Myocardial infarction is the leading of death in diabetes mellitus, and diabetics appear to be particularly sensitive to cardiac ischemia. Mechanisms of this increased ischemic sensitivity in the diabetic myocardium will be defined and measured during years 01-03. Subsequently, I will attempt to determine whether they are altered by the type and degree of diabetic control during years 04-05 of this proposal. The pancreatic B-cell cytotoxin alloxan will be used in rabbits to induce diabetes mellitus. A rabbit colony with mild, chronic diabetes will be established in which no treatment is required for survival. This mild diabetic - no treatment group will be compared to an age-matched non-diabetic group to determine if untreated mild diabetes increases myocardial sensitivity to ischemic injury. The mild diabetic untreated group will then be compared to mild diabetic groups treated with insulin to determine if treatment of mild diabetes affects the myocardial sensitivity to ischemia. Similar comparisons will be made between a more severe, insulin-dependent diabetic group relative to a non-diabetic control group and between insulin-dependent diabetic groups which are maintained in either """"""""poor"""""""" or """"""""tight"""""""" glycemic control with different insulin regimens. Following coronary artery ligation, the area of ischemia and subsequent infarction will be measured and compared in the diabetic and non-diabetic groups. In addition, parallel groups will be assessed for changes in left ventricular function following infarction, including a) contractility, b) diastolic compliance, c) myocardial levels of ATP, creating phosphate, triglyceride, lactate, edema, and calcium, d) coronary arterial vasodilatory function, and e) metabolic-mechanical coupling efficiency. Healing and repair of the infarcted myocardium will be assessed from 1 to 60 days post-infarction by measuring resistance to ventricular rupture, scar size, thickness and elasticity, and the amount of active repair as defined by activity of the key collagen synthetic enzymes prolyl hydroxylase and lysyk oxidase as well as by collagen and elastin content and collagen type and cross-link density.
