Sex and Atrial Fibrillation Independently Stratify Cardiac Remodeling and Outcomes in Heart Failure with Preserved Ejection Fraction

Background/Objectives: Atrial fibrillation (AF) is common in heart failure with preserved ejection fraction (HFpEF) and is associated with worse symptoms and prognosis. Emerging evidence suggests that sex modifies the AF–HFpEF relationship through differences in atrial remodeling, comorbidity burden, and hemodynamic vulnerability. This study aimed to evaluate how sex and AF jointly relate to differences in cardiac structure, clinical characteristics, and outcomes in HFpEF. Methods: We retrospectively analyzed 622 patients with HFpEF admitted between January 2019 and May 2023. Patients were categorized into four predefined clinical subgroups: women without AF, women with AF, men without AF, and men with AF. The primary endpoint was first rehospitalization for HF decompensation. Results: Over a mean follow-up of 48.6 ± 16.4 months, 181 patients (29.1%) were rehospitalized for worsening HF, with the highest event burden observed in men with AF. Sex and AF were each associated with distinct clinical and remodeling profiles, without significant sex-by-AF interaction effects. AF was independently associated with a higher risk of HF rehospitalization (HR 1.45, 95% CI 1.06–1.99, p = 0.021), whereas female sex was protective (HR 0.71, 95% CI 0.53–0.97, p = 0.032). Men with AF exhibited the most adverse remodeling profile, characterized by the largest unindexed left atrial and left ventricular dimensions, the highest prevalence of significant tricuspid regurgitation, and the lowest event-free survival (HR 1.92, 95% CI 1.23–2.99, p = 0.004). In contrast, women with AF more frequently displayed concentric remodeling and significant mitral regurgitation. Independent predictors of rehospitalization included higher NYHA functional class and lower left ventricular EF within the preserved EF range. Conclusions: Sex and AF were independently associated with substantial differences in cardiac structure, clinical characteristics and prognosis in HFpEF. Men with AF represent the highest-risk subgroup, driven by more advanced structural remodeling and valvular dysfunction. These findings suggest that simple sex- and rhythm-based classification may provide complementary information for risk stratification and management in HFpEF. Further validation in independent cohorts is warranted.