Defining New Pathways for Complex Human Heart Failure and Arrhythmia

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Project Summary Normal cardiac function requires synchronization of structural and electrical molecules within the heart. Defects affecting cardiac excitability linked to sudden cardiac death affect ½ million people, and those affecting contractile function, such as in the case of cardiomyopathy, impact another 5.7 million patients in the U.S. each year. However, often overlooked are cardiovascular (CV) phenotypes that result in both electrical and contractile dysfunction. This relationship between contractile and electrical elements is critically important to understand in the patient with congenital heart disease (CHD). There are now more adults (ACHD) living with CHD than children, and in this population the most common late manifestation of CHD is a severely complex phenotype hallmarked by both heart failure and arrhythmia. The ACHD community recognizes the importance of each of these entities, and has set forth high-priority areas of study surrounding heart failure and arrhythmia, with the goal of using models aimed at the ‘cellular keystones underlying CHD’. This proposal embraces that focus, shifting from the study of each of these late CV sequela independently, and taking a broader look at the complex CHD phenotypes that result in both electrical and contractile dysfunction. We have identified a molecule which we believe has both CV electrical and contractile consequences, thereby serving as a good foundational model to study complex phenotypes resulting in combination arrhythmia and heart failure. Ankyrins are a membrane- associated protein directly linked with targeting ion channels in myocytes, neurons and other excitable cells. In heart, ankyrins-B and –G, which function to support myocyte actin/spectrin in the cytoskeleton and function in cellular organization, transport, gating and post-translational modification, are associated with critical membrane ion channels. Canonical AnkG is required for normal NaV1.5 channel targeting in the heart. However, we have identified a novel ‘giant’ cardiac ankyrin-G isoform that we implicate is critical for normal cardiac structure, contractility and electrical conduction. Mice lacking ‘Giant AnkG’ display a dilated and thinned left ventricle with reduced systolic function, consistent with a dilated cardiomyopathy phenotype. These same mice also exhibit electrical dysfunction including ventricular arrhythmia and high-degree heart block. Our new preliminary data support our central hypothesis: A single ankyrin gene produces two separate molecules- each with unique roles in cardiac structural and electrical function. We hypothesize that novel cardiac Giant AnkG functions via a unique sodium-channel independent mechanism leading to regulation myocyte structure, membrane organization and abnormal intra- and inter-cellular signaling. Ultimately, loss of function of this large gene product leads to altered myocardial contraction and defective electrical function.