Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Mengying Huang; Zhenxing Liao; Xin Li; Zhen Yang; Xuehui Fan; Yingrui Li; Zhihan Zhao; Siegfried Lang; Lukas Cyganek; Xiaobo Zhou; Ibrahim Akin; Martin Borggrefe; Ibrahim El-Battrawy

doi:10.3389/fphar.2021.675003

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Front Pharmacol. 2021 May 7:12:675003. doi: 10.3389/fphar.2021.675003. eCollection 2021.

Authors

Mengying Huang¹, Zhenxing Liao^{1

2}, Xin Li^{1

3}, Zhen Yang^{1

2}, Xuehui Fan^{1

4}, Yingrui Li¹, Zhihan Zhao¹, Siegfried Lang^{1

5}, Lukas Cyganek^{5

6}, Xiaobo Zhou^{1

4

5}, Ibrahim Akin^{1

5}, Martin Borggrefe^{1

5}, Ibrahim El-Battrawy^{1

5}

Affiliations

¹ First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany.
² North Sichuan Medical College, Nanchong, China.
³ College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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, China.
⁵ DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Mannheim, Germany.
⁶ Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.

Abstract

Aims: The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated. Methods: This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to examine the drug effects on hERG channel gating kinetics. Results: Ajmaline, amiodarone, ivabradine, flecainide, quinidine, mexiletine and ranolazine inhibited the hERG channel current (I_Kr) less strongly in hiPSC-CMs from the SQTS1-patient (SQT1-hiPSC-CMs) comparing with cells from the healthy donor (donor-hiPSC-CMs). Quinidine and mexiletine reduced, but ajmaline, amiodarone, ivabradine and ranolazine increased the time to peak of I_Kr similarly in SQT1-hiPSC-CMs and donor-hiPSC-CMs. Although regarding the shift of activation and inactivation curves, tested drugs showed differential effects in donor- and SQT1-hiPSC-CMs, quinidine, ajmaline, ivabradine and mexiletine but not amiodarone, flecainide and ranolazine reduced the window current in SQT1-hiPSC-CMs. Quinidine, ajmaline, ivabradine and mexiletine differentially changed the time constant of recovery from inactivation, but all of them increased the time constant of deactivation in SQT1-hiPSC-CMs. Conclusion: The window current-reducing and deactivation-slowing effects may be important for the antiarrhythmic effect of ajmaline, ivabradine, quinidine and mexiletine in SQT1-cells. This information may be helpful for selecting drugs for treating SQT1-patients with hERG channel mutation.

Keywords: antiarrhythmic drugs; arrhythmias; hERG channel; human-induced pluripotent stem cell-derived cardiomyocytes; short QT syndrome.