Identification of an I_Na-dependent and I_to-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient.

ABSTRACT: Brugada syndrome (BrS) is an inherited cardiac arrhythmia commonly associated with SCN5A mutations, yet its ionic mechanisms remain unclear due to a lack of cellular models. Here, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a BrS patient (BrS1) to evaluate the roles of Na⁺ currents (I_Na) and transient outward K⁺ currents (I_to) in BrS induced action potential (AP) changes. To understand the role of these current changes in repolarization we employed dynamic clamp to "electronically express" I_K1 and restore normal resting membrane potentials and allow normal recovery of the inactivating currents, I_Na, I_Ca and I_to. HiPSC-CMs were generated from BrS1 with a compound SCN5A mutation (p. A226V & p. R1629X) and a healthy sibling control (CON1). Genome edited hiPSC-CMs (BrS2) with a milder p. T1620M mutation and a commercial control (CON2) were also studied. CON1, CON2 and BrS2, had unaltered peak I_Na amplitudes, and normal APs whereas BrS1, with over 75% loss of I_Na, displayed a loss-of-I_Na basal AP morphology (at 1.0?Hz) manifested by a reduced maximum upstroke velocity (by ~80%, p?to densities of BrS1 and CON1 were comparable and increased from 1.0?Hz to 0.1?Hz by ~ 100%. These data indicate that a repolarization deficit could be a mechanism underlying BrS.

SUBMITTER: Ma D 

PROVIDER: S-EPMC6062539 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature