Heart failure with supranormal ejection fraction: is it the new Ariadne's string?

Heart failure with supranormal ejection fraction (HFsnEF) is an emerging and incompletely characterized phenotype within the heart failure (HF) spectrum. Although no universally accepted LVEF threshold for HFsnEF has been established and different definitions have been used across published studies, for the purposes of this review HFsnEF is operationally defined as HF with a left ventricular ejection fraction (LVEF) > 65%. Importantly, a supranormal LVEF should not be interpreted as evidence of enhanced ventricular performance. Patients with HFsnEF may exhibit smaller left ventricular (LV) volumes, concentric remodeling, increased myocardial stiffness, impaired longitudinal deformation, reduced stroke volume and preload reserve, and elevated filling pressures, particularly during exercise. HFsnEF is unlikely to represent a single disease entity; rather, it encompasses heterogeneous pathophysiological substrates and clinical phenotypes, including hypertensive and cardiometabolic remodeling, valvular heart disease, hypertrophic cardiomyopathy (HCM), transthyretin cardiac amyloidosis (ATTR-CM), and other conditions associated with hyperdynamic ventricular function. Accordingly, the diagnostic evaluation should extend beyond recognition of an elevated LVEF and systematically identify the underlying phenotype and potentially treatable causes through comprehensive echocardiography, myocardial deformation imaging, cardiac magnetic resonance, disease-specific testing, and exercise or invasive hemodynamic assessment when indicated. Therapeutic evidence specific to HFsnEF remains limited. No randomized clinical trial has specifically evaluated conventional HF pharmacotherapy in a population prospectively defined by LVEF > 65%; therefore, evidence for conventional HF and cardiometabolic therapies is derived predominantly from broader HFpEF populations or subgroup analyses and should be regarded as indirect rather than definitive evidence for HFsnEF. In contrast, recognition of specific underlying diseases, particularly ATTR-CM, HCM, and significant valvular heart disease, may permit evidence-based disease-specific treatment. This review summarizes the epidemiology, pathophysiology, and clinical phenotypes of HFsnEF and proposes a practical phenotype-guided approach to diagnosis and management. Standardized definitions and prospective trials specifically addressing patients with LVEF > 65% are needed to establish evidence-based therapeutic strategies for this population.