Reversible Fibroblast Trajectories Regulated by MR Underlie Diastolic Dysfunction.
Meral D, Mamazhakypov A, Koca D, Mukherjee D, Kamaras C et al.
Mineralocorticoid receptor (MR) activation in cardiac fibroblasts drives diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) through a distinct fibroblast subtype different from myofibroblasts in heart failure with reduced ejection fraction. Preclinical study in male and female mice using aldosterone/high-salt diet and high-fat diet models, with single-nucleus RNA sequencing and fibroblast-specific MR deletion experiments. This provides the first mechanistic evidence that MR antagonists' clinical benefits in HFpEF operate through fibroblast-specific pathways rather than cardiomyocyte effects. The reversible nature of aldosterone-induced changes suggests potential for disease modification with MR antagonist therapy.
Strategic Signal
This mechanistic validation strengthens the clinical rationale for MR antagonists in HFpEF, where spironolactone and finerenone have shown modest but meaningful benefits in recent trials. The fibroblast-specific mechanism differentiates HFpEF from heart failure with reduced ejection fraction, supporting targeted therapy development and potentially more precise patient selection. US and EU cardiologists gain clearer biological justification for MR antagonist use in HFpEF patients with cardiorenal or cardiometabolic comorbidities.