Abstract 407: Modeling Atrial Fibrillation in a Dish Using Atrial iPSC Derived Cardiomyocytes

Abstract

Mutations in multiple genes have been linked with familial atrial fibrillation (AF) but the underlying pathophysiologic mechanisms and implications for therapy remain poorly understood. To characterize the electrophysiological phenotype of an AF-linked SCN5A mutation and assess novel mechanism-based therapies, we generated patient-specific atrial induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a carrier with an SCN5A-E428K mutation and an unaffected family member using a differentiation protocol optimized for atrial differentiation generated atrial iPSC-CMs. The atrial iPSC-CMs carrying SCN5A-E428K displayed increased window and late Na+ current (INa,L), increased beating frequency and irregularity with triggered beats and prolongation of the action potential duration (APD) versus control atrial iPSC-CMs. The multi-electrode array (MEA) recordings of mutant atrial iPSC-CMs showed spontaneous arrhythmogenic activity with beat-to-beat irregularity. We further showed that targeted inhibition of the INa,L with ranolazine normalized the aberrant electrophysiologic phenotype in the SCN5A-E428K atrial iPSC-CMs and mexiletine reversed the sodium channel gating defects, and reduced beating frequency and irregularity. Our study illustrates the potential use of atrial iPSC-CMs for modeling AF in a dish, elucidating the underlying cellular mechanisms, and identifying novel mechanism-based therapies custom-tailored for individual patients.

Long Non-Coding RNAs in Atrial Fibrillation: Pluripotent Stem Cell-Derived Cardiomyocytes as a Model System

“…Hong et al [ 161 ] also developed an AF model using patient-derived iPSCs to characterize the electrophysiological properties of a known familial AF linked with an E428K mutation on SCN5A (sodium voltage-gated alpha subunit 5). Atrial iPSC-CMs with this mutation showed an increased window for the late sodium current (I Na,L ), increased beating rate, prolonged APD, and spontaneous arrhythmogenic activity.…”