Ibrahim El-Battrawy1,2, Zhihan Zhao1,2, Huan Lan1,2,3, Lukas Cyganek2,4, Christoph Tombers1, Xin Li1, Fanis Buljubasic1,2, Siegfried Lang1,2, Malte Tiburcy2,5, Wolfram-Hubertus Zimmermann2,5, Jochen Utikal2,6,7, Thomas Wieland2,8, Martin Borggrefe1,2, Xiao-Bo Zhou1,2,3, Ibrahim Akin1,2. 1. First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. 2. DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim and Göttingen, Mannheim, Germany. 3. Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China. 4. Stem Cell Unit, Heart Research Center Göttingen, Göttingen, Germany. 5. Institute of Pharmacology and Toxicology, University of Göttingen, Göttingen, Germany. 6. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg. 7. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany. 8. Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Abstract
Aims: Our aim is to investigate the arrhythmogenic mechanism in arrhythmogenic right ventricular cardiomyopathy (ARVC)-patients by using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and results: Human-induced pluripotent stem cell-derived cardiomyocytes were generated from human skin fibroblasts of two healthy donors and an ARVC-patient with a desmoglein-2 (DSG2) mutation. Patch clamp, quantitative polymerase chain reaction, and calcium imaging techniques were employed for the study. The amplitude and maximal upstroke velocity (Vmax) of action potential (AP) in ARVC-cells were smaller than that in healthy donor cells, whereas the resting potential and AP duration (APD) was not changed. The reduced Vmax resulted from decreased peak sodium current. The reason for undetected changes in APD may be the counter-action of reduced transient outward, small conductance Ca2+-activated, adenosine triphosphate-sensitive, Na/Ca exchanger (INCX) currents, and enhanced rapidly delayed rectifier currents. Isoprenaline (Iso) reduced INCX and shortened APD in both donor and ARVC-hiPSC-CMs. However, the effects of Iso in ARVC-cells are significantly larger than that in donor cells. In addition, ARVC-hiPSC-CMs showed more frequently than donor cells arrhythmogenic events induced by adrenergic stimulation. Conclusion: Cardiomyocytes derived from the ARVC patient with a DSG2 mutation displayed multiple ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation. These may underlie the arrhythmogenesis in ARVC patients.
Aims: Our aim is to investigate the arrhythmogenic mechanism in arrhythmogenic right ventricular cardiomyopathy (ARVC)-patients by using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and results: Human-induced pluripotent stem cell-derived cardiomyocytes were generated from human skin fibroblasts of two healthy donors and an ARVC-patient with a desmoglein-2 (DSG2) mutation. Patch clamp, quantitative polymerase chain reaction, and calcium imaging techniques were employed for the study. The amplitude and maximal upstroke velocity (Vmax) of action potential (AP) in ARVC-cells were smaller than that in healthy donor cells, whereas the resting potential and AP duration (APD) was not changed. The reduced Vmax resulted from decreased peak sodium current. The reason for undetected changes in APD may be the counter-action of reduced transient outward, small conductance Ca2+-activated, adenosine triphosphate-sensitive, Na/Ca exchanger (INCX) currents, and enhanced rapidly delayed rectifier currents. Isoprenaline (Iso) reduced INCX and shortened APD in both donor and ARVC-hiPSC-CMs. However, the effects of Iso in ARVC-cells are significantly larger than that in donor cells. In addition, ARVC-hiPSC-CMs showed more frequently than donor cells arrhythmogenic events induced by adrenergic stimulation. Conclusion: Cardiomyocytes derived from the ARVC patient with a DSG2 mutation displayed multiple ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation. These may underlie the arrhythmogenesis in ARVC patients.
Authors: Karyn M Austin; Michael A Trembley; Stephanie F Chandler; Stephen P Sanders; Jeffrey E Saffitz; Dominic J Abrams; William T Pu Journal: Nat Rev Cardiol Date: 2019-09 Impact factor: 32.419
Authors: Andreas Brodehl; Hans Ebbinghaus; Marcus-André Deutsch; Jan Gummert; Anna Gärtner; Sandra Ratnavadivel; Hendrik Milting Journal: Int J Mol Sci Date: 2019-09-06 Impact factor: 5.923
Authors: Ibrahim El-Battrawy; Jonas Müller; Zhihan Zhao; Lukas Cyganek; Rujia Zhong; Feng Zhang; Mandy Kleinsorge; Huan Lan; Xin Li; Qiang Xu; Mengying Huang; Zhenxing Liao; Alexander Moscu-Gregor; Sebastian Albers; Hendrik Dinkel; Siegfried Lang; Sebastian Diecke; Wolfram-Hubertus Zimmermann; Jochen Utikal; Thomas Wieland; Martin Borggrefe; Xiaobo Zhou; Ibrahim Akin Journal: Front Cell Dev Biol Date: 2019-11-01