Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue

Abstract

Abstract Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action potential (AP) durations compared to ventricular-like CMs. We then generated confluent atrial-like CM sheets and interrogated them using optical mapping techniques. Atrial-like CM sheets (~1 cm in diameter) showed uniform AP propagation, and rapid re-entrant rotor patterns, as seen in AF could be induced. Anti-arrhythmic drugs were tested on single atrial-like CMs and cell sheets. Flecainide profoundly slowed upstroke velocity without affecting AP duration, leading to reduced conduction velocities (CVs), curvatures and cycle lengths of rotors, consistent with increased rotor organization and expansion. By contrast, consistent with block of rapid delayed rectifier K+ currents (Ikr) and AP prolongation in isolated atrial-like CMs, dofetilide prolonged APs and reduced cycle lengths of rotors in cell sheets without affecting CV. In conclusion, using our hESC-derived atrial CM preparations, we demonstrate that flecainide and dofetilide modulate reentrant arrhythmogenic rotor activation patterns in a manner that helps explain their efficacy in treating and preventing AF.