Ionic Mechanisms of Disopyramide Prolonging Action Potential Duration in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Huan Lan; Qiang Xu; Ibrahim El-Battrawy; Rujia Zhong; Xin Li; Siegfried Lang; Lukas Cyganek; Martin Borggrefe; Xiaobo Zhou; Ibrahim Akin

doi:10.3389/fphar.2020.554422

Ionic Mechanisms of Disopyramide Prolonging Action Potential Duration in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Front Pharmacol. 2020 Oct 12:11:554422. doi: 10.3389/fphar.2020.554422. eCollection 2020.

Authors

Huan Lan¹, Qiang Xu^{2

3}, Ibrahim El-Battrawy^{2

4}, Rujia Zhong², Xin Li², Siegfried Lang^{2

4}, Lukas Cyganek^{5

6}, Martin Borggrefe^{2

4}, Xiaobo Zhou^{1

2

4}, Ibrahim Akin^{2

4}

Affiliations

¹ 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.
² First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany.
³ Department of Histology and Embryology, Southwest Medical University, Luzhou, China.
⁴ DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, Mannheim, Germany.
⁵ DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.
⁶ Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.

Abstract

Short QT syndrome (SQTS) is associated with tachyarrhythmias and sudden cardiac death. So far, only quinidine has been demonstrated to be effective in patients with SQTS type 1(SQTS1). The aim of this study was to investigate the mechanisms of disopyramide underlying its antiarrhythmic effects in SQTS1 with the N588K mutation in HERG channel. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS1 and a healthy donor, patch clamp, and calcium imaging measurements were employed to assess the drug effects. Disopyramide prolonged the action potential duration (APD) in hiPSC-CMs from a SQTS1-patient (SQTS1-hiPSC-CMs). In spontaneously beating SQTS1-hiPSC-CMs challenged by carbachol plus epinephrine, disopyramide reduced the arrhythmic events. Disopyramide enhanced the inward L-type calcium channel current (I_Ca-L), the late sodium channel current (late I_Na) and the Na/Ca exchanger current (I_NCX), but it reduced the outward small-conductance calcium-activated potassium channel current (I_SK), leading to APD-prolongation. Disopyramide displayed no effects on the rapidly and slowly activating delayed rectifier and ATP-sensitive potassium channel currents. In hiPSC-CMs from the healthy donor, disopyramide reduced peak I_Na, I_Ca-L, I_Kr, and I_SK but enhanced late I_Na and I_NCX. The results demonstrated that disopyramide may be effective for preventing tachyarrhythmias in SQTS1-patients carrying the N588K mutation in HERG channel by APD-prolongation via enhancing I_Ca-L, late I_Na, I_NCX, and reducing I_SK.

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