Heart Failure with Supranormal Ejection Fraction: An Emerging High-Risk Phenotype Within the Preserved Ejection...

Background: Heart failure with supranormal ejection fraction (HFsnEF) has recently emerged as a distinct phenotype within the preserved ejection fraction spectrum. However, its clinical profile, underlying mechanisms, and prognostic significance remain incompletely understood. Methods: A systematic review was conducted according to PRISMA recommendations. PubMed, Scopus, and EMBASE were searched from inception to May 2026 for studies investigating HFsnEF. Demographic, clinical, laboratory, echocardiographic, prognostic, and therapeutic data were extracted. Weighted descriptive analyses were performed to compare HFsnEF and conventional heart failure with preserved ejection fraction (HFpEF) populations. Random-effects meta-analyses of study-specific event rates were conducted for all-cause mortality and for the composite endpoint of cardiovascular death or heart failure hospitalization. Results: Fourteen studies involving 17,158 HFpEF patients and 7493 HFsnEF patients were included. Compared with HFpEF, HFsnEF patients exhibited broadly similar clinical, laboratory, haemodynamic, and treatment profiles, with a higher prevalence of women and a lower prevalence of coronary artery disease representing the most consistent clinical differences. Conventional laboratory parameters and natriuretic peptide concentrations showed substantial overlap between groups. Echocardiographically, HFsnEF was characterized by significantly smaller left ventricular end-systolic dimensions and volumes and higher ejection fraction despite similar stroke volume and cardiac output. Mechanistic studies further demonstrated significantly higher end-systolic elastance and lower ventriculo-arterial coupling ratios despite comparable arterial elastance, supporting the presence of distinct ventricular-vascular mechanical properties. Prognostic analyses consistently identified HFsnEF as a phenotype associated with adverse clinical outcomes. Pooled event-rate analyses demonstrated significantly higher rates of both all-cause mortality and the composite endpoint of cardiovascular death or heart failure hospitalization in HFsnEF compared with HFpEF. Emerging evidence also suggests a potential benefit of sodium-glucose cotransporter-2 inhibitors in this population. Conclusions: HFsnEF appears to represent a distinct and potentially high-risk phenotype within the preserved ejection fraction spectrum. Its characteristic structural, haemodynamic, and prognostic features challenge the traditional assumption that progressively higher ejection fraction necessarily reflects better cardiovascular health. Further prospective studies incorporating advanced imaging and haemodynamic assessment are needed to refine its pathophysiological characterization and therapeutic management.