Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges

Abstract

In the infarcted myocardium, necrotic cardiomyocytes release danger signals, activating an intense inflammatory response. Inflammatory pathways play a crucial role in regulation of a wide range of cellular processes involved in injury, repair, and remodeling of the infarcted heart. Proinflammatory cytokines, such as tumor necrosis factor α and interleukin 1, are markedly upregulated in the infarcted myocardium and promote adhesive interactions between endothelial cells and leukocytes by stimulating chemokine and adhesion molecule expression. Distinct pairs of chemokines and chemokine receptors are implicated in recruitment of various leukocyte subpopulations in the infarcted myocardium. For more than the past 30 years, extensive experimental work has explored the role of inflammatory signals and the contributions of leukocyte subpopulations in myocardial infarction. Robust evidence derived from experimental models of myocardial infarction has identified inflammatory targets that may attenuate cardiomyocyte injury or protect from adverse remodeling. Unfortunately, attempts to translate the promising experimental findings to clinical therapy have failed. This review article discusses the biology of the inflammatory response after myocardial infarction, attempts to identify the causes for the translational failures of the past, and proposes promising new therapeutic directions. Because of their potential involvement in injurious, reparative, and regenerative responses, inflammatory cells may hold the key for design of new therapies in myocardial infarction.

Figure 1

The post-infarction inflammatory reaction exerts both protective and detrimental actions on the infarcted heart. Necrotic cardiomyocytes release danger signals that activate innate immune responses leading to induction of cytokines and chemokines. CXC and CC Chemokines bind to glycosaminoglycans on the endothelial surface and mediate recruitment of neutrophils and mononuclear cells in the infarcted area. Infiltrating leukocytes exert a wide range of protective and detrimental actions on the infarcted heart. It has been proposed that infiltrating neutrophils may extend ischemic injury exerting cytotoxic, and pro-apoptotic actions on cardiomyocytes. Moreover, leukocyte-derived secretory products may have negative inotropic effects and proteases may increase matrix degradation causing adverse remodeling of the infarcted heart. Other actions of leukocytes may be protective. Thus, leukocyte subsets may phagocytose dead cells and matrix debris and may promote repair by activating endothelial cells and fibroblasts. Recent studies have suggested that subsets of myeloid cells may also exert pro-survival and regenerative actions on cardiomyocytes.

Figure 2

The consequences of excessive, prolonged and expanded inflammatory responses on the remodeling infarcted heart. Overactive or prolonged inflammation may accentuate matrix degradation by stimulating protease activation. Increased cytokine expression may increase cardiomyocyte apoptosis and suppress contractility. Defects in spatial containment of the post-infarction inflammatory response may result in extension of inflammatory injury in the viable myocardial areas leading to expansion of fibrosis. Impaired negative regulation of post-infarction inflammation may cause adverse dilative remodeling and accentuate systolic dysfunction.