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Canadian Journal of Cardiology

The Importance of Gender to Understand Sex Differences in Cardiovascular Disease

  • Author Footnotes
    ‡ These authors contributed equally to this work.
    Paul J. Connelly
    Footnotes
    ‡ These authors contributed equally to this work.
    Affiliations
    Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
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  • Author Footnotes
    ‡ These authors contributed equally to this work.
    Zahra Azizi
    Footnotes
    ‡ These authors contributed equally to this work.
    Affiliations
    Centre for Outcomes Research and Evaluation, McGill University Health Centre Research Institute, Montréal, Québec, Canada
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  • Pouria Alipour
    Affiliations
    Centre for Outcomes Research and Evaluation, McGill University Health Centre Research Institute, Montréal, Québec, Canada
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  • Christian Delles
    Correspondence
    Dr Christian Delles, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Tel.: +44 141 330 2749.
    Affiliations
    Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
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  • Louise Pilote
    Correspondence
    Corresponding authors: Dr Louise Pilote, Centre for Outcomes Research and Evaluation, Divisions of Clinical Epidemiology and General Internal Medicine, McGill University Health Centre Research Institute, 5252 Boulevard de Maisonneuve, Montréal, Québec, H3A 1A1, Canada. Tel.: +1-514 934-1934 ext 44722; fax: +1-514 843-1676.
    Affiliations
    Centre for Outcomes Research and Evaluation, McGill University Health Centre Research Institute, Montréal, Québec, Canada

    Divisions of Clinical Epidemiology and General Internal Medicine, McGill University Health Centre Research Institute, Montréal, Québec, Canada
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  • Valeria Raparelli
    Affiliations
    Department of Translational Medicine, University of Ferrara, Ferrara, Italy

    University of Alberta, Faculty of Nursing, Edmonton, Alberta, Canada
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  • Author Footnotes
    ‡ These authors contributed equally to this work.
Published:February 12, 2021DOI:https://doi.org/10.1016/j.cjca.2021.02.005

      Abstract

      Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. There is robust evidence of heterogeneity in underlying mechanism, manifestation, prognosis, and response to treatment of CVD between male and female patients. Gender, which refers to the socially constructed roles, behaviours, expressions, and identities of individuals, is an important determinant of CV health, and its consideration might help in attaining a broader understanding of the observed sex differences in CVD. Established risk factors such as hypertension, dyslipidemia, diabetes mellitus, obesity, and smoking are well known to contribute to CVD. However, despite the differences in CVD risk between male and female, most studies looking into the magnitude of effect of each risk factor have traditionally focused on male subjects. While biological sex influences disease pathophysiology, the psycho-socio-cultural construct of gender can further interact with this effect. Behavioural, psychosocial, personal, cultural, and societal factors can create, repress, or strengthen underlying biological CV health differences. Although mechanisms of action are largely unclear, it is suggested that gender-related factors can further exacerbate the detrimental effect of established risk factors of CVD. In this narrative review, we explore the current literature investigating the role of gender in CV risk and its impact on established risk factors as a fundamental step toward precision medicine.

      Résumé

      Les maladies cardiovasculaires (MCV) sont la principale cause de morbidité et de mortalité à l’échelle mondiale. Des données robustes témoignent de l’hétérogénéité entre hommes et femmes concernant le mécanisme sous-jacent, la manifestation, le pronostic et la réponse au traitement de MCV. Le genre, qui renvoie à une construction sociale des rôles, des comportements, de l’expression et de l’identité individuelle, est un déterminant important de la santé cardiovasculaire (CV), et sa prise en compte pourrait aider à mieux comprendre les différences observées entre les sexes à l’égard des MCV. Il est bien connu que les facteurs de risque établis comme l’hypertension, la dyslipidémie, le diabète, l’obésité et le tabagisme jouent un rôle dans les MCV. Toutefois, malgré les différences entre hommes et femmes sur le plan des MCV, la plupart des études examinant l’ampleur de l’effet de chaque facteur de risque se sont habituellement concentrées sur des sujets de sexe masculin. Bien que le sexe biologique influence la physiopathologie de la maladie, la construction psycho-socio-culturelle du genre peut également interagir avec celle-ci. Les facteurs comportementaux, psychosociaux, personnels, culturels et sociétaux peuvent créer, réprimer ou renforcer les différences biologiques sous-jacentes en matière de santé CV. Les facteurs liés au genre, bien que leurs mécanismes soient peu connus, pourraient exacerber l’effet délétère des facteurs de risque établis de MCV. Dans cet article de synthèse, nous explorons la littérature actuelle qui se penche sur la part du genre dans le risque de maladie CV et sur son effet sur les facteurs de risque établis, étape essentielle vers une médecine de précision.
      Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide.
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      • Abate K.H.
      • et al.
      Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.
      Despite growing awareness of the role of sex and gender in the management of CVD, female patients continue to experience delays in diagnosis and treatment,
      • Bugiardini R.
      • Ricci B.
      • Cenko E.
      • et al.
      Delayed care and mortality among women and men with myocardial infarction.
      ,
      • Melberg T.
      • Kindervaag B.
      • Rosland J.
      Gender-specific ambulance priority and delays to primary percutaneous coronary intervention: a consequence of the patients’ presentation or the management at the emergency medical communications center?.
      are referred to and participate less in cardiac rehabilitation,
      • Colella T.J.
      • Gravely S.
      • Marzolini S.
      • et al.
      Sex bias in referral of women to outpatient cardiac rehabilitation? A meta-analysis.
      are not sufficiently represented in clinical trials,
      • Jin X.
      • Chandramouli C.
      • Allocco B.
      • et al.
      Women’s participation in cardiovascular clinical trials from 2010 to 2017.
      and as a consequence may often suffer worse outcomes.
      In the medical literature, the terms “sex” and “gender” are sometimes interchangeably used, generating confusion. Sex refers to the biological characteristics of an individual as determined by chromosomal complement and sex hormones. The impact of these biological factors on CV risk are well established.
      • Feldman R.D.
      Sex-specific determinants of coronary artery disease and atherosclerotic risk factors: estrogen and beyond.
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      Sex-specific considerations in guidelines generation and application.
      For example, low levels of estrogen in younger females are associated with an increased risk of CVD,
      • Morselli E.
      • Santos R.S.
      • Criollo A.
      • et al.
      The effects of oestrogens and their receptors on cardiometabolic health.
      ,
      • Jacobsen B.K.
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      • Heuch I.
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      Does age at natural menopause affect mortality from ischemic heart disease?.
      and declining estrogen levels after menopause, in addition to advancing age, are associated with unfavourable lipid profiles,
      • Kilim S.R.
      • Chandala S.R.
      A comparative study of lipid profile and oestradiol in pre-and post-menopausal women.
      blood pressure (BP) elevation, and increased CV risk.
      Women's Health Initiative Steering Committee
      Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.
      Moreover, pregnancy-related complications, such as gestational diabetes and preeclampsia, may alter this risk, as well as endocrine disorders, such as polycystic ovarian syndrome, which may promote CVD.
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular Health After Maternal Placental Syndromes (CHAMPS): population-based retrospective cohort study.
      ,
      • Veltman-Verhulst S.M.
      • van Rijn B.B.
      • Westerveld H.E.
      • et al.
      Polycystic ovary syndrome and early-onset preeclampsia: reproductive manifestations of increased cardiovascular risk.
      Beyond sex, gender derives from the social, cultural, and behavioural factors that may modulate health.
      • Clayton J.A.
      • Tannenbaum C.
      Reporting sex, gender, or both in clinical research?.
      ,
      • Schiebinger L.
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      Gender matters in biological research and medical practice.
      Gender is a multidimensional concept that incorporates identity (ie, an inner sense of masculinity, femininity, or gender nonconformity), role (ie, societal and environmental expectations), relationships (ie, interpersonal interactions and dynamics), and institutionalised gender (ie, distribution of power in political, educational, social institutions in society).
      Canadian Institutes of Health Research
      Sex, gender and health research.
      Gender may significantly influence health-related behaviours and interact with CV risk factors.
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • et al.
      Sex- versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      Importantly, these concepts may intersect and interact with one another.
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      • et al.
      Sex and gender: modifiers of health, disease, and medicine.
      A greater understanding of both sex and gender differences is required to drive improvements in diagnosis, treatment, and outcomes. In this narrative review, based on our prior work on the topic and available literature, we summarise current knowledge of the role of gender in the development of CV risk, its impact on established CV risk factors, and the means by which it can be measured in clinical research. Use of the terms males/men and females/women can be somewhat confusing. Here, we use the terms male and female as referring to biological sex and man and woman to gender as well as when these factors are not clear.

      Gender and CV Risk

      Gender contributes to CV health of women and men both directly and indirectly through the acquisition of other risk factors (Table 1). As such, the role of each gender domain (ie, identity, roles, relations, institutions) and its interaction with biological sex in CVD manifestation, progression, and outcome deserve further investigation. The mechanisms by which detrimental characteristics ascribed to women in most cultures (ie, poverty, low-level jobs, and lower pay) modify CVD risk are multifaceted.
      Table 1Studies assessing gender dimensions and cardiovascular disease
      StudyParticipantsAnalysisGender-related variableResults
      Ranges in parentheses are 95% confidence intervals.
      Gender identity
      Whang et al. (2009)
      • Whang W.
      • Kubzansky L.D.
      • Kawachi I.
      • et al.
      Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study.
      Nurses’ Health Study Cohort: 63,469 women without previous coronary heart disease/stroke in 1992Association between depression and CHD and SCD in women; outcome: CHD/SCD; exposure: depressionDepression: Mental Health Index (MHI-5) < 53CHD: HR 1.49 (1.11-2.00, for MHI-5 score < 53

      SCD: HR 2.33 (1.47-3.70
      Shanmugasegaram et al. (2012)
      • Shanmugasegaram S.
      • Russell K.L.
      • Kovacs A.H.
      • Stewart D.E.
      • Grace S.L.
      Gender and sex differences in prevalence of major depression in coronary artery disease patients: a meta-analysis.
      Systematic review and meta-analysis: 8 studies; n = 2072; 24.6% femaleTo examine whether women with CAD experience greater prevalence of major depression than men with CADDepressionPooled analysis, women vs men: OR 1.77 (1.21-2.58), P < 0.1
      Meijer et al. (2013)
      • Meijer A.
      • Conradi H.J.
      • Bos E.H.
      • et al.
      Adjusted prognostic association of depression following myocardial infarction with mortality and cardiovascular events: individual patient data meta-analysis.


      Doyle et al. (2015)
      • Doyle F.
      • McGee H.
      • Conroy R.
      • et al.
      Systematic review and individual patient data meta-analysis of sex differences in depression and prognosis in persons with myocardial infarction: a MINDMAPS study.
      Systematic review and meta-analysis: 16 studies, 10,175 patients; age 56-65, mean age 61, 28% femaleAssociation between post-MI depression and prognosisDepression (after MI)Pooled analyses: all-cause mortality HR 1.32 (1.26-1.38); CV events HR 1.19 (1.14-1.24).

      Men, all-cause mortality: HR 1.38 (1.30-1.47).

      Women, all-cause mortality: HR 1.22 (1.14-1.31)
      Xu et al. (2015)
      • Xu X.
      • Bao H.
      • Strait K.
      • et al.
      Sex differences in perceived stress and early recovery in young and middle-aged patients with acute myocardial infarction.
      VIRGO study: 3572 AMI patients; 2397 female, ages 18-55Sex difference in perceived stress in young and middle-aged patients presenting with AMIModerate perceived stressAdjusted mean difference in 1-month recovery associated with sex and baseline perceived stress: angina-related QOL Beta −3.50 (−5.68 to −1.33); SF-12 MCS score Beta −1.96 (−2.96 to −0.96)
      Gender role
      Nyberg et al. (2013)
      • Nyberg S.T.
      • Fransson E.I.
      • Heikkilä K.
      • et al.
      Job strain and cardiovascular disease risk factors: meta-analysis of individual-participant data from 47,000 men and women.
      Systematic review and meta-analysis: 8 studies; n = 47,045; mean age 45.1, 29.2% femaleAssociation between job strain and traditional risk factors of heart diseaseJob strainAge and sex adjusted: diabetes OR 1.35 (1.15-1.57), smoking OR 1.23 (1.16-1.3), physical inactivity OR 1.43 (1.36-1.51), obesity OR 1.19 (1.11-1.28), Framingham risk score ≥ 20 OR 1.19 (1.08-1.31)
      Kivimaki et al. (2006)
      • Kivimäki M.
      • Virtanen M.
      • Elovainio M.
      • et al.
      Work stress in the etiology of coronary heart disease: a meta-analysis.
      Systematic review and meta-analysis: 14 studies; 83,014 employeesAssociation between work stress, as indicated by job strain, effort-reward imbalance, and organisational injustice, with RR of CHDJob strain, organisational injustice, effort-reward imbalanceSex-adjusted RR of CHD for high job strain: 1.43 (1.15-1.84).

      Sex-adjusted RR of CHD for higher organisational injustice: 1.62 (1.24-2.1).

      Sex-adjusted RR of CHD for effort-reward imbalance: RR 2.52 (1.63-3.90)
      Torquati et al. (2018)
      • Torquati L.
      • Mielke G.I.
      • Brown W.J.
      • Kolbe-Alexander T.
      Shift work and the risk of cardiovascular disease. A systematic review and meta-analysis including dose-response relationship.
      Systematic review and meta-analysis: 21 studies; 173,010 participantsAssociation between shiftwork and CVDShift workCVD events: effect size (OR) 1.17 (1.09-1.25), I2 = 67.0%
      Kang et al. (2012)
      • Kang M.-Y.
      • Park H.
      • Seo J.-C.
      • et al.
      Long working hours and cardiovascular disease: a meta-analysis of epidemiologic studies.
      Systematic review and meta-analysis: 11 studies, 15,923 participants, age 20-65, mean age 52.6, 22.6% femaleAssociation between long work hours and CVDLong/overtime work hours vs regularCVD: OR 1.37 (1.11-1.70)
      Gender relationships
      Kilpi et al. (2015)
      • Kilpi F.
      • Konttinen H.
      • Silventoinen K.
      • Martikainen P.
      Living arrangements as determinants of myocardial infarction incidence and survival: a prospective register study of over 300,000 Finnish men and women.
      Population-based registry: adults aged 40-60, Finland 1995-2007; n = 302,885, 49.9% femaleAssociation between living arrangements and MI incidence and fatalityLiving arrangement: marital partner, cohabitation, living with others, living aloneHR for MI, reference married: men: cohabitation 1.34 (1.20-1.49), living with others 1.42 (1.29-1.56), living alone 1.49 (1.39-1.60); women: cohabitation 1.30 (1.03-1.65), living with others 1.60 (1.33-1.93), living alone 1.45 (1.26-1.66).

      HR for MI first-day fatality, reference married: men: cohabitation 1.35 (1.14-1.60), living with others 2.35 (2.02-2.74), living alone 2.22 (1.99-2.49); women: cohabitation 1.82 (1.25-2.65), living with others 1.76 (1.30-2.37), living alone 1.35 (1.09-1.67).

      HR for MI long-term fatality, reference married: men: cohabitation 1.23 (1-1.51), living with others 2.46 (2.05-2.95), living alone 2.05 (1.80-2.34); women: cohabitation 2.21 (1.42-3.44), living with others 1.95 (1.41-2.70), living alone 1.26 (1-1.59)
      Ikeda et al. (2008)
      • Ikeda A.
      • Iso H.
      • Kawachi I.
      • et al.
      Living arrangement and coronary heart disease: the JPHC study.
      Prospective cohort study: 1990-2004, 90,987 Japanese, age 40-69, 47,594 femaleImpact of living arrangements on the incidence of CHD and mortality as well as all-cause mortalityLiving arrangementsMen: HR for CHD incidence (reference spouse): alone 1.23 (0.74-2.02), spouse + parent 0.90 (0.54-1.5), spouse + child 1.06 (0.83-1.35), spouse + child + parent 1.04 (0.76-1.41), child 0.84 (0.52-1.37), child + parent 1.17 (0.63-2.16); HR for CHD mortality (reference spouse): alone 1.43 (0.73-2.81), spouse + parent 0.57 (0.23-1.42), spouse + child 1.11 (0.79-1.57), spouse + child+ parent 1.01 (0.63-1.62), child 1.54 (0.86-2.76), child + parent 0.81 (0.25-2.65).

      Women: HR for CHD incidence (reference spouse): alone 1.77 (0.92-3.39), spouse + parent 3.03 (1.36-6.75), spouse + child 2.11 (1.33-3.35), spouse + child + parent 2 (1.1-3.94), child 2 (1.16-3.43), child + parent 1.17 (0.27-4.98); HR for CHD mortality (reference spouse): alone 2.72 (1.37-5.38), spouse + parent 1.45 (0.42-4.97), spouse + child 1.26 (0.69-2.30), spouse + child + parent 1 (0.36-2.79), child 1.85 (0.95-3.62), child + parent 2.73 (0.78-9.51)
      Institutionalised gender
      Backholer et al. (2016)
      • Backholer K.
      • Peters S.A.E.
      • Bots S.H.
      • et al.
      Sex differences in the relationship between socioeconomic status and cardiovascular disease: a systematic review and meta-analysis.
      Systematic review and meta-analysis: 116 studies, >22 million individuals, 35% femaleEstimate of the sex differences in the RRs of SES on the risk of incident CHD, stroke, and CVD in the general populationEducation, deprivation, occupation, incomeCHD: education RR: women 1.66 (1.46-1.88), men 1.30 (1.15-1.48);

      area deprivation RR: women 1.83 (1.61-2.07), men 1.5 (1.38-1.63);

      occupation RR: women 1.59 (1.28-1.97), men 1.50 (1.25-1.80);

      income RR: women 2.48 (1.53-4), men 2.01 (1.47-2.74).

      CVD: education RR: women 1.66 (1.43-1.92), men 1.42 (1.25-1.63);

      area deprivation RR: women 1.75 (1.55-1.98), men 1.60 (1.45-1.76);

      occupation RR: women 1.80 (1.51-2.40), men 1.74 (1.38-2.20);

      income RR: women 1.46 (1.43-1.50), men 1.36 (1.34-1.39).
      Tang et al. (2015)
      • Tang K.L.
      • Rashid R.
      • Godley J.
      • Ghali W.A.
      Association between subjective social status and cardiovascular disease and cardiovascular risk factors: a systematic review and meta-analysis.
      Systematic review and meta analysis: 10 studies; n = 981-8152; 34%-74% femaleAssociation between SSS and the odds of CAD, hypertension, diabetes, obesity, and dyslipidemiaLow vs high SSS: an individual’s perception of his or her own position in the social and socioeconomic hierarchyORs:

      CAD 1.82 (1.10-2.99), hypertension 1.88 (1.27- 2.79), diabetes 1.90 (1.25-2.87), dyslipidemia 3.68 (2.03-6.64), obesity 1.57 (0.95-2.59);

      Male: hypertension 1.57 (1.03-2.38), diabetes, 1.99 (1.40-2.84), obesity 1.02 (0.76-1.37);

      Female: hypertension 1.77 (1.27-2.49), diabetes 2.14 (1.34-3.42), obesity 1.66 (0.88-3.13).

      Meta regression comparing females vs males: not significant.
      Rosengren et al. (2019)
      • Rosengren A.
      • Smyth A.
      • Rangarajan S.
      • et al.
      Socioeconomic status and risk of cardiovascular disease in 20 low-income, middle-income, and high-income countries: the Prospective Urban Rural Epidemiologic (PURE) study.
      Large-scale prospective cohort study: the PURE study: 367 urban communities, 302 rural communities, 20 countries, age 35-70; n = 17,241; 53.6% femaleAssociation between education, household wealth, and CVD mortalityEducation (low vs high level)Major CV events: high-income countries HR 1.23 (0.96-1.58), middle-income countries HR 1.59 (1.42-1.78), low-income countries HR 2.23 (1.79-2.77).

      CV mortality: high-income countries HR 1.50 (1.14-1.98), middle-income countries HR 1.80 (1.58-2.06), low-income countries HR 2.76 (2.29-3.31).

      No sex-stratified results provided.
      Gender score (all dimensions)
      Pelletier et al. (2016)
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • et al.
      Sex- versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      GENESIS-PRAXY, a prospective observational cohort study: n = 909; 2009-2013, age 18-55, 30% femaleAssociations between gender and sex with recurrent ACS and MACE (eg, ACS, cardiac mortality, revascularisation) over 12 months in patients with ACSGender score: household primary earner, personal income, number of hours per week spent doing housework, level of stress at home, Bem Sex-Role Inventory masculinity score, Bem Sex-Role Inventory femininity scoreHypertension OR 1.85 (1.04-3.29), diabetes OR 2.07 (1.00-2.39), depressive symptoms OR 2.68 (1.61-4.44), anxious symptoms OR 3.62 (2.17-6.01), recurrent ACS OR 4.50 (1.05-19.27)
      Azizi et al. (2020)
      • Azizi Z.
      • Bender U.
      • Tadiri C.
      • et al.
      Sex and gender factors and the cardiovascular health of canadians.
      CCHS database: cycle 2014; n = 63,522; 55.27% femaleAssociation between a gender index created from a composite measure of gender-related factors and biological sex in predicting CVHGender score: household size, perceived life stress, education level, sense of belonging to community, marital status, incomeCANHEART score: CVH Beta −0.43 (−0.51 to −0.36)
      ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAD, coronary artery disease; CCHS, Canadian Community Health Survey; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; CVH, cardiovascular health; GENESIS-PRAXY, Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond Premature Acute Coronary Syndrome; HR, hazard ratio; MACE, major adverse cardiac events; MI, myocardial infarction; OR, odds ratio; PURE, Prospective Urban Rural Epidemiologic; QOL, quality of life; RR, relative risk; SCD, sudden cardiac death; SES, socioeconomic status; SSS, subjective social status; VIRGO, Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients.
      Ranges in parentheses are 95% confidence intervals.

      Gender identity

      Gender identity describes a person’s intrinsic sense of their gender (ie, man, woman, nonbinary, gender-neutral or fluid, etc). It is important to note that gender identity may be the same (cisgender), or different (transgender, gender-neutral) from biological sex. The underlying mechanism between gender identity and CVD risk is poorly understood and is likely mediated through other gender domains. Personality traits, stress level at work and home, emotional intelligence, depression, anxiety and childhood trauma are examples of this dimension
      Canadian Institutes of Health Research
      Sex, gender and health research.
      ,
      • Johnson J.L.
      • Greaves L.
      • Repta R.
      Better science with sex and gender: a primer for health research.
      ,
      • Tadiri C.P.
      • Raparelli V.
      • Abrahamowicz M.
      • et al.
      Methods for prospectively incorporating gender into health sciences research.
      (Table 1).
      Personality traits including anger, hostility, type D (distressed) personality, and psychosocial stress are associated with an adverse CVD prognosis.
      • Pedersen S.S.
      • von Känel R.
      • Tully P.J.
      • Denollet J.
      Psychosocial perspectives in cardiovascular disease.
      • Steptoe A.
      • Kivimäki M.
      Stress and cardiovascular disease: an update on current knowledge.
      • Xu X.
      • Bao H.
      • Strait K.
      • et al.
      Sex differences in perceived stress and early recovery in young and middle-aged patients with acute myocardial infarction.
      The impact of stress in increasing CVD is not uniform in men and women. Moderate to high stress level is associated with worse recovery after myocardial infarction (MI), including decreased angina-related and overall quality of life.
      • Xu X.
      • Bao H.
      • Strait K.
      • et al.
      Sex differences in perceived stress and early recovery in young and middle-aged patients with acute myocardial infarction.
      Similarly, depression is recognised as a risk factor for CVD that can worsen outcomes with ischemic heart disease (IHD) and stroke.
      • Yang L.
      • Korhonen K.
      • Moustgaard H.
      • Silventoinen K.
      • Martikainen P.
      Pre-existing depression predicts survival in cardiovascular disease and cancer.
      Women are twice as likely than men to develop depression during their lifetime,
      • Kuehner C.
      Why is depression more common among women than among men?.
      which consequently increases cardiac events.
      • Hare D.L.
      • Toukhsati S.R.
      • Johansson P.
      • Jaarsma T.
      Depression and cardiovascular disease: a clinical review.
      • Vaccarino V.
      • Badimon L.
      • Corti R.
      • et al.
      Ischaemic heart disease in women: are there sex differences in pathophysiology and risk factors? Position paper from the Working Group on Coronary Pathophysiology and Microcirculation of the European Society of Cardiology.
      • Whang W.
      • Kubzansky L.D.
      • Kawachi I.
      • et al.
      Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study.
      Women with increased negative affect also have increased body mass index, BP, and CV events.
      • Whittaker K.S.
      • Krantz D.S.
      • Rutledge T.
      • et al.
      Combining psychosocial data to improve prediction of cardiovascular disease risk factors and events: the National Heart, Lung, and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation study.
      Stress and psychological factors’ contribution to poor CVD outcomes is complex; however, it has been hypothesised that even exposure to trauma at a young age leads to an increased susceptibility to adverse lifestyle behaviours such as substance abuse, poor diet, and sedentary lifestyle.
      • Greaney J.L.
      • Surachman A.
      • Saunders E.F.H.
      • Alexander L.M.
      • Almeida D.M.
      Greater daily psychosocial stress exposure is associated with increased norepinephrine-induced vasoconstriction in young adults.

      Gender roles

      There are several gendered aspects that contribute to the roles of individuals in society: primary earner status, employment status, occupation type, paid and unpaid (ie, caregiving) work hours, caregiver responsibilities, household responsibilities, and number of children
      Canadian Institutes of Health Research
      Sex, gender and health research.
      ,
      • Johnson J.L.
      • Greaves L.
      • Repta R.
      Better science with sex and gender: a primer for health research.
      ,
      • Tadiri C.P.
      • Raparelli V.
      • Abrahamowicz M.
      • et al.
      Methods for prospectively incorporating gender into health sciences research.
      ,
      • Johnson J.L.
      • Greaves L.
      • Repta R.
      Better science with sex and gender: facilitating the use of a sex and gender-based analysis in health research.
      (Table 1). Roles largely vary across cultures, so their effect on CV risk might be different among countries.
      A recent study demonstrated that young women with acute coronary syndrome (ACS) are less likely to have primary earner status and have lower personal income, compared with men with ACS.
      • Pelletier R.
      • Ditto B.
      • Pilote L.
      A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome.
      Job strain has been shown to negatively affect cardiometabolic risk factors (diabetes, smoking, physical inactivity, obesity),
      • Nyberg S.T.
      • Fransson E.I.
      • Heikkilä K.
      • et al.
      Job strain and cardiovascular disease risk factors: meta-analysis of individual-participant data from 47,000 men and women.
      which in turn increases the risk of IHD and mortality.
      • Nyberg S.T.
      • Fransson E.I.
      • Heikkilä K.
      • et al.
      Job strain and cardiovascular disease risk factors: meta-analysis of individual-participant data from 47,000 men and women.
      ,
      • Kivimäki M.
      • Kawachi I.
      Work stress as a risk factor for cardiovascular disease.
      Other studies have also shown dose-response associations between shift work
      • Torquati L.
      • Mielke G.I.
      • Brown W.J.
      • Kolbe-Alexander T.
      Shift work and the risk of cardiovascular disease. A systematic review and meta-analysis including dose-response relationship.
      and longer work hours
      • Kang M.-Y.
      • Park H.
      • Seo J.-C.
      • et al.
      Long working hours and cardiovascular disease: a meta-analysis of epidemiologic studies.
      with increased risk of CV events.
      • Torquati L.
      • Mielke G.I.
      • Brown W.J.
      • Kolbe-Alexander T.
      Shift work and the risk of cardiovascular disease. A systematic review and meta-analysis including dose-response relationship.
      ,
      • Kang M.-Y.
      • Park H.
      • Seo J.-C.
      • et al.
      Long working hours and cardiovascular disease: a meta-analysis of epidemiologic studies.
      Conversely, while women and men with the same occupational level may have a similar response to stress at work, women’s stress level remains high even after work, which may be due to greater household and child care responsibilities,
      • Frankenhaeuser M.
      • Lundberg U.
      • Fredrikson M.
      • et al.
      Stress on and off the job as related to sex and occupational status in white-collar workers.
      ,
      • Lundberg U.
      Stress hormones in health and illness: the roles of work and gender.
      suggesting a more detrimental effect of those factors on women’s CV health.

      Gender relations

      Gender relations refer to the relationship and interaction of individuals based on their gender identity (ie, marital/relationship status, family or local network, social support, and availability of caretaker (for self)).
      Canadian Institutes of Health Research
      Sex, gender and health research.
      ,
      • Johnson J.L.
      • Greaves L.
      • Repta R.
      Better science with sex and gender: a primer for health research.
      ,
      • Tadiri C.P.
      • Raparelli V.
      • Abrahamowicz M.
      • et al.
      Methods for prospectively incorporating gender into health sciences research.
      Such factors have important impact on overall disease outcomes
      • Rook K.S.
      • Dooley D.
      Applying social support research: Theoretical problems and future directions.
      ,
      • White-Williams C.
      • Rossi L.P.
      • Bittner V.A.
      • et al.
      Addressing social determinants of health in the care of patients with heart failure: a scientific statement from the American Heart Association.
      (Table 1). Marital stress has been shown to increase the risk of recurrent cardiac events in women with established IHD.
      • Orth-Gomer K.
      • Wamala S.P.
      • Horsten M.
      • et al.
      Marital stress worsens prognosis in women with coronary heart disease: the Stockholm Female Coronary Risk Study.
      A recent study investigating living arrangements and CVD outcome showed that women living with a spouse and children are 2 times more likely to have IHD compared with those living with just a spouse.
      • Ikeda A.
      • Iso H.
      • Kawachi I.
      • et al.
      Living arrangement and coronary heart disease: the JPHC study.
      Married men had a lower risk of MI incidence independent from other socioeconomic factors such as education, occupation, income, wealth, and employment.
      • Kilpi F.
      • Konttinen H.
      • Silventoinen K.
      • Martikainen P.
      Living arrangements as determinants of myocardial infarction incidence and survival: a prospective register study of over 300,000 Finnish men and women.
      Moreover, living alone in men and cohabitation in women were associated with a greater risk of fatality after MI compared with being married.
      • Kilpi F.
      • Konttinen H.
      • Silventoinen K.
      • Martikainen P.
      Living arrangements as determinants of myocardial infarction incidence and survival: a prospective register study of over 300,000 Finnish men and women.

      Institutionalised gender

      Institutionalised gender (ie, educational attainment level, socioeconomic status [SES], Gender Inequality Index)
      Canadian Institutes of Health Research
      Sex, gender and health research.
      ,
      • Johnson J.L.
      • Greaves L.
      • Repta R.
      Better science with sex and gender: a primer for health research.
      ,
      • Tadiri C.P.
      • Raparelli V.
      • Abrahamowicz M.
      • et al.
      Methods for prospectively incorporating gender into health sciences research.
      refers to the distribution of wealth, power, and opportunity in society (Table 1). Studies have shown that lower SES is associated with increased risk of IHD and stroke. Women with a low education level are at 34% and 23% higher risks of IHD and CVD, respectively, compared with men with low education.
      • Backholer K.
      • Peters S.A.E.
      • Bots S.H.
      • et al.
      Sex differences in the relationship between socioeconomic status and cardiovascular disease: a systematic review and meta-analysis.
      Moreover, lower subjective SES (one’s perception of one’s socioeconomic position) has been associated with acquiring traditional risk factors and the development of CVD.
      • Tang K.L.
      • Rashid R.
      • Godley J.
      • Ghali W.A.
      Association between subjective social status and cardiovascular disease and cardiovascular risk factors: a systematic review and meta-analysis.
      Currently, women make up 60% of the world’s poor and 66% of world’s illiterate population.
      World Health Organisation
      Noncommunicable diseases: a priority for women’s health and development.
      The lower SES of women is a significant predictor of CV death and MI regardless of angiographic coronary artery disease extent, chest pain, and other traditional risk factors.
      • Shaw L.J.
      • Bairey Merz C.N.
      • Bittner V.
      • et al.
      Importance of socioeconomic status as a predictor of cardiovascular outcome and costs of care in women with suspected myocardial ischemia. Results from the National Institutes of Health, National Heart, Lung and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation (WISE).
      Furthermore, women are less likely to be insured through their employment and are more likely to be financially dependent,
      • Bartz D.
      • Chitnis T.
      • Kaiser U.B.
      • et al.
      Clinical advances in sex- and gender-informed medicine to improve the health of all: a review.
      thereby reducing access to health care services. Such institutionalised gender factors result in higher morbidity and decreased healthy life-years.
      These factors and their impact on CV health are gendered in that they show different prevalence and impact on diseases not solely due to male-female biological differences but in relation to differences in roles, relationships, and identity between men and women in society.

      Gender—A Modifier of Established Cardiovascular Risk Factors

      The Framingham Heart Study coined the term coronary risk factors (hypertension, smoking, diabetes and dyslipidemia) as major determinants of CVD risk, and these were later described as “traditional” risk factors.
      • Dawber T.R.
      • Moore F.E.
      • Mann G.V.
      Coronary heart disease in the Framingham study.
      ,
      • Mahmood S.S.
      • Levy D.
      • Vasan R.S.
      • Wang T.J.
      The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective.
      Although males and females share these risk factors, their prevalence differs across the life span and some factors are more potent in females than in males. Risk-assessment tools, such as the Framingham Heart Score, that utilise only traditional risk factors underestimate CV risk in women owing to the absence of psychosocial assessment and to the estimation of short-term CV risk instead of lifetime risk, which is more suitable in female patients, who live longer.
      • Lakoski S.G.
      • Greenland P.
      • Wong N.D.
      • et al.
      Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on Framingham risk score: the Multi-Ethnic Study Of Atherosclerosis (MESA).
      The identification of “nontraditional” risk factors has furthered our understanding of CVD risk and how these factors can contribute to differences in CVD between men and women (Fig. 1). Sex differences in these established CV risk factors have been reviewed extensively elsewhere.
      • Feldman R.D.
      Sex-specific determinants of coronary artery disease and atherosclerotic risk factors: estrogen and beyond.
      However, the role of gender in modifying these risk factors and how gender can potentially explain well known sex differences is less well described or understood. Below, we provide examples of this relationship. For each risk factor, we first briefly report on sex differences, followed by data, when available, on the role of gender for understanding the observed sex differences in CVD risk factors.
      Figure thumbnail gr1
      Figure 1Traditional and nontraditional cardiovascular (CV) risk factors: biological sex, gender, and their interaction as modifiers of CV health. Established (traditional and nontraditional) CV risk factors interact with both sex and gender to influence CV risk and disease. DM, diabetes mellitus.

      Blood pressure

      A prospective UK Biobank study of almost 500,000 individuals has demonstrated an 80% higher relative risk of MI in female patients with hypertension compared with male patients.
      • Millett E.R.
      • Peters S.A.
      • Woodward M.
      Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants.
      Sex differences in BP are mediated by variations in the renin-angiotensin-aldosterone, bradykinin, and nitric oxide systems and are thought to be predominantly sex hormone mediated.
      • Regitz-Zagrosek V.
      • Kararigas G.
      Mechanistic pathways of sex differences in cardiovascular disease.
      These differences begin in adolescence, when males demonstrate higher BP than females,
      • Dasgupta K.
      • O’Loughlin J.
      • Chen S.
      • et al.
      Emergence of sex differences in prevalence of high systolic blood pressure: analysis of a longitudinal adolescent cohort.
      and extend into later life where more males have hypertension until the sixth decade, after which it is more prevalent in females.
      • Benjamin E.J.
      • Virani S.S.
      • Callaway C.W.
      • et al.
      Heart disease and stroke statistics—2018 update: a report from the American Heart Association.
      In a longitudinal BP analysis of 32,833 individuals, females exhibited a sharper incline in BP, commencing in and persisting from their third decade, compared with males.
      • Ji H.
      • Kim A.
      • Ebinger J.E.
      • et al.
      Sex differences in blood pressure trajectories over the life course.
      This divergence in BP trajectory may influence CVD risk later in life and mediate the sex differences observed in CVD, which present differently between sexes. The cause of this progressive BP elevation in females is unknown and potentially multifaceted. The influence of sex-related hormonal, genetic, and epigenetic differences on BP are evident and likely to play a significant role.
      • Colafella K.M.M.
      • Denton K.M.
      Sex-specific differences in hypertension and associated cardiovascular disease.
      However, gendered social, economic, and environmental factors may facilitate alterations in vascular biology and alter BP in women. In a recent analysis of 59,805 French adults from the Constances cohort, relative SES, particularly education inequality, demonstrated stronger associations with hypertension prevalence in women compared with men,
      • Neufcourt L.
      • Deguen S.
      • Bayat S.
      • Zins M.
      • Grimaud O.
      Gender differences in the association between socioeconomic status and hypertension in France: a cross-sectional analysis of the Constances cohort.
      thereby demonstrating the potential impact of gender on BP.

      Smoking

      Smoking is another leading risk factor that substantially increases CVD risk.
      • Huxley R.R.
      • Woodward M.
      Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies.
      ,
      • Reitsma M.B.
      • Fullman N.
      • Ng M.
      • et al.
      Smoking prevalence and attributable disease burden in 195 countries and territories 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015.
      The interaction between CVD, sex, and smoking first became evident in a prospective study of ~ 25,000 individuals, where the relative risk of MI in women who smoke exceeded that of men by > 50%.
      • Prescott E.
      • Hippe M.
      • Schnohr P.
      • Hein H.O.
      • Vestbo J.
      Smoking and risk of myocardial infarction in women and men: longitudinal population study.
      In a meta-analysis of more than 2.4 million individuals and more than 44,000 IHD events, compared with nonsmokers, women who smoked had a 25% higher relative risk for IHD than men who smoked.
      • Huxley R.R.
      • Woodward M.
      Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies.
      Whether the etiology of this excess risk in women is a consequence of gender-mediated smoking behaviours or cigarette toxin–sex interaction is unknown. However, because smoking prevalence, consumption, and cumulative exposure is higher in men, this risk factor appears to be more potent in women and therefore potentially sex mediated.
      • Reitsma M.B.
      • Fullman N.
      • Ng M.
      • et al.
      Smoking prevalence and attributable disease burden in 195 countries and territories 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015.
      ,
      Centers for Disease Control and Prevention
      Cigarette smoking among adults—United States 2006.
      • Woodward M.
      • Lam T.H.
      • Barzi F.
      • et al.
      Smoking, quitting, and the risk of cardiovascular disease among women and men in the Asia-Pacific region.
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Do smoking habits differ between women and men in contemporary Western populations? Evidence from half a million people in the UK Biobank study.

      Physical activity and obesity

      Physical activity is inversely associated with CV mortality, with or without established CVD.
      • Liu Y.
      • Shu X.-O.
      • Wen W.
      • et al.
      Association of leisure-time physical activity with total and cause-specific mortality: a pooled analysis of nearly a half million adults in the Asia Cohort Consortium.
      • Arem H.
      • Moore S.C.
      • Patel A.
      • et al.
      Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship.
      • Moholdt T.
      • Lavie C.J.
      • Nauman J.
      Sustained physical activity, not weight loss, associated with improved survival in coronary heart disease.
      In the Women’s Health Study, physical activity reduced IHD and stroke independently from traditional CV risk factors.
      • Chomistek A.K.
      • Cook N.R.
      • Rimm E.B.
      • et al.
      Physical activity and incident cardiovascular disease in women: is the relation modified by level of global cardiovascular risk?.
      Importantly, females across the spectrum of CV risk benefited from regular exercise. This association is also true for females with diabetes.
      • Hu F.B.
      • Stampfer M.J.
      • Solomon C.
      • et al.
      Physical activity and risk for cardiovascular events in diabetic women.
      In the INTERHEART (The Effect of Potentially Modifiable Risk Factors Associated with Myocardial Infarction) case-control study of 15,152 cases of MI, the protective effect of exercise was greater in females (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.4-0.6) than in males (OR 0.8, 95% CI 0.7-0.9).
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      Despite the potential beneficial effects of exercise on CVR risk, women are generally less physically active than men.
      • Guthold R.
      • Stevens G.A.
      • Riley L.M.
      • Bull F.C.
      Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1.9 million participants.
      This reduction in physical activity may be attributed to the prioritisation of social roles traditionally ascribed to women, including caregiving and chores in the home setting, and promotes adverse cardiometabolic risk factors in women compared with men.
      • Lee S.K.
      • Khambhati J.
      • Varghese T.
      • et al.
      Comprehensive primary prevention of cardiovascular disease in women.
      ,75 61,
      • Mosca L.
      • Mochari-Greenberger H.
      • Dolor R.J.
      • Newby L.K.
      • Robb K.J.
      Twelve-year follow-up of American women’s awareness of cardiovascular disease risk and barriers to heart health.
      • Mosca L.
      • Mochari-Greenberger H.
      • Dolor R.J.
      • Newby L.K.
      • Robb K.J.
      Twelve-year follow-up of American women’s awareness of cardiovascular disease risk and barriers to heart health.
      • Franco O.H.
      • Steyerberg E.W.
      • Hu F.B.
      • Mackenbach J.
      • Nusselder W.
      Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease.
      • Levitzky Y.S.
      • Pencina M.J.
      • D’Agostino R.B.
      • et al.
      Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study.
      • Wexler D.J.
      • Grant R.W.
      • Meigs J.B.
      • Nathan D.M.
      • Cagliero E.
      Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
      • Keyhani S.
      • Scobie J.V.
      • Hebert P.L.
      • McLaughlin M.A.
      Gender disparities in blood pressure control and cardiovascular care in a national sample of ambulatory care visits.
      • Shiroma E.J.
      • Lee I.M.
      Physical activity and cardiovascular health: lessons learned from epidemiological studies across age, gender, and race/ethnicity.
      Consequently, obesity rates are higher in females compared with males and continue to rise.
      • Collaboration N.R.F.
      Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants.
      In heart failure (HF), females who are obese demonstrate greater increases in left ventricular mass than obese males.
      • Kuch B.
      • Muscholl M.
      • Luchner A.
      • et al.
      Gender specific differences in left ventricular adaptation to obesity and hypertension.
      Obesity affects almost 50% of patients with HF with preserved ejection fraction,
      • Beale A.L.
      • Meyer P.
      • Marwick T.H.
      • Lam C.S.
      • Kaye D.M.
      Sex differences in cardiovascular pathophysiology: why women are overrepresented in heart failure with preserved ejection fraction.
      which occurs more commonly in females. Lower rates of obesity are observed in HF with reduced ejection fraction, which in turn is more prevalent in males. This observation suggests the presence of a sex-obesity interaction, that may be driven by a gender-influenced utilisation of exercise.

      Diabetes

      Type 2 diabetes elevates the risk for CVD in both sexes. A meta-analysis of participant level data including almost 1 million individuals with no previous vascular disease has demonstrated that diabetes doubles the risk of CV mortality due to IHD or ischemic stroke in males and triples the risk in females.
      • Gnatiuc L.
      • Herrington W.G.
      • Halsey J.
      • et al.
      Sex-specific relevance of diabetes to occlusive vascular and other mortality: a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies.
      Mortality was 6 times higher in middle-aged females (35-59 years) with diabetes compared with those without. Comparatively, mortality was doubled for men in this age group. Indeed, the female protective CV advantage evident in the wider population before menopause is lost in this condition.
      • Regensteiner J.G.
      • Golden S.
      • Huebschmann A.G.
      • et al.
      Sex differences in the cardiovascular consequences of diabetes mellitus: a scientific statement from the American Heart Association.
      Importantly, in individuals with ACS, a higher prevalence of adverse psychological factors (primary earner status, depression, anxiety, and worse physical health perceptions) is observed in women with diabetes, compared with women without diabetes and men with diabetes.
      • Peters T.M.
      • Pelletier R.
      • Behlouli H.
      • Rossi A.M.
      • Pilote L.
      Excess psychosocial burden in women with diabetes and premature acute coronary syndrome.
      These findings may in part explain the increased risk in women and exemplifies the intersection between sex and gender in the modulation of CV risk.

      Dyslipidemia

      Dyslipidemia is a major contributor to CVD mortality and morbidity. Compared with age-matched females, males a have a more pro-atherogenic lipid profile with lower high-density lipoprotein and higher low-density lipoprotein and triglycerides.
      • Ethun K.
      Sex and gender differences in body composition, lipid metabolism, and glucose regulation.
      Interestingly, in a prospective study of young males and females with acute MI (VIRGO [Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients]), lipid measurements taken after post-MI discharge were more favourable in female patients compared with male patients.
      • Lu Y.
      • Zhou S.
      • Dreyer R.P.
      • et al.
      Sex differences in lipid profiles and treatment utilization among young adults with acute myocardial infarction: results from the VIRGO study.
      This is despite young females with AMI having a higher risk of mortality compared with young males. In the VIRGO cohort, there were no differences in statin adherence by sex, suggesting that dyslipidemia may not be a major factor contributing to differences in outcomes observed between sexes, at least in younger age categories, albeit novel lipid factors such as lipoprotein (a) may prove to be more significant in females.
      • Lu Y.
      • Zhou S.
      • Dreyer R.P.
      • et al.
      Sex differences in lipid profiles and treatment utilization among young adults with acute myocardial infarction: results from the VIRGO study.

      Sex- and Gender-Based Analysis Approaches

      The paucity of data regarding the effect of gender on CVD risk is a consequence of the lack of standardised methods to measure gender and is a limitation in the data provided (Table 1). Thus, creating a sex- and gender-based framework to analyze and report outcomes is imperative
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • et al.
      Sex- versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      ,
      • Pelletier R.
      • Ditto B.
      • Pilote L.
      A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome.
      ,
      • Lippa R.
      • Connelly S.
      Gender diagnosticity: a new bayesian approach to gender-related individual differences.
      • Smith P.M.
      • Koehoorn M.
      Measuring gender when you don’t have a gender measure: constructing a gender index using survey data.
      • Lacasse A.
      • Pagé M.G.
      • Choinière M.
      • et al.
      Conducting gender-based analysis of existing databases when self-reported gender data are unavailable: the GENDER Index in a working population.
      • Hoffman R.M.
      • Borders L.D.
      Twenty-five years after the Bem Sex-Role Inventory: a reassessment and new issues regarding classification variability.
      • Heilbrun A.B.
      Measurement of masculine and feminine sex role identities as independent dimensions.
      • Bem S.L.
      The measurement of psychological androgyny.
      • Tannenbaum C.
      • Ellis R.P.
      • Eyssel F.
      • Zou J.
      • Schiebinger L.
      Sex and gender analysis improves science and engineering.
      (Fig. 2). Moreover, it is debated whether the effect of gender is better captured by a composite measure of gender (ie, encompassing all gender domains) rather than by individual gender-related factors.
      • Tadiri C.P.
      • Raparelli V.
      • Abrahamowicz M.
      • et al.
      Methods for prospectively incorporating gender into health sciences research.
      Figure thumbnail gr2
      Figure 2How to include, assess, and measure gender in prospective and retrospective studies—the suggested Gender Outcomes International Group: To Further Well-Being Development (GOING-FWD) approach.
      • Tadiri C.P.
      • Raparelli V.
      • Abrahamowicz M.
      • et al.
      Methods for prospectively incorporating gender into health sciences research.
      ,

      Raparelli VR, Norris CM, Bender U, et al. The Gender Outcomes International Group: To Further Well-Being Development (GOING-FWD) methodology on identification and inclusion of gender factors in retrospective cohort studies [preprint]. Research Square rs-51246.

      ,
      • Pilote L.
      • Norris C.M.
      • Raparelli V.
      • et al.
      Gender Outcomes International Group: To Further Well-Being Development (GOING-FWD).
      Several approaches have been used to assess and measure gender in health sciences. Gender was first assessed in 1970s-1980s with the concept of masculinity and femininity.
      • Heilbrun A.B.
      Measurement of masculine and feminine sex role identities as independent dimensions.
      ,
      • Bem S.L.
      The measurement of psychological androgyny.
      ,
      • Cook E.P.
      Psychological androgyny: a review of the research.
      Androgyny (andro = male; gyne = female) was a framework for interpreting similarities and differences in individuals based on a the degree that they traditionally ascribed themselves as men (masculine characteristics) and women (feminine characteristics).
      • Cook E.P.
      Psychological androgyny: a review of the research.
      The Bem Sex-Role Inventory (BSRI) is a measure of masculinity and femininity and is an example of a questionnaire used to assess gender identity. It assesses how people identify themselves psychologically and assesses each person’s personality traits. This score was also used to examine psychological androgyny.
      • Hoffman R.M.
      • Borders L.D.
      Twenty-five years after the Bem Sex-Role Inventory: a reassessment and new issues regarding classification variability.
      • Heilbrun A.B.
      Measurement of masculine and feminine sex role identities as independent dimensions.
      • Bem S.L.
      The measurement of psychological androgyny.
      The major limitation of this tool is its focus only on personality traits and disregard of other dimensions of gender.
      In 1990, Lipa and Connelly
      • Lippa R.
      • Connelly S.
      Gender diagnosticity: a new bayesian approach to gender-related individual differences.
      introduced a gender diagnosticity approach which refers to gender as the bayesian probability of an individual to be a man or a woman on the basis of a set of gender-related diagnostic factors which may vary across different populations and times. Gender diagnosticity can provide a measurable metric of change in gender-related factors over time, rather than fixed gender stereotypes, and generally has greater predictive utility.
      • Lippa R.
      • Connelly S.
      Gender diagnosticity: a new bayesian approach to gender-related individual differences.
      Recently the GENESIS-PRAXY (Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond-Premature Acute Coronary Syndrome) investigators
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • et al.
      Sex- versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      ,
      • Pelletier R.
      • Ditto B.
      • Pilote L.
      A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome.
      built a composite measure of gender, the GENESIS-PRAXY Gender Index (GGI), to assess the impact of gender variables from all dimensions to resolve the inherent statistical difficulties associated with addressing a large amount of gender-related variables and to distinguish the effect of gender from sex on CVD risk factors and outcomes. This study is unique in its creation of a gender index based on several gender-related variables using principal component analysis and propensity score methods, referred to as the GENESIS-PRAXY methodology. This approach was derived in accordance with the study of gender diagnosticity by Lippa and Connelly.
      • Lippa R.
      • Connelly S.
      Gender diagnosticity: a new bayesian approach to gender-related individual differences.
      GGI was calculated through the construction of a propensity score, which was derived from coefficient estimates in the logistic regression model with biological sex as dependent variable and gender variables as covariates. Gender variables including number of hours per week doing housework, primary responsibility doing housework, level of stress at home, BSRI femininity score, lower personal income, and not being primary earner were correlated with biological female sex. The propensity score for each person was defined as the conditional probability of being female versus male based on gender-related variables. The GGI ranges from 0 to 100, with higher scores relating to characteristics traditionally ascribed to women.
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • et al.
      Sex- versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      ,
      • Pelletier R.
      • Ditto B.
      • Pilote L.
      A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome.
      Of note, a higher GGI (ie, feminine characteristics, higher number of hours per week doing housework, primary responsibility doing housework, higher level of stress at home, BSRI femininity score, lower personal income, not being primary earner) were associated with an increased risk of CV risk factors including hypertension, diabetes, and depression and greater risk of recurrent ACS over 12 months independently from sex.
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • et al.
      Sex- versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      This is partly because traditional CV risk factors are further potentiated by gendered factors in a way that is more detrimental to women than men. Indeed, the inclusion of the GGI in another population-based study revealed that individuals in a general population with feminine gender characteristics, regardless of sex, exhibit poorer CV health.
      • Azizi Z.
      • Bender U.
      • Tadiri C.
      • et al.
      Sex and gender factors and the cardiovascular health of canadians.

      Future Directions

      Despite numerous attempts to investigate gender disparities in CV outcomes, the impact of sex- and gender-related aspects on CV risk factors and the concept of gendered risk factors as possible modifiable targets for CVD prevention are underdeveloped. Limited awareness of the role that gender plays in etiology, process of care, and outcome of CVD spans from clinical scientists to practicing clinicians. Therefore, the inclusion of gender-related factors in addition to established CV risk factors in clinical studies is imperative to understand and improve disease prevention and outcomes (Fig. 2). Such aspects are even more relevant in the era of precision medicine, which aims to provide tailored disease management, taking into account genetic, psychosocial, and environmental influences.
      • Cirillo D.
      • Catuara-Solarz S.
      • Morey C.
      • et al.
      Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare.
      Much enthusiasm is placed in innovative methods such as advanced biomedical artificial intelligence to significantly improve risk prediction. However, to truly improve prediction, these methods must incorporate the important dimensions of sex and gender in algorithms to fully realise the potential of precision medicine.

      Conclusion

      The understanding of CV risk in both female and male individuals is far from fully elucidated. Gender is an evolving and dynamic process influenced by the social context in which each person is embedded, and its expression may differ across various environments (domestic, racial, socioeconomic, geopolitical) and time. Gender-related characteristics that shape an individual from early life to adulthood can interact with each other and with sex, which can ultimately affect the CV well-being of each individual. Indeed, based on the present review, the future CV research agenda should focus on assessing and comparing gender-related factors associated with CV health within different sexes, so as to achieve more individualised approaches in medicine.

      What Is Needed

      • Create sex disaggregated data for traditional and nontraditional risk factors.
      • Understand the intersectionality between sex and gender.
      • Formulate a standardised method to measure gender.

      Funding Sources

      P.J.C. and C.D. are supported by supported by the (Centre of Research British Heart Foundation Excellence Awards RE/13/5/30177 and RE/18/6/34217 ). Z.A. is a postdoctoral fellow and L.P. is a principal investigator of the GOING-FWD (Gender Outcomes International Group: To Further Well-Being Development) Consortium, which is funded by the GENDER-NET Plus ERA-NET Initiative (project ref. no. GNP-78), the Canadian Institutes of Health Research ( GNP-161904 ), “La Caixa” Foundation (ID 100010434 , code LCF/PR/DE18/52010001), the Swedish Research Council ( 2018-00932 ), and the Austrian Science Fund ( FWF, I 4209 ). L.P. holds a James McGill Chair at McGill University. V.R. is a co–principal investigator of the GOING-FWD Consortium and was funded by the Scientific Independence of Young Researcher Program of the Italian Ministry of University, Education, and Research ( RBSI14HNVT ).

      Disclosures

      The authors have no conflicts of interest to disclose.

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