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 infarction in the Global Utilization of t-PA and Streptokinase Trial of thrombolytic therapy sustained larger infarcts compared to younger patients, and had greatly reduced recovery of contractile function in the infarct zone. We found that augmented myocardial injury also occurred in isolated, buffer perfused hearts obtained from elderly 24 month Fischer 344 rats following ischemia and reperfusion compared to hearts from 6 month Fischer adults, supporting a myocardial source of the increased damage. 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 hydroxyl 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 by 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 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. The causative role of electron transport damage in OH production will tested by comparing the extent of reperfusion injury and OH production in hearts of each age reperfused in the presence and absence of inhibitors of mitochondrial electron transport. These studies will determine if the aging heart is subject to increased mitochondrially-derived 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 additional damage and decreased recovery observed in the aging heart in both experimental and clinical situations. An understanding of the mechanisms of excess injury in the aging heart will be required to design adjunctive treatment strategies to supplement the benefit of successful thrombolysis in the higher risk elderly patient. The PI has focused his study of the mechanisms of oxidative injury during ischemia and reperfusion on the aging heart, since oxidative injury is likely to be enhanced in aging tissue, and oxidative mechanisms have potential clinical importance in view of the increased mortality in elderly patients with myocardial infarction.
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