| dc.description.abstract | Cardiovascular disease has resulted in an increased risk of premature deaths for the 104 million Americans with prediabetes or diabetes and has accounted for approximately 65% of total diabetic deaths annually. Clinical manifestations of diabetic heart disease include left ventricular hypertrophy, diastolic and systolic dysfunction, and diabetic cardiac autonomic neuropathy, which are regularly observed at varying severities in persons with type 2 diabetes. The Zucker diabetic fatty (ZDF) rat has shown promise as a model of diabetic heart disease since it resembles the blending of cardiac diseases seen in humans and as such can be utilized to investigate diabetic heart disease and therapeutic interventions. We chose to investigate the impact of exercise on diabetic heart disease in the ZDF rat, and to explore a novel mechanism. The objectives of the dissertation were to investigate the cardiac dysfunction in the ZDF model, determine whether aerobic exercise training can reverse electrocardiographic (ECG) and hemodynamic changes induced by diabetes, and identify whether cardiac edema may be one of the factors contributing to diabetic heart disease and a possible target of exercise. Myocardial edema is an imbalance between vascular permeability, lymphatic vessels, lymph flow, and cardiac function. It is unknown if diabetes causes myocardial edema. Little is known about the impact of diabetes on the lymphatic system and its receptors, vascular endothelial growth factor receptor 3 (VEGFR-3) and lymphatic endothelial receptor 1(LYVE-1). These receptors are responsible for the uptake of their respective ligands, VEGF-C and hyaluronan. Each receptor's expression is regulated by prospero homeobox protein 1(PROX-1), which is the master switch for the lymphangiogenesis. Myocardial fluid imbalances have been implicated in the fibrosis and hypertrophy associated with common cardiovascular diseases, which makes edema a suitable target for possible interventions. Diabetes in the ZDF rat caused crucial changes in R wave amplitudes (p<0.001), heart rate variability (p<0.01), QT intervals (p<0.001) and QTc intervals (p<0.001). R wave amplitude augmentation in sedentary diabetic rats from baseline to termination was ameliorated by exercise, resulting in R wave amplitude changes in exercised diabetic rats similar to control rats. Of these changes, aerobic exercise training was only able to correct R wave amplitude changes. In addition, exercise had beneficial effects in this diabetic rat model with regards to ECG correlates of left ventricular mass. Of the 24 hemodynamic parameters tested, 15 were negatively affected by diabetes. The debility of diabetic heart disease was evident in the diastolic filling, isovolumic contraction, ejection, and isovolumic relaxation phases. Importantly, exercise training restored 13 of the 15 hemodynamic parameters affected by diabetes. However, we did not observe differences in left ventricular weights, a direct measure of myocardial edema, or alterations in the levels of VEGF-C, VEGFR-3, LYVE-1, or hyaluronan. We were able to observe systemic differences in plasma interleukin (IL)-2 levels, reductions in dP/dtmax, and differences in PROX-1 protein levels and DNA binding activity that were suggestive of the presence of myocardial edema in the ZDF rat. However, these alterations are indirect measures of myocardial edema, therefore we were unable to conclude in the 19 week old ZDF rat if myocardial edema exists and plays a role in diabetic heart disease. | |
