Investigating and Resolving Cardiotoxicity Induced by COVID‐19 Treatments using Human Pluripotent Stem Cell‐Derived Cardiomyocytes and Engineered Heart Tissues
Abstract Coronavirus disease 2019 continues to spread worldwide. 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‐derived ca...
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| Format: | Article |
| Language: | English |
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Wiley
2022-10-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202203388 |
| _version_ | 1828202317576404992 |
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| author | He Xu Ge Liu Jixing Gong Ying Zhang Shanshan Gu Zhongjun Wan Pengcheng Yang Yage Nie Yinghan Wang Zhan‐peng Huang Guanzheng Luo Zhongyan Chen Donghui Zhang Nan Cao |
| author_facet | He Xu Ge Liu Jixing Gong Ying Zhang Shanshan Gu Zhongjun Wan Pengcheng Yang Yage Nie Yinghan Wang Zhan‐peng Huang Guanzheng Luo Zhongyan Chen Donghui Zhang Nan Cao |
| author_sort | He Xu |
| collection | DOAJ |
| description | Abstract Coronavirus disease 2019 continues to spread worldwide. 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‐derived cardiomyocytes (hCMs) represent a powerful tool for assessing drug‐induced 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‐seq analysis reveals that the expression of genes that regulate cardiomyocyte function, such as sarcomere organization (TNNT2, MYH6) and ion homeostasis (ATP2A2, HCN4), is significantly altered after drug treatments. Using high‐throughput 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‐induced cardiotoxicity. |
| first_indexed | 2024-04-12T11:44:54Z |
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| id | doaj.art-54b3a39839eb4d72ab17a20b2f238715 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-12T11:44:54Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-54b3a39839eb4d72ab17a20b2f2387152022-12-22T03:34:22ZengWileyAdvanced Science2198-38442022-10-01930n/an/a10.1002/advs.202203388Investigating and Resolving Cardiotoxicity Induced by COVID‐19 Treatments using Human Pluripotent Stem Cell‐Derived Cardiomyocytes and Engineered Heart TissuesHe Xu0Ge Liu1Jixing Gong2Ying Zhang3Shanshan Gu4Zhongjun Wan5Pengcheng Yang6Yage Nie7Yinghan Wang8Zhan‐peng Huang9Guanzheng Luo10Zhongyan Chen11Donghui Zhang12Nan Cao13Center of Translational Medicine The First Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaThe Seventh Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaNational & Local Joint Engineering Research Center of High‐throughput Drug Screening Technology State Key Laboratory of Biocatalysis and Enzyme Engineering Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine Hubei University Wuhan 430062 ChinaThe Seventh Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaThe Seventh Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaNational & Local Joint Engineering Research Center of High‐throughput Drug Screening Technology State Key Laboratory of Biocatalysis and Enzyme Engineering Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine Hubei University Wuhan 430062 ChinaNational & Local Joint Engineering Research Center of High‐throughput Drug Screening Technology State Key Laboratory of Biocatalysis and Enzyme Engineering Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine Hubei University Wuhan 430062 ChinaThe Seventh Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaThe Seventh Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaCenter of Translational Medicine The First Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaMOE Key Laboratory of Gene Function and Regulation State Key Laboratory of Biocontrol School of Life Sciences Sun Yat‐Sen University Guangdong 510275 ChinaThe Seventh Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaNational & Local Joint Engineering Research Center of High‐throughput Drug Screening Technology State Key Laboratory of Biocatalysis and Enzyme Engineering Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine Hubei University Wuhan 430062 ChinaThe Seventh Affiliated Hospital Zhongshan School of Medicine Sun Yat‐Sen University Guangdong 510080 ChinaAbstract Coronavirus disease 2019 continues to spread worldwide. 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‐derived cardiomyocytes (hCMs) represent a powerful tool for assessing drug‐induced 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‐seq analysis reveals that the expression of genes that regulate cardiomyocyte function, such as sarcomere organization (TNNT2, MYH6) and ion homeostasis (ATP2A2, HCN4), is significantly altered after drug treatments. Using high‐throughput 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‐induced cardiotoxicity.https://doi.org/10.1002/advs.202203388cardiotoxicityengineered heart tissuehigh throughput screeninghuman pluripotent stem cell‐derived cardiomyocytesrepurposed drugs for COVID‐19 |
| spellingShingle | He Xu Ge Liu Jixing Gong Ying Zhang Shanshan Gu Zhongjun Wan Pengcheng Yang Yage Nie Yinghan Wang Zhan‐peng Huang Guanzheng Luo Zhongyan Chen Donghui Zhang Nan Cao Investigating and Resolving Cardiotoxicity Induced by COVID‐19 Treatments using Human Pluripotent Stem Cell‐Derived Cardiomyocytes and Engineered Heart Tissues Advanced Science cardiotoxicity engineered heart tissue high throughput screening human pluripotent stem cell‐derived cardiomyocytes repurposed drugs for COVID‐19 |
| title | Investigating and Resolving Cardiotoxicity Induced by COVID‐19 Treatments using Human Pluripotent Stem Cell‐Derived Cardiomyocytes and Engineered Heart Tissues |
| title_full | Investigating and Resolving Cardiotoxicity Induced by COVID‐19 Treatments using Human Pluripotent Stem Cell‐Derived Cardiomyocytes and Engineered Heart Tissues |
| title_fullStr | Investigating and Resolving Cardiotoxicity Induced by COVID‐19 Treatments using Human Pluripotent Stem Cell‐Derived Cardiomyocytes and Engineered Heart Tissues |
| title_full_unstemmed | Investigating and Resolving Cardiotoxicity Induced by COVID‐19 Treatments using Human Pluripotent Stem Cell‐Derived Cardiomyocytes and Engineered Heart Tissues |
| title_short | Investigating and Resolving Cardiotoxicity Induced by COVID‐19 Treatments using Human Pluripotent Stem Cell‐Derived Cardiomyocytes and Engineered Heart Tissues |
| title_sort | investigating and resolving cardiotoxicity induced by covid 19 treatments using human pluripotent stem cell derived cardiomyocytes and engineered heart tissues |
| topic | cardiotoxicity engineered heart tissue high throughput screening human pluripotent stem cell‐derived cardiomyocytes repurposed drugs for COVID‐19 |
| url | https://doi.org/10.1002/advs.202203388 |
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