Key result
Dofetilide and bepridil decreased the electro-mechanical window in hiPSC-CMs by 157.9% and 192.3% respectively, whereas ranolazine and mexiletine had little effect, demonstrating its utility for TdP risk classification.
Why the study?
Outliers such as bepridil, mexiletine, and ranolazine remained among the 28 compounds in the CiPA validation study evaluating drug-induced torsade de pointes risk in hiPSC-CMs.
The electro-mechanical window in hiPSC-CMs can accurately classify drugs into high and low TdP risk, offering a useful in vitro marker for proarrhythmia risk assessment.
hiPSC-CM electro-mechanical window may aid preclinical TdP risk stratification; leaves open clinical translation pending validation studies.
Evaluation of drug-induced cardiotoxicity is still challenging to avoid adverse effects, such as torsade de pointes (TdP), in non-clinical and clinical studies. Numerous studies have suggested that human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful platform for detecting drug-induced TdP risks. Comprehensive in vitro Proarrhythmia Assay (CiPA) validation study suggested that hiPSC-CMs can assess clinical TdP risk more accurately than the human ether-a-go-go-related assay and QT interval prolongation. However, there were still some outliers, such as bepridil, mexiletine, and ranolazine, among the CiPA 28 compounds in the CiPA international multi-site study using hiPSC-CMs. In this study, we assessed the effects of the positive compound dofetilide, the negative compound aspirin, and several CiPA compounds (bepridil, mexiletine, and ranolazine) on the electromechanical window (E-M window), which were evaluated using multi-electrode array assay and motion analysis, in hiPSC-CMs. Similar to previous in vivo studies, dofetilide, which has a high TdP risk, decreased the E-M window in hiPSC-CMs, whereas aspirin, which has a low TdP risk, had little effect. Bepridil, classified in the high TdP-risk group in CiPA, decreased the E-M window in hiPSC-CMs, whereas ranolazine and mexiletine, which are classified in the low TdP-risk group in CiPA, slightly decreased or had little effect on the E-M window of hiPSC-CMs. Thus, the E-M window in hiPSC-CMs can be used to classify drugs into high and low TdP risk.
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Yanagida et al. (2022) studied Drug-induced cardiotoxicity (Torsade de Pointes risk). Proarrhythmic drugs (dofetilide, bepridil, ranolazine, mexiletine) vs. Baseline and aspirin (negative control) was evaluated on Electro-mechanical (E-M) window. Dofetilide and bepridil decreased the electro-mechanical window in hiPSC-CMs by 157.9% and 192.3% respectively, whereas ranolazine and mexiletine had little effect, demonstrating its utility for TdP risk classification.
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