A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes.

Boris Rudic, Ibrahim Akin, Xiaobo Zhou, Martin Borggrefe, Thomas Wieland, Jochen Utikal, Wolfram-Hubertus Zimmermann, Sebastian Diecke, Siegfried Lang, Hendrik Dinkel, Jonas Müller, Ibrahim El-Battrawy, Rujia Zhong, Zhenxing Liao, Mengying Huang, Mandy Kleinsorge, Qiang Xu, Xin Li, Huan Lan, Zhihan Zhao, Lukas Cyganek, Sebastian Albers

Journal: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2020;21(9):1410-1421

PMID: 31106349

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Abstract

AIMS

Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

METHODS AND RESULTS

Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS.

CONCLUSION

Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.

Address: First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany.; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Institute of Pharmacology and Toxicology, University of Göttingen, Göttingen, Germany.; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.; Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

DOI: 10.1093/europace/euz122

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MeSH Terms: Action Potentials, Ajmaline, Brugada Syndrome, Cardiotonic Agents, Case-Control Studies, Cellular Reprogramming Techniques, Cnidarian Venoms, Death, Sudden, Cardiac, Humans, Induced Pluripotent Stem Cells, Loss of Function Mutation, Male, Middle Aged, Morpholines, Mutation, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Niacinamide, Patch-Clamp Techniques, Phenotype, Tachycardia, Ventricular, Voltage-Gated Sodium Channel Blockers