ACUTE CORONARY SYNDROMES: A ROLE FOR INFLAMMATION AND ITS RESOLUTION
Janos G. Filep, M.D.,
University of Montreal, Montreal, and Maisonneuve-Rosemont Hospital, Montreal, QC, Canada
Inflammation contributes to many of the characteristics of plaques from nascent lesions to rupture of fibrous cap that precipitate acute coronary syndromes (ACS). Substantial evidence supports that inflammatory pathways govern the collagen metabolism, macrophage polarization, generation of lipid/necrotic core, microscopic calcification and outward remodeling, characteristic features of the unstable plaque. Plaque rupture triggers thrombus formation, accumulation of neutrophils at culprit lesions, which can facilitate entrapping leukocytes and propagation of thrombosis. Elevated plasma levels of neutrophil-derived myeloperoxidase predict adverse outcomes in patients with ACS. Limiting excessive inflammatory responses requires countervailing mechanisms. Indeed, the inflammatory reaction normally also involves a resolution phase governed by specialized pro-resolving mediators (SPMs). The SPM families include annexin A1 and IL-10, as well as lipid mediators, such as lipoxins, resolvins, and maresins arising from omega-3 polyunsaturated fatty acids. These mediators can efficiently inhibit inflammatory cell influx, reduce production of pro-inflammatory mediators and oxidative stress, and restore defective efferocytosis and fibrous cap thinning. Thus, the risk of ACS depends critically on the prevailing balance between pro-inflammatory and resolution pathways. An emerging concept is that resolution mechanisms are defective in coronary artery disease, thereby aggravating ACS risk. Lower plasma levels of aspirin-triggered lipoxin A4 increases the risk for atherosclerosis and high fat diet associates with defective inflammation resolution. Conversely, therapeutic administration of resolvins decreases leukocyte trafficking into injured arteries, and dietary omega-3 fatty acid supplementation or over-expression of 12/15-lipoxygenase, a key SPM biosynthetic enzyme results in better cardiovascular outcomes. Thus, promoting resolution of inflammation represents a promising novel therapeutic approach for reducing ACS risk or for the treatment of acute coronary artery disease. (Grant support: CIHR).