Sex as a Key Determinant of Peripheral Artery Disease: Epidemiology, Differential Outcomes, and Proposed Mechanisms

Atherosclerotic peripheral artery disease (PAD) is associated with functional limitations and an increased risk of poor cardiovascular outcomes. Although men are traditionally viewed at higher risk of PAD than women, the true prevalence and incidence is inconsistent among available reports. Some of this variability is due to differences in PAD related symptoms among women as well as sex-based differences in diagnostic tests, such as the ankle-brachial index, and it is critical for future epidemiologic studies to account for these differences. Generally, women with PAD experience greater functional impairment and decline then men and are less likely to receive guideline-directed medical therapy. In some settings, women are also more likely to present at later stages of disease and more often undergo lower limb amputation than men. Animal data exploring the biological underpinnings of these sex differences are limited, but several mechanisms have been postulated, including differential plaque morphology, alterations in the immune response, and hormonal variation and protection. Epidemiologic data suggest a link between inflammation and PAD and also reveal sex differences in lipid profiles associated with risk of PAD. In this review, we discuss available data on sex differences in PAD with additional focus on potential biological explanations for these differences. We also emphasize important knowledge gaps in this area, including under-representation of women in PAD clinical trials, to help guide future investigations and eliminate sex disparities in PAD.