Transcriptional Effects of Candidate COVID-19 Treatments on Cardiac Myocytes

Area of Science:

• Cardiology
• Virology
• Pharmacology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease linked to significant morbidity, mortality, and cardiac complications like cardiomyopathy.
• Repurposing existing drugs is a strategy to accelerate COVID-19 treatment development.
• The cardiac effects of repurposed drugs, particularly concerning the angiotensin-converting enzyme 2 receptor (ACE2) pathway, require thorough investigation.

Purpose of the Study:

• To investigate the impact of repurposed drugs on cardiac cells at a molecular level.
• To identify potential adverse effects of specific repurposed drugs on cardiac gene expression programs.

Main Methods:

• Human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) were exposed to five repurposed drugs: remdesivir, lopinavir/ritonavir, lopinavir/ritonavir/interferon beta (INF-β), hydroxychloroquine, and chloroquine.
• Transcriptional profiling via RNA sequencing was employed to analyze global gene expression changes in treated hiPSC-CMs compared to controls.

Main Results:

• RNA sequencing revealed significant alterations in gene programs associated with calcium handling and endoplasmic reticulum stress response.
• Lopinavir/ritonavir and lopinavir/ritonavir/interferon-beta exhibited the most prominent changes in cardiac gene expression.
• Differential gene expression analysis data is accessible online for further exploration.

Conclusions:

• Transcriptional profiling of hiPSC-CMs treated with repurposed COVID-19 drugs identified potentially detrimental changes.
• Lopinavir/ritonavir and lopinavir/ritonavir/interferon-beta demonstrated unfavorable effects on key cardiac gene programs, suggesting potential negative impacts on heart function.