the extracellular connective tissue (1–5). Atherosclerotic plaques, which comprise foam cells, extracellular lipid, and fibroelastic tissue, are thus formed. Inflammation also leads to systemic effects, including the production and release of chemicals recognized as markers of inflammation (3,4). Several population studies have shown a relation between elevated blood levels of C-reactive protein and other inflammatory markers and the subsequent development of clinical manifestations of atherosclerosis, including coronary heart disease (3,4,6). Other studies have shown that C-reactive protein has a causative role in endothelial dysfunction and damage (7). What is unclear about atherosclerosis is the selective development of severe disease in a vascular region (e.g., coronary arteries, cerebral arteries, iliofemoral arteries) in the setting of risk factors, including hyperlipidemia and hypertension, which affect the entire vascular system. Disease triggered by random infection of various regions of the vascular system is a possible explanation (4,8,9). Various microorganisms or their associated agents, including Chlamydia pneumoniae and cytomegalovirus, have been identified in vascular lesions, and an association with the risk of clinical disease has been shown. However, large clinical trials have failed to show a beneficial effect on clinical disease in subjects treated with antimicrobial agents (9). Inflammation is also important in the development of secondary alterations in plaques producing complicated plaques that predispose to clinical disease. Specifically, apoptosis of vascular smooth muscle cells and collagen degradation produced by metalloproteinases released from macrophages predispose to plaque erosion or rupture, thrombosis, and clinical disease (10,11). Increased numbers of macrophages have been demonstrated in these so-called “vulnerable plaques” with adverse characteristics, including a thin fibrous capsule or an already ruptured capsule (12). Such plaques have been shown to have other features of inflammation, including temperature elevation (4). Attempts to detect such plaques noninvasively and to reduce inflammation in the plaques are under way (3,4). Inflammation is also involved in creating a thrombogenic state that leads to local thrombus formation (3,4,13). In this issue of the Journal, Meuwissen et al. (14) demonstrate more explicitly that plaque inflammation is an important pathobiological process linking complicated vulnerable atherosclerotic plaques to unstable angina pectoris. Previous work had shown that certain plaque morphologies are associated with unstable angina pectoris. Meuwissen et al. now show that atherectomy specimens from such lesions contain more macrophages than do those from controls. In the study, 79 patients with unstable (n 46) or stable (n 33) angina underwent directional coronary atherectomy for culprit lesions. Lesions on coronary angiograms were classified as simple (concentric and eccenAm J Med. 2003;114:607– 608. From the University of Texas Medical School at Houston, Houston, Texas. Requests for reprints should be addressed to L. Maximilian Buja, MD, University of Texas Medical School at Houston, 6431 Fannin – JJL 410, Houston, Texas 77030, or L.Maximilian.Buja@uth.tmc.edu.