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Sci Rep. 2018 Jul 26;8(1):11246. doi: 10.1038/s41598-018-29574-5.

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

Author information

1
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Republic of Singapore.
2
Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore, 169857, Republic of Singapore.
3
Department of Cardiology, National Heart Centre Singapore, Singapore, 169609, Republic of Singapore.
4
Defense Medical and Environmental Research Institute, DSO National Laboratories, Singapore, 117510, Republic of Singapore.
5
University at Buffalo, State University of New York, Buffalo, NY, 14214, USA.
6
Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
7
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
8
University at Buffalo, State University of New York, Buffalo, NY, 14214, USA. rr32@buffalo.edu.
9
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Republic of Singapore. heming_wei@yahoo.com.
10
Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore, 169857, Republic of Singapore. heming_wei@yahoo.com.

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 (INa) and transient outward K+ currents (Ito) in BrS induced action potential (AP) changes. To understand the role of these current changes in repolarization we employed dynamic clamp to "electronically express" IK1 and restore normal resting membrane potentials and allow normal recovery of the inactivating currents, INa, ICa and Ito. 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 INa amplitudes, and normal APs whereas BrS1, with over 75% loss of INa, displayed a loss-of-INa 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, Ito 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.

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