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High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023
Comprehensive Cardiotoxicity Assessment of COVID-19 Treatments Using Human-Induced Pluripotent Stem Cell-Derived
Shota Yanagida1,2, Ayano Satsuka1, Sayo Hayashi1
1Division of Pharmacology, National Institute of Health Sciences (NIHS), Kawasaki, Kanagawa 210-9501, Japan.
Abstract:
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.
Insights
Human stem cell-derived heart cells (hiPSC-CMs) assessed COVID-19 drug cardiotoxicity. Hydroxychloroquine showed proarrhythmic risk, while other COVID-19 treatments had low risk, indicating hiPSC-CMs are useful for safety testing.
Area of Science:
- Cardiovascular Research
- Drug Safety and Toxicology
- Stem Cell Biology
Background:
- COVID-19 treatments are under development, necessitating safety assessments.
- Hydroxychloroquine has been linked to cardiotoxicity, including TdP.
- Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a model for evaluating drug-induced cardiotoxicity.
Purpose of the Study:
- To assess the proarrhythmic risk of COVID-19 treatments using hiPSC-CMs.
- To evaluate cardiotoxicity of repurposed drugs with diverse mechanisms of action.
- To determine if hiPSC-CMs can comprehensively assess COVID-19 treatment cardiotoxicity.
Main Methods:
- Utilized hiPSC-CMs for drug-induced cardiotoxicity assessment.
- Employed multi-electrode array systems for field potential analysis.
- Performed motion analysis to evaluate contraction and relaxation dynamics.
- Measured electromechanical window (EMW) to assess drug effects on cardiac function.
Main Results:
- Hydroxychloroquine induced early afterdepolarizations and concentration-dependent EMW reduction.
- Remdesivir, favipiravir, camostat, and ivermectin showed minimal effects on hiPSC-CM electrophysiology and contractility.
- Hydroxychloroquine demonstrated significant proarrhythmic risk, unlike the other tested COVID-19 treatments.
Conclusions:
- hiPSC-CMs are a valuable tool for nonclinical assessment of COVID-19 treatment cardiotoxicity.
- Hydroxychloroquine poses a proarrhythmic risk, while other tested COVID-19 drugs exhibit low cardiotoxic potential.
- This study validates hiPSC-CMs for comprehensive safety evaluations of potential therapeutics.
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