Elderly patients have a markedly increased morbidity and mortality following acute myocardial infarction. Despite successful thrombolysis at 90 minutes, patients older than age 75 with acute myocardial infarction in the angiographic substudy of the Global Utilization of t-PA and Streptokinase (GUSTO) Trial of thrombolytic therapy sustained larger infarcts compared to younger patients, and had greatly reduced recovery of contractile function in the infarct zone at followup. We tested if augmented myocardial injury would also occur in isolated, buffer perfused hearts, supporting a myocardial source of the increased damage. Hearts obtained from 24 month Fischer 344 rats sustained greater injury following 25 minutes of global stop-flow ischemia and 30 minutes of reperfusion than hearts from 6 month Fischer adults. Aging hearts had decreased recovery of developed pressure and increased release of enzyme markers of tissue injury. Thus, both elderly patients and isolated hearts from an animal model of aging sustain greater myocardial damage following successful reperfusion of severe ischemia compared to adult controls. We hypothesize that a more rapid evolution of ischemic mitochondrial injury contributes to the increased damage-in the aging heart. We propose that greater mitochondrial injury increases mitochondrial production of the very reactive and damaging hydryoxyl radical (.OH) during reperfusion. We will compare the evolution of ischemic injury in the two independent populations of cardiac mitochondria (subsarcolemmal and interfibrillar) obtained from isolated, buffer perfused adult and elderly Fischer 344 rat hearts. The .OH-generating capability of isolated mitochondria from ischemic elderly and adult hearts will be measured y the salicylate hydroxylation method. We propose that increased ischemic electron transport damage in the elderly heart will lead to greater .OH production. Mitochondrial antioxidant activity will be measured prior to and following ischemia, to determine if reduced antioxidant defenses also contribute to injury in the aging heart. We will determine if mitochondrial and myocyte injury during reperfusion is increased in the elderly heart, and if it can be reduced by intervention with a .OH scavenger. These studies will determine if the aging heart is subject to increased oxyradical production in the setting of decreased mitochondrial antioxidant defenses, amplifying oxidative injury to mitochondria and myocytes during reperfusion. Excess oxidative injury could contribute to the greater myocardial damage and decreased recovery observed in the aging heart during reperfusion in both experimental and clinical situations.