Human iPSC-derived cardiomyocytes accurately reflect the pharmacological and toxicological effects of cardiac glycosides seen in isolated intact hearts, supporting their use as a screening tool for cardioactive compounds.
hiPSC-CMs may model cardiac glycoside effects on electrophysiology and arrhythmogenesis; supports their use as a screening tool but clinical translation remains unproven.
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 Ca(2+)-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 Ca(2+) channel blocker, reduced Ca(2+)-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 Ca(2+)-peak amplitude and proarrhythmic effect of both glycosides. These results suggested that FPD and Ca(2+)-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.
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Guo et al. (2011) studied this question.