Modes of myocardial cell injury and cell death in ischemic heart disease.

Abstract

The manifestations and mechanisms of myocardial cell injury and cell death in response to impaired coronary perfusion and thrombosis continue to be the collective subject of ongoing investigation because of intrinsic scientific interest and relevance for the diagnosis and treatment of patients with ischemic heart disease. An extensive body of evidence has documented the cellular and subcellular alterations that accompany the progressive reduction in high-energy ATP in response to oxygen and substrate deprivation affecting all cell types, including cardiac myocytes.1 2 3 The characteristic pattern of ischemic cell injury involves fluid and electrolyte alterations, with loss of K+ and Mg2+ and accumulation of water, Na+, Cl−, H+ (acidosis), and Ca2+; cytoplasmic, organellar, and cellular swelling with plasma membrane blebbing; and margination and clumping of nuclear chromatin. These cellular changes are due to progressive impairment of membrane composition, structure, and function.1 The transition from reversible to irreversible injury is characterized by the development of a severe membrane permeability defect that allows the unregulated influx of divalent and trivalent cations, including calcium.1 Subsequently, the swollen cells develop physical defects (holes) in their cell membranes and rupture. These features of cell injury with cell swelling have been shown to involve cardiac myocytes subjected to hypoxia in vitro and cardiac muscle during the evolution of myocardial infarction in vivo.1 3 Myocardium undergoing ischemic death ultimately exhibits some variant of coagulation necrosis and elicits an inflammatory response with an initial influx of neutrophils.3 The underlying membrane damage to ischemic myocytes is the basis for the diagnosis of myocardial infarction by pathology laboratory and nuclear cardiology methods. Recently, considerable attention has been directed to another form of cell death, referred to as apoptosis.1 2 Although apoptosis was initially characterized as a …