title: Pharmacoelectrophysiology of viral-free induced pluripotent stem cell-derived human cardiomyocytes.
abstract: 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.
authors.affiliation: Research and Development Unit, National Heart Centre Singapore, Singapore 168752, Singapore.
authors.forename: Ashish
authors.initials: A
authors.lastname: Mehta
authors.forename: YingYing
authors.initials: Y
authors.lastname: Chung
authors.forename: Glen Lester
authors.initials: GL
authors.lastname: Sequiera
authors.forename: Philip
authors.initials: P
authors.lastname: Wong
authors.forename: Reginald
authors.initials: R
authors.lastname: Liew
authors.forename: Winston
authors.initials: W
authors.lastname: Shim
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000889:Anti-Arrhythmia Agents