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Given the urgent need for effective treatments, many clinical trials are ongoing through repurposing approved drugs. However, clinical data regarding the cardiotoxicity of these drugs are limited. Human pluripotent stem cell\u2010derived cardiomyocytes (hCMs) represent a powerful tool for assessing drug\u2010induced cardiotoxicity. Here, by using hCMs, it is demonstrated that four antiviral drugs, namely, apilimod, remdesivir, ritonavir, and lopinavir, exhibit cardiotoxicity in terms of inducing cell death, sarcomere disarray, and dysregulation of calcium handling and contraction, at clinically relevant concentrations. Human engineered heart tissue (hEHT) model is used to further evaluate the cardiotoxic effects of these drugs and it is found that they weaken hEHT contractile function. RNA\u2010seq analysis reveals that the expression of genes that regulate cardiomyocyte function, such as sarcomere organization (<jats:italic>TNNT2, MYH6<\/jats:italic>) and ion homeostasis (<jats:italic>ATP2A2, HCN4<\/jats:italic>), is significantly altered after drug treatments. Using high\u2010throughput screening of approved drugs, it is found that ceftiofur hydrochloride, astaxanthin, and quetiapine fumarate can ameliorate the cardiotoxicity of remdesivir, with astaxanthin being the most prominent one. These results warrant caution and careful monitoring when prescribing these therapies in patients and provide drug candidates to limit remdesivir\u2010induced cardiotoxicity.<\/jats:p>","DOI":"10.1002\/advs.202203388","type":"journal-article","created":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T21:35:07Z","timestamp":1662154507000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Investigating and Resolving Cardiotoxicity Induced by COVID\u201019 Treatments using Human Pluripotent Stem Cell\u2010Derived Cardiomyocytes and Engineered Heart Tissues"],"prefix":"10.1002","volume":"9","author":[{"given":"He","family":"Xu","sequence":"first","affiliation":[{"name":"Center of Translational Medicine The First Affiliated Hospital Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangdong 510080 China"},{"name":"NHC Key Laboratory of Assisted Circulation (Sun Yat\u2010Sen University)  Guangzhou 510080 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ge","family":"Liu","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangdong 510080 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jixing","family":"Gong","sequence":"additional","affiliation":[{"name":"National &amp; 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