Multiscale mapping of transcriptomic signatures for cardiotoxic drugs

Area of Science:

• Cardiovascular Toxicology
• Genomics
• Transcriptomics

Background:

• Drug-induced cardiotoxicity is a significant concern in pharmaceutical development.
• Tyrosine kinase inhibitors (TKIs) are widely used but can pose cardiovascular risks.
• Understanding the molecular mechanisms of TKI cardiotoxicity is crucial for drug safety.

Purpose of the Study:

• To identify gene expression signatures associated with cardiotoxicity induced by FDA-approved TKIs.
• To investigate the cellular pathways affected by cardiotoxic TKIs in human cardiomyocytes.
• To integrate transcriptomic data with genomic information for predicting cardiotoxicity.

Main Methods:

• Utilized bulk transcriptomic profiling of human induced-pluripotent-stem-cell-derived cardiomyocytes.
• Employed singular value decomposition to identify drug-selective expression patterns.
• Integrated transcriptomic outlier analysis with whole-genome sequencing.

Main Results:

• Identified affected cellular pathways including energy metabolism, contractile function, and extracellular matrix dynamics.
• Demonstrated that TKI responses can occur in both cardiomyocytes and fibroblasts.
• Successfully reidentified a known cardiotoxicity-linked genomic variant and predicted novel ones.

Conclusions:

• mRNA expression profiles, when integrated with genomic and single-cell data, provide multiscale signatures for cardiotoxicity.
• These signatures can inform drug development and patient stratification strategies.
• This approach offers a comprehensive method for assessing drug-induced cardiotoxicity.