Coronavirus disease 2019 (COVID-19) continues to spread across the globe, with numerous clinical trials underway seeking to develop and test effective COVID-19 therapies, including remdesivir. Several ongoing studies have reported hydroxychloroquine-induced cardiotoxicity, including development of torsade de pointes (TdP). Meanwhile, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to serve as a tool for assessing drug-induced cardiotoxicity, such as TdP and contraction impairment. However, the cardiotoxicity of COVID-19 treatments has not been fully assessed using hiPSC-CMs. In the present study, we focused on drug repurposing with various modes of actions and examined the TdP risk associated with COVID-19 treatments using field potential using multi-electrode array (MEA) system and motion analysis with hiPSC-CMs. Hydroxychloroquine induced early after depolarization, while remdesivir, favipiravir, camostat and ivermectin had little effect on field potentials. We then analyzed electromechanical window (EMw), which is defined as the difference between field potential and contraction-relaxation durations. Hydroxychloroquine decreased EMw of hiPSC-CMs in a concentration-dependent manner. In contrast, other drugs have little effect. Our data suggest that hydroxychloroquine has proarrhythmic risk and other drugs have low proarrhythmic risk. Thus, hiPSC-CMs represent a useful tool for assessing the comprehensive cardiotoxicity caused by COVID-19 treatments in non-clinical settings.

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Predicting drug-induced side effects in the cardiovascular system is very important because it can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although chronic assessment of cardiac contractility is an important issue in safety pharmacology, an in vitro evaluation system has not been fully developed. We previously developed an imaging-based contractility assay system to detect acute cardiotoxicity using human iPS cell-derived cardiomyocytes (hiPSC-CMs). To extend the system to chronic toxicity assessment, we examined the effects of the antihepatitis C virus (HCV) drug candidate BMS-986094, a guanosine nucleotide analogue, which was withdrawn from phase 2 clinical trials because of unexpected contractility toxicities. Additionally, we examined sofosbuvir, another nucleotide analogue inhibitor of HCV that has been approved as an anti-HCV drug. Motion imaging analysis revealed the difference in cardiotoxicity between the cardiotoxic BMS-986094 and the less toxic sofosbuvir in hiPSC-CMs, with a minimum of 4 days of treatment. In addition, we found that BMS-986094-induced contractility impairment was mediated by a decrease in calcium transient. These data suggest that chronic treatment improves the predictive power for the cardiotoxicity of anti-HCV drugs. Thus, hiPSC-CMs can be a useful tool to assess drug-induced chronic cardiotoxicity in non-clinical settings.