Biological sex and gender have a great influence on health, disease presentation, and clinical outcomes. Historically, medical research and clinical practice have treated the male body as the standard, often viewing female physiology and symptoms as deviations, except in reproductive health. Women have been historically underrepresented in randomized controlled trials (RCTs), even for conditions disproportionately affecting them. This underrepresentation stems in part from historical events such as the thalidomide tragedy,¹ which prompted the exclusion of women of reproductive age from RCTs due to perceived risk.

Compounding this underrepresentation, the distinction between sex (biological attributes) and gender (socially constructed roles and behaviors) has frequently been overlooked. Gender exists on a spectrum and intersects race, age, disability, and socioeconomic status, all of which influence health outcomes. Neglecting these factors in cardiovascular (CV) research has contributed to persistent disparities in diagnosis, treatment, and outcomes. Despite similar lifetime CV disease prevalence, women remain underrepresented in RCTs.² A systematic review of CV trials from 2017-2023 reported that women comprised only 41% of participants overall, with particularly low representation in procedural trials and studies addressing arrhythmias or coronary heart disease.³ Enrollment of women in acute coronary syndrome (ACS) trials has stagnated at 25-28%, well below the 38% of patients with ACS who are women.³

Nevertheless, although vascular diseases remain among the leading causes of morbidity and mortality worldwide, women demonstrate distinct clinical patterns, including differences in symptom presentation, disease severity, and representation in RCTs, thereby limiting the generalizability and applicability of existing vascular research findings. Peripheral artery disease (PAD) exemplifies these disparities.^4,5 In PAD, women more frequently present with atypical or asymptomatic disease. Women with PAD tend to have more advanced disease, poorer functional status, and greater ambulatory limitations at comparable ankle-brachial index values.⁴ Moreover, outcome disparities are substantial: women experience higher rates of above-knee amputation, increased periprocedural mortality, and higher all-cause mortality following PAD.⁴ Management disparities in risk-factor modification, including suboptimal lipid control, underuse of antiplatelet therapy, and lower rates of revascularization, further exacerbate risk.⁶ The current guidelines highlight the persistent underrepresentation of women in contemporary PAD cohorts and randomized trials, despite a high prevalence among women >40 years of age.^4,5 This gap constrains the evidence base for sex-specific management strategies, emphasizing the urgent need for enhanced inclusion.

Atherosclerosis also demonstrates sex-specific patterns. Women generally experience delayed plaque initiation and slower progression, likely influenced by hormonal status, with plaques displaying fewer features associated with vulnerability and rupture. Carotid and coronary imaging studies, including integrated analyses of the ATHEROREMO-IVUS (European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis—Intravascular Ultrasound Study), IBIS-3 (Integrated Biomarker and Imaging Study-3), and PREDICTION (Prediction of Progression of Coronary Artery Disease and Clinical Outcome Using Vascular Profiling of Shear Stress and Wall Morphology) trial data, confirm sex differences in plaque morphology and coronary dimensions.^7,8

Venous thromboembolism (VTE) similarly illustrates the complexity of sex-related vascular risk. Hormonal exposure and pregnancy increase VTE risk in women, yet recurrence patterns differ. Meta-analyses suggest higher recurrence among men despite fewer provoking factors, indicating potential intrinsic susceptibility.⁹ Sex-specific biology underpins these observations. Estrogen confers vascular protection through anti-inflammatory, antioxidant, and endothelial-stabilizing mechanisms, attenuating atherosclerotic and aneurysmal progression. Declining estrogen levels post menopause may contribute to worse outcomes in women. Conversely, androgens are associated with adverse remodeling and aneurysm formation in experimental models. Genetic factors, including X-linked gene expression and escape from X inactivation, may also modulate extracellular matrix remodeling, inflammation, and vascular susceptibility.⁹ These findings support integrating sex into VTE risk stratification and developing sex-informed anticoagulation strategies.⁹

Aortic aneurysm (AA) disease further reflects sex differences arising from lifestyle, hormonal, anatomical, and genetic factors. Women are less likely to undergo surgical intervention for thoracic AA and face unique risks related to pregnancy.¹⁰ Epidemiologic studies highlight sex-based differences in disease progression, with estrogen-mediated vascular protection in premenopausal women and anatomical and physiological variations contributing to sexual dimorphism in prevalence and outcomes.¹⁰ Women are more likely than men to experience AA rupture at smaller diameters, with approximately 30% of ruptures occurring below 5.5 cm compared with 8% in men, and an overall threefold higher rupture risk at similar aneurysm sizes.^11-13 Consequently, lower repair thresholds (5 cm for women vs. 5.5 cm for men) have been recommended.¹¹ Women also tend to have smaller native aortic diameters and weaker aortic wall strength, making indexed measurements potentially more appropriate than absolute size.^12,13 Additionally, women have higher perioperative mortality after both endovascular and open AA repair, partly due to more challenging vascular anatomy, such as shorter and narrower aortic necks.¹³ Thus, these disparities further highlight the need for sex-specific aortic disease surveillance and treatment.

Advancing precision vascular care requires the systematic integration of sex and gender into research, guideline development, and clinical practice. Regulatory mandates for sex-disaggregated analyses represent critical progress, but meaningful change depends on consistent implementation. Recognizing sex and gender as core clinical variables is essential to improving diagnosis, optimizing therapy, and reducing persistent inequities. Addressing the unique biological, hormonal, and social factors contributing to vascular disease in women promises more effective, equitable prevention, diagnosis, and treatment strategies. Ultimately, advancing women's vascular health is not solely about equitable trial enrollment but about ensuring care is tailored to the realities of female physiology, risk, and lived experience.

References

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