Molecular, cellular, and pharmacological characterization of a new modality of familial arrhythmia

Objective

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial type of life-threatening arrhythmias which typically manifest with exercise or emotional stress. To date, most cases of CPVT have been linked to mutations in genes involved in Ca²⁺ regulation. Thus, shaping the current state of understanding CPVT as a Ca2+-driven arrhythmia. However, more than 30% of cases diagnosed with CPVT lack mutations in Ca2+-handling genes, indicating that other mechanisms may play a role. Recently, the host lab has identified a novel SCN5A variant, the gene encoding for the cardiac Na+ channels (NaV1.5, p.I1333V, “IV”), in CPVT patients. Thus, raising the possibility that Na⁺ channelopathies may also contribute to stress-induced ventricular arrhythmias. Despite, there is currently no established framework for how such NaV1.5 variants might lead to the CPVT phenotype. Using state-of-the art electrophysiological and optical techniques, I will (O1) assess changes in channel kinetics and coupled gating using single-channel recordings, whereas using voltage-clamp fluorometry I will examine how the IV affects the channel’s voltage sensing apparatus; (O2) establish the cellular hallmarks of Na+-driven CPVT in human stem-cell-derived cardiomyocytes; and (O3) pharmacologically discriminate Na+-driven CPVT from the major arrhythmia caused by NaV1.5 gain of function, long QT type 3. By accomplishing the three objectives, I will provide a detailed molecular, cellular, and pharmacological understanding of Na+-driven CPVT, a potentially new type of familial, syncopal disease. Thus, providing enough evidence for SCN5A to be included in the CPVT screening pool, leading to improved diagnostic outcomes. In turn, this will reveal more CPVT-linked SCN5A variants and, most importantly, save lives. Ultimately, the MSCA fellowship will provide me with a diverse and multidisciplinary training towards the path to become an independent physician-scientist in cardiac electrophysiology.