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Adverse effects of hydroxychloroquine and azithromycin on contractility and arrhythmogenicity revealed by human engineered cardiac tissues
Journal of Molecular and Cellular Cardiology ( IF 5 ) Pub Date : 2020-12-27 , DOI: 10.1016/j.yjmcc.2020.12.014
Andy On-Tik Wong , Bimal Gurung , Wing Sum Wong , Suet Yee Mak , Wan Wai Tse , Chloe M. Li , Deborah K. Lieu , Kevin D. Costa , Ronald A. Li , Roger J. Hajjar

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic as declared by World Health Organization (WHO). In the absence of an effective treatment, different drugs with unknown effectiveness, including antimalarial hydroxychloroquine (HCQ), with or without concurrent administration with azithromycin (AZM), have been tested for treating COVID-19 patients with developed pneumonia. However, the efficacy and safety of HCQ and/or AZM have been questioned by recent clinical reports. Direct effects of these drugs on the human heart remain very poorly defined. To better understand the mechanisms of action of HCQ +/− AZM, we employed bioengineered human ventricular cardiac tissue strip (hvCTS) and anisotropic sheet (hvCAS) assays, made with human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCMs), which have been designed for measuring cardiac contractility and electrophysiology, respectively. Our hvCTS experiments showed that AZM induced a dose-dependent negative inotropic effect which could be aggravated by HCQ; electrophysiologically, as revealed by the hvCAS platform, AZM prolonged action potentials and induced spiral wave formations. Collectively, our data were consistent with reported clinical risks of HCQ and AZM on QTc prolongation/ventricular arrhythmias and development of heart failure. In conclusion, our study exposed the risks of HCQ/AZM administration while providing mechanistic insights for their toxicity. Our bioengineered human cardiac tissue constructs therefore provide a useful platform for screening cardiac safety and efficacy when developing therapeutics against COVID-19.



中文翻译:

羟氯喹和阿奇霉素对人体工程心脏组织显示的收缩力和心律失常的不利影响

由世界卫生组织(WHO)宣布,由严重急性呼吸系统综合症冠状病毒2(SARS-CoV-2)引起的2019年冠状病毒疾病(COVID-19)爆发已成为全球大流行。在没有有效的治疗方法的情况下,已经测试了不同疗效未知的药物,包括抗疟疾羟氯喹(HCQ),是否同时与阿奇霉素(AZM)一起给药,用于治疗COVID-19并发肺炎。然而,最近的临床报告对HCQ和/或AZM的功效和安全性提出了质疑。这些药物对人心脏的直接作用仍然非常不清楚。为了更好地了解HCQ +/- AZM的作用机制,我们采用了生物工程化的人心室心脏组织带(hvCTS)和各向异性片(hvCAS)分析,由人多能干细胞(hPSC)衍生的心室心肌细胞(hvCM)制成,它们分别用于测量心脏收缩力和电生理。我们的hvCTS实验表明,AZM诱导了剂量依赖性的负性肌力作用,HCQ可加重这种作用。如hvCAS平台所揭示的那样,电生理学上,AZM延长了动作电位并诱导了螺旋波的形成。总体而言,我们的数据与报道的HCQ和AZM在QTc延长/室性心律不齐和心力衰竭发展方面的临床风险一致。总之,我们的研究暴露了HCQ / AZM给药的风险,同时提供了有关其毒性的机理见解。

更新日期:2021-01-16
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