Pathophysiology -- Role of Inflammation, Plaque Disruption, and Thrombosis Prediman K. Shah Cedars-Sinai Medical Center, Los Angeles, California, USA In recent years, medical researchers have learned a great deal about the pathophysiology of atherosclerotic coronary artery plaque formation and the tendency of plaques to rupture, causing intracoronary thrombosis and acute myocardial ischemia. In this review, Dr. Shah described the series of pathophysiologic events that lead from an intact and stable atherosclerotic plaque to a ruptured plaque and myocardial infarction, including the major role played by inflammation. Dr. Shah began by pointing out that we have learned a great deal in recent years about the pathophysiology of atherosclerotic plaque rupture in acute coronary syndromes. He said: "It is becoming increasingly clear that inflammation plays an important role in the progression from stable atherosclerotic plaque to ruptured plaque causing acute thrombosis and coronary artery occlusion. The question is, how do we get from that initial stable point to the acute crisis of myocardial infarction?" Dr. Shah said that a key event in this process is the rupture of the fibrous cap of the atherosclerotic plaque. Interestingly, the majority of infarcts develop from lesions that do not appear to be significantly occluded on angiography. Why? The involved vessels undergo remodeling with expansion of the adventitia in a compensatory response to the partial occlusion caused by atherosclerotic lesions. As a result, the lumen is not significantly compromised for a long period of time. In addition to adventitial remodeling, two features contribute to the plaque rupture process: the lipid core of the plaque and an inflammatory infiltrate that lies over the lipid core and under the fibrous cap, with the latter becoming thinner as the plaque evolves. The key question is What keeps the fibrous cap of the plaque intact? The answer is collagen and other extracellular matrix components. The thinning of the cap and its eventual rupture are associated with a loss of collagen and other matrix components. Ultimately, these changes are due to dysregulation of matrix homeostasis leading to matrix breakdown. Breakdown is mediated by enzymes such as metalloproteinases and serine proteases, which are secreted by activated inflammatory cells in the infiltrate underlying the fibrous cap. These enzymes have been found in lipid taken from vulnerable plaques. Oxidized low-density lipoprotein (LDL)-cholesterol, which is present in the lipid cores of atherosclerotic lesions, can activate inflammatory cells and cause them to produce enzymes such as MMP-9, a metalloproteinase. LDL can also suppress production of tissue inhibitors of metalloproteinase enzymes, resulting in further enzymatic activity and collagen loss, leading to further weakness of the fibrous cap. Clearly, Dr. Shah concluded, we have learned a great deal about this pathophysiologic process: The important role of inflammation in the progression from stable atherosclerotic lesions to plaque rupture and acute coronary thrombosis is intriguing. In the coming years, we hope to learn even more, including how to use this knowledge effectively to reduce the morbidity and mortality associated with coronary artery disease. Reporter: Andre Weinberger, MD Copyright 2000-2013 by HESCO International, Ltd. All rights reserved..