Arrhythmias cause 50% of deaths in patients with cardiomyopathy and heart failure. Recent findings have highlighted the importance of Ca2+-activated kinases and phosphatases in activating gene programs driving morphological and functional changes in cardiomyopathy. One focus of our previous studies has been the arrhythmogenic potential of Ca2+/calmodulin-activated protein kinase (CaMK) II in normal cardiomyocytes with drug-induced action potential prolongation. More recently, we have developed evidence for an arrhythmogenic phenotype in cardiomyopathy that consists of increased CaMKII expression and activity, action potential and QT interval prolongation, disordered intracellular Ca2+ homeostasis, and arrhythmias or sudden death. The goal of this Project is to test the hypothesis that CaMKII is a molecular link between functional and morphological phenotypes, and thus a contributor to arrhythmia susceptibility in cardiomyopathy. To accomplish this goal, two distinct and well-characterized mouse models with cardiomyopathy, increased CaMKII activity, and arrhythmias will be interbred with mice that we have developed with cardiac-specific expression of a CaMKII inhibitory protein, or an inactive control. Using these tools, we will determine the effect of chronic CaMKII inhibition on the arrhythmogenic and the morphological and functional phenotypes in cardiomyopathy. To further understand the mechanisms underlying the salutary effects of CaMKII inhibition, we will determine the effect of chronic, cardiac-targeted CaMKII inhibition on potential downstream signaling pathways. These experiments will target an arrhythmogenic molecular mechanism and build from single molecule assays to biochemical, histological, and functional studies in the whole heart. Delineation of the role of CaMKII in arrhythmogenesis will be an important step in developing new antiarrhythmic therapies in patients with heart failure.
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