Harnessing an extrinsic molecular switch for the treatment of NaV1.5 arrhythmogenic syndromes

Cardiac voltage-gated sodium channels (NaV1.5) are critical for genesis and propagation of action potentials (AP) in the heart. Alteration in NaV1.5 function contribute to a wide spectrum of inherited and acquired forms of cardiac arrhythmias. One commonality in pathophysiology of NaV1.5 arrythmia disorders is a disruption of channel inactivation that results in increased late Na current that prevents normal cardiac repolarization. Intriguingly, NaV1.5 inactivation and late Na current is regulated by various channel auxiliary proteins. Thus, an attractive hypothesis is that the divergent clinical manifestations of inherited and acquired arrhythmias may stem from changes in channel interacting proteins in addition to defective channel gating. Recent work suggests that the unconventional fibroblast growth factor homologous factor (FHF1-4), a channel auxiliary subunit, tunes this intrinsic process and alter pathophysiology. Here, based on preliminary data, I hypothesize that FHFs tune late current for NaV1.5 in an isoform specific manner to dictate arrhythmogenic phenotype. To test this possibility, we will use a variety of innovative assays and models including, patient-derived from induced pluripotent stem cells (iPSC-CMs) and heart failure adult mouse ventricular myocytes (HF-aMVM), to determine the role of FHF isoform-specific regulation for pathogenesis of inherited and acquired arrhythmias (aim 1). Specifically, I will use a combination of low-noise single-channel patch clamp and imaging techniques to probe FHFs-dependent changes of late Na current in HEK cells, but also in patient derived iPSC-CMs and HF-aMVM, reflecting the inherited and acquired cardiac arrhythmias. Furthermore, I have engineering an FHF based tool for inhibition of late Na current. I propose to test the efficacy of this tool in LQT3 iPSC cardiomyocytes and in HF-aMVM (aim 2). To do so, we will use single-channel recordings and genetically encoded voltage indicators to probe the efficacy of our recently developed FHF-based peptide on modulating late Na current, as well as in shaping the cardiac action potential in patient-derived iPSC-CM and HF-aMVM. In all, this proposal promises to establish a new framework for mechanistic understanding of inherited and acquired arrhythmogenic syndromes that may spur the development of new therapies for life-threatening arrhythmias.