The contribution of blood components to myocardial ischemia reperfusion injury and the benefits of vitamin E in the diabetic heart

Abstract

Type 2 diabetes is a major risk factor in cardiovascular disease especially ischemic heart disease. The American Diabetes Association advocates that all diabetics are at risk for coronary myocardial infarctions (MI). Restoration of blood flow to the area of the myocardium that has undergone ischemia is the most important therapeutic goal in treating MI. However, restoration of blood to the myocardium contributes to further damage to the ischemic area. This phenomenon is known as ischemia-reperfusion (I-R) injury. Previous studies have found that experimentally induced diabetic animals are more susceptible to I-R injury compared to non-diabetic animals. One reason why diabetic hearts may be more susceptible to I-R injury may be due to the increased oxidative stress in diabetics. Diabetics also suffer from increased blood coagulation possibly due to increased thrombin activity. Thrombin, independent of its role in coagulation, may be contributing to additional myocardial damage following ischemia. This dissertation describes three experiments: First, determine if a non-thrombogenic dose of thrombin impairs cardiac recovery and compliance in isolated non-diabetic rat hearts using a red cell perfusate following 30 minutes of global ischemia. Second, determine if type 2 diabetic rats exhibit increased platelet microparticle formation (PMP), increased thrombin activity and increased coagulability. Third, determine if MI's were larger in diabetic rat hearts compared to non-diabetics and if vitamin E reduced MI size and improve cardiac function following coronary artery occlusion. We found that a non-thrombogenic thrombin dose significantly reduced recovery from global I-R and reduced myocardial compliance. Thrombin may act as a contributing factor in cardiovascular pathology independent of its role in coagulation. We found that thrombin production is increased 30 fold in type 2 diabetic rats compared to non-diabetic rats and PMP production is significantly increased in diabetics possibly resulting in a hypercoagulable state. Finally, we show that MI's are significantly larger in type 2 diabetic hearts compared to non-diabetics. Treatment with Vitamin E significantly reduced MI size and improved left ventricular function in treated diabetic rats compared to non-treated rats. These results help to explain the increased cardiovascular injury seen in the diabetic heart. Vitamin E may be a useful adjuvant to help diabetics reduce oxidative stress, minimizing cardiac damage done by oxidation compounds and activated blood coagulation components in the diabetic heart.