Irreversible ischemic myocardial cell injury developes in an increasing number of cells as the duration of coronary occlusion is prolonged. The present study quantitates myocardial necrosis produced by 40 minutes, 3 hours, or 6 hours of temporary circumflex coronary occlusion (CO) followed by 2 to 4 days of reperfusion, or by 24 or 96 hours of permanent circumflex ligation in pentobarbital anesthetized open chest dogs. After 40 minutes of ischemia, myocyte necrosis was subendocardial but with increasing duration of coronary occlusion, irreversible injury progressed as a wavefront toward the subepicardium. Transmural necrosis was 38 +/- 4% after 40 min, 57 +/- 7% after 3 hours, 71 +/- 7% after 6 hours and 85 +/- 2% after 24 hours of ischemic injury. These results document the presence of a subepicardial zone of ischemic but viable myocardium which is available for pharmacologic or surgical salvage for at least three and perhaps six hours following circumflex occlusion in the dog.

The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs.

Cells made ischemic rapidly manifest many distinct structural and functional alterations as a consequence of the depletion of their energy stores. In attempting to determine which of these are causally related to the eventual cell death, the authors have emphasized the relationship to the reversibility of the ischemic injury. Two phenomena have consistently characterized irreversibly in contrast to reversibly injured ischemic cells: the inability to restore mitochondrial function and evidence of plasma membrane damage. Studies in the authors' laboratory are reviewed that have focused on the pathogenesis, biochemical nature, and the relationship to irreversible cell injury of both of these alterations. A number of mitochondrial abnormalities are related to changes in long-chain acyl-CoA metabolism with inhibition of adenine nucleotide translocation and potentiation of a Ca2+-dependent increase in the permeability of the inner mitochondrial membrane. These changes are reversible upon reoxygenation only when the large increase in intracellular Ca2+ content that accompanies the phospholipid depletion from other cellular membranes is prevented. This disorder in phospholipid metabolism is felt to be the critical lesion that produces irreversible cell injury in ischemia. It affects the endoplasmic and sarcoplasmic reticular membranes of liver and myocardial cells, respectively, and probably the plasma membranes of both. It is prevented by pretreatment with chlorpromazine. An activation of endogenous phospholipases by an elevated, cytosolic free Ca2+ ion concentration is suggested as the mechanism underlying this phospholipid disturbance. The central role of intracellular Ca2+ in the initiation and functional consequences of ischemic cell injury are emphasized.

Myocardial ischemia: the pathogenesis of irreversible cell injury in ischemia.

Numerous studies have been conducted over the past 10 years on the effects of calcium antagonists on regional myocardial ischemia and infarct size. Verapamil, for example, reduced the degree of adenosine triphosphate degradation during 15 minutes of coronary occlusion followed by reperfusion in an anesthetized canine preparation. It also preserved the ultrastructural appearance of mitochondria in myocardium subjected to 1 hour of ischemia. Using an 8-hour permanent coronary artery occlusion model in which risk zone was assessed with radioactive microspheres and infarct size determined by tetrazolium staining, verapamil, administered 1 hour after occlusion, resulted in a modest decrease in infarct size. In a reperfusion model in which anesthetized dogs were subjected to 3 hours of coronary artery occlusion followed by 3 hours of reperfusion, verapamil decreased infarct size when it was administered during the period of ischemia, but failed to decrease infarct size when administered only during the reperfusion phase, i.e., after 3 hours of ischemia. Although verapamil is known to have negative inotropic effects, the newer calcium antagonist agent nisoldipine is less negatively inotropic, and might therefore be preferable in the situation of compromised hemodynamics. In a 6-hour permanent coronary artery occlusion model, nisoldipine decreased infarct size without decreasing left ventricular contractility. Most published reports support the concept that calcium antagonists decrease infarct size in models of experimental infarction. Of 4 major clinical studies, only 1 has shown that calcium antagonists are capable of reducing infarct size in man. However, in most of these studies, drug therapy commenced relatively late—4 or more hours after symptoms. In order for these drugs to demonstrate beneficial effects, the risk zone may have to be small and the degree of collateral flow adequate, the drug may have to be given very early or even before coronary occlusion (in a prophylactic fashion) and administration of the drug may have to be coupled to early coronary reperfusion.

Effects of calcium antagonists on infarcting myocardium

The effects of 5 mM potassium cyanide (KCN) on creatine phosphokinase (CPK) release and cellular morphology were studied. Rat hearts were perfused with substrate-deficient media gassed with O2 or N2 (O2 medium, N2 medium) at 37 C, and effluent was collected for creatine phosphokinase analysis. Tissue fixation was with glutaraldehyde for light and electron microscopy. Experiments included the following: a) continuous perfusion with O2- or N2-medium in the presence of KCN; b) 45 or 60 minutes of perfusion with N2-medium followed by O2-medium for 15 or 180 minutes, respectively; c) 45 minutes of perfusion with N2-medium with KCN added 15 minutes before reoxygenation with O2-medium plus KCN; (4) 60 minutes of N2-medium plus KCN followed by O2-medium plus KCN for 180 minutes; d) as a control for irreversible injury, 21 minutes of perfusion with calcium-free O2-medium followed by 2.5 mM calcium-O2-medium ("calcium paradox"). The following results were seen: a) Initial CPK release occurred about 30 minutes later from hearts perfused with O2-medium plus KCN than from hearts perfused with N2-medium plus KCN. b) Upon reoxygenation after either 45 or 60 minutes of anoxia, hearts had a sudden peak of oxygen-induced CPK release. Most irreversibly injured cells were massively swollen and had sarcolemmal defects and contraction bands. Reversibly injured cells in the same hearts resembled normal myocardium. A previously unrecognized third population of cells is described. These cells were characterized by contraction bands but were not swollen, had intact sarcolemma, and contained both normal and damaged mitochondria with intramatrical calcium accumulation granules. It could not be determined if these cells were reversibly injured or in an early stage of irreversible injury. c) KCN added 15 minutes before reoxygenation of hearts after 45 minutes of anoxia inhibited the sudden peak of oxygen-induced CPK release but not a slow sustained release. Small to moderate numbers of cells in these hearts contained contraction bands. d) After 60 minutes, KCN completely inhibited both oxygen-induced CPK release and contraction band formation. e) Addition of calcium to calcium-free hearts caused both massive CPK release and contraction band formation. It is concluded that: the beginning of CPK release from oxygenated KCN-inhibited hearts requires about 30 minutes longer than from anoxic hearts; KCN can inhibit both oxygen-induced CPK release and contraction bands in irreversibly injured rat myocardial cells; sudden contracture of myocardial cells as occurs in the calcium paradox can result in massive CPK release; contraction bands occur in nonswollen cells, hence contraction bands can occur independently of massive cell swelling or membrane rupture. It is postulated that there may be two stages of irreversible myocardial injury; a) loss of control of contraction and b) progressive loss of mitochondrial and membrane integrity.

Oxygen-induced enzyme release after irreversible myocardial injury. Effects of cyanide in perfused rat hearts.

The critical events that lead to the transition from reversible to irreversible injury remain unclear Studies are reviewed that have suggested that a rise in cytosolic free Ca2+ initiates plasma membrane bleb formation and a sequence of events that leads ultimately to cell death In recent studies, we have measured changes in cytosolic free Ca2+, mitochondrial membrane potential, cytosolic pH, and cell surface blebbing in relation to the onset of irreversible injury and cell death following anoxic and toxic injury to single hepatocytes utilizing multiparameter digitized video microscopy (MDVM) MDVM is an emerging new technology that permits single living cells to be labeled with multiple probes whose fluorescence is responsive to specific cellular parameters of interest Fluorescence images specific for each probe are collected over time, and then digitized and stored Image analysis and processing then permits quantitation of the spatial distribution of the various parameters within the single living cells Our results indicate the following: (1) formation of plasma membrane blebs accompanies all types of injury in hepatocytes; (2) cell death is a rapid event, initiated by rupture of a plasma membrane bleb, and is coincident with the onset of irreversible injury; (3) an increase of cytosolic free Ca2+ is not the stimulus for bleb formation or the final common pathway leading to cell death; (4) a decrease of mitochondrial membrane potential precedes loss of cell viability; (5) cytosolic pH falls by more than 1 pH unit during chemical hypoxia This acidosis protects against the onset of cell death

Calcium and pH in anoxic and toxic injury

Explosive swelling of myocardial cells irreversibly injured by transient ischemia.

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Explosive swelling of myocardial cells irreversibly injured by transient ischemia.