Basic mechanisms and influences upon ischemic myocardial dysfunction and the development of tissue injury and infarction will be investigated. In Project A, isolated buffer and blood-perfused rabbit hearts will be used to study the metabolic, structural and functional changes which occur during a 90-180 min period of moderate or severe ischemia, a time period which embraces the transition from reversible to irreversible injury. The degree of ischemia which exists in the central and border zones of an infarction will be modelled to investigate 1) The effects of global ischemia of different degrees of severity and duration, 2) The separate components of the ischemic injury process (coronary arterial pressure, flow and oxygen delivery reduction, "paradoxical" systolic stretch, ischemic contracture, glycolysis, contractile work and metabolic demand, calcium accumulation, edema, substrate type (glucose vs. free fatty acid), phosphate and adenosine leakage, autolysis, reduced redox state, acidosis, and reperfusion), 3) Consequences of "primary" ischemia in comparison to "relative" ischemia, and 4) Post-ischemic depression of cardiac function. In Project B, a standardized coronary artery ligation protocol will be used to study the evolution from acute ischemia to the final infarct, in terms of final infarct size and adequacy of healing as assessed by resistance to ventricular aneurysm and rupture. Serial cross-sections of the heart will be used to define maps of regional perfusion (14C-antipyrine technique and NADH fluorescence photography), enzyme depletion, connective tissue replacement and capillary density from the acute postligation period until 8 weeks thereafter and thereby study mechanisms which govern the transition from ischemia to infarction and which affect the healing and repair process. The peri-infarction border zone will be studied in detail and attempts will be made to alter final infarct size by influencing selected processes which can affect survival in the border zone. Factors which affect the development of postinfarction aneurysm or rupture will be studied. The hypothesis that myocardial tissue can develop resistance to ischemia will be tested by raising animals in an environment of forced exercise and/or hypoxia and/or chronic acidosis.