MOLECULAR BASIS OF HEART FAILURE

Columbia University Health Sciences, New York NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the applicant's abstract) Calcium (Ca) is a critical regulator of cardiomyocyte contractile function. Cardiac excitation contraction (EC) coupling requires activation of the Ca release channel/ryanodine receptor (RyR2) in the sarcoplasmic reticulum (SR) by signals transmitted via the voltage-gated Ca channel/dihydropyridine receptor (DHPR) in the transverse (T) tubule. Altered a homeostasis due to an as yet unidentified defect in EC coupling has been proposed as a possible contributory factor to the pathogenesis of heart failure. In the failing heart a defect in Ca signaling could result from a number of abnormalities including one or more of the following: 1) changes in the expression of Ca handling proteins; 2) post-translational modifications of Ca handling proteins; 3) anatomical changes in cardiomyocytes and/or extracellular matrix; 4) decreased myofilament responsiveness to Ca. To establish that a defect in any of the above is causal in the pathogenesis of heart failure, it is necessary to demonstrate that introducing the defect in Ca signaling can cause heart failure or correcting the defect can restore normal cardiac function. The goal of this proposal is to identify specific molecular defect(s) in Ca handling that contribute to the pathogenesis of heart failure. The investigators have access to a unique human model of heart failure: human myocardium from pre- (dysfunctional) and post- (normal function) left ventricular assist device (LVAD) implantation patients. Animal models of heart failure that are physiologically relevant to human heart failure have been developed to test hypothesis regarding the etiology of contractile dysfunction in the failing heart. The investigators propose: Aim 1 to use pre- (failing) and post-LVAD (normalized function) myocardial samples to obtain data comparing Ca signaling and EC coupling in normalized and failing myocardium obtained from the same patient; Aim 2 to use well defined animal models of heart failure to analyze Ca signaling and EC coupling during the progression of heart failure at four levels: 1) isolated functional systems (including RyR2 single channel properties), 2) integrated cellular function (including Ca transients), 3) biochemical studies examining the levels of expression (mRNA and protein) of Ca handling molecules; Aim 3 to test the hypothesis that a defect in activation of RyR2 is present in cardiomyocytes from failing hearts compared to cardiomyocytes from normal hearts and to induce defects in EC coupling in cardiomyocytes from normal hearts and to induce defects in EC coupling in cardiomyocytes by transfecting mutant RyR2 channels and by overexpressing IP3 receptors and to determine whether specific molecular defects can cause altered Ca handling, defective EC coupling and heart failure in transgenic mice.