Patients with diabetes mellitus (DM) are subject to a high incidence of death and morbidity due to heart failure, especially following myocardial infarction (MI). These observations suggested and subsequent studies confirmed the presence of a diabetic cardiomyopathy (DBCM), indepenent of macrovascular CAD. In experimental DBCM, multiple mechanial abnormalities and potential mechanisms have been documented. However, the manifestations and mechanisms of DBCM in patients are not well understood. Using strips of myocardium obtained from patients with CAD and DM (CAD/DM) undergoing coronary bypass grafting, we have recently shown depression of the force-frequency relationship (FFR despite the fact that basal ventricular function was normal. This myocardial abnormality in CAD/DM is similar but less severe than that observed in dilated cardiomyopathy and mitral regurgitation and is reversible by forskolin, indicating that its proximate mechanism is likely a defect(s) in excitation-contraction coupling (ECC). This proposal has three aims, to be undertaken in CAD/DM patients and CAD controls: 1) delineate whether there is an in vivo counterpart of in vitro FFR depression in CAD/DM, 2) systematically study the processes involved in ECC in CAD/DM and determine if identified defects cause FFR depression, and 3) test for correlations between abnormal FFR/ECC and markers of both the metabolic effects of DM and associated vasculopathy in order to begin to characterize upstream mechanisms of DBCM. Patients will be recruited at both the University of Vermont and the New York Hospital-Cornell Medical Center. We will employ an integrated, collaborative approach including in vivo and in vitro determination of the FFR, in vitro quantification of ECC, and assessment of defects in glycolysis and vasculopathy in DM myocardium. A major strength of our experimental strategy is correlation, on an individual patient basis, of in vitro FFR depression with other variables of interest. Our long- term plan is to define the steps linkin abnormal carbohydrate metabolism and/or vasculopathy in DM to DBCM and ultimately design rational treatments.
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