Human heart failure is a clinical syndrome of diverse etiology characterized by weakened cardiac contractions. Despite the many causes, preliminary experiments suggest that heart failure (HF) may have a common pathology at the cellular and molecular levels. The PI has identified a reduction in the ability of Ca2+ influx to trigger the [Ca 2+]i transient in ventricular myocytes from the hearts of animals in HF. This defect, called cellular HF , leads to clinical HF when accompanied by betaAR desensitization and/or downregulation. Our observation in pressure overload HF is strongly supported by preliminary findings with gene targeted mouse models of dilated cardiomyopathy HF (MLP knockout mouse) and viral myocardiopathy HF(CVB3 mouse). This raises the possibility that in animal models of HF, there are at least two features that develop over time: cellular HF and betaAR desensitization and/or down-regulation. Our proposed work will examine this hypothesis at the cellular level using state-of-the-art methods including high-speed confocal [Ca 2+]i imaging and whole cell patch-clamp techniques. We will examine excitation-contraction (EC) coupling by measuring membrane currents while recording whole-cell [Ca 2+]i transients, Ca2+ sparks and cellular contractions. Three specific questions will be addressed during the proposed work. (1). What EC coupling defects underlie and/or contribute to cellular HF? (2). How does betaAR signaling affect the EC coupling defects in HF? (3). How do specific pharmacological and molecular therapies alter the EC coupling defects in HF? This project exploits new methods developed by the PI using (Ca 2+]i imaging at high temporal and spatial resolution to investigate HF. The proposed work should increase specific knowledge of the cellular and molecular defects in HF and lay the foundation for novel therapeutic approaches to the treatment of HF.
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