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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 < 0.001) and AP amplitude (p < 0.001), and an increased phase-1 repolarization pro-arrhythmic AP morphology (at 0.1 Hz) in ~25% of cells characterized by marked APD shortening (~65% shortening, p < 0.001). Moreover,  I  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.

scientific reports

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