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Updated: Aug 30, 2025
High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023
Investigating and Resolving Cardiotoxicity Induced by COVID-19 Treatments using Human Pluripotent Stem Cell-Derived
He Xu1,2, Ge Liu3, Jixing Gong4
1Center of Translational Medicine, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangdong, 510080, China.
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.
Insights
Four antiviral drugs show cardiotoxicity in human stem cell models, impacting heart cell function. Astaxanthin and other drugs may mitigate remdesivir
Area of Science:
- Cardiovascular Toxicology
- Stem Cell Biology
- Drug Repurposing
Background:
- Coronavirus disease 2019 (COVID-19) treatment relies on drug repurposing, but cardiotoxicity data is limited.
- Assessing drug-induced cardiotoxicity is crucial for patient safety during pandemics.
Purpose of the Study:
- To evaluate the cardiotoxicity of four repurposed antiviral drugs: apilimod, remdesivir, ritonavir, and lopinavir.
- To investigate potential therapeutic agents to counteract drug-induced cardiotoxicity.
Main Methods:
- Utilized human pluripotent stem cell-derived cardiomyocytes (hCMs) and human engineered heart tissue (hEHT) models.
- Assessed drug effects on cell viability, sarcomere structure, calcium handling, and contractile function.
- Employed RNA-sequencing (RNA-seq) to analyze gene expression changes.
- Conducted high-throughput screening to identify cardiotoxicity-mitigating compounds.
Main Results:
- Apilimod, remdesivir, ritonavir, and lopinavir induced cardiotoxicity in hCMs and hEHT models at clinical concentrations.
- Drug treatments led to cell death, sarcomere disarray, impaired calcium handling, and reduced contractile function.
- RNA-seq revealed significant alterations in genes regulating cardiomyocyte function and ion homeostasis.
- Ceftiofur hydrochloride, astaxanthin, and quetiapine fumarate ameliorated remdesivir-induced cardiotoxicity, with astaxanthin showing the strongest effect.
Conclusions:
- Repurposed antiviral drugs can exhibit significant cardiotoxicity, necessitating careful patient monitoring.
- Astaxanthin shows promise as a therapeutic agent to mitigate remdesivir-induced cardiotoxicity.
- hCMs and hEHT models are valuable tools for preclinical assessment of drug cardiotoxicity.
