Key result
Physiological pacing of hiPSC-vCMs successfully detects field potential prolongation and arrhythmias from higher-risk drugs.
Why the study?
Spontaneous beating at variable frequencies in hiPSC-CMs affects repolarization, prompting electrical pacing at physiological rates to standardize testing conditions for drug proarrhythmic risk.
Electrical pacing of hiPSC-vCMs at physiological rates using MEA provides a feasible method to assess drug proarrhythmic potential and correctly predict the risk of CiPA reference compounds.
Paced hiPSC-vCM MEA assays merit further development for CiPA screening; leaves open clinical translation and human validation.
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for the assessment of drug proarrhythmic potential through multielectrode array (MEA). HiPSC-CM cultures beat spontaneously with a wide range of frequencies, however, which could affect drug-induced changes in repolarization. Pacing hiPSC-CMs at a physiological heart rate more closely resembles the state of in vivo ventricular myocytes and permits the standardization of test conditions to improve consistency. In this study, we systematically investigated the time window of stable ion currents in high-purity hiPSC-derived ventricular cardiomyocytes (hiPSC-vCMs) and confirmed that these cells could be used to correctly predict the proarrhythmic risk of Comprehensive In Vitro Proarrhythmia Assay (CiPA) reference compounds. To evaluate drug proarrhythmic potentials at a physiological beating rate, we used a MEA to electrically pace hiPSC-vCMs, and we recorded regular field potential waveforms in hiPSC-vCMs treated with DMSO and 10 CiPA reference drugs. Prolongation of field potential duration was detected in cells after exposure to high- and intermediate-risk drugs; in addition, drug-induced arrhythmia-like events were observed. The results of this study provide a simple and feasible method to investigate drug proarrhythmic potentials in hiPSC-CMs at a physiological beating rate.
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Bai et al. (2020) studied Drug proarrhythmic potential. 10 CiPA reference drugs with electrical pacing vs. DMSO was evaluated on Field potential duration and arrhythmia-like events. Electrical pacing of hiPSC-vCMs at a physiological rate successfully detected field potential duration prolongation and arrhythmia-like events after exposure to high- and intermediate-risk drugs.
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