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. 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. 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. A higher absolute burden of HFpEF in women does not by itself establish a stronger adiposity effect. Community cohorts found adiposity associated with incident HFpEF in both sexes without consistent formal sex interaction. The visceral-fat and waist interactions identified in this targeted review involved different exercise-pressure outcomes, arose from a single cohort lineage with 39 overlapping participants, and require independent replication. STEP-HFpEF and SUMMIT did not detect sex heterogeneity in principal clinical benefits. STEP detected greater total-weight reduction in women; SUMMIT reported different body-weight interaction P values in its Results text and Table 2. Sex should currently guide measurement, stratification, and interaction-powered research, not treatment eligibility. Heart failure with preserved ejection fraction (HFpEF) can limit exercise even when the heart’s pumping percentage is preserved. Obesity is linked to a higher risk of HFpEF and may contribute to the condition, but it does not by itself establish the diagnosis or explain why an individual patient developed it. HFpEF is more common in women. This does not automatically mean that body fat has a stronger effect or that treatment responses differ by sex. We reviewed relationships between body fat, organ function, and treatment response. Community studies linked obesity to future HFpEF in both sexes without clear evidence of a stronger association in either. One preliminary cohort finding linked abdominal visceral fat to higher exercise heart-filling pressure more strongly in women; independent confirmation was not identified in the literature reviewed through 21 October 2026. Semaglutide and tirzepatide trials did not detect clear sex differences in their main clinical benefits, although semaglutide produced greater weight loss in women. These findings do not prove equal treatment effects. Current evidence supports measuring sex carefully, but not using sex alone to select or withhold treatment. Better studies should follow specific fat stores, menopausal status and hormone use, heart and muscle function, and health outcomes over time.
Biological sex is a fundamental determinant of the pathogenesis and progression of cardiovascular disease (CVD). Despite extensive research on sex differences in human populations and whole-animal preclinical models, studies directly comparing male- and female-derived cells within defined cardiovascular cell types remain limited. Although human and in vivo studies have clearly highlighted the importance of sex differences, their complex systemic environments can make it difficult to disentangle cell-associated effects from the effects of circulating hormones and interactions among multiple cell types. Accordingly, this narrative review integrates evidence primarily from studies of isolated cardiovascular cells, supplemented where appropriate by relevant in vivo and clinical findings, to examine the reported contributions of hormonal signaling, sex chromosome complement, and related pathophysiological mechanisms. The reviewed studies report sex-associated cellular differences related to hormonal signaling and, in specific experimental models, sex chromosome complement. Across three major pathophysiological domains—oxidative stress, nitric oxide signaling, and inflammatory responses—the direction and magnitude of the reported differences vary according to cell type, tissue or vascular origin, species, and experimental conditions. Collectively, this review provides an integrated overview of reported sex-associated differences in cardiovascular cells and the hormonal, chromosomal, and pathophysiological factors that may contribute to them. The available evidence highlights the need for further direct male–female comparisons at the cellular level relevant to CVD, while complementary multicellular and in vivo approaches remain necessary to determine the relevance of cellular findings at the tissue and organ levels. Such studies may provide a stronger foundation for developing sex-informed precision therapies for CVD.
Endovascular thrombectomy (EVT) is the standard treatment for large vessel occlusion stroke, with stent retriever (SR) and contact aspiration (CA) as the predominant frontline techniques. Although sex-related differences in EVT outcomes are increasingly recognized, whether the comparative effectiveness of SR versus CA differs by sex remains unclear. This study evaluated sex-related heterogeneity in outcomes between frontline SR and CA using the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke (TREAT-AIS). TREAT-AIS is a multicenter prospective EVT registry. Patients with anterior circulation stroke who received frontline SR or CA alone were included; those treated with combined techniques were excluded. We assessed the EVT technique-by-sex interaction in the overall cohort and performed sex-stratified propensity score matching (PSM) to evaluate 3-month functional and safety outcomes. Of 1,752 patients, a significant technique-by-sex interaction was observed for independent functional outcome (modified Rankin Scale 0–2; P for interaction = 0.016): CA was associated with this outcome among female (adjusted odds ratio [aOR], 3.39; 95
Rigorous integration of sex and gender is essential to ensure equitable outcomes in psycho-oncological interventions. This study assessed the quality of sex and gender reporting in randomized controlled trials (RCTs) of psycho-oncology interventions using the Sex and Gender Equity in Research (SAGER) guidelines. A systematic review of RCTs of psycho-oncology interventions indexed in PubMed and published between 2020 and 2025 was conducted. Adherence to the SAGER guidelines was coded dichotomously at the item level and summarized using total scores. Item-level frequencies, analyses by tumor entity, and exploratory regression models were used to characterize reporting patterns and their correlates. Of the 404 trials included, more than half (55.2
Impaired placentation and placental dysfunction are drivers of early-onset preeclampsia (EOPE), yet our understanding of the molecular changes underlying the placental pathology is incomplete. DNA methylation (DNAme) is one tool that has been used to identify molecular patterns associated with EOPE; however previous studies have only examined EOPE-associated DNAme on the autosomes. This is the first study to identify sex chromosome associated EOPE DNAme. DNAme array data (450K and EPICv1 arrays) from 843 placentas (XX = 386, XY = 457) from public datasets were analysed. We identified X and Y chromosome DNAme differences between EOPE (n = 63) and non-preeclamptic preterm births (n = 71). We also identified sex chromosome DNAme associated with eoPRED score, a DNAme -based score of EOPE-associated placental pathology, using all samples (n = 843). Linear modelling for sex chromosomal DNAme was sex-stratified, and an interaction test was used to determine if significant results were sex-specific. We identified numerous sex-linked differentially methylated cytosines (DMCs) with EOPE in the individual datasets/array platforms and 15 high-confidence and high-effect associations that were present across array platforms. There were more X chromosome EOPE DMCs identified in XY than XX samples, yet most associations were not sex-specific after testing for an interaction with sex. We observed similar associations whether the clinical diagnosis of EOPE or eoPRED score were used; however, we identified more DMCs using eoPRED score. This is the first study to evaluate placental DNAme on the X and Y chromosomes in EOPE. We observe significant findings on the sex chromosomes including genes such as ACE2, MBLN3, and MIR503HG which may have relevance to the pathophysiology of EOPE. Impaired placental development and function is a feature of early-onset preeclampsia (EOPE), a severe pregnancy complication. We do not fully understand the molecular changes underlying EOPE; however, we know that DNA methylation, a chemical mark on DNA, can be measured to identify changes associated with EOPE. Typically, human cells have 22 pairs of autosomal chromosomes and one pair of sex chromosomes; females have two X chromosomes (XX) and males one X and one Y chromosome (XY). This is the first study to investigate and identify an association between EOPE and X and Y chromosome DNA methylation in the placenta. We used DNA methylation data from 843 placentas (XX = 386, XY = 457). We identified differences in X and Y chromosome DNA methylation associated with EOPE-pathology. Most differences in DNA methylation were observed in both males and females. Some of the associations were in genes which may have relevance to the pathophysiology of EOPE in the placenta. Our study highlights that there are important findings on the X and Y chromosomes that have been missed by their routine exclusion in previous studies. • This is the first study to identify EOPE associations on the sex chromosomes • Most X chromosome associations were not sex-specific, but were present in both sexes • X-chromosome inactivation may reduce the effect size of X chr DMCs in XX samples • DNA methylation at X-linked genes ACE2 and MBLN3 may be relevant to the pathophysiology of EOPE
