2025 AHA科学声明：外周血管疾病的性别差异

AORTIC DISEASE

## Epidemiology, Risk Factors, and Screening

Aortopathy refers to a group of conditions that weaken the aortic wall, leading to aortic aneurysm (thoracic as cending, descending, and abdominal), aortic dissection, or both (in addition to other acute aortic syndromes: in tramural hematoma and penetrating aortic ulcer). Aor topathy can be a sporadic/degenerative, nonsyndromic heritable thoracic aortic disease or familial disease, in cluding Marfan syndrome or Loeys-Dietz syndrome. The estimated composite death rate of aortopathies globally has increased from 2.49 per 100000 in 1990 to 2.78 per 100000 in 2010. 5

Within the spectrum of aortopathies, sex-based dif ferences exist along the care-axis continuum from prediagnosis screening through postintervention out comes. 6 Women have a lower incidence of aortopathies in general but a higher risk of rupture than men for all pathologies (Table1).

Women affected by aortopathy tend to be diagnosed at a significantly older age and to have a greater like lihood of presenting with more severe or symptomatic disease compared with men (Table1). 33 Aortic disease screening is recommended only for abdominal aortic aneurysms (AAAs) on the basis of disease incidence and prevalence. Thus, sex differences exist in formal screen ing guidelines with some variation in recommendations, depending on the recommending society. The Ameri can College of Cardiology/American Heart Association guidelines recommend AAA screening for men ${\tt\ge}65$ years of age with a history of smoking but list screening as reasonable in women ${\tt\ge}65$ years of age with a history of smoking. 13 Screening is recommended in both men and women ${\tt\ge}65$ years of age who have first-degree rela tives with AAA. The Society for Vascular Surgery guide lines recommend AAA screening in men or women 65 to 75 years of age with a history of tobacco use and sug gest screening in men or women ${\geq}65$ years of age who have first-degree relatives with AAA. 14 The US Preventive Services Task Force does not make a recommendation for or against AAA screening in women 65 to 75 years of age with a history of smoking or a family history of AAA, citing insufficient evidence to assess benefit versus harm of screening. 34 Medicare policy currently offers a 1-time AAA screening duplex ultrasound examination for women beneficiaries with a family history of AAA. 35 The lack of comprehensive, evidence-based screening guide lines for women is influenced by the low prevalence of disease and underrepresentation in scientific trials. This may contribute to their more severe and delayed presen tation state at the time of diagnosis.

The risk factors for the development of aortopathy are similar between men and women and include smoking, hypertension, age, CVD, and family history. 36 There is a higher risk of AAA development in women who had a relative with an AAA compared with men with a relative with an AAA. Furthermore, the prevalence of AAAs was higher in relatives of women patients with a diagnosis of an AAA compared with the relatives of men with a diagnosis of an AAA. 37 For syndromic aortopathies such as Marfan syndrome (autosomal dominant, caused by a mutation in FBN1 ), men are more likely than women to have aortic root dilation, aortic regurgitation, and thoracic aortic aneurysms, whereas mitral valve prolapse, arach nodactyly, and scoliosis are more common in women. 38 Sex differences exist in dilatation severity (more severe in men), but there is no difference in progression rates by age or sex. 39 In Loeys-Dietz syndrome (autosomal domi nant, caused by a mutation in SMAD2 , SMAD3 , TGFB2 , TGFB3 , TGFBR1 , or TGFBR2 ), there is evidence of sex differences in outcomes based on mutation. For TGFBR1 mutations, $90\%$ of men had an aortic event by 60 years of age compared with $50\%$ of women, and the propor tion of men presenting with aortic dissection was higher than in women. 40 No sex differences exist in outcomes in patients with TGFBR2 or in clinical presentation, screen ing, or treatment recommendations. However, counseling and aortic imaging are recommended before pregnancy in patients with syndromic aortopathy, nonsyndromic her itable thoracic aortic disease, Turner syndrome, bicuspid aortic valve with aortic dilation, or another aortopathy.

The presentation of aortic pathology in women at more advanced ages is likely multifactorial but due in part to growing evidence of the protective effect of estrogen hormones on AAA formation and growth. 41 The biochemical pathway is affected by modulation of matrix metalloproteinase activity, downregulation of cytokines, immune cell migration, and other immune mediators at key points in the pathophysiological process in AAA development. 42 Moreover, larger AAAs in women have been associated with earlier onset of menopause, further supporting the protective effect of estrogen exposure on aneurysmal progression. 41 Biomechanical studies have revealed decreased uniaxial tensile strength in female aortas compared with male aortas, which may contrib ute to the increased rupture risk observed in women. 43 It is unclear whether the growth rate of aortic aneu rysms differs according to sex; limited evidence exists, and available data are conflicting. What remains clear is that women have a significantly higher risk of rupture; in the UK Small Aneurysm Trial, women were 3 times as likely to rupture as men at equivalent sizes. Further more, women experience rupture at smaller sizes, and up to $30\%$ occur at diameters ${\tt<}5.5$ cm compared with $8\%$ in men at the same size threshold. 44 Given the differ ences in normal aortic size, being 2 to $6\ \mathsf{m m}$ smaller in women, it has been postulated that aortic size index or

Table 1. Aortic Disease: Sex-Specific Epidemiology, Risk Factors, and Clinical Outcomes

||Epidemiology|Sex-specific differences| Clinical outcomes| |---|---|---|---| |TAA|TAA and dissection combined?||| ||Women 9.1 per 100000 per y| Aortic root reconstruction (root replacement, Ross, or valve-sparing root operations; P ||

Table 1. Continued

||Epidemiology| Sex-specific differences|Clinical outcomes| |---|---|---|---| |AAA|174/100000 per y in women| Rupture risk (Sweden Malmo28):|After open repair for| ||354/100000 pery in men24,25|5.6/100000 person-y| intact and ruptured AAA,| |||Women 3/100000|women have a higher| ||Women present 5-10 y older than |Men 8.4/100000|mortality rate.26| ||men26.27|Growthrate|Elective EVAR was| |||Women 2.0-3.5 mmly|used more commonly| |||Men 1.6-2.4 mm/y29-31|for men compared with| |||Repair criteria or threshold|women (82.1% vs 74.1%;| |||Women 5.0 cm|P=0.01).32| |||Men 5.5 cm| EVAR: women have a| ||| Both sexes: symptomatic or rapid growth|higher access arterial| ||||injury rate, more frequent| |||3.0-3.9 cm: every 3 y|returns to operating room,| |||Women 4.0-4.4 cm: annually|longer ICU stays, and| |||Men 4.0-4.9 cm: annually|longer hospital LOS.| |||Women ≥4.5 cm: every 6 mo|Open: women have high-| |||Men ≥5.0 cm: every 6 mo|er intraoperative morbidity| |||| and longer ICU stays.26|

AAA indicates abdominal aortic aneurysm; EVAR, endovascular aortic aneurysm repair; ICU, intensive care unit; IMH, intramural hematoma; LOS, length of stay; PAU, penetrating aortic ulcer; TAA, thoracic aortic aorta; TBAD, type B aortic dissection; and TEVAR, thoracic endovascular aortic aneurysm repair.

aortic height index be used to index for these body size differences instead of using aortic diameters for repair thresholds. 45–50

Treatment Choices and Outcomes

The natural history and outcomes after treatment for aortopathies tend to yield less favorable results in wom en compared with men. 51 Unfortunately, this is not con fined to distinct locations of the aorta or the means of intervention. Treatment threshold and criteria for repair for the 3 broad categories of aortopathies and their sub groups are outlined in Table1. There are sex-specific treatment thresholds only for AAA (5.5 cm for men, 5.0 cm for women) as shown by large population-based studies, but women have been underrepresented in ran domized controlled trials (RCTs; ${<}4\%$ for small aneu rysm trials); thus, the recommendations are based on weak evidence.

In women, repair of aortopathies also becomes impor tant in the context of pregnancy. Women with Marfan or Loeys-Dietz syndrome are at high risk for arterial dis section and uterine rupture during pregnancy and the postpartum period. 52 This is hypothesized to be related to the hyperdynamic state and effect of sex hormones on the vasculature. 53 Surgery before pregnancy is rec ommended in patients with Marfan syndrome or non syndromic heritable thoracic aortic disease for aortic diameters ${\tt>}4.5$ cm, bicuspid aortic valve and sporadic aortic diameter ${\tt>}5.0$ cm, and Turner syndrome and aor tic size index ${\geq}2.5\subset\!\mathsf{m}/\mathsf{m}^{2}.$ . 13 Surgery before pregnancy is reasonable in patients with Loeys-Dietz syndrome with TGFB2 or TGFB3 and aortic diameter ${\tt\ge}4.5$ cm. 13 A mul tidisciplinary team–based approach with a maternal-fetal medicine specialist and cardiologist is recommended.

Surveillance imaging (transthoracic echocardiography or magnetic resonance imaging) is recommended during each trimester and for several weeks postpartum. Deliv ery by cesarean section is recommended in patients with chronic aortic dissection and is reasonable in patients with aortic root or ascending aorta aneurysm diameter ${\ge}4.5$ cm; if otherwise appropriate, vaginal delivery is rec ommended in patients with aortopathy and aortic diam eter ${<\!4.0}$ cm. 13

Endovascular thoracic and AAA repair (thoracic endo vascular aortic aneurysm repair/endovascular aortic aneurysm repair) is the most common modality currently used for aortic aneurysmal disease repair. Women are more likely to undergo open surgery for an elective AAA repair compared with men. 32 This imbalance in the use of endovascular repair in women is heavily influenced by anatomical features more commonly found in women that disqualify them on the basis of the instructionsfor-use criteria for endovascular aortic aneurysm repair devices (ie, vessel size, inadequate proximal neck). 54

The Canadian Thoracic Aortic Collaborative performed an analysis that revealed that despite comparable rates of aortic arch repair between the sexes, women were sig nificantly less likely to receive an aortic root reconstruc tion compared with men. 12 Furthermore, they identified that the mortality and stroke rate in women after tho racic aortic surgery with hypothermic circulatory arrest was significantly higher than in their male counterparts. This is significant because higher morbidity and mortal ity rates have consistently been reported in women after open AAA surgery as well. 55

Aortic dissections confer significant morbidity and mortality risk to all patients affected by this disease process. A large retrospective analysis of patients with type B dissections demonstrated that women were more

frequently managed medically compared with men, but the adjusted, propensity-weighted regression demon strated no significant effects on in-hospital mortality according to sex. 23 Women are less likely to present with complicated type B aortic dissection (malperfusion or rupture) but more likely to present with high-risk features (refractory hypertension and pain). 22,56,57 The results after endovascular treatment of aortic dissection have varied, and further inquiry is needed. With regard to thoracic endovascular aortic aneurysm repairs, women have been found to have higher mortality rates at 30 days and 1 year after repair. 15

Other adverse postoperative outcomes have been dis proportionately reported in women. 58 For example, higher type II endoleak rates have been described after thoracic endovascular aortic aneurysm repair for complicated type B dissections, as well as higher overall endoleak rates after endovascular aortic aneurysm repair. 59 An increasing body of literature highlights the importance of frailty and its influence on postoperative outcomes and quality of life. A retrospective analysis of patients with thoracoabdominal aortic aneurysm found that women had significantly higher frailty metrics compared with their male counterparts at the time of diagnosis and, as a result, are less likely to be offered intervention/surgery. 60 Sex differences have been identified in other outcomes, including length of stay, discharge, and readmission after aortic intervention. A large analysis of patients from the American College of Surgeons National Surgical Quality Improvement Program database who underwent aortic aneurysm (AAA, thoracic aortic aneurysm, and thora coabdominal aortic aneurysm) surgery illustrated that women had a higher unplanned readmission rate after aortic aneurysm surgery and were twice as likely to be discharged to a care facility instead of their home. 61

Underrepresentation Within Trials/Potential Sources and Solutions for Disparities

Women were significantly underrepresented in many of the seminal RCTs comparing endovascular with open repair of AAAs and in industry-sponsored trials test ing new devices; the participation-to-prevalence ratio is consistently ${<\!0.8.^{62-65}}$ Thus, the conclusions drawn from these studies may offer limited applicability to the fe male population and may explain the poor performance of endovascular devices in women. Although women make up the minority of patients affected by aortic an eurysm and dissection, they present with more severe and complicated disease and have worse natural his tory and postprocedural outcomes compared with men. RCTs centered on defining sex-specific thresholds for repair of aortopathies are needed in women such as the planned multinational WARRIORS trial (Women’s Abdominal Aortic Aneurysm Research: Repair Im mediately or Routine Surveillance). 66 Moving forward,

given the sex-based disparities within CVDs, women need to be meaningfully represented in research tri als (participation-to-prevalence ratio goal, 0.8–1.2) and specific primary or secondary analyses powered to answer sex-specific research questions to ensure that the disparity gap is closed. Ongoing study of access to care, early diagnosis/detection, preventive interventions, and equitable inclusion in trials is required to address this sex-based disparity in medicine and to optimize the course of care for women affected by this pathology. 6 Table1 summarizes sex-specific epidemiology, risk fac tors, and clinical outcomes for aortic disease.

PERIPHERAL ANEURYSMS AND DISSECTING ARTERIOPATHIES

Peripheral aneurysms and dissecting arteriopathies com prise a wide range of familial and acquired systemic and localized vascular conditions, including fibromuscular dysplasia (FMD), vascular Ehlers-Danlos syndrome, vis ceral and peripheral aneurysms, and cervical and visceral artery dissections. A summary of each of the conditions and the known epidemiology, risk factors, sex-specific differences, and current research are summarized in Table2.

Previous studies have demonstrated a female pre dominance of FMD (between 5:1 and 9:1) and vascu lar Ehlers-Danlos syndrome (7:3). 68,69,81 Among patients with FMD, the female predominance is most apparent for the multifocal type of FMD, with more balanced sex distribution for the focal type of FMD, which has been postulated to be a distinct disease process. 81,82 Popliteal artery aneurysms and visceral dissections, however, are significantly more common in men, with a male:female prevalence of 20:1 and 7:3, respectively. A female predominance for splenic artery aneurysms has been reported. 83

Despite sex differences in the prevalence of these conditions, no sex-specific risk factors have been con sistently identified. In cervical artery dissections, previous work has consistently demonstrated a slight male pre dominance $(\approx\!57\%$ male); however, it has been hypothe sized that this may be more a result of sex differences in risk factors (eg, smoking, cervical trauma resulting from heavy lifting) than underlying hormonal or genetic differ ences. 79 Women who are diagnosed with cervical artery dissection tend to be younger (mean age, 41.0 years) than their male counterparts (46.4 years). 79

Popliteal artery aneurysms are common in men with AAA and screening-detected aortic dilatation. 84 Some differences in outcomes by sex have been reported. For example, among patients with FMD, although male patients represent a minority of those diagnosed, they have 2-fold rates of aneurysm and dissection compared with women. 85 In vascular Ehlers-Danlos syndrome, the life expectancy for men is lower than for women (46 and

Table 2. Peripheral Aneurysms and Dissecting Arteriopathies: Sex-Specific Epidemiology, Risk Factors, and Clinical Outcomes

||Epidemiology|Risk factors| Sex-specific differences| Representation of women in research | |---|---|---|---|---| |FMD|| Known associations:|Screening:|Clinical trials:| |FMD|Mean age of diagnosis 46-53 y67|Female sex| Screening for renal FMD recommended in |None identified| |FMD|| Mechanical trauma due to increased kidney mobility7o |women with hypertension 20-50 y of age|| |FMD| No racial or ethnic propensity but more common in White individuals than Black individuals68 || and in all ages/sexes in cases of severe or resistant hypertension68 || |FMD|| Age (highest prevalence among women in 70-79 y age | Clinical presentation:|| |FMD|Sex:| group; among men in ≥80 y age group)68 | No known difference| FMD Registry and Initiative, | |||Genetic susceptibility71||North American| || female:male)68.69 Female predominance more pro- || Treatment: No known difference |Registry for FMD| || Female predominance more pro- nounced among patients with multi- focal vs focal type of FMD |Unknown, although potential|Outcomes:|| || Female predominance more pro- nounced among patients with multi- focal vs focal type of FMD | influence of sex hormones has been suggested53 ||| || Female predominance more pro- nounced among patients with multi- focal vs focal type of FMD || Women less likely to have aortic and renal dissection (OR, 0.52 and 0.26, respec- tively) || || Female predominance more pro- nounced among patients with multi- focal vs focal type of FMD ||Women more likely to have vertebral and|| |||| coronary artery dissection (OR, 1.90 and 8.55, respectively) || |||| Intracranial and renal artery aneurysm more common in women || |vEDS| Age: Mean age at diagnosis 28 y52 | Known associations: Autosomal dominant, caused | Screening:|| |vEDS||by pathological variant in|No known difference|| |vEDS| Race and ethnicity: All racial and ethnic groups | COL3A1, leads to decreased type Ill collagen | Clinical presentation: No known difference | Comparison of celiprolol with placebo in vEDS (DiSCOVER, NCT05432466) | |vEDS||||| |vEDS| Sex: Female predominance (7:3 female:male) | Sex-specific risk factors: None identified | Treatment: No known difference || |vEDS||||| |vEDS|Accounts for ||||

Table 2. Continued

||Epidemiology|Risk factors| Sex-specific differences| Representation of women in research | |---|---|---|---|---| | peripheral aneurysms | Age： Median age 59 y77 |Known associations:| Screening: No known difference |Clinical trials:| | peripheral aneurysms || Increasing age, hypertension, smoking, EDS, FMD77 || None identified| | peripheral aneurysms | Race and ethnicity: All racial and ethnic groups | Sex-specific risk factors:| Clinical presentation: No known difference |Registries:| | peripheral aneurysms ||Increased risk of rupture during|| EmboCoh Visceral | | peripheral aneurysms || pregnancy and postnatal period78 | Treatment: No known difference | Aneurysm Registry | | peripheral aneurysms | All racial and ethnic groups Sex: Location related to sex; overall, most common site is splenic artery (60%), next is hepatic artery (~200%)77 Common iliac artery (28.7%o vs 8.9%), internal iliac artery (6.6% vs 1.3%), and popliteal artery (11.1% vs 2.5%)more common in men compared with women74 Splenic artery (0.9% vs 5.1%) and renal artery (0.8% vs 6.0%) more common in women compared with men74 || Outcomes: No known difference || | peripheral aneurysms ||||| | peripheral aneurysms ||||| | peripheral aneurysms | common in women compared with men74 No sex difference in visceral artery/ renal artery aneurysm in 1 cohor78 |||| |||||| |||||| |Cervical|Age at diagnosis:| Known associations:| Screening:|Clinical trials:| |artery|Women 41.0 y| Smoking, hypercholesterol-|No known difference|| ||Men 46.4 y79|emia, diabetes, hypertension,|| Risk of recur- rence of cervical | |dissection| Race and ethnicity: All racial and ethnic groups | cervical trauma (heavy lifting.|Clinical presentation:|artery dissection| |dissection||chiropractic manipulation)79| No known difference Men more likely to have hypertension, |during preg-| ||| Sex-specific risk factors: None identified | women more likely to have migraine and pulsatile tinnitus80 |nancy/puerperium| || Slight male predominance (||||

AAA indicates abdominal aortic aneurysm; CAD, coronary artery disease; EDS, Ehlers-Danlos syndrome; FMD, fibromuscular dysplasia; OR, odds ratio; PAA, popliteal aneurysm; and vEDS, vascular Ehlers Danlos Syndrome.

54 years, respectively). 72,73 Patterns of dissection also vary by sex. 68,76 Additional research is needed to under stand the physiological mechanisms for these differ ences in presentation and outcomes.

Few clinical trials are currently targeting these condi tions, and the male:female distribution tends to reflect the population, with limited racial and ethnic diversity. The DiSCOVER trial (Clinical Trial to Compare the Efficacy of Celiprolol to Placebo in Patients With Vascular EhlersDanlos Syndrome; NCT05432466) compares celiprolol with placebo in vascular Ehlers-Danlos syndrome. Preclini cal work in murine models of Marfan syndrome has shown promise in slowing aortic root dilatation, but clinical trans lation has been challenging. 86 Numerous registries, how ever, are enrolling participants to better understand the pathogenesis, treatment, and outcomes of patients with these rare vascular diseases. Ongoing registries targeting these arteriopathies include the North American Registry for FMD; European/International FMD Registry and Ini tiative; Registry of Vascular Ehlers-Danlos; and National Heart, Lung, and Blood Institute GenTAC Registry. 38,87 These registries, which enable clinicians and researchers

to identify larger populations of patients with these con ditions, are critical to identifying and implementing effec tive screening given clinical characteristics and reducing the risk of aneurysm and dissection, which are common outcomes of these conditions. Additional work is needed to understand sex-specific risk factors that explain the female predominance of many arteriopathies, as well as additional guidelines for screening and management.

PERIPHERAL ARTERY DISEASE

Epidemiology

Prevalence of Peripheral Artery Disease in Women

Lower-extremity peripheral artery disease (PAD) affects ${\approx}8.5$ million people in the United States and 230 mil lion people worldwide. 88,89 When an ankle-brachial index (ABI) ${<\!0.90}$ is used to define PAD, the prevalence is sim ilar in men and women. 88–91 In the CHS (Cardiovascular Health Study), a population-based study of people ${\tt\ge}65$ years of age in the United States, PAD prevalence was $13.8\%$ in men and $1\uparrow1.4\%$ in women $(P{=}0.49)$ ). Men with

PAD had higher prevalences of other coexistent CVDs than women with PAD $\langle56\%$ versus $40\%;$ ${\cal P}{<}0.001$ ). 90 In MESA (Multi-Ethnic Study of Atherosclerosis), a population-based study of people without clinically evi dent CVD at baseline, the prevalence of ABI ${<\!0.90}$ was $3.7\%$ in women and $3.7\%$ in men. 91

Among 3174 participants in the observational longi tudinal CRIC (Chronic Renal Insufficiency Cohort) with mild to moderate chronic kidney disease followed up for a median of 5.9 years, the incidence of new PAD during follow-up was $21.7\%$ in women compared with $12.6\%$ in men. 92 This finding differed meaningfully from the CHS, which reported PAD incidence rates of $9.2\%$ in 1389 women and $9.0\%$ in 2289 men during a 6-year follow-up. CRIC results also differed from those of the ARIC lon gitudinal study (Atherosclerosis Risk in Communities), in which the incidence of PAD was $\approx\!14\%$ in 759 men and $\approx\!14\%$ in 892 women over 10 years of follow-up. Reasons for the higher incidence of PAD among women compared with men in the CRIC study are unclear but may be due to intrinsic differences in ABI measurement between men and women (described later) and to the fact that men may be more susceptible to medial arterial calcinosis than women, which is common in chronic kidney disease. 93

In MESA, the prevalence of ABI 0.90 to 0.99, con sistent with mild PAD, was more than twice as high in women compared with men ( $10.3\%$ versus $4.0\%$ ; ${\cal P}{<}0.001$ ), and the prevalence of ABI 1.00 to 1.09, just below the normal ABI range of 1.10 to 1.40, was signifi cantly higher in women $735.5\%$ versus 21.1%; $_{P<0.01}$ ). 91 These data suggest that ABI values may be intrinsically lower in women compared with men even in the absence of PAD. Consistent with this, in the MESA cohort with out any CVD or risk factors, the ABI in women was 0.02 lower than in men. 94 This phenomenon should not affect PAD diagnosis in individual patients but could result in an overestimation of the prevalence of mild PAD in women in large population studies. 95

Race, Female Sex, and PAD

The prevalence of PAD is higher among Black women compared with White women. 89–91,95 In a Markov chain Monte Carlo analysis, the estimated lifetime risk of PAD was $27.6\%$ in Black women and $19\%$ in White women. 96 In a study from the late 20th century that combined data from 7 community-based studies, the prevalence of PAD was approximately twice as high in Black women and American Indian women compared with White women. 88 However, data on the prevalence of PAD in American Indian women are limited.

Risk Factors for PAD

Risk factors for PAD include cigarette smoking, diabe tes, hypertension, dyslipidemia, and inflammation. 95,97,98 People with PAD have lower socioeconomic status and lower education levels than people without PAD; data on the association of air pollution with PAD have been

mixed. 99–102 In a systematic review, compared with not currently smoking cigarettes, current cigarette smoking was more strongly associated with PAD among women than among men. 103 There were no significant sex dif ferences in the risk of former versus never smoking or the risk of current versus never smoking in women com pared with men. 103 In the UK Biobank study $(94\%$ White) of 500207 people $(54.5\%$ women), smoking was more strongly associated with risk of hospitalization for PAD among women compared with men. 104 However, it is un clear whether these associations apply to more diverse populations or to other outcomes in people with PAD who are not hospitalized for PAD. In a population-based study from Sweden, men with PAD were significantly more likely to have a history of cigarette smoking than women with PAD. 105 Two epidemiological studies reported that low alcohol intake was associated with a lower preva lence of PAD in men but not in women. 95 However, in a study from Edinburgh, this sex difference was no longer observed after adjustment for social class. Overall, data on sex differences in associations of alcohol with PAD are mixed. 95 Table3 summarizes sex-specific epidemiol ogy, risk factors, and clinical outcomes for PAD.

Sex Differences in PAD Symptoms

Intermittent claudication, consisting of exertional calf pain that does not begin at rest and that resolves within 10 minutes of rest, is the most classic symptom of PAD. 124 However, most people with PAD do not report classic intermittent claudication symptoms, and many report no exertional leg symptoms (ie, are asymptomatic). 107 Among people with PAD, rates of atypical leg symp toms and asymptomatic PAD are higher in women than men. 105,108,125,126 In the WALCS study (Walking and Leg Circulation Study) of 460 patients with PAD, women had a higher prevalence of spinal stenosis, peripheral neurop athy, and knee arthritis than men, and these comorbidities were associated with a higher prevalence of atypical leg symptoms. 108 The higher prevalence of atypical leg symp toms and asymptomatic PAD in women compared with men, perhaps due to a higher prevalence of comorbidities that contribute to atypical leg symptoms or lower physi cal activity in women, respectively, could result in higher rates of underdiagnosis of PAD in women than men. A study of Australian primary care practices performed ABI testing in 2489 patients $34.7\%$ women) without a prior diagnosis of PAD who had established CVD or multiple CVD risk factors. 127 Rates of previously undiagnosed PAD were $31.8\%$ in women and $25.7\%$ in men. 127

Functional Impairment, Functional Decline, and Quality of Life in Women With PAD

In people without PAD, men have larger muscles, greater strength, and faster walking speeds than women. 110,128

Table 3. Sex-Specific Differences in Prevalence, Characteristics, Outcomes, and Treatment of PAD

||What is known|Sex-specific differences|Additional considerations| |---|---|---|---| | Epidemiology| The prevalence of PAD is ≈10%-15% in epidemiological studies of people ≥65 y of age. In clinical settings, 20%-30% of people ≥65 y of age and 50-64 y of age with a history of diabetes or smok- ing have PAD.106 Older age, cigarette smoking, diabe- tes, hypertension, dyslipidemia, Black race, high levels of inflammation, and chronic kidney disease are associated with higher rates of PAD.106 | In the CHS of community-dwelling men and women ≥65 y of age, the prevalence of ABI ||

Table 3. Continued

||What is known|Sex-specific differences|Additional considerations| |---|---|---|---| |Lower-extremity| Lower-extremity revascularization is recommended by guidelines to ||| |revascularization| is recommended by guidelines to improve walking performance and quality of life in patients with disabling ischemic leg symptoms who do not respond to guideline-recommended | Compared with men, women undergo lower- extremity revascularization at an older age and more commonly for CLTI than for claudication | Women have smaller arteries than men, which could affect response to revascularization procedures. Future studies of endovascular devices for lower-extremity revascularization should include sufficient proportions of women and study sex differences in outcomes. | |revascularization||In some studies of lower-extremity revasculariza-| Women have smaller arteries than men, which could affect response to revascularization procedures. Future studies of endovascular devices for lower-extremity revascularization should include sufficient proportions of women and study sex differences in outcomes. | |revascularization||tion, men were more likely to be treated with surgi-| Women have smaller arteries than men, which could affect response to revascularization procedures. Future studies of endovascular devices for lower-extremity revascularization should include sufficient proportions of women and study sex differences in outcomes. | |revascularization| quality of life in patients with disabling ischemic leg symptoms who do not respond to guideline-recommended medical therapy or exercise.111 Lower-extremity revascularization is recommended by guidelines to pre- vent imb loss in patients with CLT11 |cal intervention, whereas women were more likely|| |revascularization||tobe treated with endovascular procedures.11.17|| |revascularization||Data are mixed on sex differences in lower-|| ||||| ||| In 1 study from the VQl registry (N=7332, ≈45% female), there were no sex differences in rates of || |||reintervention or major adverse limb events after|| ||| endovascular treatment for claudication. However, among 8100 individuals (45% female) undergo- || ||| among 8100 individuals (45% female) undergo- ing endovascular treatment for CLTI, women had || ||| lower mortality and lower amputation rates com- pared with men.122 || ||| In a meta-analysis of 40 studies, after lower- extremity revascularization,women had higher || ||||| ||| mortality, amputation, early graft thrombosis, and other adverse outcomes at 30-d follow-up. However, after 30 d of follow-up, there were no ||

ABI indicates ankle-brachial index; ACE, angiotensin-converting enzyme; CHS, Cardiovascular Health Study; CLTI, chronic limb-threatening ischemia; CMS, Centers for Medicare & Medicaid Services; MESA, Multi-Ethnic Study of Atherosclerosis; PAD, peripheral artery disease; and VQI, Vascular Quality Initiative.

Similarly, among people with PAD, women have less leg strength, smaller calf muscle area, slower walking speed, and shorter 6-minute walk than men. 109,126 In the WALCS cohort of 460 people with PAD, sex differences in the distance achieved during the 6-minute walk test were attenuated but remained statistically significant after adjustment for sex differences in strength. 108 In WALCS participants with PAD followed up for 47 months, com pared with men, women had significantly higher rates of becoming unable to walk for 6 minutes without stopping, greater declines in walking velocity, and greater declines in 6-minute walk distance and were more likely to report becoming newly unable to walk up and down a flight of stairs or walk one-quarter of a mile without assistance. 109 These sex differences were no longer statistically signifi cant after adjustment for sex differences in calf muscle area. 109 Sex differences in cardiopulmonary fitness and calf muscle hemoglobin oxygen saturation have also been documented in people with PAD. 129,130

Sex Differences in PAD Treatment

In both men and women, PAD is associated with signifi cantly increased rates of all-cause mortality and cardio vascular events compared with people without PAD. 131 In both men and women, compared with a reference (normal) ABI value of 1.1 to 1.20, lower ABI values are associated significantly with higher rates of all-cause mortality, cardiovascular mortality, and major coronary events. 131 To prevent cardiovascular events, all people

with PAD should be treated with high-intensity statin therapy, with the goal of attaining at least a $50\%$ re duction in low-density lipoprotein cholesterol, and with guideline-recommended antiplatelet or antithrombotic drugs. 111 However, guideline-recommended therapies are underused in both men and women with PAD. 132,133 In a systematic review of sex differences in the manage ment of atherosclerotic CVD, multiple but not all studies from the United States, Europe, and the United Kingdom reported that women with PAD were less likely than men with PAD to receive statin medications, antiplate let drugs, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker medications. 118,134–137 Some studies reported lower adherence rates to statin or antiplatelet therapy in women compared with men. 137 In 1 study, women were less likely than men to be pre scribed a statin after lower-extremity revascularization but were more likely than men to report that a clinician recommended a statin. 118 The Women’s Health Initiative showed no statistically significant effects of estrogen plus progesterone or estrogen alone on the incidence of PAD. 138,139

Sex Differences in Exercise Therapy and PAD

Supervised and structured home-based exercise are first-line therapies for PAD-related walking disability. 111 Supervised exercise is covered by the Centers for Medi care & Medicaid Services and typically consists of walking exercise 3 times weekly at a center in the presence of an exercise physiologist or nurse. 106 Structured home-based

walking exercise also significantly improves walking im pairment in PAD and is recommended by American Heart Association/American College of Cardiology guidelines as first-line therapy for PAD. 106,140 According to statistical tests for interaction, effects of supervised and structured home-based exercise have not differed significantly be tween men and women. 112,113,141 For example, in an in dividual participant-level meta-analysis of 309 patients with PAD, 132 $(42.7\%)$ were female, and the effects of supervised treadmill exercise did not significantly differ between women and men. 112 Similarly, in a randomized clinical trial of 194 participants with PAD ( $50\%$ wom en), the effects of a structured home-based walking exercise program significantly improved 6-minute walk distance by 53 m, and results did not differ significantly between men and women. 113 However, among patients with symptomatic PAD and Medicare insurance, women were significantly less likely than men to be enrolled in supervised exercise. 142 Reasons for this sex difference were not reported. 142 In 2 clinical trials, adherence to su pervised exercise sessions was similar between men and women. 141,143

Female Sex and Lower-Extremity Revascularization

Compared with men, women undergo lower-extremity revascularization at an older age and more commonly undergo revascularization for chronic limb-threatening ischemia than for intermittent claudication. 115–118 In some studies of lower-extremity revascularization, women were more likely than men to be treated with endovascular procedures, whereas men were more likely to be treated with open surgery. 115,144 In a study of 58247 patients $(4\,1\,\%$ women) who underwent endovascular revascular ization of 106073 arteries, there were no sex differences in rates of iliac artery stenting compared with percuta neous transluminal angioplasty alone. However, women were significantly less likely than men to receive stenting of the femoropopliteal arteries and more likely to receive angioplasty alone. 116 Women were significantly more likely to undergo reintervention in the femoropopliteal arteries (hazard ratio, 1.28) and more likely to develop occlusions in the iliac (hazard ratio, 1.42) or femoropopliteal (hazard ratio, 1.19) arteries than men. 116 Other studies showed no sex differences in patency or showed improved lowerextremity outcomes after lower-extremity revasculariza tion in women compared with men. 119,120 Among 7332 patients $(\approx\!47\%$ female) in the Vascular Quality Initiative registry undergoing endovascular treatment for claudica tion between 2010 and 2015, there were no sex differ ences in rates of reintervention or rates of major adverse limb events at the 5-year follow-up. 122 In contrast, among 8100 individuals ( $45\%$ female) undergoing endovascular treatment for chronic limb-threatening ischemia, women had significantly lower rates of major amputation or mor tality compared with men. 122 The IN.PACT superficial femoral artery randomized clinical trial demonstrated that

paclitaxel-coated balloon angioplasty was superior to percutaneous angioplasty for treating superficial femoral artery atherosclerosis associated with intermittent clau dication, and no sex differences in primary patency, safe ty, rates of clinically driven target lesion revascularization, or mortality rates were identified in post hoc analyses. 121 In a meta-analysis of 40 studies that compared sex dif ferences in adverse events after lower-extremity revas cularization, women had higher mortality, amputation, early graft thrombosis, embolization, and cardiac, stroke, and pulmonary complications at the 30-day follow-up, but there were no sex differences in survival, primary or secondary patency of the revascularized limb, or limb sal vage at time points ${\tt>}30$ days after revascularization. 123 In the early 21st century, women undergoing femoropopli teal bypass graft procedures who were taking hormone replacement therapy had significantly reduced primary graft patency and higher rates of graft failure when pros thetic bypass materials were used. 145

Future Research on Sex Differences in PAD

Future research should define the degree to which PAD is underdiagnosed in women and identify reasons for the higher prevalence of PAD in Black women and American Indian women in the United States compared with White women in the United States. Future research should es tablish the incidence and prevalence of PAD in women from racial and ethnic groups that are traditionally un derrepresented in scientific investigation in the United States. Sex differences in associations of atherosclerotic disease risk factors with PAD, when they exist, should be defined. Optimal methods to improve prescription rates and adherence to guideline-recommended therapy in women should be identified. 146 Future studies of devices for lower-extremity revascularization should be sure to include adequate numbers of women, including women from all ethnic and racial groups, because optimal de vices may differ according to sex differences in artery size or compliance. 146

ATHEROSCLEROTIC EXTRACRANIAL CAROTID ARTERY DISEASE

Epidemiology and Risk Factors

Stroke remains the third leading cause for death and disability in the United States, with $62\%$ of strokes of ischemic type. 114 From 1990 to 2019, the number of in cident strokes increased by $70\%$ overall, with a smaller increase ( $\cdot15\%$ in incident strokes for individuals ${<}70$ years of age. The 5 greatest risk factors for stroke are systolic hypertension, high body mass index, high fasting glucose, smoking, and ambient particulate matter pollu tion, which is the least appreciated. 114 In 2019, $56\%$ of strokes occurred in women. 147 Young women $(<\!45$ years

of age) have a higher or similar stroke incidence com pared with men of a similar age. 148 In middle age, men have a higher incidence of stroke, which then changes for postmenopausal women: Women ${\tt>}80$ years of age have a higher stroke risk. 114,149 There are sex-related unique risk factors for stroke related to pregnancy, with an increase in long-term risk after preeclampsia, at older age at menopause, and with the use of exogenous estro gen therapy. 148 As with CVD in general, there are health disparities with risk of stroke. Even after adjustment for age, insurance status, and education, Black women and Hispanic women ${\geq}70$ years of age had a $76\%$ to $77\%$ higher risk of stroke. 150

Up to $15\%$ of ischemic strokes are related to athero sclerotic carotid artery disease. 151 Traditional cardiovas cular risk factors of age, hypertension, hyperlipidemia, tobacco use, diabetes, and elevated body mass index are also associated with carotid artery disease. 152 On a mac rovascular level, women have relatively larger areas of the internal and external carotid arteries (outflow) com pared with common carotid arteries (inflow) relative to men, who have the opposite (larger inflow compared with outflow), which may affect the development of carotid atherosclerotic plaque. 153 Changes in endothelial vascu lar function and arterial stiffness with age are ultimately linked to the development of systolic hypertension. 154

Sex Differences in Carotid Atherosclerotic Plaque

A recent systematic review and meta-analysis of sex differences in carotid atherosclerosis for carotid plaque composition, morphology, and size revealed important insights into sex-related differences 155 in patients with both symptomatic and asymptomatic carotid artery dis ease. There was heterogeneity among the studies in the meta-analysis related to plaque size and carotid calcifications, likely related to differences in study popu lations. 155 Women had smaller plaque size, whether mea sured as maximum wall thickness in a 1-dimensional size, wall area as a 2-dimensional size, or wall volume as a 3-dimensional size. However, there was no sex-related difference in the normalized wall index, which accounts for the total vessel size. There was no sex difference in the amount of calcification relative to the total plaque volume. Atherosclerotic plaques in men are more likely to have a lipid-rich necrotic core (odds ratio, 1.87 $[95\%$ CI, 1.36–2.57]) compared with women, and this differ ence is amplified in symptomatic patients, in whom the odds ratio increased to 3.27 $95\%$ CI, 2.38–4.50) versus 1.79 ( $95\%$ CI, 1.16–2.76) for asymptomatic patients ( P for subgroup difference $\mathord{\succ}=\!\!0.03$ ). Intraplaque hemorrhage (IPH) is seen more commonly in men (odds ratio, 2.52 $[95\%$ CI, 1.74–3.66]). Therefore, overall plaque composi tion for women has less lipid-rich necrotic core and IPH compared with men. From this meta-analysis, it appears

that men with carotid atherosclerotic plaques have a greater volume of IPH and lipid-rich necrotic core with relatively less calcification compared with women, who have a greater relative degree of calcification compared with IPH and lipid-rich necrotic core. 155 The differences in plaque composition are related to stroke risk. Inde pendently of maximum plaque thickness and cardiovas cular risk factors, IPH is independently associated with stroke. 156,157 Although women overall have a lower bur den of IPH in carotid plaque compared with men, a re cent study showed a significant increase in risk of stroke for asymptomatic women with IPH (hazard ratio, 3.37 $[95\%$ CI, 1.81–6.25] for women versus 1.67 $[95\%$ CI, 0.98–2.79] for men). 157

Evaluation for Carotid Artery Disease

The US Preventive Services Task Force recommended against screening for asymptomatic carotid artery disease in the general population again in 2021. 158 However, it is important to consider that this recommendation does not apply to individuals with a history of stroke or any signs or symptoms of transient ischemic attack. There are missed opportunities to talk with patients about symptoms that may be consistent with prior transient ischemic attack even if they are currently asymptomatic in the clinic. For symptomatic patients, carotid ultrasound and computed tomography angiography are the traditional first-line tests for carotid artery disease, depending on the tim ing of the clinical presentation. However, these imaging studies are unable to adequately assess for the presence of IPH. IPH is best evaluated by magnetic resonance im aging. Overall, there are limited data about sex-specific risks for stroke based on carotid plaque composition, and this remains an important opportunity for future research.

Treatment Options for Carotid Artery Stenosis and Outcomes

All patients with carotid artery stenosis should be rec ommended to follow a lifestyle approach with Mediter ranean diet, exercise, and smoking cessation, in addition to being started on guideline-directed medical therapy with antiplatelets, lipid-lowering agents, blood pres sure reduction, and glycemic control. 159–164 The use of guideline-directed medical therapy is indicated for both reduction in cerebrovascular events and other sys temic complications of CVD. There is no uniform use of guideline-directed medical therapy for primary and secondary prevention of stroke in the setting of carotid artery disease among diverse populations. 165 Access to medications and comprehensive medical treatment ap proaches can vary significantly according to the social determinants of health. 166 There are limited sex-related data on the gaps in the use of guideline-directed medi cal therapy for asymptomatic carotid artery stenosis.

There is an opportunity for future research to under stand differences in aspirin benefit depending on de gree of carotid artery stenosis for women compared with men. A recent analysis used a carotid plaque score from a subset of the MESA study (with $57\%$ women) to dem onstrate an overall net benefit using a 5-year number needed to treat with an increasing amount of carotid atherosclerosis (carotid plaque score ${\geq}2$ ) in the setting of an atherosclerotic CVD risk of $5\%$ to $20\%$ . In com parison, with high atherosclerotic CVD risk of ${\tt>}20\%$ , there was a favorable risk-benefit ratio with any degree of carotid plaque. 167 Future research should further in vestigate the degree of asymptomatic carotid artery stenosis and associated imaging characteristics that are associated with the greatest benefit in the use of aspirin for primary prevention of stroke in women.

Women have historically been underrepresented in clinical trials for treatment of carotid artery steno sis with either transfemoral carotid artery stenting or carotid endarterectomy (CEA), with even more striking disparity noted with inadequate racial and ethnic repre sentation in clinical trials. 168 Contemporary large insti tutional and population studies no longer demonstrate the higher perioperative risk of stroke after CEA seen in the ACAS trial (Asymptomatic Carotid Atheroscle rosis Study) 169 for asymptomatic disease or NASCET trial (North American Symptomatic Carotid Endarterec tomy Trial) 170 and ESCT trial (European Carotid Surgery Trial) 171 for symptomatic disease, which were all limited by underrepresentation of women in these historical landmark trials. 172 For both asymptomatic and symp tomatic patients undergoing CEA in CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial), no significant differences were seen in the risk of perioperative stroke or death between female and male patients. 173 In CREST-2, there remained limited partici pation from women and people of underrepresented races and ethnicities in the clinical trial of treatment of carotid artery stenosis. 174 For symptomatic patients undergoing CEA, there was no significant difference in overall risk of stroke with CEA between women and men in 99495 participants from 30 studies. 175 Inno vative strategies are needed to improve the participa tion of diverse participants in studies of carotid artery revascularization. For individuals at high surgical risk for CEA, trans–carotid artery revascularization has a lower stroke and death rate for women and men compared with transfemoral carotid artery stenting. 176 The Soci ety for Vascular Surgery guidelines on the management of extracranial cerebrovascular disease do not provide specific recommendations on the treatment of carotid artery stenosis according to sex. However, Rockman et al 172 illustrate a thoughtful approach to considering options for revascularization for women with carotid artery disease in a recent systematic review. A recent trans–carotid artery revascularization database review

noted similar outcomes between men and women after trans–carotid artery revascularization but with the significant limitation that there was inadequate repre sentation of women in the study to determine whether there is a true difference in outcomes between men and women. 177 Future studies will need a large cohort of women after trans–carotid artery revascularization.

Future Research on Sex Differences in Extracranial Carotid Artery Disease

Future work in extracranial carotid artery disease should include diverse cohorts of women to explore the relation ship between race and ethnicity and health disparities on outcomes after carotid artery revascularization, risk of stroke, and carotid plaque composition. In particular, there is an opportunity to understand whether there are sex-related differences in carotid artery intervention for asymptomatic disease. Table4 summarizes sex-specific epidemiology, risk factors, and clinical outcomes for ath erosclerotic extracranial carotid artery disease.

ATHEROSCLEROTIC RENAL ARTERY DISEASE

Epidemiology

Renal artery stenosis is due predominantly to athero sclerotic plaque in adults $\scriptstyle(>90\%)$ ) compared with FMD, which is a more common cause in younger patients. 182 The CHS found that atherosclerotic renal artery steno sis (ARAS), defined as ${\ge}60\%$ diameter stenosis, was present in $6.8\%$ of adults ${\tt>}65$ years of age, with Black Americans making up $23\%$ of the study population. 183 ARAS was independently associated with increasing age, elevated low-density lipoprotein cholesterol, and systolic hypertension.

Treatment Choices/Outcomes

Overall, RCTs (STAR [The Benefit of Stent Placement and Blood Pressure and Lipid-Lowering for the Prevention of Progression of Renal Dysfunction Caused by Athero sclerotic Ostial Stenosis of the Renal Artery], 184 ASTRAL [Angioplasty and Stenting for Renal Artery Lesions], 185 and CORAL [Cardiovascular Outcomes in Renal Ath erosclerotic Lesions] 180 ) have failed to show convincing benefit of renal artery stenting for changes in blood pres sure, renal function, or pulmonary edema. Enrollment of women in these RCTs ranged from $27\%$ to $50\%$ . Only the CORAL trial reported outcomes according to sex. In this trial, no differences were found in the main outcome based on sex.

Given the lack of clear clinical benefit for revascular ization (stenting) for ARAS, there are inadequate data to fully understand the sex-related differences or disparities

Table 4. Extracranial Carotid Artery, Mesenteric Artery, and Renal Artery Atherosclerosis: Sex-Specific Epidemiology, Risk Factors, and Clinical Outcomes

||Epidemiology|Risk factors|Clinical outcomes| |---|---|---|---| | Atherosclerotic extracranial carotid artery disease |Young women (age |||

AMI indicates acute mesenteric ischemia; ARAS, atherosclerotic renal artery stenosis; CEA, carotid endarterectomy; CMI, chronic mesenteric ischemia; CORAL, Car diovascular Outcomes in Renal Atherosclerotic Lesions; CREST, Carotid Revascularization Endarterectomy Versus Stenting Trial; IPH, intraplaque hemorrhage; LRNC, lipid-rich necrotic core; RCT, randomized controlled trial; and TF-CAS transfemoral carotid artery stenting.

seen for different ethnic and racial groups. A small exploratory study found that despite the same severity of renal artery stenosis, Black patients had higher rates of severe or refractory hypertension. 179 In a cohort of older Black patients referred for coronary angiography, $19\%$ had ${\mathrm{>}}70\%$ diameter renal artery stenosis refrac tory hypertension or history of flash pulmonary edema, with bilateral renal artery stenosis in $26\%$ of the patients with ARAS. 186 Black Americans overall are at increased risk of chronic kidney disease and end-stage renal dis ease requiring hemodialysis. Further study is needed to better understand contemporary rates of ARAS in Black Americans with refractory hypertension and symptoms of pulmonary edema or progressive kidney dysfunction. Further studies are also needed to explore sex-related differences in outcomes for renal artery stenting in the setting of hemodynamically significant ARAS for patients with resistant hypertension or a history of congestive heart failure.

ATHEROSCLEROTIC MESENTERIC ARTERY DISEASE

Epidemiology and Clinical Presentation

Atherosclerotic mesenteric artery disease involves the celiac artery, superior mesenteric artery, or inferior mes enteric artery. The spectrum of clinical presentations with mesenteric ischemia ranges from acute to chronic or acute on chronic.

Table 4 summarizes sex-specific epidemiology, risk factors, and clinical outcomes for atherosclerotic mesen teric artery disease.

Women and Mesenteric Ischemia

Sex-related factors influencing acute mesenteric artery ischemia include thrombotic events that occur acutely in the setting of underlying vascular atherosclerosis. These events can be influenced by the use of exogenous hor mones related to either oral contraceptives or hormone replacement therapy. In addition, women are historical ly undertreated with statin and aspirin in the setting of known vascular disease, which could lead to silent pro gression of mesenteric artery atherosclerosis. 187

The development of chronic mesenteric ischemia (CMI) typically involves significant atherosclerosis of at least 2 of the mesenteric arteries, with 1 vessel being the superior mesenteric artery. Although less com mon, nonatherosclerotic causes such as malignancy, vasculitis, radiation injury, and other autoimmune dis orders can lead to CMI. 188 The classic presentation of CMI occurs beginning in the fifth or sixth decade and involves abdominal discomfort, which occurs 15 to 30 minutes after eating as a result of the postpran dial increase in mesenteric blood flow that gradually resolves over the next few hours. Women are 3 times as likely to be affected by CMI than men. 181 CMI com monly occurs in elderly patients with underlying vascu lar disease. One study of patients with PAD undergoing angiography found that $25\%$ had significant stenosis of ${>}50\%$ in either the celiac or superior mesenteric artery. 189 The incidence of symptomatic CMI is rare and represents ${<}2\%$ of atheromatous revascular ization procedures. 190 A meta-analysis from 2012 encompassing almost 1800 patients from 43 stud ies reported mortality rates of $3.5\%$ after endovascu lar treatment versus $7.2\%$ of those treated with open

Table 5. Vasculitis: Sex-Specific Epidemiology, Risk Factors, and Clinical Outcomes

||Epidemiology|Risk factors| Sex-specific differences| Representation of women in research | |---|---|---|---|---| |Large-vessel vasculitis ||||| |GCA| Age: >50y Incidence greatest in those 70-80 y of age Race and ethnicity: Predominantly White Sex: 2-3:1 female:male | Known associations: HLA-DRB1*04 allele PTPN22, VEGF, NOS2, ERAP1, REL, and PRKQC gene polymorphisms Sex-specific risk factors: Unknown | Clinical presentation: Men: >2-fold risk of aortic aneurysm194 Women: Axillary involvement more common195 Treatment: Treatment failure 5-fold higher in women with prednisone-onlyregiens6.7 Outcomes: Similar rates of mortality between men and women198 | Clinical trials: Appropriate sex representation in clinical trials199,200 Ongoing registries: VCRC: Giant Cell Arteritis Longitudinal Study | | Takayasu arteritis | Age: Women: 15-30 y of age Men:25-34and 50-74yofage Sex: 5:1 female:male Race and ethnicity: Geographic predominance: Asia, Northern Europe, Mediterranean, North America201 | Known association: HLA-B*52202 Sex-specific risk factors: Unknown | Clinical presentation203: Similar severity between sexes Women: Aortic arch branch vessel involvement (Numano type l) Men: Renal artery stenosis, extensive aortic lesions and abdominal aortic aneurysms (Numano type V), hypertension Treatment: No known differences Outcome: Mortality 2 times higher in women vs men204 | Clinical trials: Appropriate sex representation in clinical trials205 Ongoing registries: VCRC: Longitudinal Study for Takayasu's Arteritis | | Medium-vessel vasculitis ||||| |PAN| Age: 5th and 6th decades206 Sex: 1.5:1 male:female201 Race and ethnicity: Any background | Known association: Associated with hepati- tis B and C infection CECR1 loss-of- function mutation, pres- ents in childhood207 Sex-specific risk factors: Unknown | Clinical presentation: Women more commonly present with cutaneous polyarteritis nodosa Treatment: No known differences Outcome: No difference in mortaity between sexes208 | Clinical trials: Appropriate sex representation in clinical trials209 Ongoing registries: VCRC: Longitudinal Protocol for Polyarteritis Nodosa | | Kawasaki disease | Age: ||||

Table 5. Continued

||Epidemiology|Risk factors|Sex-specific differences| Representation of women in research | |---|---|---|---|---| | VEXAS syndrome* | Known association:|Clinical presentation:|Clinical trials:|| ||| Missense mutations in |May cause GCA or PAN223|None| ||Sex:|codon 41 of UBA1221|Treatment:| Ongoing registries: AIDAregistry (NCT05200715) | || Nearly exclusively affects men221,222 | Sex-specific risk factors:|No known differences| Ongoing registries: AIDAregistry (NCT05200715) | ||| X-linked gene, women|Outcome:| Ongoing registries: AIDAregistry (NCT05200715) | || Race and ethnicity: Not known |protected by|No known differences| Ongoing registries: AIDAregistry (NCT05200715) | |||unmutated allele223|| Ongoing registries: AIDAregistry (NCT05200715) | | Single-organ vasculitis||||| | Isolated aortitis | Age: ≈40-71y | Known association: Spectrum of disease | Clinical presentation:| Clinical trials: None Ongoing registries: | | Isolated aortitis ||with GCA, Takayasu ar-| High rates of aortic aneurysm No known sex difrences2425 | Clinical trials: None Ongoing registries: | | Isolated aortitis | Sex: ≈70% female224 |teritis, and lgG4-related|| Clinical trials: None Ongoing registries: | ||Race and ethnicity:|aortitis| Treatment: No known differences || ||Any background| Sex-specific risk factors:|Outcome:|| |||Unknown| No known differences||

AIDA indicates AutoInflammatory Disease Alliance International; GCA, giant cell arteritis; IgG4, immunoglobulin G4; PAN, polyarteritis nodosa; RISE, Rheumatology Informatics System for Effectiveness; VCRC, Vasculitis Clinical Research Consortium; VEXAS, vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic; and VPPRN, Vasculitis Patient-Powered Research Network. \*Recently described large- and medium-vessel vasculitis. Not currently included in the 2012 International Chapel Hill Consensus Conference Nomenclature of Vas culitides. 226 Classifications adapted from the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. 226

revascularization. Furthermore, perioperative compli cation was reported in roughly one-third of patients undergoing open revascularization compared with only $13\%$ after endovascular intervention. 191 Although open revascularization for CMI amassed higher morbidity and mortality, fewer patients had return of ischemic symptoms, and graft patency/durability was signifi cantly higher at the 5-year follow-up. Because of the low diagnosis frequency of symptomatic CMI, a pau city of data exist affording further insights based on sex. A small ex vivo study of human small intestines found that the female small intestines demonstrated better protection against ischemia/reperfusion injury with an ameliorated inflammatory response. 192 Further research into cellular and molecular mechanisms may prove useful in understanding sex-based differences surrounding ischemic insults to the intestines.

Future Research on Sex Differences in Mesenteric Atherosclerotic Disease

There are inadequate data on differences in outcomes after revascularization for acute myocardial infarction and CMI related to patient sex and diverse cohorts. It is important to note that $80\%$ of patients with CMI isch emia symptoms were initially misdiagnosed with gas troesophageal reflux disease or as needing alternative medical therapies instead of having CMI. It will be im portant to understand differences in time to diagnosis for CMI in diverse patient populations because groups affected by health disparities may have a longer time to diagnosis. 193 The presence of atherosclerosis in other vascular territories such as lower-extremity PAD, coro

nary artery disease, or cerebrovascular disease helps to identify individuals at increased risk for mesenteric artery ischemia. Future work could be done with artificial intelligence to assess the presence of atherosclerosis on imaging to help predict risk of future ischemic events such as CMI.

VASCULITIS

Vasculitides are a collection of rare diseases character ized by vascular inflammation, which results in a wide range of clinical presentations both across and within disease entities. The International Chapel Hill Consen sus Conference of 2012 standardized the classifications of systemic vasculitides by the type of vessel most often affected (Table5), although it is common for involve ment to extend to arteries outside of the traditional spec trum. 226 Large-vessel vasculitides (those that affect the aorta and its major branches) and medium-vessel vascu litides (those that affect visceral arteries and veins) most often lead to manifestations of PVD. Patients may pres ent with claudication of the upper or lower extremities, stroke or transient ischemic attack symptoms, and vas cular aneurysms, dissections, or stenoses. Small-vessel vasculitides affect arterioles, capillaries, and venules and have a wide spectrum of presentations ranging from glo merular nephritis to palpable purpura. These syndromes rarely cause medium- or large-vessel stenotic or aneu rysmal lesions and therefore are not discussed as part of this scientific statement. Systemic lupus erythematosus, rheumatoid arthritis, and sarcoidosis can have a vasculitic component but are also not discussed because smallvessel involvement predominates.

Epidemiology and sex predilection vary by vasculitis type. Giant cell arteritis is the most common vasculitis in the United States, with an age- and sex-adjusted prevalence rate of 204 per 100000 individuals ${\tt\ge}50$ years of age. 227 Giant cell arteritis and Takayasu arte ritis have a strong female predominance, whereas medium- and variable-vessel vasculitides and immuno globulin G4–related aortitis either have a slight male predilection or affect men and women equally. 227,228 Clinical features of each vasculitis often vary by sex (Table5). For example, the aortic arch branch vessels are more commonly affected in women with Takayasu arteritis, whereas abdominal aortic and renal artery involvement is more common in men. 202 The mecha nism for sex-specific clinical phenotypes is unknown. One notable exception is VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), a recently discovered, X-linked, male-predominant condi tion that has been linked to hematologic and systemic inflammatory conditions, including giant cell arteritis and polyarteritis nodosa. This syndrome is caused by acquired missense mutations in the UBA1 gene that encodes the E1 enzyme, which is the main mediator of cellular ubiquitylation. 223

High-quality investigations into the diagnosis, treat ment, and prognosis of these vasculitides are needed, with special attention to the effect of sex (Table5). There is often a delay of weeks to months between symptom onset and vasculitis diagnosis, which has been associ ated with later treatment initiation and worse clinical out comes. 229 These delays are multifactorial and related to nonspecific symptoms at disease onset, lack of specific serological markers, and need for multispecialty consul tation to synthesize clinical, imaging, and histopathologi cal features to reach a diagnosis. Data evaluating the role of sex and access to care on diagnostic delay are limited and inconclusive. 230 Similarly, sex-based treat ment disparities are unknown. Long-term follow-up data from a national registry in Korea found a 2-fold increased mortality in women with Takayasu arteritis compared with men, but these data did not account for the different prev alence of the disease between sexes. Mortality in Behçet disease, however, is significantly higher among men despite similar sex prevalence, an observation reflective of the greater severity of disease in this population. 213 It is incompletely understood whether there is a sex-based difference in timing of diagnosis and treatment initiation and how this affects long-term prognosis.

 Figure. Sex differences in PVD. There are significant sex-based differences and disparities in epidemiology, risk factors, diagnosis, treatment, and outcomes of peripheral vascular disease (PVD). ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CEA, carotid endarterectomy; FMD, fibromuscular dysplasia; GCA, giant cell arteritis; PAD, peripheral artery disease; TA, Takayasu arteritis; and vEDS, vascular Ehlers Danlos syndrome.

Table 6. Summary Table: Peripheral Vascular Disease in Women: Current State, Gaps, and Proposed Research Priorities to Achieve Health Equity

||Current state|Gaps| Research priorities to achieve health equity| |---|---|---|---| |Aortic disease| Incidence of aortopathy higher in men compared with women || Further understand sex-specific natural history of disease | | (TAA, AAA, and acute aortic || Sex-specific risk factors aortopathy occurrence and growth not well established || | acute aortic syndromes, including aortic dissection, penetrating aortic | Women present with more advanced age and pathology. | Consensus screening guidelines for women | Sex-specific screening and surveillance protocols | || No dedicated literature on racial and ethnic differences in outcomes by sex || Further research on intersectionality of race and ethnicity and sex for aortic disease | |hematoma)| Lack of consistent size thresholds for repair in women vs men | Consensus on sex-specific size threshold for treatment | Further research for repair thresholds for women with aortopathy | |hematoma)| Women tend to have a higher growth rate of aneurysm size/diameter ||| |hematoma)| Women have highersk for rupture at smaller aortic diameters ||| |hematoma)| smaller aortic diameters Women have worse prognosis compared with men after diagnosis with aortopathy (higher mortality, more complications, less likely to be offered repair) | Equity in outcomes after diagnosis and intervention | with smalle diameter delivery systems to accommodate smaller access vessels | |hematoma)||| Improved representation in RCTs for aortic disease trials | |hematoma)||| Research to decrease bias in treatment selection forwomen and improve patient centered care | |PAD| PAD is twice as common in Black women compared with White women. | Few data exist on the prevalence of PAD in women who are American Indian. | Develop interventions to eliminate the higher prevalence of PAD in women who are Black or American Indian | || women compared with White women. PAD is approximately twice as common in American Indian women compared with White women ||| || women compared with White women. PAD is approximately twice as common in American Indian women compared with White women | lence among Black women, American IndianwmenandWhitewmnin | Collect data to establish the prevalence of PAD among women from multipleracial and ethnic groups in the United States | ||| More data are needed to better define the prevalence of PAD in women from ethnic groups that are raditionally underrepre- || ||| Reasons for sex differences in the prevalence of asymptomatic PAD and PAD associated with atypical leg symptoms are unknown | Delineate the cause of sex differences in PAD symptoms Develop interventions to reduce rates of undiagnosed PAD in women | || men to be asymptomatic or to present with atypical leg symptoms ||| || In some studies, women were less likely to be taking a statin medication to prevent cardiovascular events | Reasons for lower rates of statin use in women with PAD compared with men with PAD are unknown | Develop interventions to improve rates of statin use by women with PAD | || In randomized clinical trials, women attain similar benefit from supervised || Identify methods to help al women with PAD gain access to exercise therapy | ||exercise therapy as men.| Data are needed to understand why women with PAD were lesslikely to participate in supervised exercise programs than men with PAD. || |||| Identify methods to maximize exercise adherence, either at home or in a supervised setting, among women with PAD | | of supervised exercise, women were significantly less likely than men to have |||| ||||| || for exercise therapy, women were more likely than men to participate. ||| ||||Identifythe most optimal types of| | Women have smaller arteries than men. Women typically present forWomen typically present for revascularization with later stages ofrevascularization with later stages of PAD than men. || Little is known about whether optimal methods and endovascular devices for lower-extremity revascularization differ between men and women. | revascularization procedures for women according to disease location and severity | | After lower-extremity revascularization for claudication, outcomes may be |||| ||||| || for claudication, outcomes may be similar between men and women, but data are mixed. After lower-extremity revascularization ||| ||||| || for CLTl, women may have lower rates of revascularization and lower rates of ||| || mortality, but data are inconsistent.|||

Table 6. Continued

||Current state|Gaps|Research priorities to achieve health equity| |---|---|---|---| | Atherosclerotic extracranial carotid artery disease | Black women and Hispanic women ≥70 y of age had a 76%-77% higher risk of stroke than White women | Reasons for racial and ethnic disparities in outcomes in stroke among women are ill described | Further research to limit racial and ethnic disparities among women with carotid disease | | Atherosclerotic extracranial carotid artery disease | Women with carotid disease are prescribed GDMT less frequently than men with carotid disease | Understanding reasons forlow prescription and use of GDMT | Explore the systems-based changes to improve GDMT use for primary and secondary prevention of stroke due to carotid artery disease among diverse populations | | Atherosclerotic extracranial carotid artery disease | Low representation of women in RCTs despite population-based screening efforts and equal prevalence of carotid disease as men | Understanding reasons for lower representation of women in carotid treatment RCTs | Innovative patient, community, and systems- based strategies to increase enrollment of women in RCTs | | Atherosclerotic extracranial carotid artery disease | Overall, carotid plaque composition for women has less LRNC and IPH compared with men | Reasons for differences in plaque composition are unknown. | Basic and translational studies to understand the underlying causes for sex differences in plaque composition | | Atherosclerotic renal artery disease | Sex-based differences were not routinely reported in natural history studies and RCTs of ARAS | Sex-based differences are unknown given the lack of clear clinical benefit for revascularization (stenting) for ARAS in both sexes | Sex-based studies are needed to determine clear benefit for renal artery stenting and appropriate clinical circumstances | | Atherosclerotic mes- enteric artery disease | Higher prevalence of CMI in women compared with men | Understand contributors to higher risk for CMI in women compared with men Improve GDMT for secondary prevention of vascular events for women with PAD and mesenteric atherosclerosis | Enroll more women in research studies of CMI Understand the vascular biology underlying AMI and CMI in women to determine the sex- related plaque characteristics to guide medical treatment | |Arteriopathies| Significant differences in male:female predominance for many arteriopathies | Sex-specific risk factors that explain striking male and female predominance in different arteriopathies are not well understood. Treatments to prevent/delay complications and data on how these may differ by sex are limited. | Expanding and diversifying registries Translation of treatments evaluated in preclinical murine models to clinical testing Development of novel methodologies and collaborative strategies to facilitate treatment studies in rare disease | |Vasculitis| Limited high-quality evidence overall with even less investigation of sex-based diferences and disparities | Many vasculitides are poorly understood and treated according to expert consensus and historical regimens | Prioritize patient enrollment in ongoing registries to better understand these disease entities |

AAA indicates abdominal aortic aneurysm; AMI, acute mesenteric ischemia; ARAS, atherosclerotic renal artery stenosis; CLTI, chronic limb-threatening ischemia; CMI, chronic mesenteric ischemia; CMS, Centers for Medicare & Medicaid Services; GDMT, guideline-directed medical therapy; IPH, intraplaque hemorrhage; LRNC, lipid-rich necrotic core; PAD, peripheral artery disease; RCT, randomized clinical trial; and TAA, thoracic aortic aorta.

Few clinical trials have assessed treatment strate gies, but the participants enrolled in these trials reflect the sex predilection of the disease. 199,205 For vasculitides that have other systemic manifestations such as Behçet disease, patients with aggressive vascular involvement have been excluded from landmark trials. 231 Vascular manifestations are a leading cause of death in patients with vasculitis, which highlights the importance of includ ing this high-risk population in future scientific endeav ors. 216 However, it is important to remember that the rarity of these vasculitides and the broad spectrum of disease without strict diagnostic criteria make clinical tri als and dedicated investigations into sex-related dispari ties challenging. Most data to date have emerged from small local or regional cohorts. Collaborations such as the Vasculitis Foundation’s Vasculitis Patient-Powered Research Network, UK and Ireland Vasculitis Rare Disease Group Vasculitis Registry, and Joint Vasculitis Registry in German-speaking countries bring clinicians, researchers, and patients together around the common goal of advancing care and engaging patients in research

endeavors. The Vasculitis Foundation offers resources for patients to learn about opportunities to engage in ${\tt>}25$ potential clinical trials and multiple different registries, including the Vasculitis Patient-Powered Research Net work, which is a partnership between the Vasculitis Foun dation and the Vasculitis Clinical Research Consortium. Patients can enroll in the Vasculitis Pregnancy Registry, which seeks to improve the understanding of pregnancy characteristics and outcomes among women with vascu litis. These initiatives offer promise to better understand sex differences in short- and long-term outcomes in patients with vasculitis outside of the limitations of tra ditional study design. 205,232 As the care of patients with vasculitis advances, it is important for frontline clinicians to provide patients with resources of different modali ties to learn about their disease. Although both men and women most often turn to health care professionals for medication information, women are more likely to use online resources, support groups, and package inserts, whereas men are more likely to use their partner as a secondary source of information. 233 Understanding how

each patient receives information and providing them with those appropriate resources can help strengthen the therapeutic alliance, enhance health literacy, and improve clinical outcomes.

CONCLUSIONS

There are significant sex-based differences and dispari ties in epidemiology, risk factors, diagnosis, treatment, and outcomes of PVD (Figure). Particularly noteworthy are the delayed presentation and higher mortality of women from acute aortic syndromes, worse outcomes after aortic re pair, and higher likelihood of being offered medical treat ment for type A aortic dissection. Women are strikingly disproportionately represented in arteriopathies such as FMD and CMI. Among Medicare beneficiaries with PAD, women were less likely to participate in supervised exer cise therapy compared with men. 142 Women are under represented in RCTs of PVD. These numerous disparities provide opportunities to pursue health equity for women with PVD, and it is imperative that future research, includ ing basic and translational research, incorporates sexbased variables in their design and reporting (Table6). Within the inequities for women exist other racial and so ciodemographic disparities that further exacerbate sexbased differences. We applaud policies for inclusion such as those mandated by the Executive Order in Advancing Women’s Health Research and Innovation and the Na tional Institutes of Health, which obligate inclusion of sex-, race-, and ethnicity-based enrollment and reporting as appropriate to the research question under study. 234–236 The impact of such inclusion policies on mitigating sexbased disparities in PVD is unknown but should be as sessed in future research.

Sex is a biologic variable determined by chromosomal composition, and gender is a “multidimensional social construct related to norms and societal expectations that

Disclosures

exist within a historical and cultural context.” 237 Both sex and gender affect human health and disease, and it is recommended that both sex and gender be included in CVD research and reporting. 238 These terms are often used interchangeably in the literature, and it was not possible to strictly divide the 2 terms in this document to adequately describe their influence on PVD. Certainly, the study of PVD going forward will benefit from the dis tinction between sex and gender and the inclusion of both constructs in research design and reporting.

ARTICLE INFORMATION

The American Heart Association makes every effort to avoid any actual or poten tial conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Spe cifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advi sory and Coordinating Committee on December 11, 2024, and the American Heart Association Executive Committee on January 16, 2025. A copy of the document is available at https://professional.heart.org/statements by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 215-356-2721 or email Meredith.Edelman@wolterskluwer.com

The American Heart Association requests that this document be cited as fol lows: Kim ESH, Arya S, Bryce Y, Gornik HL, Long CA, McDermott MM, Pollak AW, Rowe VL, Sullivan AE, Whipple MO; on behalf of the American Heart Association Council on Peripheral Vascular Disease; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medi cine; Council on Quality of Care and Outcomes Research; and Stroke Council. Sex differences in peripheral vascular disease: a scientific statement from the American Heart Association . Circulation. 2025;151:e•••–e•••. doi: 10.1161/ CIR.0000000000001310

The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit https://professional.heart.org/statements. Se lect the “Guidelines & Statements” drop-down menu, then click “Publication Development.”

Permissions: Multiple copies, modification, alteration, enhancement, and dis tribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions. A link to the “Copyright Permissions Request Form” appears in the second paragraph (https://www.heart.org/en/about-us/ statements-and-policies/copyright-request-form).

Writing Group Disclosures

| Writing group member | Employment | Research grant | Other research support | Speakers' bureau/ honoraria | Expert witness | Ownership interest | Consultant/ advisory board |Other| |---|---|---|---|---|---|---|---|---| |Esther S.H. Kim| Atrium Health, Sanger Heart and Vascular Institute |None|None|None|None|None|None|None| | Shipra Arya| Stanford University School of Medicine | VAHSR (VAmerit I01HX003215)+ |None|None|None|None|Gore Medical*|None| |Yolanda Bryce| Memorial Sloan Kettering Cancer Center |None|None| Boston Scientifict; ShockWave Medical, Inct |None|None|None|None| |Heather L. Gornik| University Hospitals, Harrington Heart Vascular Institute |None|None|None|None|None|None|None| |Chandler A. Long| Duke University Medical Center |None|None|None|None|None|None|None|

( Continued )

Writing Group Disclosures Continued

| Writing group member |Employment|Research grant| Other research support | Speakers'bureau/ honoraria | Expert witness | Ownership interest | Consultant/ advisory board |Other| |---|---|---|---|---|---|---|---|---| | Mary M. McDermott | Northwestern University, Feinberg School of Medicine | NHLBIt; National Institute on Agingt | ACI Medicalt; Marst |None|None|None|None|None| |Amy West Pollak|Mayo Clinic|None|None|None|None|None| J Medicine (unpaid)* |None| | Vincent Lopez Rowe | Geffen School of Medicine at UCLA |None|None|None|None|None|None|None| | Alexander E. Sullivan | Vanderbilt University Medical Center |None|None|None|None|None|None|None| |Mary O. Whipple| University of Minnesota School of Nursing |None|None|None|None|None|None|None|

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $\S5000$ or more during any 12-month period, or $5\%$ or more of the person’s gross income; or (b) the person owns $5\%$ or more of the voting stock or share of the entity, or owns $\S5000$ or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. \*Modest.

†Significant.

Reviewer Disclosures

|Reviewer|Employment| Research grant | Other research support | Speakers' bureau/honoraria | Expert witness | Ownership interest | Consultant/ advisory board |Other| |---|---|---|---|---|---|---|---|---| | Daniel Joseph Bertges | University of Vermont Medical Center |None|None|None|None|None|None|None| |Julie Brittenden| University of Aberdeen (United Kingdom) |None|None|None|None|None|None|None| |Leslie Cho|Cleveland Clinic|None|None|None|None|None|None|None| | Timothy William Ingraham Clark | Penn Presbyterian Medical Center |None|None|None|None|None|None|None|

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Ques tionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $\S5000$ or more during any 12-month period, or $5\%$ or more of the person’s gross income; or (b) the person owns $5\%$ or more of the voting stock or share of the entity, or owns $\S5000$ or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.

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