Advertisement
Canadian Journal of Cardiology

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

  • Amanda Morrison
    Affiliations
    Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    Search for articles by this author
  • Aaron W. Aday
    Correspondence
    Corresponding author: Dr Aaron W. Aday, 2525 West End Avenue, Suite 300, Nashville, Tennessee 37203, USA. Tel.: +1-615-875-8788; fax: +1-615-322-3837.
    Affiliations
    Vanderbilt Translational and Clinical Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    Search for articles by this author
Published:February 26, 2022DOI:https://doi.org/10.1016/j.cjca.2022.02.021

      Abstract

      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.

      Résumé

      La maladie artérielle périphérique (MAP) d’origine athéroscléreuse entraîne une baisse des capacités fonctionnelles et un risque accru de résultats cardiovasculaires défavorables. Bien que les hommes soient d’habitude considérés comme exposés à un risque plus élevé de MAP que les femmes, les rapports disponibles ne sont pas unanimes quant à la prévalence et à l’incidence réelles des MAP. Cette absence de consensus est en partie attribuable à des différences dans les symptômes des MAP chez les femmes ainsi qu’à des différences liées au sexe qui influent sur les tests diagnostiques, comme l’indice de pression systolique; il sera donc essentiel de tenir compte de ces différences dans les futures études épidémiologiques. En général, les femmes atteintes d’une MAP présentent un déficit et une détérioration des capacités fonctionnelles plus sévères que les hommes, et sont moins susceptibles de recevoir un traitement médical fondé sur des lignes directrices. Dans certains contextes, les femmes sont également plus susceptibles de consulter aux stades plus avancés de la maladie, et subissent plus souvent que les hommes l’amputation d’un membre inférieur. Il existe peu de données tirées d’études chez l’animal explorant les fondements biologiques de ces différences entre les sexes, mais plusieurs hypothèses ont été avancées pour les expliquer, notamment la morphologie différente des plaques, les altérations de la réponse immunitaire, les variations hormonales et la protection d’origine hormonale. Les données épidémiologiques laissent entrevoir un lien entre l’inflammation et les MAP, et révèlent des différences entre les sexes quant aux profils lipidiques associés au risque de MAP. Dans cette revue, nous analysons les données disponibles sur les différences entre les sexes en ce qui a trait aux manifestations de la MAP et nous présentons des explications biologiques plausibles de l’origine de ces différences. Nous soulignons également les grandes lacunes en matière de connaissances dans ce domaine, notamment en ce qui a trait à la sous-représentation des femmes dans les essais cliniques sur les MAP, afin d’orienter les études ultérieures et d’éliminer les disparités entre les sexes dans l’étude des MAP.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Gerhard-Herman M.D.
        • Gornik H.L.
        • Barrett C.
        • et al.
        2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        Circulation. 2017; 135: e726-e779
        • Aday A.W.
        • Matsushita K.
        Epidemiology of peripheral artery disease and polyvascular disease.
        Circ Res. 2021; 128: 1818-1832
        • Gutierrez J.A.
        • Aday A.W.
        • Patel M.R.
        • Jones W.S.
        Polyvascular disease: reappraisal of the current clinical landscape.
        Circ Cardiovasc Interv. 2019; 12e007385
        • Song P.
        • Rudan D.
        • Zhu Y.
        • et al.
        Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis.
        Lancet Glob Health. 2019; 7: e1020-e1030
        • Allison M.A.
        • Ho E.
        • Denenberg J.O.
        • et al.
        Ethnic-specific prevalence of peripheral arterial disease in the United States.
        Am J Prev Med. 2007; 32: 328-333
        • Bauersachs R.
        • Zeymer U.
        • Brière J.B.
        • Marre C.
        • Bowrin K.
        • Huelsebeck M.
        Burden of coronary artery disease and peripheral artery disease: a literature review.
        Cardiovasc Ther. 2019; 2019: 8295054
        • Pradhan A.D.
        • Aday A.W.
        • Beckman J.A.
        The big MAC attack on peripheral artery disease.
        Circulation. 2020; 141: 1211-1213
        • Man J.J.
        • Beckman J.A.
        • Jaffe I.Z.
        Sex as a biological variable in atherosclerosis.
        Circ Res. 2020; 126: 1297-1319
        • Rossi A.M.
        • Pilote L.
        Let's talk about sex...and gender!.
        Circ Cardiovasc Qual Outcomes. 2016; 9: S100-S101
        • Sigvant B.
        • Wiberg-Hedman K.
        • Bergqvist D.
        • et al.
        A population-based study of peripheral arterial disease prevalence with special focus on critical limb ischemia and sex differences.
        J Vasc Surg. 2007; 45: 1185-1191
        • Hirsch A.T.
        • Criqui M.H.
        • Treat-Jacobson D.
        • et al.
        Peripheral arterial disease detection, awareness, and treatment in primary care.
        JAMA. 2001; 286: 1317-1324
        • Brevetti G.
        • Bucur R.
        • Balbarini A.
        • et al.
        Women and peripheral arterial disease: same disease, different issues.
        J Cardiovasc Med (Hagerstown). 2008; 9: 382-388
        • McDermott M.M.
        • Fried L.
        • Simonsick E.
        • Ling S.
        • Guralnik J.M.
        Asymptomatic peripheral arterial disease is independently associated with impaired lower extremity functioning: the women's health and aging study.
        Circulation. 2000; 101: 1007-1012
        • Tomczyk S.
        • Treat-Jacobson D.
        Claudication symptom experience in men and women: is there a difference?.
        J Vasc Nurs. 2009; 27: 92-97
        • Oka R.K.
        • Szuba A.
        • Giacomini J.C.
        • Cooke J.P.
        Gender differences in perception of PAD: a pilot study.
        Vasc Med. 2003; 8: 89-94
        • Stoffers H.E.
        • Rinkens P.E.
        • Kester A.D.
        • Kaiser V.
        • Knottnerus J.A.
        The prevalence of asymptomatic and unrecognized peripheral arterial occlusive disease.
        Int J Epidemiol. 1996; 25: 282-290
        • Wang J.C.
        • Criqui M.H.
        • Denenberg J.O.
        • McDermott M.M.
        • Golomb B.A.
        • Fronek A.
        Exertional leg pain in patients with and without peripheral arterial disease.
        Circulation. 2005; 112: 3501-3508
        • Jensen S.A.
        • Vatten L.J.
        • Romundstad P.R.
        • Myhre H.O.
        The prevalence of intermittent claudication. Sex-related differences have been eliminated.
        Eur J Vasc Endovasc Surg. 2003; 25: 209-212
        • Haine A.
        • Kavanagh S.
        • Berger J.S.
        • et al.
        Sex-specific risks of major cardiovascular and limb events in patients with symptomatic peripheral artery disease.
        J Am Coll Cardiol. 2020; 75: 608-617
        • Feinglass J.
        • McDermott M.M.
        • Foroohar M.
        • Pearce W.H.
        Gender differences in interventional management of peripheral vascular disease: evidence from a blood flow laboratory population.
        Ann Vasc Surg. 1994; 8: 343-349
        • McDermott M.M.
        • Greenland P.
        • Liu K.
        • et al.
        Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment.
        JAMA. 2001; 286: 1599-1606
        • Collins T.C.
        • Suarez-Almazor M.
        • Bush R.L.
        • Petersen N.J.
        Gender and peripheral arterial disease.
        J Am Board Fam Med. 2006; 19: 132-140
        • McDermott M.M.
        • Greenland P.
        • Liu K.
        • et al.
        Sex differences in peripheral arterial disease: leg symptoms and physical functioning.
        J Am Geriatr Soc. 2003; 51: 222-228
        • McDermott M.M.
        • Ferrucci L.
        • Liu K.
        • et al.
        Women with peripheral arterial disease experience faster functional decline than men with peripheral arterial disease.
        J Am Coll Cardiol. 2011; 57: 707-714
        • Gardner A.W.
        • Parker D.E.
        • Montgomery P.S.
        • Khurana A.
        • Ritti-Dias R.M.
        • Blevins S.M.
        Gender differences in daily ambulatory activity patterns in patients with intermittent claudication.
        J Vasc Surg. 2010; 52: 1204-1210
        • Aboyans V.
        • Criqui M.H.
        • Abraham P.
        • et al.
        Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
        Circulation. 2012; 126: 2890-2909
        • Hiatt W.R.
        • Hoag S.
        • Hamman R.F.
        Effect of diagnostic criteria on the prevalence of peripheral arterial disease: the San Luis Valley Diabetes study.
        Circulation. 1995; 91: 1472-1479
        • Smith F.B.
        • Lee A.J.
        • Price J.F.
        • van Wijk M.C.
        • Fowkes F.G.
        Changes in ankle brachial index in symptomatic and asymptomatic subjects in the general population.
        J Vasc Surg. 2003; 38: 1323-1330
        • Aboyans V.
        • Criqui M.H.
        • McClelland R.L.
        • et al.
        Intrinsic contribution of gender and ethnicity to normal ankle-brachial index values: the Multi-Ethnic Study of Atherosclerosis (MESA).
        J Vasc Surg. 2007; 45: 319-327
        • Hiramoto J.S.
        • Katz R.
        • Weisman S.
        • Conte M.
        Gender-specific risk factors for peripheral artery disease in a voluntary screening population.
        J Am Heart Assoc. 2014; 3e000651
        • Allison M.A.
        • Hiatt W.R.
        • Hirsch A.T.
        • Coll J.R.
        • Criqui M.H.
        A high ankle-brachial index is associated with increased cardiovascular disease morbidity and lower quality of life.
        J Am Coll Cardiol. 2008; 51: 1292-1298
        • London G.M.
        • Guerin A.P.
        • Pannier B.
        • Marchais S.J.
        • Stimpel M.
        Influence of sex on arterial hemodynamics and blood pressure: role of body height.
        Hypertension. 1995; 26: 514-519
        • Newman A.B.
        • Siscovick D.S.
        • Manolio T.A.
        • et al.
        Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study: Cardiovascular Heart Study (CHS) Collaborative Research Group.
        Circulation. 1993; 88: 837-845
        • Murabito J.M.
        • D'Agostino R.B.
        • Silbershatz H.
        • Wilson W.F.
        Intermittent claudication: a risk profile from The Framingham Heart Study.
        Circulation. 1997; 96: 44-49
        • Meijer W.T.
        • Hoes A.W.
        • Rutgers D.
        • Bots M.L.
        • Hofman A.
        • Grobbee D.E.
        Peripheral arterial disease in the elderly: the Rotterdam Study.
        Arterioscler Thromb Vasc Biol. 1998; 18: 185-192
        • Allison M.A.
        • Criqui M.H.
        • McClelland R.L.
        • et al.
        The effect of novel cardiovascular risk factors on the ethnic-specific odds for peripheral arterial disease in the Multi-Ethnic Study of Atherosclerosis (MESA).
        J Am Coll Cardiol. 2006; 48: 1190-1197
        • Whiteman M.C.
        • Deary I.J.
        • Lee A.J.
        • Fowkes F.G.
        Submissiveness and protection from coronary heart disease in the general population: Edinburgh Artery Study.
        Lancet. 1997; 350: 541-545
        • Hooi J.D.
        • Kester A.D.M.
        • Stoffers H.E.J.H.
        • Overdijk M.M.
        • van Ree J.W.
        • Knottnerus J.A.
        Incidence of and risk factors for asymptomatic peripheral arterial occlusive disease: a longitudinal study.
        Am J Epidemiol. 2001; 153: 666-672
        • Selvin E.
        • Erlinger T.P.
        Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000.
        Circulation. 2004; 110: 738-743
        • Criqui M.H.
        • Vargas V.
        • Denenberg J.O.
        • et al.
        Ethnicity and peripheral arterial disease: the San Diego Population Study.
        Circulation. 2005; 112: 2703-2707
        • Kannel W.B.
        • McGee D.L.
        Update on some epidemiologic features of intermittent claudication: the Framingham Study.
        J Am Geriatr Soc. 1985; 33: 13-18
        • Murabito J.M.
        • Evans J.C.
        • Nieto K.
        • Larson M.G.
        • Levy D.
        • Wilson P.W.
        Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study.
        Am Heart J. 2002; 143: 961-965
        • Fowkes F.G.
        • Housley E.
        • Riemersma R.A.
        • et al.
        Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study.
        Am J Epidemiol. 1992; 135: 331-340
        • McDermott M.M.
        • Liu K.
        • Criqui M.H.
        • et al.
        Ankle-brachial index and subclinical cardiac and carotid disease: the multi-ethnic study of atherosclerosis.
        Am J Epidemiol. 2005; 162: 33-41
        • Eraso L.H.
        • Fukaya E.
        • Mohler 3rd, E.R.
        • Xie D.
        • Sha D.
        • Berger J.S.
        Peripheral arterial disease, prevalence and cumulative risk factor profile analysis.
        Eur J Prev Cardiol. 2014; 21: 704-711
        • Jacob-Brassard J.
        • Al-Omran M.
        • Hussain M.A.
        • et al.
        Temporal trends in hospitalization for lower extremity peripheral artery disease in Ontario: the importance of diabetes.
        Can J Cardiol. 2021; 37: 1507-1512
        • Hackam D.G.
        The peripheral arterial disease pandemic: no let-up in sight.
        Can J Cardiol. 2021; 37: 1496-1497
        • Matsushita K.
        • Sang Y.
        • Ning H.
        • et al.
        Lifetime risk of lower-extremity peripheral artery disease defined by ankle-brachial index in the United States.
        J Am Heart Assoc. 2019; 8e012177
        • Kullo I.J.
        • Bailey K.R.
        • Kardia S.L.
        • Mosley Jr., T.H.
        • Boerwinkle E.
        • Turner S.T.
        Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy (GENOA) study.
        Vasc Med. 2003; 8: 237-242
        • Vogt M.T.
        • Cauley J.A.
        • Kuller L.H.
        • Hulley S.B.
        Prevalence and correlates of lower extremity arterial disease in elderly women.
        Am J Epidemiol. 1993; 137: 559-568
        • Ostchega Y.
        • Paulose-Ram R.
        • Dillon C.F.
        • Gu Q.
        • Hughes J.P.
        Prevalence of peripheral arterial disease and risk factors in persons aged 60 and older: data from the National Health and Nutrition Examination Survey 1999-2004.
        J Am Geriatr Soc. 2007; 55: 583-589
        • Colantonio L.D.
        • Hubbard D.
        • Monda K.L.
        • et al.
        Atherosclerotic risk and statin use among patients with peripheral artery disease.
        J Am Coll Cardiol. 2020; 76: 251-264
        • Paquet M.
        • Pilon D.
        • Tetrault J.P.
        • Carrier N.
        Protective vascular treatment of patients with peripheral arterial disease: guideline adherence according to year, age and gender.
        Can J Public Health. 2010; 101: 96-100
        • Sigvant B.
        • Wiberg-Hedman K.
        • Bergqvist D.
        • Rolandsson O.
        • Wahlberg E.
        Risk factor profiles and use of cardiovascular drug prevention in women and men with peripheral arterial disease.
        Eur J Cardiovasc Prev Rehabil. 2009; 16: 39-46
        • Saxon J.T.
        • Safley D.M.
        • Mena-Hurtado C.
        • et al.
        Adherence to guideline-recommended therapy-including supervised exercise therapy referral-across peripheral artery disease specialty clinics: insights from the international PORTRAIT registry.
        J Am Heart Assoc. 2020; 9e012541
        • Altin S.E.
        • Castro-Dominguez Y.S.
        • Kennedy K.F.
        • et al.
        Predictors of underutilization of medical therapy in patients undergoing endovascular revascularization for peripheral artery disease.
        JACC Cardiovasc Interv. 2020; 13: 2911-2918
        • Singh N.
        • Ding L.
        • Magee G.A.
        • Shavelle D.M.
        • Kashyap V.S.
        • Garg P.K.
        Discharge prescription patterns for antiplatelet therapy following lower extremity peripheral vascular intervention.
        Circ Cardiovasc Interv. 2020; 13e008791
        • Treat-Jacobson D.
        • McDermott M.M.
        • Beckman J.A.
        • et al.
        Implementation of supervised exercise therapy for patients with symptomatic peripheral artery disease: a science advisory from the American Heart Association.
        Circulation. 2019; 140: e700-e710
        • Divakaran S.
        • Carroll B.J.
        • Chen S.
        • Shen C.
        • Bonaca M.P.
        • Secemsky E.A.
        Supervised exercise therapy for symptomatic peripheral artery disease among Medicare beneficiaries between 2017 and 2018: participation rates and outcomes.
        Circ Cardiovasc Qual Outcomes. 2021; 14e007953
        • Treat-Jacobson D.
        • McDermott M.M.
        • Bronas U.G.
        • et al.
        Optimal exercise programs for patients with peripheral artery disease: a scientific statement from the American Heart Association.
        Circulation. 2019; 139: e10-e33
        • Egorova N.
        • Vouyouka A.G.
        • Quin J.
        • et al.
        Analysis of gender-related differences in lower extremity peripheral arterial disease.
        J Vasc Surg. 2010; 51 (e371; discussion 378-9): 372-378
        • Hussain M.A.
        • Lindsay T.F.
        • Mamdani M.
        • Wang X.
        • Verma S.
        • Al-Omran M.
        Sex differences in the outcomes of peripheral arterial disease: a population-based cohort study.
        CMAJ Open. 2016; 4: E124-E131
        • McGinigle K.L.
        • Browder S.E.
        • Strassle P.D.
        • Shalhub S.
        • Harris L.M.
        • Minc S.D.
        Sex-related disparities in intervention rates and type of intervention in patients with aortic and peripheral arterial diseases in the National Inpatient Sample Database.
        J Vasc Surg. 2021; 73 (e2087): 2081-2089
        • Lo R.C.
        • Bensley R.P.
        • Dahlberg S.E.
        • et al.
        Presentation, treatment, and outcome differences between men and women undergoing revascularization or amputation for lower extremity peripheral arterial disease.
        J Vasc Surg. 2014; 59 (e403): 409-418
        • Freisinger E.
        • Malyar N.M.
        • Reinecke H.
        • Unrath M.
        Low rate of revascularization procedures and poor prognosis particularly in male patients with peripheral artery disease: a propensity score matched analysis.
        Int J Cardiol. 2018; 255: 188-194
        • Lefebvre K.M.
        • Chevan J.
        The persistence of gender and racial disparities in vascular lower extremity amputation: an examination of HCUP-NIS data (2002-2011).
        Vasc Med. 2015; 20: 51-59
        • Choi K.H.
        • Park T.K.
        • Kim J.
        • et al.
        Sex differences in outcomes following endovascular treatment for symptomatic peripheral artery disease: an analysis from the K-VIS ELLA registry.
        J Am Heart Assoc. 2019; 8e010849
        • Dreyer R.P.
        • van Zitteren M.
        • Beltrame J.F.
        • et al.
        Gender differences in health status and adverse outcomes among patients with peripheral arterial disease.
        J Am Heart Assoc. 2014; 4e000863
        • Alsaigh T.
        • Di Bartolo B.A.
        • Mulangala J.
        • Figtree G.A.
        • Leeper N.J.
        Bench-to-bedside in vascular medicine: optimizing the translational pipeline for patients with peripheral artery disease.
        Circ Res. 2021; 128: 1927-1943
        • Krishna S.M.
        • Omer S.M.
        • Golledge J.
        Evaluation of the clinical relevance and limitations of current pre-clinical models of peripheral artery disease.
        Clin Sci (Lond). 2016; 130: 127-150
        • Hamm Jr., T.E.
        • Kaplan J.R.
        • Clarkson T.B.
        • Bullock B.C.
        Effects of gender and social behavior on the development of coronary artery atherosclerosis in cynomolgus macaques.
        Atherosclerosis. 1983; 48: 221-233
        • Adams M.R.
        • Kaplan J.R.
        • Clarkson T.B.
        • Koritnik D.R.
        Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys.
        Arteriosclerosis. 1985; 5: 192-200
        • Adams M.R.
        • Kaplan J.R.
        • Koritnik D.R.
        • Clarkson T.B.
        Pregnancy-associated inhibition of coronary artery atherosclerosis in monkeys: evidence of a relationship with endogenous estrogen.
        Arteriosclerosis. 1987; 7: 378-384
        • Adams M.R.
        • Kaplan J.R.
        • Manuck S.B.
        • et al.
        Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys: lack of an effect of added progesterone.
        Arteriosclerosis. 1990; 10: 1051-1057
        • Miyoshi N.
        • Horiuchi M.
        • Inokuchi Y.
        • et al.
        Novel microminipig model of atherosclerosis by high fat and high cholesterol diet, established in Japan.
        Vivo. 2010; 24: 671-680
        • Al-Mashhadi R.H.
        • Sørensen C.B.
        • Kragh P.M.
        • et al.
        Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant.
        Sci Transl Med. 2013; 5: 1-10
        • Douglas G.
        • Hale A.B.
        • Patel J.
        • et al.
        Roles for endothelial cell and macrophage Gch1 and tetrahydrobiopterin in atherosclerosis progression.
        Cardiovasc Res. 2018; 114: 1385-1399
        • Samokhin A.O.
        • Lythgo P.A.
        • Gauthier J.Y.
        • Percival M.D.
        • Bromme D.
        Pharmacological inhibition of cathepsin S decreases atherosclerotic lesions in Apoe-/- mice.
        J Cardiovasc Pharmacol. 2010; 56: 98-105
        • de Bakker M.
        • Timmerman N.
        • van Koeverden I.D.
        • et al.
        The age- and sex-specific composition of atherosclerotic plaques in vascular surgery patients.
        Atherosclerosis. 2020; 310: 1-10
        • Okura H.
        • Asawa K.
        • Kubo T.
        • et al.
        Incidence and predictors of plaque rupture in the peripheral arteries.
        Circ Cardiovasc Interv. 2010; 3: 63-70
        • Narula N.
        • Dannenberg A.J.
        • Olin J.W.
        • et al.
        Pathology of peripheral artery disease in patients with critical limb ischemia.
        J Am Coll Cardiol. 2018; 72: 2152-2163
        • Naghavi M.
        • Libby P.
        • Falk E.
        • et al.
        From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I.
        Circulation. 2003; 108: 1664-1672
        • Libby P.
        • Buring J.E.
        • Badimon L.
        • et al.
        Atherosclerosis. Nat Rev Dis Primers. 2019; 5: 56
        • Kaneko K.
        • Kawasaki T.
        • Masunari S.
        • Yoshida T.
        • Omagari J.
        Determinants of extraaortic arterial 18F-FDG accumulation in asymptomatic cohorts: sex differences in the association with cardiovascular risk factors and coronary artery stenosis.
        J Nucl Med. 2013; 54: 564-570
        • Ridker P.M.
        • Stampfer M.J.
        • Rifai N.
        Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease.
        JAMA. 2001; 285: 2481-2485
        • Pradhan A.D.
        • Shrivastava S.
        • Cook N.R.
        • Rifai N.
        • Creager M.A.
        • Ridker P.M.
        Symptomatic peripheral arterial disease in women: nontraditional biomarkers of elevated risk.
        Circulation. 2008; 117: 823-831
        • Ding N.
        • Yang C.
        • Ballew S.H.
        • et al.
        Fibrosis and inflammatory markers and long-term risk of peripheral artery disease: the ARIC study.
        Arterioscler Thromb Vasc Biol. 2020; 40: 2322-2331
        • Kremers B.
        • Wubbeke L.
        • Mees B.
        • Ten Cate H.
        • Spronk H.
        • Ten Cate-Hoek A.
        Plasma biomarkers to predict cardiovascular outcome in patients with peripheral artery disease: a systematic review and meta-analysis.
        Arterioscler Thromb Vasc Biol. 2020; 40: 2018-2032
        • Varlamov O.
        • Bethea C.L.
        • Roberts Jr., C.T.
        Sex-specific differences in lipid and glucose metabolism.
        Front Endocrinol (Lausanne). 2014; 5: 241
        • Wang X.
        • Magkos F.
        • Mittendorfer B.
        Sex differences in lipid and lipoprotein metabolism: it's not just about sex hormones.
        J Clin Endocrinol Metab. 2011; 96: 885-893
        • Aday A.W.
        • Lawler P.R.
        • Cook N.R.
        • Ridker P.M.
        • Mora S.
        • Pradhan A.D.
        Lipoprotein particle profiles, standard lipids, and peripheral artery disease incidence.
        Circulation. 2018; 138: 2330-2341
        • Zheng Z.J.
        • Rosamond W.D.
        • Chambless L.E.
        • et al.
        Lower extremity arterial disease assessed by ankle-brachial index in a middle-aged population of African Americans and whites: the Atherosclerosis Risk in Communities (ARIC) study.
        Am J Prev Med. 2005; 29: 42-49
        • Blais C.
        • Rochette L.
        • Ouellet S.
        • Huynh T.
        Complex Evolution of epidemiology of vascular diseases, including increased disease burden: from 2000 to 2015.
        Can J Cardiol. 2020; 36: 740-746
        • Farber A.
        • Rosenfield K.
        • Menard M.
        The BEST-CLI trial: a multidisciplinary effort to assess which therapy is best for patients with critical limb ischemia.
        Tech Vasc Interv Radiol. 2014; 17: 221-224