Sex Differences in Peripheral Artery Disease

Abstract

Peripheral artery disease (PAD) is a prevalent condition that confers substantial morbidity and mortality and remains underdiagnosed as well as undertreated in the overall population. Although PAD prevalence is similar or higher in women compared with men, associations of traditional and nontraditional risk factors with PAD and clinical manifestations of PAD differ by sex and may contribute to delayed or lack of diagnosis in women. Such sex-based differences in the manifestation of PAD may arise from sexual dimorphism in the vascular substrate in health as well as sex variation in the responses to vascular stressors. Despite the availability of proven therapies for improving symptoms and reducing risk of ischemic cardiovascular and limb events among patients with diagnosed PAD, important sex differences in treatment and outcomes have been observed. We provide an overview of current knowledge regarding sex differences in the epidemiology, pathophysiology, clinical presentation, and management of PAD.

Keywords: adult; cardiovascular disease; incidence; prevalence; risk factor.

Figure 1.. Sex Differences in Responses to Vascular Stressors and Sequelae.

A conventional paradigm proposes that when the same arterial structural and functional substrate is exposed to stressors, sex differences in response to these stressors lead to variations in manifest peripheral vascular disease including the predominance of aortic aneurysm and dissection in men as well as the likely higher prevalence of classic atherosclerotic lower extremity disease in women that also tends to present more as multivessel disease in women compared to men. Emerging evidence suggests that intrinsic sex differences in the arterial substrate, arising from genetic or epigenetic factors, likely also contribute to sexual dimorphism in vascular disease phenotypes.

Figure 2.. Sex-Agnostic and Sex-Specific Risk Factors for Peripheral Arterial Disease.

A number of sex-agnostic risk factors for peripheral arterial disease have been identified, with smoking being among the most prominent and potentially contributing a more substantial burden of disease risk in women compared to men, based on analyses of tobacco metabolite associations. The excess burden and multivessel predominance of peripheral arterial disease in women may also arise from a sex-specific predisposition for endothelial dysfunction and, in turn, arterial dysfunction and disease in the setting of age-related estrogen deficiency occurring either with or without a preceding vascular disorder of pregnancy event.