Ibrahim El-Battrawy1,2, Sebastian Albers1,2, Lukas Cyganek2,3, Zhihan Zhao1,2, Huan Lan1,2,4, Xin Li1, Qiang Xu1, Mandy Kleinsorge2,3, Mengying Huang1, Zhenxing Liao1, Rujia Zhong1, Boris Rudic1, Jonas Müller1, Hendrik Dinkel1, Siegfried Lang1,2, Sebastian Diecke5, Wolfram-Hubertus Zimmermann2,6, Jochen Utikal2,7,8, Thomas Wieland2,9, Martin Borggrefe1,2, Xiaobo Zhou1,2,4, Ibrahim Akin1,2. 1. First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. 2. DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany. 3. Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany. 4. 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. 5. Max Delbrück Center for Molecular Medicine, Berlin, Germany. 6. Institute of Pharmacology and Toxicology, University of Göttingen, Göttingen, Germany. 7. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. 8. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany. 9. Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Francesco Santoro; Pasquale Crea; Pier Luigi Pellegrino; Rosa Cetera; Domenico Gianfrancesco; Mohammad Abumayyaleh; Dattilo Giuseppe; Marta Allegra; Nastasia Mancini; Girolamo D'Arienzo; Andreas Mȕgge; Assem Aweimer; Francesco Bartolomucci; Ibrahim Akin; Ibrahim El-Battrawy; Natale Daniele Brunetti Journal: J Cardiovasc Electrophysiol Date: 2022-06-21 Impact factor: 2.942
Authors: Federico Migliore; Nicolò Martini; Leonardo Calo'; Annamaria Martino; Giulia Winnicki; Riccardo Vio; Chiara Condello; Alessandro Rizzo; Alessandro Zorzi; Luigi Pannone; Vincenzo Miraglia; Juan Sieira; Gian-Battista Chierchia; Antonio Curcio; Giuseppe Allocca; Roberto Mantovan; Francesca Salghetti; Antonio Curnis; Emanuele Bertaglia; Manuel De Lazzari; Carlo de Asmundis; Domenico Corrado Journal: Front Cardiovasc Med Date: 2022-07-22