Key result
Intrinsic cardiomyopathy linked to ~6.1-fold higher death or HF rehospitalization vs hemodynamic loading in HFsnEF.
Why the study?
Heart failure with supranormal ejection fraction (HFsnEF, LVEF >=65%) represents a high-risk subset of HFpEF, yet the drivers of prognosis within this heterogeneous population remain poorly understood.
Does an intrinsic cardiomyopathy phenotype increase the risk of all-cause death or heart failure rehospitalization compared to a hemodynamic loading phenotype in patients with heart failure with supranormal ejection fraction (LVEF ≥65%)?
Cohort (n=200)
Does an intrinsic cardiomyopathy phenotype increase the risk of all-cause death or heart failure rehospitalization compared to a hemodynamic loading phenotype in patients with heart failure with supranormal ejection fraction (LVEF ≥65%)?
In patients with heart failure with supranormal ejection fraction (LVEF ≥65%), an intrinsic cardiomyopathy etiology (HCM, amyloidosis, or Fabry disease) confers a more than six-fold higher risk of all-cause death or HF rehospitalization compared to hemodynamic loading etiologies, despite younger patient age.
Background Heart failure with supranormal ejection fraction (HFsnEF, LVEF ≥65%) represents a high-risk subset of HFpEF, yet the drivers of prognosis within this heterogeneous population remain poorly understood. Purpose To delineate the distinct clinical, mechanical, and electrophysiological phenotypes of HFsnEF and determine their impact on clinical outcomes. Methods We retrospectively analyzed 200 consecutive HFsnEF patients admitted between December 2017 and December 2024. Patients were categorized into two etiological phenotypes: Group A (Hemodynamic Loading, n=88), comprising valvular, hypertensive, ischemic, or arrhythmia-induced heart failure; and Group B (Intrinsic Cardiomyopathy, n=112), comprising hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and Fabry disease. Echocardiographic mechanics, electromechanical parameters, and event-free survival were systematically compared. Multivariable Cox models identified predictors of the composite endpoint of all-cause death or HF rehospitalization. Results Despite identical LVEF values (median 69% in both groups), Group B patients were significantly younger than Group A (56.0 vs. 68.8 years, P<0.001) and had a lower prevalence of atrial fibrillation (8.9% vs. 38.6%). Mechanistically, Group B demonstrated more severe diastolic stiffness (septal E/e’ ratio 14.3 vs. 12.7, P<0.001) and a distinct “electromechanical fingerprint”, including a two-fold higher prevalence of isolated QRS widening and etiology-specific PR-interval deviations. Subgroup analyses revealed a prognostic hierarchy: infiltrative cardiomyopathies (amyloidosis/Fabry) carried the highest risk, whereas isolated HCM showed outcomes comparable to Group A. In multivariable analyses, the Intrinsic Cardiomyopathy phenotype was the strongest independent predictor of the composite endpoint (adjusted HR 6.125; 95% CI 2.151–17.443; P=0.001), overriding the survival advantage expected from younger age. Conclusions In HFsnEF, supranormal LVEF masks profound pathophysiological heterogeneity. The Intrinsic Cardiomyopathy phenotype represents a malignant endotype characterized by marked diastolic stiffness and electromechanical uncoupling, conferring substantially worse outcomes independent of age and comorbidities.
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Chen et al. (2026) conducted a cohort in Heart failure with supranormal ejection fraction (HFsnEF, LVEF ≥65%) (n=200). Intrinsic Cardiomyopathy phenotype (hypertrophic cardiomyopathy, cardiac amyloidosis, and Fabry disease) vs. Hemodynamic Loading phenotype (valvular, hypertensive, ischemic, or arrhythmia-induced heart failure) was evaluated on Composite endpoint of all-cause death or HF rehospitalization (HR 6.125, 95% CI 2.151-17.443, p=0.001). Intrinsic cardiomyopathy phenotype independently predicted higher all-cause death or HF rehospitalization vs hemodynamic loading in HFsnEF (adjusted HR 6.125; 95% CI 2.151-17.443; P=0.001).
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