Novel Calcitropes as Targets for Cardiomyopathy Treatment

Technical Abstract Principal Investigator: Satin, Jonathan Proposal Number: PR220724 This application addresses the topic area of Cardiomyopathy. Cardiovascular diseases are the leading cause of death in the United States and the incidence of cardiomyopathies are rising. As many as 1 in 500 adults may have cardiomyopathy, and is a leading cause of heart failure, with cost of care in the Veterans Affairs system exceeding $3.5 billion. Dilated cardiomyopathy (DCM) is not a nosographic entity per se; rather DCM is defined as enlarged ventricular chambers and contractile dysfunction leading to heart failure (HF). The majority of DCM cases are secondary to hypertension, followed by idiopathic DCM and less common genetic mediated DCM. Current HF therapies that focus on blocking sympathetic nervous system activated pathways improve survival but do not halt the progression of cardiomyopathies. Our labs discovered that a key molecule called Rad dynamically controls the activity of L-type calcium channels (LTCC) in the myocardium. Deletion of Rad in cardiomyocytes increases LTCC activity. Using cardiomyocyte-restricted Rad-knockout mice we discovered that cardiac output is stably increased into aging, and is commensurate with enhanced LTCC activity. Exciting preliminary findings from the cRadKO model motivated the present study because we found that in the absence of myocardial-restricted Rad there was a stable positive inotropic effect that provided improvement in the setting of cardiomyopathies including dilated cardiomyopathy and in the presence of pressure overload. Hypothesis: 1) Augmentation of myocardial Ca2+ handling by disrupting Rad-inhibition of LTCC function provides positive inotropic support for failing heart in acquired cardiomyopathy and dilated cardiomyopathy. 2) An interplay of protein interactions contributes to Rad-mediated channel control. To test these hypotheses, we will first probe the molecular basis for Rad function. We will interleave molecular studies with determination of the types of cardiomyopathy that are candidates for Rad-targeted therapeutics. The two Specific Aims of this proposal integrate at the level of identifying appropriate populations (Aim 2) to be candidates for tools discovered to interfere with Rad –LTCC complex function (Aim 1). Both Aims incorporate testing potential novel therapeutics on a human heart explant preparation. Specific Aim 1 is to perform a head-to-head trial of PDE inhibitors vs Rad-reduction in human and mouse (in vivo) models of cardiomyopathy. We will use complementary ex vivo (human) and in vivo (mouse) platforms to evaluate the ability of Rad reduction to restore systolic heart function. Specific Aim 2 is to evaluate the contribution of a Rad-LTCC signaling axis that couples myocardial activity to proadaptive transcriptional changes. In this Aim our framework rests in Rad-LTCC as an upstream signaling node for initiating and linking cardiac excitability to transcriptional changes. Short-term impact. Successful completion of the proposed studies will motivate new translational directions targeting Rad as a novel therapeutic for reversing the progression of heart failure. At the molecular signaling level, new insight will be gleaned about how excitability sensed by the LTCC is converted into the initiation of transcriptional signaling. Long-term impact. Rad-interference therapeutics are projected to treat the failing heart by boosting heart function and potentially reversing pathological functional and structural remodeling, based on our early pre-clinical studies. This stands to improve the quality of life of the United States Veteran population, and their beneficiaries.