Background-Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts. Methods and Results-Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes. Conclusions-Defective

Inflammation constitutes a complex, highly conserved cascade of molecular and cellular events. Inflammation has been labeled as “the fire within,” is highly regulated, and is critical to host defense and tissue repair. In general, inflammation is beneficial and has evolved to promote survival. However, inflammation can also be maladaptive when chronically activated and sustained, leading to progressive tissue injury and reduced survival. Examples of a maladaptive response include rheumatologic disease and atherosclerosis. Despite evidence gathered by Virchow over 100 years ago showing that inflammatory white cells play a role in atherogenesis, atherosclerosis was until recently viewed as a disease of passive cholesterol accumulation in the subendothelial space. This view has been supplanted by considerable basic scientific and clinical evidence demonstrating that every step of atherogenesis, from the development of endothelial cell dysfunction to foam cell formation, plaque formation and progression, and ultimately plaque rupture stemming from architectural instability, is driven by the cytokines, interleukins, and cellular constituents of the inflammatory response. Herein we provide an overview of the role of inflammation in atherosclerotic cardiovascular disease, discuss the predictive value of various biomarkers involved in inflammation, and summarize recent clinical trials that evaluated the capacity of various pharmacologic interventions to attenuate the intensity of inflammation and impact risk for acute cardiovascular events.

Key Words: infarction Ⅲ remodeling Ⅲ chemokines Ⅲ fibrosis Ⅲ wound healing M yocardial infarct healing is dependent on activation of an inflammatory cascade, followed by granulation tissue formation and deposition of collagen-based matrix. 1,2 Rapid induction of inflammatory chemokines, cytokines and adhesion molecules in the infarcted myocardium results in chemotactic recruitment of leukocytes. Neutrophils and activated macrophages clear the wound from dead cells and debris while secreting mediators that promote fibroblast growth and angiogenesis. The intense, but transient, inflammatory response is followed by repression of cytokine synthesis and activation of fibrogenic and angiogenic pathways. Activated myofibroblasts produce extracellular matrix proteins, whereas neovessels provide oxygen and nutrients necessary for the metabolically active wound. As the infarct matures, fibroblasts and vascular cells undergo apoptosis and a hypocellular collagenous scar is formed. Optimal repair of the infarcted myocardium is dependent on timely induction and suppression of inflammatory pathways and on endogenous mechanisms that ensure containment of the fibrotic response within the area of the infarct. Disturbances in the mechanisms involved in regulation of the reparative process result in formation of a defective scar with altered mechanical properties, leading to increased adverse remodeling.The chemokines are inflammatory mediators with an essential role in leukocyte trafficking. Several members of the chemokine family are markedly and consistently induced in healing infarcts, modulating the postinfarction inflammatory response through recruitment of leukocyte subpopulations. 3,4,5,6,7 The CC chemokine monocyte chemoattractant protein-1/CCL2 plays a crucial role in chemotaxis and acti-