Cardiorenal heart failure with preserved ejection fraction is caused by a reversible rise of mineralocorticoid-induced fibroblast subtypes

Abstract Heart failure with preserved ejection fraction (HFpEF) is driven by co-morbidities. While specific treatments to enable recovery of HFpEF are lacking, recent clinical trials indicate beneficial effects of mineralocorticoid receptor (MR) antagonists. Here we treated mice with aldosterone-salt to incude a cardiorenal HFpEF-like phenotype and studied progression and regression of the disease at single cell resolution. We found a distinct fibroblast subtype induced that shows partial overlap with fibroblasts found in cardiometabolic HFpEF but is different from the myofibroblast phenotype observed in heart failure with reduced EF. Notably, after aldosterone withdrawal the HFpEF-like phenotype fully recovered. The course of disease progression and regression was linked to the expression of MR target genes and basement membrane collagen subtypes in fibroblasts. MR deletion from fibroblasts prevented cardiac remodeling and diastolic dysfunction, confirming its pivotal function. In summary, our study reveals overlapping and distinct features of cardiorenal and cardiometabolic HFpEF that are involved in disease progression and recovery and may underly the beneficial effect of MR antagonists in HFpEF.