Protective responses in the ischemic myocardium.

Acute coronary syndromes and heart failure arising as a consequence of ischemic injury to the myocardium account for a large proportion of all hospital admissions and of all causes of death in industrialized nations. Medical and surgical management of these conditions consumes enormous resources each year, but current therapeutic measures fall far short of reducing death and disability from ischemic heart disease to acceptable levels. Several recently successful advances in therapy of acute coronary syndromes are based on limiting the extent of myocardial damage that ensues following occlusion of a major coronary artery by rapid restoration of blood flow. However, many patients are not suitable candidates for thrombolytic drugs or revascularization procedures, and these approaches often are applied too late to prevent irreversible damage to the myocardium. A greater understanding of the mechanisms of ischemic injury, and of endogenous defense mechanisms, could foster additional improvements in clinical care. Mechanisms of cell injury during myocardial ischemia and reperfusion Cells of all tissues undergo irreversible injury and death when deprived of oxygen and other nutrients, and many of the responses to ischemia are shared among all cell types. However, quantitative and kinetic features of ischemic injury and of cytoprotective responses to injury are distinctive for each specialized cell type and tissue, and certain responses may be unique. In the case of the mammalian heart, an extensive literature has defined a stepwise series of events that follow coronary occlusion and that determine whether cells live or die. Immediately upon cessation of blood flow, concentrations of high-energy phosphate compounds (ATP and creatine phosphate) in cardiomyocytes fall and pH rises as cells shift from oxidative metabolism to anaer-obic glycolysis. Within seconds or minutes, these abnormalities become sufficiently severe to reduce the contractile force generated by actin-myosin crossbridge formation, and subsequently to impair the function of energy-dependent ion pumps in cellular membranes. Intracellular concentrations of free calcium increase, but cytosolic levels of calcium are buffered, at least initially , by uptake of calcium into mitochondria. As mitochondrial respiration ceases, FFAs and modified lipid or phospholipid intermediates accumulate. These changes are reversible, without cell death, if blood flow is restored promptly. However, with increasing durations of ischemia, cardiomyocytes fail to maintain the integrity of cellular membranes and cell death becomes inevitable, even if blood flow is restored fully. The time course with which injury becomes irreversible is a function of many variables, including the species under study, …