CONTRIBUTION OF ENERGY DEPLETION TO HUMAN HEART FAILURE

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DESCRIPTION (the applicant's description verbatim): A critical untested biochemical hypothesis of human heart failure, as specifically emphasized by the NHLBI Special Emphasis Panel (SEP) on Heart Failure Research, is the Contribution of Energy Depletion to Heart Failure. This hypothesis suggests that energy transfer is reduced in congestive heart failure (CHF) and may limit contractile function. ATP is the biochemical fuel that sustains normal contractile function and creatine phosphate (Pcr) rapidly re-generates ATP via the creatine kinase (CK) reaction and is the major energy reserve in cardiac tissues. 31P magnetic resonance spectroscopy (MRS) is the only non-invasive means for directly studying cardiac biochemical energy metabolism. The investigators developed many of the 31P MRS techniques used today to quantify human cardiac CK metabolites and recent MRS techniques capable of detecting more subtle limitations in energy transfer. We propose here a close collaboration among experts in bioenergetics and novel imaging techniques with heart failure clinicians to combine for the first time biochemical investigations under physiological conditions with state-of-the-art assessments of contractile function and robust clinical correlates to evaluate whether energy depletion is present and contributes mechanistically to human heart failure progression. The three specific aims are: 1. To test the hypothesis that the myocardial metabolite concentrations of the CK energy reserve system are reduced in proportion to heart failure severity and predict its progression. 2. To evaluate energy reserve in heart failure, we will test the hypothesis that the response of the cardiac creatine kinase energy reserve to modulations of myocardial energy demand differs in normal and failing human myocardium. 3.To evaluate a metabolic intervention, we will test the hypothesis that oral creatine supplementation can improve myocardial energetics and thereby improve contractile function, symptoms and exercise tolerance of patients with chronic congestive heart failure.