Transcriptional changes in human pluripotent stem cell-derived cardiomyocytes induced by apilimod, remdesivir, ritonavir, and lopinavir treatment
The rapid development of safe and effective treatments for COVID-19 had become a top priority to fight against this spreading pandemic worldwide in 2019. 20%–30% of COVID-19 patients experience severe cardiovascular damage, patients with pre-existing heart complications are more likely to develop severe illness and have higher risk of death compared with patients without co-morbidities. In such a context, whether the repurposed drugs are at risk of inducing heart damage to COVID-19 patients remains unclear. Here, we demonstrated that four antiviral drugs, including apilimod, remdesivir, ritonavir, and lopinavir, exhibit cardiotoxicity at clinically relevant doses. RNA-seq analysis revealed that human pluripotent stem cell-derived cardiomyocytes (hCMs) treated by each drug had significantly different expression profiles when compared with the untreated control. The expression of genes that regulate cardiomyocyte function, such as sarcomere organization and ion hemostasis, was significantly altered after drug treatment. These results not only warrant caution and careful monitoring when prescribing the above-mentioned drugs in patients, but also provide a valuable platform for understanding the molecular mechanism underlined the toxic effects of these prospective drugs and for protective agent discovery. Overall design: To identify the transcriptomic basis of the cardiotoxic effect of the four drugs, we performed comparative gene expression profiling analysis using data from RNA-seq of hCMs with or without drug treatment.