Heart failure (HF) affects about 5 million Americans and more Medicare dollars are spent for the diagnosis and treatment of HF than for any other diagnosis. Because ATP is absolutely required to fuel normal contractile function, metabolic strategies to treat HF are an appealing investigative treatment strategy. This application focuses on augmenting depressed metabolism in HF by over-expressing the genes for specific isoforms of creatine kinase, the primary myocardial energy reserve reaction. In the failing heart there is reduced CK activity and a decrease in the myofibrillar (CK-M) and mitochondrial (CK-mito) isoforms. CK-M over-expression in murine HF, induced by thoracic aortic constriction (TAC), was recently shown to significantly improve left ventricular systolic function at rest and with stress and to increase survival, suggesting a critical role for CK energy metabolism in failing hearts. Conversely, even more recent studies suggest that depleting creatine, a substrate for the CK reaction, had no adverse effect on contractile function and survival in the myocardial infarction (MI) model of HF, suggesting no pathophysiologic role for creatine or CK in HF. This application aims to resolve this apparent controversy and to shed new, important insights into the role of CK and creatine in HF. The underlying hypothesis is that dysfunctional, viable myocytes benefit from CK over-expression but models with dense necrosis and cell loss do not. The studies will compare different HF models with and without dense necrosis during separate genetic manipulation of CK expression and creatine content. The proposal will exploit recently created cardiac-specific CK-mito over-expressing mice and noninvasive, serial magnetic resonance spectroscopy and imaging technology to assess the in vivo energetic, contractile, remodeling, and survival consequences in murine HF. The proposed studies aim to answer these timely questions and identify the mechanisms responsible for potential benefit with promise of reducing HF morbidity and mortality.
The heart uses chemical energy to fuel muscle contraction and support the body's functions at rest and during stress/exercise. This proposal will study the role of creatine kinase, a major energy reserve reaction, under conditions of stress and heart failure. These studies will evaluate the mechanisms by which creatine kinase could improve energy metabolism and heart function in the failing heart and, as such are timely, practical questions that could significantly impact heart failure morbidity and mortality.
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