The Canadian Women's Heart Health Alliance ATLAS on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women-Chapter 4: Sex- and Gender-Unique Disparities: CVD Across the Lifespan of a Woman

Open AccessPublished:September 24, 2021DOI:https://doi.org/10.1016/j.cjco.2021.09.013

      Abstract

      Women have unique sex- and gender-related risk factors for cardiovascular disease (CVD) that can present or evolve over their lifespan. Pregnancy-associated conditions, polycystic ovarian syndrome, and menopause can increase a female's risk of CVD. Women are at greater risk for autoimmune rheumatic disorders, which play a role in the predisposition and pathogenesis of CVD. The influence of traditional CVD risk factors (e.g., smoking, hypertension, diabetes, obesity, physical inactivity, depression, anxiety, and family history) is greater in women than men. Finally, there are sex differences in the response to treatments for CVD risk and comorbid disease processes. This Atlas chapter reviews sex- and gender-unique CVD risk factors that can occur across a woman's lifespan, aiming to reduce knowledge gaps and guide the development of optimal strategies for awareness and treatment.

      Brief Summary

      This Canadian Women's Heart Health Alliance Atlas chapter reviews sex- and gender-unique disparities in cardiovascular disease risk across a woman's lifespan and aims to reduce knowledge gaps in order to guide the development and evaluation of optimal awareness, treatment, and management strategies.

      Introduction

      Women have unique risk factors for cardiovascular disease (CVD) related to aspects of female reproductive biology over their lifespan, including pregnancy-associated conditions, polycystic ovarian syndrome (PCOS), and menopause.3 Women are also at greater risk for autoimmune rheumatic disorders, which play a role in both predisposition and pathogenesis of CVD. Further, differential impacts of traditional atherosclerotic CVD risk factors have been observed such that the influence of these factors on CV risk is greater in women than men.1 Finally, sex differences in response to treatments for CVD risk and comorbid disease processes have been demonstrated, relating to differences in female metabolism and elimination of drugs as well as associated comorbidities such as breast cancer, renal disease, and depression. Table 1 provides a summary of existing guidelines, recommendations, and position statements concerning the management of cardiovascular risk and disease in relation to several of the conditions reviewed in this Chapter. Thus, knowledge of the sex- and gender-unique CV risk factors in women are essential to resolving treatment gaps and critical to improving CV outcomes in women. This Atlas chapter will review these sex- and gender-unique disparities in CVD risk across a woman's lifespan, aiming to reduce knowledge gaps and guide the development of optimal strategies for awareness and treatment. Figure 1 summarizes key information included in this Chapter. As stated in the CWHHA Atlas Chapter 1, the terms “sex” and “gender” are often incorrectly used interchangeably despite clear and distinct definitions.4 Sex refers to biological constructs that are primarily associated with physical and physiological features, including hormones, genes, anatomy, and physiology typically categorized as female or male. Gender refers to socially constructed roles, behaviours, expressions, and identities, and is typically categorized as woman/girl or man/boy. In this and all chapters of the CWHHA Atlas, we try to adhere to these definitions, or in the event that source material does not clearly indicate sex versus gender data, we will defer to use of whichever term implies the greatest contextual sense.
      Table 1Summary of existing guidelines, recommendations, and position statements concerning the management of cardiovascular risk and disease in relation to other sex- and gender-unique health conditions
      ConditionDocument/GuidelineOrganization
      Contraceptive-use
      • US Medical Eligibility Criteria (US MEC) for Contraceptive Use
      • Canadian Contraception Consensus Part 4 of 4: Combined Hormonal Contraception
      • Centers for Disease Control and Prevention1
      • The Society of Obstetricians and Gynaecologists of Canada2
      Pregnancy
      • 2018 Guidelines for the Management of Hypertension in Pregnancy
      • Cardiovascular Diseases during Pregnancy Guidelines
      • Pregnancy and Heart Disease
      • Hypertension Canada3
      • European Society of Cardiology4
      • The American College of Obstetricians and Gynecologists5
      Polycystic Ovarian Syndrome (PCOS)
      • Recommendations from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome
      • The International Polycystic Ovarian Syndrome Network6
      Menopause
      • Managing Menopause Chapter 2 - Cardiovascular Disease
      • 2017 Hormone Therapy Position Statement
      • Hormone Therapy and Heart Disease
      • 2016 Recommendations on Women's Midlife Health and Menopause Hormone Therapy
      • Society of Obstetrics and Gynecology of Canada7
      • The North American Menopause Society8
      • The American College of Obstetrics and Gynecology9
      • The International Menopause Society10
      Autoimmune Rheumatic Diseases
      • Chronic pain, Diclofenac and Cardiovascular Risk: Management Algorithm
      • Clinical Practice Guidelines
      • The Canadian Rheumatology Association11
      • The American College of Rheumatology12
      Depression
      • Screening and Management of Depression in Patients with Cardiovascular Disease: State-of-the-Art Review
      • The American College of Cardiology13
      Chronic Kidney Disease
      • Kidney Disease Improving Global Outcomes (KDIGO) guidelines
      • (sex-specific recommendations under development)
      • Kidney Disease Improving Global Outcomes14
      Breast Cancer
      • Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy
      • Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy
      • Compounding Risk and Protection Model
      • Canadian Cardiovascular Society15
      • The American Society of Echocardiography/ European Association of Cardiovascular Imaging16
      • University of Alberta17
      1.Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. 2016. https://www.cdc.gov/mmwr/volumes/65/rr/rr6503a1.htm?s_cid=rr6503a1_w. Accessed August 20, 2021.
      2.Black A, Guilbert E, Costescu D, et al. No. 329-Canadian Contraception Consensus Part 4 of 4 Chapter 9: Combined Hormonal Contraception. Journal of Obstetrics and Gynaecology Canada. 2017;39(4):229-268.e225.
      3.Butalia S. Hypertension Canada's 2018 Guidelines for the Management of Hypertension in Pregnancy.34(5):526-531.
      4.Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur. Heart J. 2018 2018;39(34):3165-3241.
      5.ACOG Practice Bulletin No. 212: Pregnancy and Heart Disease. Obstetrics and gynecology. May 2019;133(5):e320-e356.
      6.Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Human reproduction. Sep 1 2018;33(9):1602-1618.
      7.Managing Menopause Chapter 2 Cardiovascular Disease. Journal of Obstetrics and Gynaecology Canada. 2014;36(9):S16-S22.
      8.The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. Jul 2017;24(7):728-753.
      9.ACOG Committee Opinion No. 565: Hormone therapy and heart disease. Obstetrics and gynecology. Jun 2013;121(6):1407-1410.
      10.Baber RJ, Panay N, Fenton A. 2016 IMS Recommendations on women's midlife health and menopause hormone therapy. Climacteric: the journal of the International Menopause Society. 2016/03/03 2016;19(2):109-150.
      11.The Canadian Rheumatology Association. Chronic pain, Diclofenac and Cardiovascular Risk: Management Algorithm. 2014. https://rheum.ca/resources/publications/. Accessed August 20, 2021.
      12.The American College of Rheumatology. Clinical Practice Guildelines. https://www.rheumatology.org/Practice-Quality/Clinical-Support/Clinical-Practice-Guidelines. Accessed August 19, 2021.
      13.Jha MK, Qamar A, Vaduganathan M, Charney DS, Murrough JW. Screening and Management of Depression in Patients With Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. Apr 16 2019;73(14):1827-1845.
      14.Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. Jun 4 2013;158(11):825-830.
      15.Virani SA, Dent S, Brezden-Masley C, et al. Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy. Can J Cardiol. Jul 2016;32(7):831-841.
      16.Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography. Sep 2014;27(9):911-939.
      17.Kirkham AA, Beaudry RI, Paterson DI, Mackey JR, Haykowsky MJ. Curing breast cancer and killing the heart: A novel model to explain elevated cardiovascular disease and mortality risk among women with early stage breast cancer. Prog Cardiovasc Dis. 2019/04//Mar - undefined 2019;62(2):116-126.
      Figure 1
      Figure 1Summary of sex- and gender-unique conditions and factors that contribute to an increase in CVD risk for women across the lifespan

      Sex-specific physiology and CVD

       Menarche, menstruation, contraception

       Menarche

      The age at which a female experiences menarche influences lifetime risk of CVD.5 Women's risks of CVD are influenced by their experiences of menstruation and use of contraceptives.6,7 In describing the distribution of age at menarche for Canadian females, Al-Sahab et al., reported that the proportions of females with early (<11.53 years), average (≥11.53 years and ≤13.91 years), and late menarche (>13.91 years) were 14.6%, 68.0% and 17.4%, respectively.8 Importantly, they noted that variations across the menarche groups were statistically significant by province of residence, household income, and family type.7 Both early and late menarche have been shown to increase the risk of CVD among women.5,7 Hispanic and black females experience an earlier age at menarche than white females.9-11 One multi-centre cohort study (n=648) observed a 4.5X greater risk of major adverse cardiac events (MACE) among women with menarche at ≤10 years and 2.5X greater risk of MACE for women with menarche at ≥15 years, compared to menarche at 12 years. There are likely multiple mechanisms that explain the association between age at menarche and CVD. For example, women who experience early menarche have been reported to have higher adult body mass index (BMI), in part due to reduced adult height; increased BMI is independently associated with CVD as well as CVD risk factors.12,13 Later menarche has been linked to PCOS and may be associated with hypercortisolism and estrogen deficiency.14

       Menstruation

      The characteristics of a woman's menstruation and the changes that occur over the menstrual cycle have important implications in the assessment of CVD risk factors, manifestations, and treatment. Menstrual cycle irregularity may be a marker of metabolic abnormalities predisposing women to an increased risk of CVD and of CVD risk factors, such as diabetes mellitus.6,15 Furthermore, CVD risk factor measurement including cholesterol, C-reactive protein, glucose, and insulin can vary throughout the menstrual cycle.16 As a result, the proportion of women identified with CVD risk factors may vary depending on the menstrual phase of evaluation.16,17 For total cholesterol, the mid-follicular phase is recommended for measurement in order to reduce false negatives. Standardization or timing of measurements to menstrual cycle phase for markers of C-reactive protein and insulin sensitivity should be considered to reduce overall variability.16 Interestingly, the menstrual cycle has been shown to impact cardiac autonomic modulation which decreases during the luteal phase of menstruation, with observed increases in incidence of arrhythmias.17

       Contraception

      Estrogen-based contraceptives, including implants, injections, patches, vaginal rings, and oral contraceptives have all been reported to increase a woman's risk of arterial and venous thrombosis.18 Despite their reliability in preventing pregnancies, combined oral contraceptive (COC) therapy has been found to increase the risk of arterial thrombosis that may result in CV events including myocardial infarction (MI) or stroke.18 CVD risk is further compounded with: COC use among women over 35 years of age; current smoking (10-fold increased risk of MI and 3 fold increased risk of stroke); the presence of poorly controlled hypertension (3-fold risk of MI/Stroke and 15-fold risk of hemorrhagic stroke); or, a history of hypertension in pregnancy (increased risk of MI and venous thromboembolic events [VTE]).19 Moreover, the risk of CVD depends on both the type of progesterone and the dosage of estrogen used, with the safest oral form of hormonal contraception being that which contains levonorgestrel and 30 μg of estrogen.20
      Women presenting with contraceptive needs must have individualized CVD risk assessment as part of the shared decision-making to determine the optimal contraceptive method. In women over 35 years of age with numerous CV risk factors, or those with established ischemic heart disease, congestive heart failure, or cerebrovascular conditions, COCs are generally contraindicated, and the recommendation is for progestogen-only contraception, or, preferably, non-hormonal methods.18,21 Finally, in clinical practice particular attention should be paid to women with metabolic syndrome (MetS) or PCOS, who, in addition to their increased CV risk, may require long-term use of contraceptives, with careful monitoring of metabolic impact, and use of alternative non-hormonal contraceptive methods as needed.22,23

       Pregnancy-Associated Risks

      Pregnancy poses a physiologic stress on the CV system as it undergoes structural and hemodynamic changes to accommodate the increase in blood volume and hence cardiac output. By 20 weeks gestation, cardiac output can increase to above 45% and stroke volume to above 25% pre-pregnancy values. Each typically plateau after 20 weeks but remain elevated until delivery.24 Heart rate increases steadily to above 20% pre-gestation values, peaking in the third trimester.25 These normal physiologic changes of pregnancy can uncover or intensify pre-pregnancy cardiac conditions (e.g., congenital and valvular heart disease, pre-existing cardiomyopathies, including cancer treatment-related cardiotoxicity) or result in new cardiac conditions (e.g., arrhythmias, peripartum cardiomyopathy, aortic dissection, and pregnancy-associated MI, including spontaneous coronary artery dissection). In Canada, cardiac diseases affect 4.7 per 100,000 deliveries and is the most common diagnosis associated with maternal mortality both during pregnancy and in the postpartum period.26 These adverse outcomes are even higher amongst women aged >40 years, with obesity, and of certain ethnic populations in Canada.
      A prospective study of Canadian women with pre-existing CVD found that 50% of serious cardiac events experienced during pregnancy (e.g., cardiac arrest or death, MI, urgent cardiac intervention, and serious arrhythmias) were preventable.27 Much of this morbidity and mortality may be avoidable through: optimization of cardiac health pre-conception; management during pregnancy and postpartum by an experienced interdisciplinary team (e.g., cardiology, maternal fetal medicine, obstetrics, and internal medicine); and, use of health systems-level interventions that identify women at risk for preventable adverse outcomes (e.g., the California Toolkit for Cardiac Disease in Pregnancy and Postpartum 28). Further, individualized patient risk assessment using validated tools (e.g., CARPREG I or II,29 Modified WHO classification of maternal CV risk 30) may aid women with known cardiac conditions in planning their pregnancy.
      Finally, emerging epidemiologic data demonstrate that common reproductive complications such as hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), preterm birth, abruption, and infertility (in total, occurring in up to 20% of pregnancies in Canada) are independent, sex-specific risk factors associated with marked increases in the risk of future CVD (e.g., premature atherosclerotic disease, arrhythmia, and heart failure).31 The recent recognition of the importance of the pregnancy and reproductive period in the CV health of women across their lifetime has led to recent emergence of the multidisciplinary field of “Cardio-obstretrics”, including expertise from cardiology and obstetrics within a team approach to enable the optimal management of CVDs and complications during pregnancy.32

       Unique considerations of clinical presentation during pregnancy and the postpartum period

      An important clinical challenge during pregnancy, and the postpartum period, is the differentiation between common symptoms of pregnancy (e.g., benign dyspnea of pregnancy) and symptoms caused by acute or worsening CVD. While clinicians generally rely on the physical examination, it is important to note that several laboratory tests (e.g., troponin and B-type natriuretic peptide), imaging tests (e.g., echocardiogram, x-ray, magnetic resonance imaging, computerized tomography), as well as electrocardiogram (ECG), holter monitors and stress tests, can be done safely in pregnancy to guide diagnosis and management without serious harms to the fetus. Interpretation of test results, however, must recognize that cut-off values for normal results during pregnancy may be different than non-pregnant reference values.

       Unique management considerations of cardiovascular disease during pregnancy

      Many common therapies for the treatment and prevention of CVD (e.g., aspirin, beta-blockers) can be safely used in pregnancy and lactation without adverse effects to the offspring.33,34 Knowledge of specific classes of medications associated with fetal harms that are generally avoided during pregnancy (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs]) should be noted.35 Individualized specialized interdisciplinary counselling and shared decision-making about medication safety during pregnancy and lactation is important with the recognition that clinical decision-making is centred upon ensuring maternal well-being.

       Current state of preconception-to-postpartum clinical care and research in Canada

      At present, the majority of preconception-to-postpartum clinical care for women with CVD, including the postpartum care of women after HDP or GDM, occurs in interdisciplinary tertiary care clinics across Canada, depending on local resources. Through the Canadian Adult Congenital Heart Network (www.cachnet.org) and the Canadian Post-Pregnancy Network (www.canadianpostpregnancynetwork.ca), researchers are leading the development of guidelines for clinical care of women from preconception to postpartum.

       Polycystic ovary syndrome

      PCOS is an endocrine disorder affecting 2.2 – 26.7% of women of reproductive ages (15 – 45 years old).36,37 The prevalence is similar across ethnic groups.38 PCOS is a ‘syndrome’ that affects the ovaries and ovulation and its three main features are: cysts in the ovaries; higher than normal levels of androgens with lower levels of estrogen, progesterone, FSH, and luteinizing hormone (LH); and, irregular or skipped menstrual cycles. It is believed that PCOS stems from factors including genetics (PCOS runs in families), insulin resistance (due to the preponderance of women with PCOS being obese), and increased levels of inflammation. PCOS is characterized by a greater tendency to obesity,39 central or visceral adiposity,39 higher rates and degree of hyperinsulinemia, insulin resistance, increased blood sugars, dyslipidemia, and hypertension.40-44 Women with PCOS also report higher levels of depression and anxiety.45 Insulin resistance and the resulting hyperinsulinemia40 contribute to the pathophysiology of metabolic complications in PCOS, including MetS,46,47 (dyslipidemia,48,49 impaired glucose tolerance 50), type 2 diabetes mellitus,50 and obstructive sleep apnea.51,52 An increased mineralocorticoid effector mechanism has been observed in PCOS, with elevated aldosterone levels and aldosterone to plasma renin activity ratios,53 potentially contributing to elevated blood pressure. These unfavourable metabolic and physiologic complications increase CV risk and women with PCOS are more likely to have increased coronary artery calcium scores and increased carotid intima-media thickness.54
      PCOS diagnosis is made from a combination of history, physical, laboratory, and imaging findings which must include two of three of the following: high androgen levels (blood tests), irregular menstrual cycles (history consistent with irregular cycles, heavier than normal flow), and cysts in the ovaries (pelvic exam, ultrasound).55 Treatment for PCOS starts with health behaviour modifications including weight loss, diet, and exercise. Hormonal (estrogen and progestin) medications in the form of oral contraceptives, patches, or vaginal rings are used to restore normal hormonal balance, regulate ovulation, and control symptoms. Pharmacologic therapy with metformin has been found useful in symptom and weight management. In a meta-analyses of 12 RCTs, metformin, when added to health behaviour modifications, was associated with lower BMI, less subcutaneous adipose tissue, and increased number of menstrual cycles at 6 months compared with health behaviour modifications and placebo.56 However, there were no differences in other anthropometric, metabolic (lipids and blood pressure), reproductive, and psychological outcomes after 6 months between lifestyle with metformin versus lifestyle with placebo. To address the mineralocorticoid effector mechanism in PCOS, spironolactone has been used to counteract hyperandrogenism, improve blood pressure, and reduce future CV risk.57

       Menopause

      Menopause is the permanent cessation of menstruation and is a retrospective diagnosis defined after 12 months of amenorrhea. Median age for natural menopause is 51.4 years in North American caucasian women, but there are notable ethnic and regional variations. Menopause before the age of 45 years is abnormal, and termed “premature” if younger than 40, and “early” if occurring between 40 and 45 years of age; it may be natural (due to primary or secondary ovarian insufficiency) or surgical (following bilateral oophorectomy). Natural menopause results in cessation of ovarian estrogen (primarily 17β-estradiol) production and elevated follicle-stimulating hormone (FSH) concentrations, while the ovary continues to synthesize and secrete testosterone. Surgical menopause leads to loss of ovarian estrogen and testosterone production.58

       Cardiovascular disease and menopause

      During their reproductive years, females are at lower risk of CVD than age-matched males. This CV “advantage” disappears after menopause.59 A history of frequent menopause-associated vasomotor symptoms (hot flashes and night sweats) has been associated with increased CV risk;60 although, a recent pooled analysis suggested that severity and timing (occurrence before or after menopause), rather than frequency, were associated with increased CVD risk.61 Data have been conflicting as to whether the type of menopause (natural vs. surgical) affects CV risk, but it has long been recognized that the timing of menopause is associated with CV risk. Early (age 40-45 years), and especially premature (age <40 years), menopause are associated with significant increases in morbidity and mortality from ischemic heart disease (IHD) and ischemic stroke.58,62,63 In a recent cohort study that included 144,260 postmenopausal women, premature menopause, compared with no premature menopause, was associated with a significant increase in risk for a composite CVD outcome that included coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism.64 For natural premature menopause, the hazard ratio was 1.36; for surgical premature menopause, the hazard ratio was 1.87, both after adjustment for conventional CVD risk factors and use of menopausal hormone therapy.64 A provocative further analysis of this database explored a marker of accelerated atherosclerosis, clonal hematopoiesis of indeterminate potential (CHIP), and found that premature menopause, especially natural premature menopause, was independently associated with CHIP among postmenopausal women.65 These findings suggested that natural premature menopause may represent a risk signal for latent genomic instability and predilection to develop CHIP and CHIP-associated CVD. The general recommendation by NAMS (North American Menopause Society) for women with premature or early menopause (surgical or natural due to primary ovarian failure) is for early initiation of menopausal hormone therapy (estrogen, with endometrial protection if the uterus is preserved) to be taken to the average age of natural menopause due to benefits observed in studies for atherosclerosis and CVD, cognition, and dementia.66
      Specific cardiovascular preventive guidance was provided in the latest (2018) American College of Cardiology/American Heart Association update on guidelines for blood cholesterol management, recognizing premature menopause as a CVD risk-enhancing factor favoring statin therapy initiation.67
      The extent to which CVD risk factors across the menopause explain racial/ethnic differences in subclinical vascular disease in late midlife women is not well documented, but was explored in a multi-ethnic cohort subset of the Study of Women's Health Across the Nation including 1357 women, mean age 60 years, and free of clinical CVD.68,69 Although race/ethnicity differences in subclinical CVD in late midlife women were identified, with thicker carotid walls in black women, wider arterial diameter in Chinese women, and less carotid plaque in black and Hispanic women compared with white women, the investigators found that CVD risk factor associations with subclinical vascular measures did not vary by race/ethnicity except for high-density lipoprotein cholesterol on common carotid artery intima-media thickness, where an inverse association between high-density lipoprotein cholesterol and common carotid artery intima-media thickness was observed in Chinese and Hispanic but not in white or black women.68
      To-date, the adverse effects of menopause on CV health have been largely attributed to hypoestrogenemia, as seen in primary ovarian insufficiency.59,70 These effects include evolution to an atherogenic cardiometabolic profile with increases in total cholesterol, low density lipoprotein (LDL)-cholesterol, and lipoprotein (a) [Lp(a)], and decreased high density lipoprotein (HDL)-cholesterol, impaired glucose tolerance, elevated blood pressure (BP), and transition to an android adipose tissue distribution (increased central obesity). Additional non-cardiometabolic effects include impaired bioactivity of nitric oxide, endothelial dysfunction, perturbation in autonomic function, activation of the renin-angiotensin system, increased oxidative stress, altered mitochondrial function, and changes in inflammatory, coagulation, and fibrinolytic cascades.70 These effects in target tissues depend, at least in part, on the type and density of estrogen receptors (ER-alpha, ER-beta and G protein-coupled estrogen receptor 1) and possibly the relative ratios of estrogens/androgens rather than estrogen(s) in isolation.71

       Menopausal hormone therapy (MHT)

      The role of MHT in CV health and disease risk remains controversial and complex, influenced by factors that include age at menopause and time since menopause, referred to as the “Timing Hypothesis, as well as interactions with pre-existing atherosclerotic vascular substrate.72,73 Of additional importance are the MHT characteristics including hormonal formulation, dose, route of estrogen administration (e.g., transdermal, oral, vaginal), whether with or without progesterone (unopposed, vs. combined estrogen and progesterone), and mode of delivery (cyclical or continuous) 58,59,62 Evidence for CV effects of MHT has accrued and evolved over the last several decades.62,74 Large observational studies and meta-analyses published in the 1980s suggested MHT prevented CVD and lowered all-cause mortality.
      However, subsequent data from multiple clinical trials, meta-analyses, and post-hoc re-analyses have shown contradicting and sometimes conflicting results regarding the role of MHT for prevention of CVD events.75-83 The general conclusions are that: 1) There is no role for MHT in secondary prevention of CVD; indeed, established atherosclerotic CVD is a contraindication to MHT,78 2) There is no clear indication for MHT in the primary prevention of CVD, except in the clinical situation of premature menopause, and 3) In the absence of contraindications (cardiovascular, oncologic), MHT can be utilized if administered early in the postmenopause for vasomotor and genitourinary indications.

      Summary

      Consideration of sex, hormonal status, and pregnancy history must all be included in the CV risk assessment, and diagnosis and treatment of women with CVD. Menstruation onset and characteristics, hypertensive or diabetic pregnancy complications, and menopausal timing and treatments are all contributory to CV health and/or disease. An awareness of increased CV risk in women with hypertensive and/or diabetic pregnancy complications, or premature menopause enables inclusion in routine CV risk assessments, with appropriate interventions, and intensified assessments and management of traditional risk factors, in order to improve long term CV outcomes in affected women. Hormonal influences on metabolic and vascular effects may be cardioprotective or disease promoting, depending upon temporal factors, concentration and proportionality, and whether endogenous or exogenous exposure. The effects of exogenous estrogens (and progesterone) are complex and controversial, influenced by both pharmacological and individual patient characteristics. There is currently no evidence to support the use of exogenous MHT for the specific purpose of primary or secondary CV risk prevention in postmenopausal women, except primary CV risk prevention in those with natural or surgical premature or early menopause.

      Sex, GEnder and the Disproportionate impact of “TRADITIONAL” CardioVascular Risk Factors

      Sex and gender differences exist in both the prevalence and impact of traditional CVD risk factors, such as smoking, sedentary behaviour, obesity, stress and a family history of CVD.84 Moreover, recent data indicate that, from a gender perspective, women face considerable barriers to access care and are less likely to be treated for their cardiac disease or predisposing conditions, or started on cardiovascular preventive medications, compared with men.85,86
      Astonishingly, modifiable risks including smoking, hypertension, diabetes, obesity, dietary patterns, sedentary behaviour, alcohol consumption, plasma apolipoproteins, and psychosocial factors account for 94% of the population-attributable risks of MI among women.87

       Smoking and hypertension

      Among women, smoking is the single most important preventable cause of CVD, particularly among women <55 years, increasing their risk 7-fold.88 Among women 45 years and older, there is a 25% increased risk in CAD conferred by cigarette smoking compared with men.89 Hypertension is the most prevalent modifiable risk factor for CVD morbidity and mortality in both men and women, and markedly increases in severity with age in women, especially those over 65 years of age, such that the prevalence of hypertension in postmenopausal women is higher than in men.90 However, a recent large population study found a sexual dimorphism in blood pressure trajectories, with onset of elevation in women as early as the third decade in life, a steeper increase persisting with age, and setting the stage for later-life CVDs that frequently present differently in women versus men.91 Yet more women than men with high BP remain undiagnosed, and even in those taking antihypertensive medications, hypertension has been found to be less well-controlled in women than in men;92 a myriad of reasons for this have been suggested including the impact of medication side effects or cost on compliance, lack of healthcare provider knowledge, and gender bias in treatments.93-95 An additive interaction between current smoking and hypertension in women on the risk of coronary heart disease (CHD) has been observed in Chinese women, suggesting that the combination of lowering BP and smoking cessation would contribute more to reducing CHD incidence than the effect of each change alone.96

       Obesity, diabetes mellitus, and dyslipidemia

      Obesity prevalence is rising among Canadian women, and increases with age.97 Rates of overweight and obesity among women in Canada vary significantly across ethnic groups, with lowest prevalence in South Asian and Southeast Asian women, and highest prevalence among black and off-reserve Indigenous women.98 Risks of CVD increase 4-fold among women in the highest BMI category compared to women in the normal BMI range and, in the Framingham Heart Study, obesity increased the risk of CAD by 64%.89 Obesity among women increases their risk of diabetes mellitus and women with diabetes have a 3-fold excess risk of fatal CAD compared with women without diabetes.89,99 Recognizing the importance of accumulated weight gain over a woman's lifespan, the recently published “Pregnancy and Maternal Obesity Part 2: Team Planning for Delivery and Postpartum Care” guideline summarizes that increased gestational weight gain and decreased post-pregnancy weight loss increase a women's lifetime risks of obesity, and encourage achievement of healthy weight pre and post-partum.100
      Elevated total cholesterol, triglycerides and LDL cholesterol, and decreased HDL cholesterol are independent atherosclerotic risk factors for CVD.101 In women, dyslipidemia contributes the highest proportion of the incidence of CVD (population attributable risk, 47.1%) compared with all other traditional risk factors for CVD.89 These differences in lipid and glucose metabolism may be due to alterations in reproductive hormone levels during mid-life (40–59 years). 102,103 Among women, C-reactive protein (CRP) is recognized as a strong CVD risk factor; indeed screening of CRP among women aged 60 and older has been recommended.104-106 Specifically among women, CRP may be a stronger predictor of future CVD than LDL cholesterol levels, and CRP and LDL are reported to identify different groups of women at higher risk of CVD.104,105 Lp(a) remains a controversial and unfolding genetic risk factor in the development of cardiovascular and calcific aortic valve diseases.107,108 Uncertainty remains as to whether elevated Lp(a) is associated with the development of pre-eclampsia during pregnancy.109 Very high Lp(a) values have been deemed an independent risk factor in women for MI and in recurrent CHD events for post-menopausal women.110,111 In other studies, elevated Lp(a) increases CVD risk in women only when paired with high total cholesterol and/or elevated LDL-cholesterol, and/or apolipoprotein B.112-115 Despite similar recommended approach to treatment of dyslipidemia, many studies have shown that women are less likely to be prescribed lipid lowering therapies or to achieve recommended cholesterol goals when treated as compared to men's outcomes.92 This lack of adherence to treatment guidelines and failure to obtain recommended treatment goals contributes to women's poorer outcomes; moreover, this disparate treatment enhances the perception of bias in treating women with known cardiac risk factors and/or manifest CVD.92

       Physical activity and diet

      Across all ages and all times of the day, Canadian women are less physically active than men and report less time spent in both moderate-to-vigorous and light physical activity, and greater time spent in sedentary activities116,117, which are well established risk factors for CVD.118,119 Further, physical fitness may play a more significant role in limiting CVD development among women.120,121 Data from the Nurses Health Study, demonstrated that diets high in red and processed meats, high fat dairy products, fried foods, salt, refined grains, and sugar increased heart disease risk among women,122 while adherence to a low-risk lifestyle, defined as not smoking, BMI <25 kg/m2, exercise ≥30 minutes/day, and top 40% of the Alternate Mediterranean Diet Score (emphasizing high intake of vegetables, fruits, nuts, legumes, whole grains, fish and moderate intake of alcohol) was associated with a lower risk of CHD and sudden cardiac death in women.123 It is over 20 years now that these health behaviour approaches were initially proposed as an effective strategy for the prevention of CHD and sudden cardiac death in women.

       Family history

      It is recommended that all individuals, both men and women, with a family history of premature CVD should be targeted for cardiovascular risk reduction interventions. Family history of CVD is an independent risk factor for premature CHD and is defined as patients having a first degree relative with CHD at age <55 years for men and/or <65 years for women. Although it has been demonstrated that women with a low Framingham risk score and a family history of premature CHD have a high prevalence of subclinical coronary atherosclerosis,124 the widely used American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator,125 developed with Pooled Cohort Equations from several large cohort studies of white and black men and women and which has largely supplanted the Framingham risk score, includes gender, age, blood pressure, tobacco use, cholesterol, race, and diabetes status, but does not include family history.

      EMERGING NOVEL CARDIOVASCULAR RISK FACTORS AND THEIR IMPACT ON WOMEN

       Autoimmune Rheumatic Diseases

      Systemic inflammation characterizes autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis and systemic lupus erythematosus, which affect 8% of the population, of whom the majority (approximately 80%) are women.126 Cardiovascular morbidity and mortality risks are greater for those with ARDs compared to the general population and to those with coronary artery disease (CAD).127,128 Rheumatoid arthritis (RA) is often considered a CV risk equivalent to diabetes in terms of endothelial damage127,129 and clinical atherosclerosis,130 with increased risk for heart failure and sudden cardiac arrest.126,128 In addition to atherosclerotic CAD and related complications, ARDs are associated with inflammatory complications of the myocardium, pericardium, valves, vasculature and/or conduction system.130 CVD manifestations have also been described in Sjögren's syndrome, a rheumatic autoimmune disease that primarily affects women in mid-life and may occur alone or in association with other autoimmune diseases, most commonly lupus and RA.131
      The impact of ARDs on CV risk and CVD manifestations in women include: premature development of CAD ten years earlier than age- and sex-matched controls;130 increased risk of accelerated atherosclerosis with silent clinical presentation leading to heart failure;126 up to 70% increased risk of MI;132 50% increased relative risk of recurrent ischemic events after percutaneous coronary interventions (PCI);133,134 and, worse health-related quality of life compared to healthy populations.135 Additionally, MetS is more prevalent in women of reproductive age with systemic lupus erythematosus.136 Awareness of the association between ARDs and CVD in women supports the importance of aggressive treatment with disease-modifying anti-rheumatic drugs (to reduce systemic inflammation), management of CVD risk factors, and careful monitoring for manifestations of CVD.

       Interplay of ARD symptoms and treatment in CVD diagnosis and risk

      ARDs can present with symptoms that are difficult to differentiate from the clinical symptoms of CVD: chest, jaw/neck, shoulder and back pain, fatigue, and dyspnea. These symptoms are often misinterpreted by practitioners, and women themselves, as being attributed to an ARD, thereby increasing the potential risk for adverse cardiac events.137 Women with ARDs also present with other co-morbid conditions, including depression,138 which may also impact CVD risk. Beyond atherosclerotic or inflammatory CAD and/or spasm, systemic inflammation in ARDs may cause myopericarditis, microvascular disease, vasculitis, valvular heart disease, and heart failure with preserved ejection fraction (HFpEF), due to myocardial fibrotic changes.
      RA-specific risk calculators using an empiric correction factor have not been successful in accurate prediction of CVD risk in patients with RA;139 however, a recently developed tool evaluated in a population of over 30,000 RA patients (78% female), using clinical data and a multi-biomarker disease activity score was found to have good predictive accuracy, with a net reclassification index of 0.19 (0.10–0.27; 95% CI) and C-index of 0.715.140 Importantly, despite ARDs predominantly occurring in females, men are often treated more intensively than women and women experience longer delays in referral to specialist care than men.141

       Summary

      ARDs primarily affect women, and systemic inflammation associated with ARDs increases the risk of premature atherosclerotic CVD in addition to disorders of the myopericardium, valves, and conduction system. Cardiac symptoms can be misinterpreted as being related to an ARD, or can be absent, despite underlying disease; therefore, careful clinical assessments, including attention to CV risk factors, and early specialist referral as indicated for suspicious symptomatology, is recommended.

       Depression

      Depression is a disorder that ranges from a mild downturn in mood in reaction to everyday life events, to a genetically predisposed, biochemically-mediated severe disorder that can render the person unable to function, become psychotic, or suicidal.142 Symptoms may commonly include low mood, loss of interest, sleep impairment, appetite disturbance, concentration and memory difficulties, with occasional progression to an inability to function at home, work, or in the community.142 Depression can be clinically assessed, diagnosed and classified by using DSM-5 142 or ICD-10 143 criteria. Several clinician or self-administered validated depression scales (Beck Depression Inventory-II;144 Hospital Anxiety and Depression Scale;145,146 Hamilton Depression Rating Scale;147 Geriatric Depression Scale;148 Patient Health Questionnaire-9;149 Cardiac Depression Scale150) are frequently used to assess depressive symptoms. In the general population, the prevalence of major depression is 1.7–2.0 fold higher in women (5.5%) than in men (3.2%).151 This is thought to be related to hormonal, biological, and psychosocial factors. 151-154

       Depression and CVD risk

      For women, in particular, having a depression history is increasingly seen to be associated with CVD development.154,155 In one study, depressed women had a risk ratio of CVD development of 1.73 compared with non depressed women.156 Depression has been reported to increase a woman's risk for adverse cardiac events by 50%-70%.157 In the NHANES III longitudinal study of adults aged <40 years, females with a history of depression or suicide attempts had greater risk of developing CVD or ischemic heart disease than their male counterparts.158 Similarly, young women (48%) have been found to have a higher rate of long-term depression/depressive symptoms than men (24%) at the time of MI.159 For post-menopausal women without previously diagnosed CHD, depressive symptoms have been associated with fatal CHD.160
      Several sex- and gender-related explanations have been proposed for the apparent correlation between depression and CVD in women, including biological and behavioural factors, as well as socioeconomic and psychosocial stressors and vulnerabilities.154 For example, women are more likely to be physically inactive,161 and to experience lower levels of control at work and lower earnings, work overload due to additional housework and childcare, single parenthood resulting in increased financial strain, loss of spouse in older age and subsequent decrease in financial resources, and additional caregiving roles (e.g., older parents).154 Additionally, for both men and women, the CVD-depression relationship is increasingly seen as being bidirectional (depression→CVD and CVD→depression).154,155 In this regard, following a cardiac diagnosis, individuals have a higher incidence of depression than is found in the general population.155 Rates of depression following a cardiac diagnosis can be up to twice as high for women compared to men.154,162,163 Women diagnosed with a cardiac condition before the age of 60 may be at particularly high-risk for depression following their diagnosis, with rates substantially higher than in their male counterparts (39% vs 22%).162

       Quality of Life

      Both women and men who experience depression following a cardiac diagnosis have a poorer quality of life than their non-depressed counterparts.155,164 This includes having a lower rate of return to work and a higher frequency of quitting work.165,166 Depressed cardiac patients have an overall worse medical prognosis, and have been found to be re-hospitalized sooner, with more frequent and longer hospitalizations.167 Post-MI depression, specifically, is associated with a 1.6 to 2.7 fold increase in the risk of adverse outcomes, including all-cause mortality, cardiac mortality, cardiac morbidity within two years of diagnosis.168 One-year mortality following MI is higher for depressed individuals than for non-depressed individuals, in both women (8.3% vs 2.7%) and men (7.0% vs 2.4%).169
      Health outcomes and quality of life for depressed women with a cardiac history are worse than depressed men and non-depressed women. Following coronary artery bypass surgery, women with a history of depression experience inferior improvement in functional status six months post-surgery compared to non-depressed women and depressed men.170 Depressed women with low social integration are at higher risk of recurrent cardiac events compared to non-depressed socially integrated women.171 Out-patient women with chronic heart failure report lower self-perceived quality of life and higher depression rates compared to male counterparts (64% vs. 44%, respectively). 172

       Treatment of depression in primary and secondary prevention of CVD

      Treating depression before the development of CHD has been shown to reduce the long-term absolute risk of serious CV events (MI or stroke) by 19%.173 Although there is no direct evidence that screening for depression leads to improved outcomes in cardiovascular populations, depression has been linked with increased morbidity and mortality, poorer risk-factor modification, lower rates of cardiac rehabilitation, and reduced quality of life. 174-176 Therefore, the American Heart Association 2008 Advisory on Depression and Coronary Heart Disease emphasized the importance of assessing depression in cardiac patients with the goal of targeting those most in need of treatment and support services.177 Jha et al., published a State of the Art Review of Screening and Management of Depression in Patients with Cardiovascular Disease to reinforce screening and best practices in medicine.178 It is recommended that screening for depressive symptoms with referral to interdisciplinary follow-up be completed with all newly diagnosed cardiac patients176,177 and that psychological supports be integrated into cardiac rehabilitation programs to improve depression outcomes.179

       Kidney Disease

      Globally, chronic kidney disease (CKD) is more prevalent in women compared to men.180,181 There is a strong inverse relationship between level of kidney function and CV risk, and not only is the slope of the risk relationship is steeper for women, but increased CV risk is demonstrated earlier in the CKD disease course.182 Highlighting the importance of addressing CKD as a CVD risk factor, the 2015 Global Burden of Disease study estimated that 19 million disability-adjusted life-years, 18 million years of life, and 1.2 million deaths lost from CVD were directly attributable to reduced kidney function.183

       Sex-differences

      Women have lower absolute glomerular filtration rates and renin angiotensin system activity compared to men.184 Endogenous estrogen is associated with lower BP in women, 106 though the effects of exogenous estrogen on kidney function, BP, and CV outcomes is less clear.185 Pregnancy complications such as gestational hypertension, GDM, and preeclampsia increase risk of CKD progression.186 Women have slower age-related loss of kidney function compared to men, likely due to sex differences, including less age-related renal nitric oxide dependence, but also gender-related factors such as greater adherence to kidney-related dietary restrictions in women (see below).187,188 Parental history of CVD is a stronger risk factor in women compared to men for CKD progression.189
      Most formulae estimating kidney function are based on serum creatinine, which in turn is influenced by factors such as muscle mass and protein intake. Muscle mass is less in females and creatinine-based formulae incorporate sex as a variable to estimate glomerular filtration rate190 and the risk of progression to kidney failure requiring dialysis or transplant.191 Angiotensin converting enzyme inhibitors and angiotensin receptor blockers in the treatment of hypertension may be less effective in females.192 In contrast to the general population, definitions of CKD-associated anemia are not sex-specific, which may lead to overestimation and overtreatment of anemia in females, a concern given erythropoiesis-stimulating agents carry some CV risk.193 In addition, females are less likely to receive arteriovenous fistulae for hemodialysis,194 and pre-dialysis fistula creation attempt may be associated with a lower risk of sudden death and CV mortality.195 Females on dialysis have a similar mortality rate as age-matched males on dialysis180, however, overestimation of dialysis adequacy has been reported due to overestimation of lean body mass in females, and higher dialysis doses have been associated with lower mortality among females but not males.196

       Gender-differences

      From a gender perspective, women have slower loss of kidney function and are more likely to choose conservative care; women are less likely to initiate dialysis or receive a kidney transplant.195 Living kidney donation is more common in women.197 Whether kidney donation increases CV risk remains under study;198,199 however, amongst women of reproductive age, living kidney donors have increased rates of gestational hypertension and preeclampsia.200

       Breast Cancer therapies

      Breast cancer is the most common malignancy among women worldwide201 and it is estimated that 1.0% of the female Canadian population are survivors of breast cancer diagnosed within the last 15 years.202 As a result of significant improvements in screening and treatment, breast cancer mortality rates in Canada have had a steady decline of nearly 50% over the past four decades. 203 With improvements in breast cancer-specific survival, CVD has emerged as an important competing risk in this population.204 Women with a personal history of breast cancer are at greater risk of dying from CVD than women without breast cancer, and for older women (>65 years) with a history of breast cancer, CVD is the leading cause of death.204,205

       CVD risk and breast cancer therapies

      Among women with a history of breast cancer, the balance of CV health with mortality can be influenced by a number of risk and protective factors that begin prior to diagnosis and extend to the post-treatment survivorship period, but active breast cancer treatment likely has the largest impact.206 CV risks that may pre-date cancer diagnosis include older age, presence of traditional CV risk factors and inflammation, while potential pre-diagnosis protective factors include lifelong non-smoking, regular physical activity, a healthy diet, and healthy body weight. A number of therapies used to treat breast cancer including anthracycline-based chemotherapy regimens, trastuzumab targeted therapy, and radiation therapy (especially for left-sided breast cancer) can cause cardiac and potentially vascular toxicity and dysfunction.207 Initial presentation of cardiovascular toxicity varies widely with individual treatment types, doses, and combinations, but can eventually manifest as heart failure, ischemic heart disease, and ultimately CVD-related death.

       Health behaviour changes after breast cancer diagnosis

      “Lifestyle” toxicity (i.e., the worsening of health behaviours including physical activity/cardiorespiratory fitness, diet, body weight, stress) is a less recognized, but equally as common consequence of breast cancer therapy that contributes to CVD risk in this population.208 Potential protective factors during breast cancer therapy include maintenance or improvement of healthy lifestyle behaviours and prophylactic heart failure medications.209,210 Following completion of treatment, practicing healthy lifestyle behaviours continues to be a key protective factor. The potential for chemotherapy-induced early menopause among women who were pre-menopausal at diagnosis (∼20% in developed countries) is an additional important CV risk that should be considered in the post-treatment setting.211

      Sex-based pharmacology of Cardiovascular drugs

      Women and men have differences in pharmacokinetics (PK) of absorption, distribution, metabolism, and excretion of drugs, as well as pharmacodynamics (PD) of receptor binding, post-receptor effects, and chemical interactions of drugs.214 Many factors contribute to observed sex differences in CVD drug pharmacology. For example, if a drug is given transdermally, the dose received by a woman may be lower than that received by a man due to higher subcutaneous fat content in women.215 Similarly, differences in levels of gastric enzymes and transporter proteins between men and women cause differences in drug absorption. Drug distribution is affected by numerous parameters that differ between men and women, including BMI, body fat, plasma volume and body water.216 However, sex differences in pharmacokinetics may be associated with adverse drug reactions in women because of higher blood concentrations and longer elimination times, rather than simply explained by differences in BMI.214
      Many uncertainties regarding sex differences in CVD drug pharmacology are attributed to lack of data due to the underrepresentation of women in randomized clinical drug trials, a recurring issue that affects women in all aspects of CVD: diagnosis, acute treatment, short- and long-term pharmaceutical treatment, and prognosis.217 Trial exclusion criteria often explicitly list women of reproductive age in the exclusion criteria due to potential for congenital malformations and litigation concerns. Furthermore, there were concerns that fluctuations in hormonal levels during the menstrual cycle could confound interpretation of drug pharmacokinetics.218 While FDA/Health Canada regulations have advanced the inclusion of women and the analyses of sex differences in drug and device treatment responses, women's participation in clinical trials has improved in some, but not in all CVD areas. In their 2018 review of the participation of women in clinical trials of CV drugs, Scott et al., reported that while women were well represented in trials of drugs for hypertension and atrial fibrillation, representation of women in trials for heart failure, CAD, and acute coronary syndromes (ACS) fell well below the participation to prevalence ratio deemed appropriate.217 Interestingly, the authors did not find evidence to support the concept that the inclusion/exclusion criteria were responsible for the underrepresentation of women in CVD trials, but rather postulated that low enrolment may be due to gender-based issues limiting participation including familial responsibilities, cultural and socio-economic barriers, difficulty accessing the study site, and concerns about study risks.
      Given the increasing focus on precision medicine, the consideration of the patients’ sex in clinical decision-making including the choice of diagnostic testing, medications and other treatments is imperative.219 Many medications are metabolized differently in women compared to men due to differences in body size and distribution volumes, sex hormone levels, activity of enzymes, and effects of routes of excretion on sex-specific responses to drugs.220 At a minimum, there is a strong need for pharmaceutical trialists to report data disaggregated according to sex, even if underpowered, to enable subsequent pooling of sex-specific data during meta-analysis.

      Conclusions

      As shown in Figure 2, CVD risks can vary across a woman's lifespan, depending on her biologic stage (i.e., puberty, pregnancy and menopause). Similarly, differential CV risks are associated with traditional atherosclerotic risk factors as well as autoimmune and depressive disorders, which are more commonly found in women. In addition, clinicians must consider sex-specific manifestations of comorbid disease processes, including autoimmune rheumatic diseases, breast cancer and kidney disease, on CV risks. Further, treatments are impacted through sex-specific biological differences in metabolism of CVD drug and/or device therapies. All of these underlying medical factors and treatment-related issues need to be approached through the lens of sex and gender in order to improve CVD outcomes in women.
      Figure 2
      Figure 2The average age of onset and average length of exposure to sex-unique and traditional factors that may contribute to increased cardiovascular risk across a woman's lifespan

      Acknowledgements

      The authors gratefully acknowledge Lisa Comber for her ongoing coordination of this Atlas. A special thanks goes to Alexa Desjarlais from the University of Calgary and Manu Sandhu and Angela Poitras from the University of Ottawa Heart Institute for their graphic design of the central chapter illustration. Thank you to Manu Sandhu for graphic design of Figure 2. This article has been submitted on behalf of the Canadian Women's Heart Health Alliance (CWHHA), a pan-Canadian network of ∼100 clinicians, scientists, allied health professionals, program administrators, and patient partners, whose aim is to develop and disseminate evidence-informed strategies to transform clinical practice and enhance collaborative action on women's cardiovascular health in Canada. The CWHHA is powered by the Canadian Women's Heart Health Centre at the University of Ottawa Heart Institute.

      Funding Sources

      Supported by the University of Ottawa Heart Institute Foundation.

      Disclosures

      S.L.M. is a member of the Novo Nordisk steering committee and is a consultant of Lantheus Medical Imaging. A.L.E.L. has received grants from Astra Zeneca. The other authors have no conflicts of interest to disclose.

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