Journal Article

Pharmacoelectrophysiology of Viral-Free Induced Pluripotent Stem Cell–Derived Human Cardiomyocytes

Ashish Mehta, YingYing Chung, Glen Lester Sequiera, Philip Wong, Reginald Liew and Winston Shim

in Toxicological Sciences

Volume 131, issue 2, pages 458-469
Published in print February 2013 | ISSN: 1096-6080
Published online October 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs309
Pharmacoelectrophysiology of Viral-Free Induced Pluripotent Stem Cell–Derived Human Cardiomyocytes

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Development of pharmaceutical agents for cardiac indication demands elaborate safety screening in which assessing repolarization of cardiac cells remains a critical path in risk evaluations. An efficient platform for evaluating cardiac repolarization in vitro significantly facilitates drug developmental programs. In a proof of principle study, we examined the effect of antiarrhythmogenic drugs (Vaughan Williams class I–IV) and noncardiac active drugs (terfenadine and cisapride) on the repolarization profile of viral-free human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Extracellular field potential (FP) recording using microelectrode arrays demonstrated significant delayed repolarization as prolonged corrected FP durations (cFPDs) by class I (quinidine and flecainide), class III (sotalol and amiodarone), and class IV (verapamil), whereas class II drugs (propranolol and nadolol) had no effects. Consistent with their sodium channel-blocking ability, class I drugs also significantly reduced FPmin and conduction velocity. Although lidocaine (class IB) had no effects on cFPDs, verapamil shortened cFPD and FPmin by 25 and 50%, respectively. Furthermore, verapamil reduced beating frequencies drastically. Importantly, the examined drugs exhibited dose-response curve on prolongation of cFPDs at an effective range that correlated significantly with therapeutic plasma concentrations achieved clinically. Consistent with clinical outcomes, drug-induced arrhythmia of tachycardia and bigeminy-like waveforms by quinidine, flecainide, and sotalol was demonstrated at supraphysiological concentrations. Furthermore, off-target effects of terfenadine and cisapride on cFPD and Na + channel blockage were similarly revealed. These results suggest that hiPSC-CMs may be useful for safety evaluation of cardioactive and noncardiac acting drugs for personalized medicine.

Keywords: human-induced pluripotent stem cells; cardiomyocytes; arrhythmia; drugs; electrophysiology

Journal Article.  6620 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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