Sex as a context-dependent modifier in obesity-related heart failure with preserved ejection fraction: adiposity, exercise hemodynamics, and treatment response

Abstract Background Sex differences in adiposity and exercise limitation have been reported in heart failure with preserved ejection fraction (HFpEF). Whether sex modifies adiposity–outcome associations remains uncertain. This targeted narrative review (through 21 October 2026) distinguishes baseline sex contrasts, sex-by-adiposity interactions, treatment-by-sex heterogeneity, and sex-conditioned mediation. Main body Community cohorts associate adiposity with incident HFpEF in both sexes without consistent sex interaction. Among the reports reviewed, a preliminary interaction was observed in a mixed HFpEF/control sample. Computed tomography-derived visceral adipose tissue was more strongly associated with raw peak exercise pulmonary capillary wedge pressure (PCWP) in women. A separate waist interaction was confined to PCWL [peak PCWP/(peak workload/body weight)]. The cohorts shared 39 participants. Both interaction findings lacked multiplicity adjustment and require independent replication. Mechanistic interpretation remains limited. Direct blood-volume studies in mixed heart-failure populations did not support generalized female hypervolemia. A small HFpEF cohort showed lower peak leg oxygen uptake per unit thigh lean mass in women, without detecting significant muscle-fat associations with oxygen uptake or its determinants. These findings, alongside inflammatory, cardiac, and vascular evidence, provide context but do not establish a sex-specific causal pathway. STEP-HFpEF detected greater placebo-adjusted weight reduction in women. No significant treatment-by-sex interaction was detected for health-status improvement in STEP-HFpEF or for the composite of cardiovascular death or worsening HF in SUMMIT. Undetected interactions do not establish equivalence, particularly with limited subgroup precision. Postrandomization weight–outcome associations do not establish mediation. Conclusions Sex may modify selected adiposity–physiology associations. Independent replication and longitudinal mechanistic studies are needed to clarify these findings. Current evidence supports using sex to refine phenotyping and research rather than determine treatment eligibility.