Mineralocorticoid receptor overactivation in heart failure with preserved ejection fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome encompassing hypertensive left ventricular remodelling with diastolic dysfunction and systemic inflammation-driven endothelial dysfunction, with possible contributions from visceral adipose tissue-associated metabolic and proinflammatory alterations. However, conventional key risk factors for HFpEF, including advanced age, female sex, obesity, diabetes, and chronic kidney disease, are closely associated with mineralocorticoid receptor (MR) overactivation through several under-recognized mechanisms, i.e. renin-independent aldosterone excess, cortisol dysregulation, and ligand-independent activation. MR overactivation promotes myocardial hypertrophy and fibrosis, vascular remodelling, and systemic inflammation, all of which are hallmark features of HFpEF. Among patients with HFpEF, the steroidal MR antagonist (MRA) spironolactone has been suggested to reduce the risk of HF-related events, while the non-steroidal MRA finerenone has significantly reduced the primary composite of total worsening HF events and cardiovascular death. Across subgroups suggestive of MR overactivation, MRA therapy has shown generally consistent efficacy and safety, although greater adiposity may be associated with greater MRA efficacy. Given the continuum of MR activation across HF stages, early therapeutic intervention targeting MR overactivation may mitigate the risk of HFpEF development and progression. Furthermore, aldosterone synthase inhibitors and MR modulators, which also attenuate MR overactivation, are being evaluated for HFpEF prevention and treatment. This paper presents the mechanistic pathways linking MR overactivation to HFpEF and highlights the potential benefits of mitigating MR activation for its prevention and treatment, calling for renewed consideration of treatment strategies in clinical practice and trial design.