Supranormal Ejection Fraction as a Clinical Red Flag: Differentiating Hemodynamic Stress From Intrinsic Cardiomyopathy in Heart Failure

To show that heart failure with supranormal ejection fraction (HFsnEF, left ventricular ejection fraction [LVEF] ≥ 65%) is not a marker of cardiac health but a specific enrichment zone for malignant cardiomyopathies and to provide a phenotypic framework for differential diagnosis.

We retrospectively analyzed 200 consecutive patients with HFsnEF admitted between December 1, 2017 and December 1, 2024. Patients were stratified into 2 phenotypes based on etiology: group A (hemodynamic loading, n=88), comprising valvular or hypertensive heart disease; and group B (intrinsic cardiomyopathy, n=112), comprising hypertrophic cardiomyopathy, cardiac amyloidosis, or Fabry disease. We compared their electromechanical profiles and event-free survival.

Despite identical LVEF (median, 69%), the 2 groups exhibited distinct clinical signatures. Group A represented a classic secondary remodeling profile (older age and atrial fibrillation). In contrast, group B patients were younger (56.0 vs 68.8 years; P<.001) yet displayed severe diastolic stiffness (septal E/e' > 13) and a distinct electromechanical fingerprint (wide QRS or PR deviations). In a fully adjusted multivariable Cox model, the intrinsic cardiomyopathy phenotype was the dominant driver of the composite end point (adjusted hazards ratio, 3.91; 95% CI, 1.71-8.93; P = .001). Notably, N-terminal pro-B-type natriuretic peptide was not an independent predictor (P = .20) in this population, indicating that structural etiology overrides hemodynamic biomarkers in determining prognosis.

An LVEF of 65% or more is not reassuring but signals underlying heterogeneity, often masking malignant intrinsic cardiomyopathies that masquerade as benign heart failure with preserved ejection fraction. A multimodal red flag approach-integrating clinical, imaging, and electrocardiographic data-is essential to trigger targeted evaluation, as standard heart failure with preserved ejection fraction management is insufficient for these high-risk phenotypes.