Following myocardial infarction (MI) both the incidence of heart failure and mortality rates are approximately two-fold higher in patients with diabetes compared to those without diabetes. This increased risk for heart failure and mortality appears to be refractory to currently available treatments. The overall hypothesis of this proposal is that diabetes leads to myocyte specific changes mediated by hyperglycemia, ANG II and ROS, which prevent myocyte hypertrophy and stimulate apoptotic pathways. Therefore, an increase in hemodynamic stress combined with diabetes leads to greater myocyte loss and impaired hypertrophic response resulting in adverse LV remodeling and accelerating the progression of contractile dysfunction and heart failure. Our preliminary data suggests that hyperglycemia and diabetes alters cardiomyocyte signaling pathways involved in the regulation of myocyte growth and apoptosis. This is supported by our observation of increased LV dysfunction and replacement fibrosis in following volume overload in Type-2 diabetic rats. Consequently, the aims of this proposal are 1) Show that the progression of cardiac dysfunction in diabetic patients will be worse than in non-diabetic subjects following transmural myocardial infarction and evaluate whether AT1 RB and allopurinol slow the progression of LV remodeling and dysfunction in diabetic patient; 2) Determine impact of diabetes and insulin resistance on the time course of LV hypertrophy, function and myocyte apoptosis in rats following the and evaluate effect of RAS blockade and xanthine oxidase inhibition are more effective in slowing the progression of LV remodeling; 3) Determine impact of in vivo insulin resistance and Type-2 diabetes on the response of isolated adult cardiomyocytes to hypertrophic and apoptotic stimuli.
In Aim 1 we will use state of the art MRI methods coupled with serum markers of collagen turnover and oxidative stress.
In Aims 2 and 3 we will use the Zucker diabetic fatty rat that exhibits many of the characteristics of human Type-2 diabetes to assess, for the first time, the effects of diabetes on LV remodeling at all levels from in vivo cardiac function, through to intra myocellular signaling pathways in isolated cells. This combination of clinical and basic science studies into the impact of diabetes on LV remodeling will enable us to identify novel treatment strategies designed to close the gap in outcomes between diabetic and non-diabetic patients with heart disease.
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