CARDIAC METABOLISM, FUNCTION AND VASCULAR DISEASE IN DIABETES MELLITUS

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The clinical sequelae of hyperglycemia-induced alterations in the generation of lipid second messengers will be examined utilizing a multidisciplinary approach incorporating biochemistry, biophysics, clinical cardiology and diabetology. Subjects with an antecedent diagnosis of diabetes, scheduled for cardiac catheterization at the request of their referring physician and meeting inclusionary criteria will be recruited during the first three years of the project and followed at regular intervals for the duration of the 5 year project. In Specific Aim 1 attention will be focused on glycolytically coupled alterations of lipid second messenger generation and ventricular hemodynamic function in the diabetic state. With each subject serving as their own internal control, alterations in phospholipase activity (assessed through quantification of coronary venous arachidonic acid and lysophospholipid content) will be examined after glucose and insulin administration in the catheterization laboratory. Concomitant alterations in global ventricular function will be assessed during altered glycolytic flux through digitally acquired high-fidelity hemodynamic data and novel model-based image processing methods. In Specific Aims 2 and 3, the rates of progression of macrovascular proximal coronary artery disease, relative to catheterization determined baseline, as a function of time averaged serum glucose levels (HbA1c) and serum lipid and insulin levels sampled at regular intervals will be examined with high performance magnetic field gradient coil MRI using a prototype quadrature 6-element phased array radiofrequency coil. Through noninvasive assessment of the rate of proximal coronary average-lumen narrowing by MRI and the level of metabolic control in two groups, the relationship between hyperglycemia, insulin levels and progression of coronary macrovascular disease will be determined. Based upon a minimum sample size of 250 subjects, a 5% - 7% projected average progression rate of annual macrovascular luminal diameter narrowing, the power to detect a difference in progression rates (average 3.5 year follow-up) in the two groups (HbA1c < 7.8 or greater than or equal to 7.8) at the .05 level of significance is .87. Collectively, this project provides a basis for the clinical interpretation of the basic science observations in Projects 1-3 and examines the feasibility for characterization of the rate of global ventricular dysfunction and macrovascular (proximal coronary artery disease progression in diabetics through noninvasive means.