Reversible Fibroblast Trajectories Regulated by MR Underlie Diastolic Dysfunction

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 performed single nucleus RNA sequencing in an aldosterone/salt-induced model of cardiorenal HFpEF in mice and compared it to the high fat diet/L-NAME model of cardiometabolic HFpEF. We found a fibroblast subtype induced that is distinct from the classical myofibroblast observed in heart failure with reduced ejection fraction. Notably, after aldosterone withdrawal the HFpEF-like phenotype fully recovered. This was linked to a restored expression of MR target genes and an upregulation of collagen III, VI, and XV in fibroblasts during recovery. MR deletion from fibroblasts prevented cardiac remodeling and diastolic dysfunction, confirming the central role of fibroblast MR in cardiorenal HFpEF. In summary, our study reveals fibroblast gene expression signatures in heart failure from different causes that may determine the response to pharmacological treatment and potential for recovery.