The mechanistic basis of infarct healing

Abstract

Myocardial infarction triggers an inflammatory cascade that results in healing and replacement of the damaged tissue with scar. Cardiomyocyte necrosis triggers innate immune mechanisms eliciting Toll-like receptor- mediated responses, activating the complement cascade and generating reactive oxygen species. Subsequent activation of NF-kappaB is a critical element in the regulation of cytokine, chemokine, and adhesion molecule expression in the ischemic myocardium. Chemokine induction mediates leukocyte recruitment in the myocardium. Pleiotropic proinflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, are also upregulated in the infarct and exert a wide range of effects on a variety of cell types. Timely repression of proinflammatory gene synthesis is crucial for optimal healing; IL-10 and TGF-beta-mediated pathways may be important for suppression of chemokine and cytokine expression and for resolution of the leukocytic infiltrate. In addition, TGF-beta may be critically involved in inducing myofibroblast differentiation and activation, promoting extracellular matrix protein deposition in the infarcted area. The composition of the extracellular matrix plays an important role in regulating cell behavior. Both structural and matricellular proteins modulate cell signaling through interactions with specific surface receptors. The molecular and cellular changes associated with infarct healing directly influence ventricular remodeling and affect prognosis in patients with myocardial infarction.