Sex and atrial fibrillation identify distinct structural and clinical phenotypes in heart failure with preserved ejection fraction
D R Hadareanu, C D Hadareanu, F M Stoiculescu, M L Iovanescu, O Munteanu-Mirea, I Donoiu, O Istratoaie, C FlorescuAbstract
Background
Atrial fibrillation (AF) commonly coexists with heart failure with preserved ejection fraction (HFpEF), worsening congestion, exercise intolerance, and clinical outcomes. Whether sex fundamentally modifies the structural and clinical consequences of AF in HFpEF remains uncertain, and current guidelines do not provide phenotypes integrating biological sex and cardiac rhythm.
Purpose
To determine how sex and AF jointly influence cardiac structure, valve disease, and the risk of heart-failure rehospitalisation in a large, real-world HFpEF cohort.
Methods
A total of 622 consecutive HFpEF patients admitted between 2019 and 2023 were retrospectively enrolled and stratified into four predefined phenotypes: women without AF (n=174), women with AF (n=170), men without AF (n=166), and men with AF (n=112). Clinical variables and comprehensive echocardiography were collected at index admission. The primary endpoint was first HF rehospitalisation. Cox regression identified independent predictors; Kaplan–Meier curves evaluated event-free survival.
Results
Over a mean follow-up of 49 ± 16 months, 181 patients (29.1%) were rehospitalised. Sex–AF interactions generated distinct structural and prognostic profiles (interaction p<0.01). Men with AF exhibited the greatest left-atrial enlargement (53 ± 10 mm), highest left-ventricular mass (246 ± 97 g), the highest prevalence of significant tricuspid regurgitation, and the poorest event-free survival (log-rank p<0.001). Women with AF demonstrated more concentric remodelling and were over-represented among those with significant mitral regurgitation. In multivariable Cox analysis, AF (HR 1.49, 95% CI 1.11–2.00, p=0.008), higher NYHA class (HR 1.53, 95% CI 1.22–1.91, p<0.001), and moderate-to-severe mitral regurgitation (HR 1.47, 95% CI 1.09–1.98, p=0.012) independently predicted rehospitalisation. Female sex (HR 0.71, 95% CI 0.53–0.95, p=0.019) and higher ejection fraction within the preserved range (HR 0.95 per 1% increase, 95% CI 0.91–0.99, p=0.009) remained protective.
Conclusion
Sex and AF define clinically meaningful HFpEF phenotypes characterised by distinct remodelling patterns and markedly divergent risks of rehospitalisation. Men with AF represent a particularly high-risk subgroup with advanced structural remodelling and right-sided valve disease. These findings introduce a simple, clinically actionable sex–rhythm framework that enhances prognostic assessment and supports personalised management in HFpEF.Cox regression analysisFor image description, please refer to the figure legend and surrounding text.Kaplan-Meier survival analysisFor image description, please refer to the figure legend and surrounding text.