Defining cardiac functional recovery in end-stage heart failure at single-cell resolution

Area of Science:

• Cardiology
• Molecular Biology
• Genomics

Background:

• Recovery of cardiac function in heart failure is a critical but poorly understood therapeutic goal.
• Left ventricular assist device (LVAD) implantation offers a unique model to study cardiac recovery.

Purpose of the Study:

• To identify cell-specific transcriptional signatures associated with cardiac recovery following LVAD implantation.
• To investigate the role of RUNX1 in cardiac recovery.

Main Methods:

• Single-nucleus RNA sequencing was performed on cardiac samples from heart failure patients with and without recovery post-LVAD, and from non-diseased donors.
• In silico perturbation of RUNX1 in macrophages and fibroblasts was conducted.
• Cardiac recovery was induced in mice via BET inhibition, and gene expression and chromatin accessibility were analyzed.

Main Results:

• Distinct cell-specific transcriptional signatures of recovery were identified, particularly in macrophages and fibroblasts.
• Inflammatory signatures were negatively correlated with recovery, while RUNX1 downregulation was associated with improved cardiac function.
• In silico and in vivo experiments demonstrated that modulating RUNX1 activity recapitulated or influenced recovery signatures.

Conclusions:

• Cardiac recovery represents a unique biological state characterized by specific cellular and molecular changes.
• RUNX1 is identified as a potential therapeutic target for promoting cardiac recovery in heart failure.