Multimodality Molecular Profiling Nominates Targetable Mechanisms in Progressive RV Dysfunction.

Area of Science:

• Cardiovascular Science
• Molecular Biology
• Genomics

Background:

• Right ventricular dysfunction (RVD) is a key mortality predictor in cardiovascular diseases.
• Understanding RVD's cellular and molecular basis is crucial for targeted therapies.
• Pulmonary artery banding (PAB) in pigs models progressive RVD.

Purpose of the Study:

• To investigate the distinct cellular and molecular alterations associated with varying degrees of RVD.
• To identify potential therapeutic targets for progressive right ventricular dysfunction.

Main Methods:

• Pigs with PAB were categorized into mild and severe RVD groups based on RV ejection fraction.
• Multi-omics analysis included single-nucleus RNA sequencing, proteomics, and phosphoproteomics.
• Histological analysis corroborated multi-omic findings.

Main Results:

• Advancing RVD led to cardiomyocyte loss, macrophage dysfunction, and endothelial/pericyte dysregulation.
• Cardiomyocyte metabolism and mitochondrial proteostasis were progressively impaired with worsening RVD.
• Severe RVD showed compromised microvasculature, ectopic HIF1 expression, and activation of the ribotoxic stress response.

Conclusions:

• Multi-omics defines the cellular and molecular landscape of progressive RVD.
• Identified pathways, including mitochondrial unfolded protein response and macrophage efferocytosis, are potential therapeutic targets.
• Further research is needed to validate these targets for RV dysfunction treatment.