Reversible Fibroblast Trajectories Regulated by MR Underlie Diastolic Dysfunction.

Area of Science:

• Cardiovascular Research
• Renal Medicine
• Endocrinology

Background:

• Heart failure with preserved ejection fraction (HFpEF) presents diverse pathophysiology, often linked to comorbidities.
• Current treatment options for HFpEF remain limited.
• Mineralocorticoid receptor (MR) antagonists show potential therapeutic benefits in HFpEF, but mechanisms are unclear.

Purpose of the Study:

• To investigate the role of MR in HFpEF pathophysiology.
• To identify specific cell types and molecular pathways involved in MR-driven HFpEF.
• To explore the therapeutic potential of targeting fibroblast MR in HFpEF.

Main Methods:

• Induction of a cardiorenal HFpEF-like phenotype in mice using aldosterone and high salt diet.
• Single-nucleus RNA sequencing of left ventricles to analyze gene expression changes.
• Generation of mice with fibroblast-specific MR deletion (MR^TCF21Cre) to assess functional consequences.

Main Results:

• Aldosterone treatment induced comparable diastolic dysfunction and structural remodeling in male and female mice, largely reversible upon withdrawal.
• Single-nucleus RNA sequencing identified significant gene expression changes in cardiomyocytes, endothelial cells, and fibroblasts, with a shift towards a distinct fibroblast subpopulation.
• Fibroblast-specific MR deletion prevented the onset of diastolic dysfunction in the HFpEF model.

Conclusions:

• HFpEF involves a distinct fibroblast subtype, differing from myofibroblasts in heart failure with reduced ejection fraction.
• MR activation is a common feature in both cardiorenal and cardiometabolic HFpEF models.
• Inhibiting fibroblast MR may underlie the beneficial effects of MR antagonists in HFpEF, offering a targeted therapeutic approach.