DIABETES MELLITUS: EFFECT ON MYOCARDIAL INFARCTION

心肌梗死是糖尿病的主要死亡原因， 糖尿病患者似乎对心脏局部缺血特别敏感。 糖尿病心肌缺血敏感性增加的机制 将在01-03年期间定义和衡量。 随后，我将 试图确定它们是否被改变的类型和程度 在本提案的04-05年期间进行糖尿病控制。 胰腺B细胞 细胞毒素四氧嘧啶将用于家兔以诱导糖尿病。 一 将建立具有轻度慢性糖尿病的兔子群体，其中没有 需要治疗才能生存。 轻度糖尿病-无治疗组 将与年龄匹配的非糖尿病组进行比较，以确定 未经治疗的轻度糖尿病增加心肌对缺血的敏感性 损伤 然后将轻度糖尿病未治疗组与轻度糖尿病未治疗组进行比较。 用胰岛素治疗的糖尿病组，以确定是否治疗轻度 糖尿病影响心肌对局部缺血的敏感性。 类似 将比较更严重的胰岛素依赖型糖尿病患者 组相对于非糖尿病对照组和胰岛素依赖性 维持在“差”或“紧”血糖水平的糖尿病组 用不同的胰岛素方案控制。 冠状动脉后 结扎后，将测量缺血和随后梗死的面积 并对糖尿病组和非糖尿病组进行比较。 此外，平行 将评估各组的左心室功能变化， 梗死，包括a）收缩性，B）舒张顺应性，c） 心肌ATP水平，产生磷酸盐，甘油三酯，乳酸盐，水肿， 和钙，d）冠状动脉血管舒张功能，和e） 代谢-机械耦合效率 愈合和修复的 梗死后1 - 60天，通过以下方法评估梗死心肌 测量心室破裂阻力、疤痕大小、厚度和 弹性，以及由组织的活性定义的主动修复量。 关键的胶原合成酶脯氨酰羟化酶和赖氨酰氧化酶 如通过胶原蛋白和弹性蛋白含量以及胶原蛋白类型和交联密度。

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.