IN VIVO MURINE CARDIAC ENERGY METABOLISM AND FUNCTION

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High-energy phosphate (HEP) metabolism fuels normal cardiac contractile function and is essential for myocellular viability. Although exciting transgenic murine models of cardiovascular pathology are now available, it has not been previously possible to noninvasively assess both cardiac energy metabolism and contractility or their regulation under physiologic conditions, due to the small cardiac dimensions (heart weights 70-200 mg) and high heart rates (-600/min) of mice. We describe here the first studies demonstrating the feasibility of doing combined non-invasive high-resolution magnetic resonance (MR) image-guided cardiac 31P spectroscopy I mice. This proposal aims to further optimize these MR imaging and spectroscopy techniques in order to provide a robust, reliable non-invasive exam for studying in vivo cardiac energy metabolism and function in wild-type and transgenic mice at physiologic heart rates. We also propose using these combined techniques to evaluate two recently described transgenic models of hypertenisve and normotensive hypertrophy. The specific aims are: Aim 1: To optimize combined 31P MR Spectroscopic and 1H MR imaging methods and to determine the normal age-associated ranges of cardiac HEP's and function in mice under physiologic conditions, Aim 2: To develop and implement an in vivo stress test for assessing murine cardiac metabolic and contractile reserve, Aim 3: To test the hypothesis that the primary metabolic abnormality resulting from ablation of the GLUT4 translocator results in a paradoxical increase in cardiac PCr/ATP ratio, and to test two hypotheses explaining potential mechanisms accounting for this confirmed observation, Aim 4: To test the hypothesis that hypertensive hypertrophy with increased ATP utilization, resulting from ablation of the endothelial-derived nitric oxide (eNOS) gene (in contrast to the normotensive hypertrophy of GLUT4 nulls), over time develops decreased energy reserve and contractile dysfunction. This first non-invasive tool for studying cardiac structure, contractile function, and bioenergetics under physiologic conditions in a single exam will be invaluable for cardiovascular investigators wishing to study the physiologic significance of transgenic manipulations in mice. It will also allow us to test specific metabolic hypotheses in two distinct hypertrophic models.