Endocrine regulation of cardiac fibrosis: implications for HFpEF

Heart failure with preserved ejection fraction (HFpEF) is a dominant heart failure phenotype in ageing populations and commonly develops on a background of hypertension, obesity, diabetes, and systemic inflammation. Myocardial fibrosis is a central structural lesion in HFpEF, but it is increasingly recognised not merely as a passive haemodynamic consequence but as an actively regulated process shaped by endocrine and metabolic signals. This review examines seven interacting hormonal axes, namely the renin-angiotensin-aldosterone system, tissue-amplified glucocorticoid signalling via 11β-HSD1, gonadal steroid deficiency, adipokine dysregulation and epicardial adipose tissue inflammation, insulin resistance, altered thyroid hormone signalling, and disordered mineral metabolism, which converge on shared profibrotic effectors, including TGF-β-Smad signalling, NADPH oxidase-derived oxidative stress, suppression of the NO-cGMP-PKG pathway, and mTOR-AMPK-FOXO dysregulation. These axes interact via self-reinforcing feedback circuits and converge on coronary microvascular dysfunction as a central pathological node, helping to explain the heterogeneity of HFpEF, its female predominance, and incomplete responses to single-pathway therapies. We distinguish clinically validated endocrine-modulating strategies, including SGLT2 inhibitors, mineralocorticoid receptor antagonism, and incretin-based therapy in selected phenotypes, from emerging tissue-targeted approaches. This endocrine framework provides a basis for phenotype-guided antifibrotic strategies in HFpEF.