This proposal aims to measure and manipulate in vivo cardiac flux through myocardial creatine kinase (CK) in mice to test the energy starvation hypothesis of heart failure (CHF). The requirement of ATP for normal cardiac contractile function is absolute and the CK reaction is the major energy reservoir of the heart. CK metabolites are reduced in CHF and predict outcomes. The first direct measures of ATP flux through CK in the human heart recently revealed dramatic 50-70% reductions in CK flux in CHF even before global [ATP] loss occurs. Despite this supporting evidence, conventional metabolic interventions have failed to augment CK pools or flux in failing hearts to directly test the energy starvation hypothesis. This application proposes the use of new transfection approaches, just developed by the investigators, to genetically over-express the factors most likely limiting CK flux in CHF and determine, in vivo, the energetic and functional consequences.
The specific aims are: 1.) to implement new clinical MR techniques in mouse studies for assessing in vivo cardiac CK metabolites, flux and function, 2.) to test the hypothesis that increasing CK expression in CHF increases in vivo cardiac CK flux and improves ventricular function, 3.) to test the hypothesis that increasing creatine transport protein expression will increase myocardial creatine, CK flux, and mechanical function in CHF, 4.) to test the hypothesis that conditional CK gene deletion will exacerbate the development of CHF and that CK rescue will provide protection. This proposal uniquely brings together novel non-invasive tools to measure in vivo cardiac CK flux, new technology to perform genetic CK manipulations, relevant animal models that capitulate characteristics of human CHF, and finally, sophisticated means to assess the functional consequences. These mouse studies offer interventions not possible in human CHF and promise new insights for this prevalent, growing disease. Lay summary: Heart failure is an important and growing cause of morbidity and mortality in the United States. Our recent observations in human heart failure guide these studies that currently can only be performed in mice. We will use state-of-the-art techniques to increase energy metabolism in failing mouse hearts and see if that improves the contraction of the heart and reduces heart failure.
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