Sex May Modify Obesity-Related Heart Failure Physiology but Not Treatment Eligibility

A targeted narrative review of obesity-related heart failure with preserved ejection fraction indicates that while sex may modify selected associations between body fat and exercise physiology, current scientific evidence does not support using sex alone to determine patient treatment eligibility. Published in Biology of Sex Differences by researchers Hao Wang and Xiao-Ce Dai, the review synthesized literature through October 21, 2026, systematically distinguishing baseline sex contrasts, sex-by-adiposity interactions, treatment-by-sex heterogeneity, and sex-conditioned mediation. Heart failure with preserved ejection fraction can severely limit exercise tolerance even when the heart’s pumping percentage remains clinically preserved. Although women experience a higher absolute burden of the condition, the authors emphasize that higher prevalence does not by itself establish a stronger adiposity effect or justify sex-differentiated clinical treatment decisions.

In observational community-based cohorts, adiposity consistently associates with incident heart failure with preserved ejection fraction across both female and male populations, yet these prospective studies demonstrate no consistent formal sex interaction. Obesity is linked to a higher risk of heart failure with preserved ejection fraction and may contribute directly to its development, but excess body fat does not by itself establish a clinical diagnosis or explain why an individual patient developed the disorder. Furthermore, while the condition presents with a higher absolute burden in women, this epidemiological disparity does not indicate that adiposity exerts a stronger causal effect in female patients. Community investigations confirm that excess body weight anticipates future disease in both sexes without evidence of stronger association in either group.

When examining exercise hemodynamics, the review identified a preliminary interaction within a mixed sample comprising patients with heart failure with preserved ejection fraction and control participants. Specifically, computed tomography-derived visceral adipose tissue was more strongly associated with raw peak exercise pulmonary capillary wedge pressure in women than in men. In contrast, a separate waist interaction did not appear with raw exercise filling pressures and was confined exclusively to PCWL, calculated as peak pulmonary capillary wedge pressure divided by the ratio of peak workload to body weight. Crucially, the review highlights that these two interaction findings evaluated different hemodynamic endpoints, emerged from a single cohort lineage that shared thirty-nine overlapping participants, and lacked adjustment for multiplicity. Because independent confirmation was not identified in the scientific literature reviewed through October 21, 2026, mechanistic interpretations of these physiological interactions remain strictly limited.

The targeted review also scrutinized mechanistic physiological investigations addressing circulating blood volume and peripheral skeletal muscle performance, identifying no support for a generalized sex-specific causal pathway. Direct blood-volume measurements conducted in mixed heart-failure populations failed to support the concept of generalized female hypervolemia. In addition, an analysis of a small cohort of patients with heart failure with preserved ejection fraction revealed lower peak leg oxygen uptake per unit of thigh lean mass in female participants compared with male participants. That investigation, however, detected no statistically significant associations between thigh muscle or adipose tissue stores and oxygen uptake or its physiological determinants. Taken alongside inflammatory, cardiac, and vascular evidence, these observations provide descriptive physiological context but do not establish a definitive sex-specific mechanism in the progression of heart failure.

In clinical trials evaluating modern pharmacotherapies, including semaglutide and tirzepatide, sex-stratified analyses revealed differences in total weight loss but demonstrated no sex heterogeneity in main clinical benefits. In the STEP-HFpEF trial evaluating semaglutide, female participants achieved greater placebo-adjusted total body-weight reduction than male participants. However, STEP-HFpEF detected no significant treatment-by-sex interaction regarding health-status improvement. Similarly, the SUMMIT trial assessing tirzepatide did not detect sex heterogeneity for its primary composite clinical endpoint of cardiovascular death or worsening heart failure events. The review also notes an analytical discrepancy in SUMMIT, which reported different body-weight interaction P values between its primary Results text and Table 2. Crucially, the authors emphasize that undetected statistical interactions do not establish therapeutic equivalence between sexes, particularly given limited subgroup precision, and postrandomization associations between weight loss and clinical outcomes do not demonstrate causal mediation.

Synthesizing these lines of evidence, the authors conclude that sex should currently guide physiological measurement, clinical phenotyping, baseline risk stratification, and interaction-powered trial research, rather than determine patient treatment eligibility or justify selecting or withholding therapy. Clarifying whether sex genuinely modifies adiposity-physiology relationships will require independent replication of preliminary hemodynamic interaction findings alongside rigorous longitudinal mechanistic investigations. The review stresses that future prospective studies must track specific regional fat depots, menopausal status, and hormone use, while examining cardiac hemodynamics, skeletal muscle performance, and long-term health outcomes over extended observation periods.

Subject of Research: Sex differences in obesity-related heart failure with preserved ejection fraction

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

Article References: Wang, H., & Dai, X.-C. (2026). Sex as a context-dependent modifier in obesity-related heart failure with preserved ejection fraction: adiposity, exercise hemodynamics, and treatment response. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-01015-3

Image Credits: AI Generated

DOI: 10.1186/s13293-026-01015-3

Keywords: heart failure with preserved ejection fraction, HFpEF, sex differences, obesity, adiposity, exercise hemodynamics, STEP-HFpEF, SUMMIT trial, context-dependent, modifier, obesity-related, heart