Reversible Fibroblast Trajectories Regulated by MR Underlie Diastolic Dysfunction

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major health issue of our time. The pathophysiology of HFpEF is diverse, linked to comorbidities, such as kidney disease or obesity, and different from heart failure with reduced ejection fraction. As a consequence, treatment options are still limited. Recent clinical trials indicate beneficial effects of MR (mineralocorticoid receptor) antagonists in HFpEF, but the underlying mechanisms are incompletely understood. METHODS AND RESULTS: ). In contrast to a previous study in heart failure with reduced ejection fraction, MR deletion prevented the onset of diastolic dysfunction, suggesting different roles for fibroblast MR in heart failure subtypes. CONCLUSIONS: Diastolic dysfunction is associated with a fibroblast subtype that is different from the myofibroblasts observed in heart failure with reduced ejection fraction. MR activation is an overlapping feature of cardiorenal and cardiometabolic disease models. Further, MR deletion from fibroblasts prevents disease progression, suggesting that the beneficial effects of MR antagonists in HFpEF are related to inhibition of fibroblast MR.