The Electrophysiological Effects of Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and in Guinea Pig Isolated Hearts

Cellular Physiology and Biochemistry

关键词: Induced pluripotent stem cell (iPSC);    Cardiomyocyte;    Langendorff isolated heart;    Cardiac glycoside;    Ca2+-cycling;    Contractility;    Arrhythmia;    Cardiotoxicity;    Microelectrode array (MEA);   

DOI  :  10.1159/000329966

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/aims Monitoring changes in the field potential (FP) of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) following compound administration has been proposed as a novel screening tool to evaluate cardiac ion channel interactions and QT liability. Here we extended the use of FP to evaluate the pharmacological and toxicological properties of cardiac glycosides. Methods FPs were recorded using microelectrode arrays (MEAs) in spontaneously beating hiPSC-CMs. The in vitro effects of ouabain and digoxin on FPs were compared with data generated on hemodynamic and ECG parameters in guinea pig Langendorff hearts. Results In hiPSC-CMs, ouabain and digoxin reduced Na⁺-spike amplitude, shortened FP duration (FPD), increased Ca²⁺-wave amplitude, and dose-dependently induced arrhythmic beats. The ouabain-induced changes observed in hiPSC-CMs correlated well with the effects seen in isolated hearts which revealed QT shortening, enhancement of contractility, and arrhythmogenesis. Nifedipine, an L-type Ca²⁺ channel blocker, reduced Ca²⁺-wave amplitude and FPD in hiPSC-CMs, and led to parallel effects of decreased ventricular contractility and shortened QT interval in isolated hearts. Further, nifedipine attenuated the Ca²⁺-peak amplitude and proarrhythmic effect of both glycosides. These results suggested that FPD and Ca²⁺-wave amplitude are comparable surrogates of QT interval and contractility of intact hearts, respectively. Conclusion hiPSC-CMs reflect similar cardiac pharmacology as seen in isolated cardiac preparations and thus are a suitable model in study of the pharmacology and toxicology of cardioactive ion channel and transporter modulators.

【 授权许可】

CC BY-NC-ND