The Energy Deprivation Hypothesis of heart failure, emphasized in the report of the NHLBI Special Emphasis Panel on Heart Failure Research, proposes that limitation in energy transfer is present in chronic heart failure (CHF) and contributes mechanistically to contractile dysfunction. Energy production in the heart is the highest of any organ and supports cardiac function at rest and with physical activity. ATP is the biochemical fuel for nearly all energy-requiring reactions. Creatine phosphate (PCr) is the major cardiac energy reserve and can rapidly re-generate ATP via the creatine kinase (CK) reaction. 31P magnetic resonance (MR) spectroscopy is the only non-invasive means for quantifying ATP and PCr in the human heart and has demonstrated reduced high-energy phosphates in animal models of CHF and in CHF patients. Although the rates of ATP turnover are critical for testing this hypothesis, it has not been previously possible to measure ATP flux through cardiac CK in humans. During the first three years of the current grant, novel MR saturation transfer methods were developed that allow, for the first time, measurements of ATP synthesis rates through CK in human hearts. The overall aim of this proposal is to exploit these new techniques so that measures of cardiac CK flux can be integrated with imaging assessment of function to describe mechano-energetic coupling, whether and how it differs in CHF patients, and whether interventions designed to alter the relationship can improve contractile function in CHF patients.
The specific aims are: 1. To test the hypothesis that cardiac energy turnover is decreased in human CHF and that this occurs in proportion to contractile dysfunction and CHF clinical severity. 2. To evaluate the relationship between metabolic reserve and contractile function in patients with and without CHF during changes in contractile performance induced by esmolol and/or dobutamine. 3. To test whether an acute intervention that improves mechano-energetic efficiency in the failing heart improves metabolic reserve and contractile function. 4. To evaluate whether a chronic intervention designed to improve metabolic parameters, oral creatine supplementation, can increase myocardial creatine and PCr contents, flux through myocardial CK, and improve contractile function, symptoms, and exercise tolerance in CHF patients. These studies directly test the importance and magnitude of the role of energy deprivation in human CHF.
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