Yanagida Shota, Satsuka Ayano, Hayashi Sayo, Ono Atsushi, Kanda Yasunari
Division of Pharmacology, National Institute of Health Sciences (NIHS), Kawasaki, Kanagawa 210-9501, Japan.
Division of Pharmaceutical Sciences, Graduated School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Toxicol Sci. 2021 Aug 30;183(1):227-239. doi: 10.1093/toxsci/kfab079.
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 this 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 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, which is defined as the difference between field potential and contraction-relaxation durations. Hydroxychloroquine decreased electromechanical window of hiPSC-CMs in a concentration-dependent manner. In contrast, other drugs had 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 nonclinical settings.
2019冠状病毒病（COVID-19）继续在全球蔓延，目前有多项临床试验正在进行，旨在研发和测试有效的COVID-19治疗方法，包括瑞德西韦。一些正在进行的研究报告了羟氯喹引起的心脏毒性，包括尖端扭转型室性心动过速（TdP）的发生。与此同时，人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）有望作为评估药物诱导的心脏毒性的工具，如TdP和收缩功能障碍。然而，尚未使用hiPSC-CMs对COVID-19治疗的心脏毒性进行全面评估。在本研究中，我们专注于具有多种作用方式的药物重新利用，并使用多电极阵列系统的场电位和hiPSC-CMs的运动分析来研究与COVID-19治疗相关的TdP风险。羟氯喹诱导早期后去极化，而瑞德西韦、法匹拉韦、卡莫司他和伊维菌素对场电位几乎没有影响。然后，我们分析了机电窗，其定义为场电位与收缩-舒张持续时间之间的差异。羟氯喹以浓度依赖性方式降低了hiPSC-CMs的机电窗。相比之下，其他药物几乎没有影响。我们的数据表明，羟氯喹有致心律失常风险，而其他药物有致心律失常风险较低。因此，hiPSC-CMs是评估非临床环境中COVID-19治疗引起的综合心脏毒性的有用工具。
