Dual-cardiotoxicity evaluation of torsadogenic risk drugs using human iPSC-derived cardiomyocytes

Abstract

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.

Keywords: Contractility; Dual-cardiotoxicity evaluation method; Field potential; Human iPSC derived cardiomyocytes; Microelectrode array; Torsadogenic risk drugs.