Cardiac fibroblast diversity in HFpEF: states, niches, interorgan drivers and targets.

Myocardial fibrosis is a key structural and prognostically adverse feature of heart failure with preserved ejection fraction (HFpEF), but its cellular and molecular drivers remain incompletely understood and are not specifically addressed by current therapies. Cardiac fibroblasts, previously considered to be largely structural, collagen-producing cells, are now recognized as being a heterogeneous family of trophic cells that integrate vascular, immune and metabolic cues to coordinate extracellular matrix remodelling. Single-cell and spatial transcriptomic analyses have resolved fibroblast states in the healthy and diseased myocardium, revealing that cardiac fibrosis in HFpEF (unlike in post-infarction scarring) results from the activation of profibrotic gene programmes across various fibroblast states, rather than the expansion of classic myofibroblasts. Hallmark programmes include increased nitrosative stress, dysregulated lipid handling and altered inflammatory signalling. These cardiac fibroblast-intrinsic alterations are further shaped by cardiac intercellular cues and by interorgan communication to the heart from the adipose tissue, bone marrow, gut, liver, lymphatic system and nervous system, positioning fibroblasts as myocardial integrators of systemic cardiometabolic stress. Emerging proof-of-concept studies in animal models of HFpEF demonstrate that selectively modulating fibroblast-specific targets can attenuate cardiac fibrosis, improve diastolic function and reduce susceptibility to arrhythmia. In this Review, we delineate HFpEF-specific fibroblast alterations, integrate cross-organ signalling networks that condition the cardiac stroma, and evaluate opportunities for fibroblast-directed therapies as next-generation antifibrotic strategies.