Key result
High TdP risk drugs prolong FPDc in hiPSC-CMs while low-risk drugs reduce contractility.
Why the study?
Alternatives to animal testing using hiPSC-derived cardiomyocytes are needed to prevent indiscriminate drug withdrawal and improve animal welfare during drug development.
A dual-cardiotoxicity evaluation method assessing both electrophysiology and contractility in hiPSC-CMs provides complementary insights that improve in vitro prediction of drug-induced cardiotoxicity.
Supports dual-parameter hiPSC-CM screening for cardiotoxicity; hypothesis-generating and requires clinical validation before adoption.
To prevent indiscriminate withdrawal of candidates when developing drugs and to improve global animal welfare, the alternative to animal testing using human induced pluripotent stem cells (hiPSCs) is being highlighted. In cardiovascular pharmacology, the Comprehensive in vitro Proarrhythmia Assay (CiPA) is a representative example combining patch-clamp data, in silico modeling, in vivo electrocardiogram, and functional assays using hiPSC-derived cardiomyocytes (hiPSC-CMs). Among these, microelectrode array (MEA) analysis has emerged as a key tool to evaluate drug-induced electrophysiological changes in hiPSC-CMs. Building on this concept, our research team previously developed an MEA-based dual-cardiotoxicity evaluation method that simultaneously assesses electrophysiological signal and contractile force. In this study, we applied the dual-cardiotoxicity assessment to 28 torsadogenic (TdP) risk drugs classified by CiPA, using hiPSC-CMs and established MEA techniques. High and intermediate TdP risk drugs induced proarrhythmic events and prolonged the corrected field potential duration (FPDc), whereas low/no TdP risk drugs tended to decrease FPDc. Interestingly, contractility was more significantly reduced by low/no TdP risk drugs than by high or intermediate TdP drugs. These findings suggest that dual-cardiotoxicity evaluation provides complementary insights beyond traditional FPD prolongation and arrhythmia-focused assays. This approach offers a more comprehensive indicator of cardiotoxic risk, potentially enhancing the predictive reliability of in vitro drug safety screening. • Dual-cardiotoxicity evaluation method by measuring field potential and contractility • Cardiotoxicity assessment of 28 CiPA TdP drugs using in-house hiPSC-derived cardiomyocytes and MEA • FPDc prolongation in high and intermediate TdP risk drugs, greater contractility reduction in low/no TdP risk drugs • Improved in vitro cardiotoxicity prediction through complementary insights beyond traditional arrhythmia-focused assays
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Lee et al. (2025) studied Drug-induced cardiotoxicity. 28 torsadogenic (TdP) risk drugs vs. Low/no TdP risk drugs vs high/intermediate TdP risk drugs was evaluated on Electrophysiological signal (FPDc) and contractile force. Dual-cardiotoxicity evaluation of 28 CiPA drugs using hiPSC-CMs showed high and intermediate TdP risk drugs prolonged FPDc, whereas low/no TdP risk drugs significantly reduced contractility.
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