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.

A Scientific Imperative as Seen Through a Sharpened Lens: Sex, Gender, and the Cardiovascular Condition

“…[6][7][8] In fact, certain apparently similar ischemic syndromes (eg, chest pain or leg claudication) can arise from relatively distinct pathophysiology in females compared to males. 6,8 This fact leads us to Circulation Research. 2022;130:433-435.…”

“…12,14 Another key theme is the paradoxical finding that when comparing females to males, traditional cardiometabolic risk factors contribute greater risk for the classic cardiovascular diseases but account for a smaller proportion of the total risk. 6,7,11,19 In effect, females are more sensitive than males to the effects of certain risk exposures; at the same time, there is evidence of substantial residual risk in females—contributed by either inadequately measured or yet unidentified key factors or both.…”

“…3,[5][6][7][8] Finally, and concerningly, is the consistent finding that available cardiovascular interventions are often not similarly effective in females compared with males, likely due to a combination of factors including sex differences in biological response, gender differences in patterns of prescribing or titrating therapies, and available therapies themselves being functionally inadequate or mismatched for the treatment of femalespecific cardiovascular conditions. [3][4][5][6]10,11 The scientific imperative is now ever clear. Notwithstanding foundational achievements to date, much of what we currently understand about cardiovascular risk in females stems from predominantly descriptive data on sex differences.…”

“…One persistent theme is how prevalent cardiac diseases with common features, including heart failure, arrhythmias, and valvular disorders, tend to present phenotypically differently in females compared with males 3–5 ; similarly, prevalent vascular diseases tend to manifest differently when involving each of the major coronary, cerebrovascular, and peripheral arterial vascular beds. 6–8 In fact, certain apparently similar ischemic syndromes (eg, chest pain or leg claudication) can arise from relatively distinct pathophysiology in females compared to males. 6,8 This fact leads us to recent guidelines 9 encouraging avoidance of the term ‘atypical’ to describe symptoms in females where the preferred adjective should perhaps more accurately be ‘understudied’.…”

“…6–8 In fact, certain apparently similar ischemic syndromes (eg, chest pain or leg claudication) can arise from relatively distinct pathophysiology in females compared to males. 6,8 This fact leads us to recent guidelines 9 encouraging avoidance of the term ‘atypical’ to describe symptoms in females where the preferred adjective should perhaps more accurately be ‘understudied’. Not surprisingly, a related theme is the persistent disparities experienced by females compared to males in rates of diagnosis, treatment, and control of conventionally defined cardiovascular conditions, attributable to many factors, including delayed or missed recognition.…”