Advertisement

The Canadian Women’s Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women — Chapter 5: Sex- and Gender-Unique Manifestations of Cardiovascular Disease

Open AccessPublished:November 22, 2021DOI:https://doi.org/10.1016/j.cjco.2021.11.006

      Abstract

      This Atlas chapter summarizes sex- and some gender-associated, and unique aspects and manifestations of cardiovascular disease (CVD) in women. CVD is the primary cause of premature death in women in Canada and numerous sex-specific differences related to symptoms and pathophysiology exist. A review of the literature was done to identify sex-specific differences in symptoms, pathophysiology, and unique manifestations of CVD in women. Although women with ischemic heart disease might present with chest pain, the description of symptoms, delay between symptom onset and seeking medical attention, and prodromal symptoms are often different in women, compared with men. Nonatherosclerotic causes of angina and myocardial infarction, such as spontaneous coronary artery dissection are predominantly identified in women. Obstructive and nonobstructive coronary artery disease, aortic aneurysmal disease, and peripheral artery disease have worse outcomes in women compared with men. Sex differences exist in valvular heart disease and cardiomyopathies. Heart failure with preserved ejection fraction is more often diagnosed in women, who experience better survival after a heart failure diagnosis. Stroke might occur across the lifespan in women, who are at higher risk of stroke-related disability and age-specific mortality. Sex- and gender-unique differences exist in symptoms and pathophysiology of CVD in women. These differences must be considered when evaluating CVD manifestations, because they affect management and prognosis of cardiovascular conditions in women.

      Résumé

      Dans le présent chapitre d’Atlas sont récapitulés les aspects et les manifestations uniques, associés au sexe et certains associés au genre, des maladies cardiovasculaires (MCV) chez les femmes. Les MCV sont la cause principale de décès prématurés chez les femmes au Canada. De nombreuses différences quant aux symptômes et à la physiopathologie existent entre les sexes. Nous avons réalisé une revue de la littérature pour déterminer les différences entre les sexes dans les symptômes et la physiopathologie, et les manifestations uniques des MCV chez les femmes. Bien que les femmes atteintes d’une cardiopathie ischémique puissent éprouver des douleurs thoraciques, la description des symptômes, le délai entre l’apparition des symptômes et l’obtention de soins médicaux, et les symptômes prodromiques sont souvent différents de ceux des hommes. Les causes de l’angine et de l’infarctus du myocarde non liées à l’athérosclérose telles que la dissection spontanée de l’artère coronaire sont principalement observées chez les femmes. La coronaropathie obstructive et non obstructive, l’anévrisme aortique et la maladie artérielle périphérique montrent de plus mauvaises issues chez les femmes que chez les hommes. Des différences entre les sexes sont observées dans la cardiopathie valvulaire et les cardiomyopathies. Le diagnostic d’insuffisance cardiaque avec fraction d’éjection préservée est plus souvent posé chez les femmes qui présentent un meilleur taux de survie après un diagnostic d’insuffisance cardiaque. L’accident vasculaire cérébral (AVC) pourrait survenir tout au long de la vie des femmes, qui sont exposées à un risque plus élevé d’incapacités liées à l’AVC et de mortalité par âge. Il existe des différences uniques entre les sexes et les genres pour ce qui est des symptômes et de la physiopathologie des MCV chez les femmes. Lors de l’évaluation des manifestations des MCV, il faut tenir compte de ces différences puisqu’elles influencent la prise en charge et le pronostic des maladies cardiovasculaires chez les femmes.
      Chapter 5 reviews current and evolving knowledge regarding sex- and some gender-unique manifestations of cardiovascular disease (CVD), including symptom presentation, pathophysiology, and outcomes, from clinical trial data, when available, and observational reports. Figure 1 summarizes the Chapter’s key concepts.
      Figure thumbnail gr1
      Figure 1Summary of sex-unique manifestations of cardiovascular disease (CVD).
      Sex refers to biological constructs that are primarily associated with physical and physiological features, including hormones, genes, and anatomical and physiological characteristics, and is usually categorized as female or male. Gender refers to socially constructed roles, behaviours, expressions, and identities, and is often categorized as women and men. At times, throughout the Atlas chapters, we use the categorization that was used in the study being cited, although we recognize that these categorizations do not, in all cases, align with the sex and gender definitions described herein.

      Symptoms of Ischemic Heart Disease

      In Canada, ischemic heart disease (IHD) is a leading cause of mortality in women.
      Public Health Agency of Canada
      Report from the Canadian Chronic Disease Surveillance System: Heart Disease in Canada, 2018.
      Annual mortality rates for IHD in women in Canada exceed rates for breast cancer by 3 times, and rates for breast and all gynecological cancers combined by more than 2 times.
      • Statistics Canada
      Table 1-1. Deaths and mortality rate, by selected grouped causes, sex and geography - Canada.
      The term, IHD, describes a group of clinical syndromes characterized by myocardial ischemia, including acute coronary syndrome (ACS), unstable angina, stable angina, non–ST-elevation myocardial infarction, and ST-elevation myocardial infarction (STEMI).
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      Heart disease and stroke statistics--2013 update: a report from the American Heart Association.
      Women are more likely than men to have angina (47% vs 32%) and less likely to have acute myocardial infarction (AMI) (32% vs 46%) as their first manifestation of IHD.
      • Murabito J.M.
      • Evans J.C.
      • Larson M.G.
      • Levy D.
      Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation.
      The age-standardized prevalence of IHD and occurrence of AMI for women and men in Canada are presented in Figure 2, and age-standardized mortality rates for IHD and all major CVD in Figure 3.
      Figure thumbnail gr2
      Figure 2Age-standardized prevalence/occurrence of major cardiovascular diseases in Canada, according to sex. Age-standardized prevalence/occurrence calculated among Canadians aged 20 years or older for ischemic heart disease (IHD), acute myocardial infarction, and stroke; 40 years and older for heart failure; and 65 years and older for dementia. Data are from: (1) Report from the Canadian Chronic Disease Surveillance System: Heart Disease in Canada, 2018
      Public Health Agency of Canada
      Report from the Canadian Chronic Disease Surveillance System: Heart Disease in Canada, 2018.
      ; (2) Stroke in Canada: Highlights from the Canadian Chronic Disease Surveillance System (https://open.canada.ca/data/en/dataset/29c7e1d2-f6c1-4eb3-89dc-f36a3c7f53f3); and (3) Dementia in Canada, including Alzheimer’s disease: Highlights from the Canadian Chronic Disease Surveillance System (https://www.canada.ca/en/public-health/services/publications/diseases-conditions/dementia-highlights-canadian-chronic-disease-surveillance.html).
      Figure thumbnail gr3
      Figure 3Age-standardized mortality rates for major cardiovascular diseases in Canada, according to sex. Age-standardized mortality calculated among Canadians aged 20 years and older for major cardiovascular diseases, ischemic heart disease, stroke, and other forms of heart disease; and, for 65 years and older, for Alzheimer’s disease. Other forms of heart disease includes International Classification of Diseases-10th Revision codes I30-I51 (including heart failure, heart valve diseases, cardiomyopathies, and arrhythmias). Data are from: (1) Statistics Canada: Deaths and age-specific mortality rates, 2019, by selected grouped causes, Table: 13-10-0392-01 (https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1310039201); (2) Statistics Canada: Deaths, by cause, Chapter IX: Diseases of the circulatory system (I00 to I99), 2019, Table: 13-10-0147-01 (https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1310014701); and (3) Statistics Canada: Population estimates on July 1st 2019, by age and sex, Table: 17-10-0005-01 (https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1710000501).
      Clinical presentation and characteristics of IHD differ among the sexes, with women presenting a varied pattern and distribution of cardiac symptoms that are distinct from that of men. Figure 4 summarizes the most common as well as additional and prodromal symptoms described by women presenting with IHD.
      • Brush Jr., J.E.
      • Krumholz H.M.
      • Greene E.J.
      • Dreyer R.P.
      Sex differences in symptom phenotypes among patients with acute myocardial infarction.
      ,
      • Khan N.A.
      • Daskalopoulou S.S.
      • Karp I.
      • et al.
      Sex differences in prodromal symptoms in acute coronary syndrome in patients aged 55yearsor younger.
      Figure thumbnail gr4
      Figure 4Symptoms commonly reported by those presenting with ischemic heart disease, women vs men. ∗ P < 0.05; ∗∗ P < 0.01.
      Most women aged 18-55 years diagnosed with AMI present with chest pain, similar in proportion to men (87.0% of women vs 89.5% of men).
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction.
      They also experience a greater number and variation of symptoms (ie, type, frequency, and quality), including prodromal symptoms (ie, fatigue, shortness of breath, and sleep disturbance),
      • Khan N.A.
      • Daskalopoulou S.S.
      • Karp I.
      • et al.
      Sex differences in prodromal symptoms in acute coronary syndrome in patients aged 55yearsor younger.
      which might delay evaluation and diagnosis. Others report chest symptoms that are common in all patients diagnosed with ACS but women experience more nausea, shoulder and upper back pain, and diaphoresis.
      • Brush Jr., J.E.
      • Krumholz H.M.
      • Greene E.J.
      • Dreyer R.P.
      Sex differences in symptom phenotypes among patients with acute myocardial infarction.
      This varied pattern and distribution of symptoms makes it difficult for health care providers and women themselves to interpret pain/symptoms as cardiac-specific.
      • Canto J.G.
      • Canto E.A.
      • Goldberg R.J.
      Time to standardize and broaden the criteria of acute coronary syndrome symptom presentations in women.
      • Kirchberger I.
      • Heier M.
      • Wende R.
      • von Scheidt W.
      • Meisinger C.
      The patient’s interpretation of myocardial infarction symptoms and its role in the decision process to seek treatment: the MONICA/KORA Myocardial Infarction Registry.
      • Pepine C.J.
      • Ferdinand K.C.
      • Shaw L.J.
      • et al.
      Emergence of nonobstructive coronary artery disease: a woman’s problem and need for change in definition on angiography.
      Sex differences in the clinical presentation of IHD are more pronounced in younger women (younger than 45-55 years) with AMI, who are more likely to present without chest pain and have higher in-hospital mortality.
      • Mozaffarian D.
      • Benjamin E.J.
      • Go A.S.
      • et al.
      Heart disease and stroke statistics--2015 update: a report from the American Heart Association.
      ,
      • Tisminetzky M.
      • Gurwitz J.H.
      • Miozzo R.
      • et al.
      Age differences in the chief complaint associated with a first acute myocardial infarction and patient’s care-seeking behavior.
      In older women (older than 65 years), sex differences are less pronounced; however, it is important to note that 50% of women aged older than 75 years who are diagnosed with AMI present without chest pain.
      • Kirchberger I.
      • Heier M.
      • Wende R.
      • von Scheidt W.
      • Meisinger C.
      The patient’s interpretation of myocardial infarction symptoms and its role in the decision process to seek treatment: the MONICA/KORA Myocardial Infarction Registry.
      Longer prehospital delays have been reported in women with chest pain who are older than 75 years and shorter prehospital delays reported in women younger than 55 years who have additional or associated symptoms (eg, shortness of breath, fatigue).
      • Tisminetzky M.
      • Gurwitz J.H.
      • Miozzo R.
      • et al.
      Age differences in the chief complaint associated with a first acute myocardial infarction and patient’s care-seeking behavior.
      Prehospital delay times are shorter in women who have an abrupt vs a gradual onset of symptoms,
      • Mirzaei S.
      • Steffen A.
      • Vuckovic K.
      • et al.
      The association between symptom onset characteristics and prehospital delay in women and men with acute coronary syndrome.
      making one wonder if delays are related to symptom recognition and/or interpretation, or the actual decision to seek care.
      • Tisminetzky M.
      • Gurwitz J.H.
      • Miozzo R.
      • et al.
      Age differences in the chief complaint associated with a first acute myocardial infarction and patient’s care-seeking behavior.
      Women are generally older than men when diagnosed (mean 20 years older), and have a higher prevalence of comorbid conditions.
      • Canto J.G.
      • Rogers W.J.
      • Goldberg R.J.
      • et al.
      Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality.
      Nevertheless, women aged 20-74 years are more likely to die within 1 year of AMI (60.0-194.7 per 1000 in women vs 20.9-175.0 per 1000 in men).
      • Pelletier R.
      • Choi J.
      • Winters N.
      • et al.
      Sex differences in clinical outcomes after premature acute coronary syndrome.
      Women post-AMI are also more likely to have heart failure (HF) or stroke.
      • Murabito J.M.
      • Evans J.C.
      • Larson M.G.
      • Levy D.
      Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation.
      Poorer prognosis has been reported in younger women (younger than 55 years) with STEMI compared with their male counterparts.
      • Canto J.G.
      • Rogers W.J.
      • Goldberg R.J.
      • et al.
      Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality.
      ,
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • et al.
      Acute myocardial infarction in women: a scientific statement from the American Heart Association.
      ,
      • Spatz E.S.
      • Curry L.A.
      • Masoudi F.A.
      • et al.
      The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) classification system: a taxonomy for young women with acute myocardial infarction.
      Defining chest pain as typical, atypical, and noncardiac according to its relation to exertion, rest, or emotional stress was derived from predominantly male cohorts and is less predictive of obstructive coronary artery disease (CAD) in women, especially those younger than 65 years.
      • Shaw L.J.
      • Bairey Merz C.N.
      • Pepine C.J.
      • et al.
      Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study: part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies.
      Improving symptom evaluation tools for women could improve detection of obstructive CAD; however, definitive data are lacking.
      • Shaw L.J.
      • Bairey Merz C.N.
      • Pepine C.J.
      • et al.
      Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study: part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies.
      Shifting the focus from the “culprit lesion,” where only obstructive CAD is considered to be diagnostic, and where nonobstructive CAD, more prevalent in women, is very often overlooked, to the “culprit patient,” where the focus on detection of adverse prognostic indicators, such as the presence of ischemia on noninvasive testing or presence of atherosclerosis on radiologic imaging, might improve the diagnosis, appropriate treatment, and prognosis of IHD and ACS in women.
      • Bairey Merz C.N.
      • Shaw L.J.
      • Reis S.E.
      • et al.
      Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study: part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease.
      Of note, the diagnostic accuracy to detect IHD/ACS in Black, Hispanic, and Asian and/or young women might improve if gender (socially constructed with identified roles and expectations), psychosocial stressors, clustering of > 3 cardiac risk factors, and other comorbidities are considered in addition to cardiac pain symptoms.
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • et al.
      Acute myocardial infarction in women: a scientific statement from the American Heart Association.

      Pathophysiology

      IHD

      Ischemia in the setting of nonobstructive epicardial CAD (INOCA) is especially prevalent in women and up to two-thirds of angiograms performed for suspected ischemia show no obstructive epicardial disease (defined as absence of ≥ 50% stenosis in any epicardial artery).
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and No Obstructive Coronary Artery Disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      More than half of women with INOCA will have evidence of underlying coronary microvascular dysfunction (CMD) on invasive coronary reactivity testing and these women are at elevated risk of adverse cardiovascular events.
      • Pacheco Claudio C.
      • Quesada O.
      • Pepine C.J.
      • Noel Bairey Merz C.
      Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease).
      The pathophysiology of INOCA is complex and might include endothelial dysfunction (epicardial or microvascular), inflammatory processes, smooth muscle cell dysfunction, arteriolar remodelling, and/or sympathetic activation. Causes of increased afterload and decreased oxygen supply, including aortic stenosis, severe hypertension, and anemia are often evident.
      • Pacheco Claudio C.
      • Quesada O.
      • Pepine C.J.
      • Noel Bairey Merz C.
      Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease).
      Further, endothelial and nonendothelial pathways contribute to reduced myocardial perfusion.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and No Obstructive Coronary Artery Disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      Traditional cardiovascular risk factors for developing CMD include hypertension, diabetes, dyslipidemia, and smoking; there is an association with inflammatory diseases including systemic lupus erythematosus.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and No Obstructive Coronary Artery Disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      Diffuse nonobstructive coronary atherosclerosis is identified in most women with INOCA, and inflammatory processes might play a role.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and No Obstructive Coronary Artery Disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      Abnormal coronary flow reserve (CFR) in response to adenosine, and abnormal coronary blood flow (CBF) to acetylcholine, which indicates abnormal microvascular function, using either invasive intracoronary measurement or noninvasive positron emission tomography, are diagnostic and prognostic indicators of CMD.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and No Obstructive Coronary Artery Disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • AlBadri A.
      • Bairey Merz C.N.
      • Johnson B.D.
      • et al.
      Impact of abnormal coronary reactivity on long-term clinical outcomes in women.
      β-Blockers, calcium channel blockers, nitrates, and/or ranolazine can be used for symptomatic relief, and statins and angiotensin converting enzyme inhibitors have been associated with improvement of symptoms and CFR in clinical trials.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      The Coronary Microvascular Angina (CorMicA) randomized controlled trial recruited 151 patients (73.5% female) with signs and symptoms of INOCA. Invasive coronary function testing, including measurement of CFR, CBF, and epicardial coronary vasospasm testing with acetylcholine were performed. In the intervention group, medical therapy was tailored according to the results: in addition to lifestyle changes, those with abnormal CFR or CBF were treated with β-blockers and statins, and angiotensin converting enzyme inhibitors were considered; those with evidence of vasospasm were treated with calcium channel blockers and nitrates. For the blinded control group, invasive CFR and CBF was performed but results were not disclosed; standard care medical therapy was provided according to physician preference. The intervention group had a significant improvement in Seattle Angina Questionnaire (SAQ) score and quality of life at 6 months over the control group.
      • Ford T.J.
      • Stanley B.
      • Good R.
      • et al.
      Stratified medical therapy using invasive coronary function testing in angina: the CorMicA Trial.
      The currently recruiting Women’s Ischemia Trial to Reduce Events in Non-Obstructive CAD (WARRIOR) trial will investigate intense medical therapy including high-intensity statin, aspirin, and angiotensin converting enzyme inhibitor, on longer-term outcomes.
      • Handberg E.M.
      • Merz C.N.B.
      • Cooper-Dehoff R.M.
      • et al.
      Rationale and design of the Women’s Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial.
      Epicardial vasomotor dysfunction and vasospasm causing ischemia is the underlying mechanism in vasospastic angina, also known as Prinzmetal, or variant angina. Vascular smooth muscle hyper-reactivity, and endothelial and autonomic nervous system dysfunction are involved in its pathogenesis.
      • Rodriguez Ziccardi M.
      • Hatcher J.D.
      Prinzmetal Angina. StatPearls. Treasure Island.
      Cigarette smoking is an established risk factor.
      • Beltrame J.F.
      • Crea F.
      • Kaski J.C.
      • et al.
      International standardization of diagnostic criteria for vasospastic angina.
      The Japanese population are at higher risk, particularly Japanese women.
      • Rodriguez Ziccardi M.
      • Hatcher J.D.
      Prinzmetal Angina. StatPearls. Treasure Island.
      Diagnostic criteria include: (1) angina—typically occurring at rest and often nocturnally that is responsive to nitrate therapy; (2) transient ischemic ST changes; and (3) coronary artery spasm on coronary angiography.
      • Beltrame J.F.
      • Crea F.
      • Kaski J.C.
      • et al.
      International standardization of diagnostic criteria for vasospastic angina.
      Provocative invasive testing in the cardiac catheterization laboratory including ergonovine and/or acetylcholine can be used in patients with suspected but not confirmed vasospasm. Treatment is comprised of smoking cessation, calcium channel blocker therapy, and/or long-acting nitrates.
      • Beltrame J.F.
      • Crea F.
      • Kaski J.C.
      • et al.
      International standardization of diagnostic criteria for vasospastic angina.
      The long-term prognosis is good although there is a small risk of sudden cardiac death.
      • Bory M.
      • Pierron F.
      • Panagides D.
      • Bonnet J.L.
      • Yvorra S.
      • Desfossez L.
      Coronary artery spasm in patients with normal or near normal coronary arteries. Long-term follow-up of 277 patients.
      Myocardial infarction in the setting of nonobstructed coronary arteries (MINOCA) represents 6% of all AMIs and is diagnosed more frequently in women, younger patients, and African-American patients.
      • Pacheco Claudio C.
      • Quesada O.
      • Pepine C.J.
      • Noel Bairey Merz C.
      Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease).
      ,
      • Pasupathy S.
      • Air T.
      • Dreyer R.P.
      • Tavella R.
      • Beltrame J.F.
      Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.
      Despite better survival than patients with obstructive CAD, 12-month mortality rates of 4.7% have been reported.
      • Pacheco Claudio C.
      • Quesada O.
      • Pepine C.J.
      • Noel Bairey Merz C.
      Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease).
      Table 1 summarizes the underlying mechanisms for MINOCA.
      • Reynolds H.R.
      • Maehara A.
      • Kwong R.Y.
      • et al.
      Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women.
      ,
      • Tamis-Holland J.E.
      • Jneid H.
      • Reynolds H.R.
      • et al.
      Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association.
      Table 1Mechanisms and diagnosis of MINOCA
      Potential underlying mechanisms of MINOCA
      MINOCA is defined according to the fourth universal definition of myocardial infarction with no lesions ≥ 50% in an epicardial coronary artery, with an ischemic basis, after excluding overt noncardiac causes of elevation in troponin (sepsis, pulmonary embolism, tachyarrhythmias, hypertensive crisis, etc), or nonischemic cause of myocardial injury, such as myocarditis.34
      Diagnostic testing
      Coronary plaque disruption (eg, plaque rupture, or ulceration, erosion, calcific nodules)Coronary angiogram

      IVUS

      OCT
      Epicardial coronary vasospasmCoronary vasoreactivity testing (acetylcholine, ergonovine)
      Coronary microvascular dysfunctionCoronary function testing (CFR, IMR)

      Myocardial PET
      Spontaneous coronary artery dissectionCoronary angiogram

      IVUS

      OCT
      Hypercoagulable disorders

      Coronary emboli

      Paradoxical emboli
      Hypercoaguable work-up

      TTE, TEE, bubble contrast echocardiography
      Takotsubo or other cardiomyopathy
      Takotsubo or other cardiomyopathy/myocarditis are considered nonischemic causes of myocardial injury diagnosed in up to 21% of cases of MINOCA and must be considered in the differential diagnosis.35
      Cardiac MRI

      TTE
      Myocarditis
      Takotsubo or other cardiomyopathy/myocarditis are considered nonischemic causes of myocardial injury diagnosed in up to 21% of cases of MINOCA and must be considered in the differential diagnosis.35
      Cardiac MRI

      TTE
      CFR, coronary flow reserve; IMR, index of myocardial resistance; IVUS, intravascular ultrasound; MINOCA, myocardial ischemia with non-obstructive coronary artery disease; MRI, magnetic resonance imaging; OCT, optical coherence tomography; PET, positron emission tomography; TEE, transesophageal echocardiogram; TTE, transthoracic echocardiogram.
      MINOCA is defined according to the fourth universal definition of myocardial infarction with no lesions ≥ 50% in an epicardial coronary artery, with an ischemic basis, after excluding overt noncardiac causes of elevation in troponin (sepsis, pulmonary embolism, tachyarrhythmias, hypertensive crisis, etc), or nonischemic cause of myocardial injury, such as myocarditis.
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      Takotsubo or other cardiomyopathy/myocarditis are considered nonischemic causes of myocardial injury diagnosed in up to 21% of cases of MINOCA and must be considered in the differential diagnosis.
      • Saw J.
      • Poulter R.
      • Fung A.
      • Wood D.
      • Hamburger J.
      • Buller C.E.
      Spontaneous coronary artery dissection in patients with fibromuscular dysplasia: a case series.
      Identification of such unique pathophysiologic mechanisms requires a high index of suspicion on viewing coronary angiograms, and if inconclusive, additional invasive imaging including intracoronary vascular ultrasound (IVUS), or optical coherence tomography might be helpful. IVUS can be used to assess coronary artery plaque and plaque burden, disruption, and ulceration.
      • Handberg E.M.
      • Merz C.N.B.
      • Cooper-Dehoff R.M.
      • et al.
      Rationale and design of the Women’s Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial.
      Intracoronary optical coherence tomography imaging is useful in identifying high-risk plaques as well as characteristic intramural hematoma seen in spontaneous coronary artery dissection (SCAD),
      • Beltrame J.F.
      • Crea F.
      • Kaski J.C.
      • et al.
      International standardization of diagnostic criteria for vasospastic angina.
      ,
      • Bory M.
      • Pierron F.
      • Panagides D.
      • Bonnet J.L.
      • Yvorra S.
      • Desfossez L.
      Coronary artery spasm in patients with normal or near normal coronary arteries. Long-term follow-up of 277 patients.
      and cardiac magnetic resonance imaging can provide insight on etiological mechanisms.
      • Tamis-Holland J.E.
      • Jneid H.
      • Reynolds H.R.
      • et al.
      Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association.
      A recently published study on coronary optical coherence tomography and cardiac magnetic resonance imaging in the workup of MINOCA revealed a cause in 84.5% of patients when one or both imaging modalities were used. An ischemic etiology was identified in 63.8% of women (most commonly plaque disruption such as plaque rupture) whereas a nonischemic cause was found in 20.7%.
      • Reynolds H.R.
      • Maehara A.
      • Kwong R.Y.
      • et al.
      Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women.
      It should be emphasized that MINOCA is a “working diagnosis,” and if any of the foregoing etiologies are identified, then the ACS is attributed to that specific entity.
      SCAD is an increasingly recognized condition that primarily affects women (89% of new SCAD cases in British Columbia, Canada) and refers to the spontaneous separation of the coronary arterial wall creating a false lumen filled with intramural hematoma.
      • Saw J.
      • Starovoytov A.
      • Humphries K.
      • et al.
      Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes.
      Angiographically, there are 3 types of SCAD, the most common being type 2 (diffuse long and smooth stenosis), with no differences in baseline characteristics or outcomes according to subtype.
      • Saw J.
      • Aymong E.
      • Sedlak T.
      • et al.
      Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes.
      Symptoms and signs are those of ACS; myocardial ischemia, ventricular arrhythmias, and sudden cardiac death can ensue.
      • Saw J.
      • Aymong E.
      • Sedlak T.
      • et al.
      Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes.
      SCAD presents most frequently in younger women (younger than 55 years of age); however, studies have also reported its occurrence in older and postmenopausal women.
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      Figure 5 summarizes the principal factors and conditions associated with SCAD. It is associated with fibromuscular dysplasia (in up to 63% of cases), peripartum state, multiparity (≥ 4 births), connective tissue disorders, systemic inflammatory conditions, hormonal therapy, stress, and intense exercise.
      • Saw J.
      • Poulter R.
      • Fung A.
      • Wood D.
      • Hamburger J.
      • Buller C.E.
      Spontaneous coronary artery dissection in patients with fibromuscular dysplasia: a case series.
      Although definitive data are lacking, the predominance of female sex and relationship to pregnancy suggest that female sex hormones might play a role in SCAD pathophysiology.
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • et al.
      Acute myocardial infarction in women: a scientific statement from the American Heart Association.
      SCAD comprises 1%-4% of AMI patients,
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      accounts for 35% of AMI in women younger than the age of 50 years,
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      is the main cause of AMI in women younger than age 40 years, and the main cause of pregnancy-associated AMI.
      • Tweet M.S.
      • Kok S.N.
      • Hayes S.N.
      Spontaneous coronary artery dissection in women: what is known and what is yet to be understood.
      Emotional stressors (eg, death of family member) appear to be more common in women compared with physical stressors (eg, extreme isometric exercise) in men
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      ; however, approximately one-third of patients cannot recall any significant emotional or physical stress before their SCAD event.
      Figure thumbnail gr5
      Figure 5Associated conditions and risk factors for spontaneous coronary artery dissection. Modified from Hayes et al.
      • Hayes S.N.
      • Tweet M.S.
      • Adlam D.
      • et al.
      Spontaneous coronary artery dissection: JACC State-of-the-Art Review.
      with permission from Elsevier.
      Correct diagnosis and recognition of SCAD as the underlying cause of the ACS is imperative—conservative management of stable patients is warranted in most cases. Percutaneous coronary intervention has been observed to result in an increased risk of procedural complications, and generally poorer outcomes in SCAD patients, especially those with distal disease. Most patients are managed conservatively, unless they are at high risk, defined as severe proximal disease in 2 or more vessels and/or the presences of ongoing ischemia or hemodynamic instability.
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      ,
      • Alfonso F.
      • Paulo M.
      • Lennie V.
      • et al.
      Spontaneous coronary artery dissection: long-term follow-up of a large series of patients prospectively managed with a “conservative” therapeutic strategy.
      Expert consensus suggests 3-5 days of in-hospital monitoring after presentation; extension of the dissection or new recurrent SCAD have been observed in approximately 5%-10% of SCAD patients.
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      Later recurrence of SCAD has been reported in 10%-30% of resolved cases and ongoing surveillance is required.
      • Hayes S.N.
      • Tweet M.S.
      • Adlam D.
      • et al.
      Spontaneous coronary artery dissection: JACC State-of-the-Art Review.
      Good blood pressure control is paramount and β-blocker therapy has been associated with reduced SCAD recurrence in an observational study.
      • Saw J.
      • Humphries K.
      • Aymong E.
      • et al.
      Spontaneous coronary artery dissection: clinical outcomes and risk of recurrence.
      Less clear is the use and duration of dual antiplatelet therapy with aspirin and clopidogrel in the setting of medical therapy without percutaneous coronary intervention. Statin therapy should be reserved for those with hyperlipidemia.
      • Hayes S.N.
      • Tweet M.S.
      • Adlam D.
      • et al.
      Spontaneous coronary artery dissection: JACC State-of-the-Art Review.
      Concomitant noncoronary fibromuscular dysplasia is highly prevalent in patients with SCAD (42%-86% depending on the number of territories, renal, iliac, or cerebrovascular),
      • Saw J.
      • Poulter R.
      • Fung A.
      • Wood D.
      • Hamburger J.
      • Buller C.E.
      Spontaneous coronary artery dissection in patients with fibromuscular dysplasia: a case series.
      and should be pursued with dedicated imaging. A history of migraines, anxiety, and depression is also common (20%-33% prevalence) in SCAD patients.
      • Kok S.N.
      • Hayes S.N.
      • Cutrer F.M.
      • et al.
      Prevalence and clinical factors of migraine in patients with spontaneous coronary artery dissection.
      ,
      • Liang J.J.
      • Tweet M.S.
      • Hayes S.E.
      • Gulati R.
      • Hayes S.N.
      Prevalence and predictors of depression and anxiety among survivors of myocardial infarction due to spontaneous coronary artery dissection.

      Atherosclerotic disease

      Obstructive CAD

      CAD, including AMI, is the leading CVD-related cause of emergency department visits, hospitalizations, and death among Canadian women, resulting in nearly 14,000 deaths per year.
      • Norris C.M.
      • Yip C.Y.Y.
      • Nerenberg K.A.
      • et al.
      State of the science in women’s cardiovascular disease: a Canadian perspective on the influence of sex and gender.
      Sex-specific pathophysiological mechanisms exist in the development of coronary atherosclerosis. In most women who present with ACS, the underlying mechanism is due to the formation of thrombus caused by a rupture of atherosclerotic plaque composed of accumulation of infiltrating macrophages and low-density lipoproteins, with subsequent limitation of blood flow to the myocardium.
      • Shufelt C.L.
      • Pacheco C.
      • Tweet M.S.
      • Miller V.M.
      Sex-specific physiology and cardiovascular disease.
      ,
      • Falk E.
      • Nakano M.
      • Bentzon J.F.
      • Finn A.V.
      • Virmani R.
      Update on acute coronary syndromes: the pathologists’ view.
      However, women, especially younger women, are more likely to present with plaque erosion, where a discontinuation of the endothelium is identified, without evidence of plaque rupture of the fibrous cap.
      • Falk E.
      • Nakano M.
      • Bentzon J.F.
      • Finn A.V.
      • Virmani R.
      Update on acute coronary syndromes: the pathologists’ view.
      Sex differences in atherosclerosis formation and plaque instability are not completely understood. Estrogen might play a role in slowing lesion progression, through decreased inflammatory activation, increased vasodilation, and decreased low-density lipoprotein oxidation and binding,
      • Ouyang P.
      • Michos E.D.
      • Karas R.H.
      Hormone replacement therapy and the cardiovascular system lessons learned and unanswered questions.
      potentially explaining the lower prevalence of obstructive CAD and plaque rupture in premenopausal women.
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • et al.
      Acute myocardial infarction in women: a scientific statement from the American Heart Association.
      Beyond sex-based physiological differences, feminine gender, which reflects social norms and expectations ascribed to women, was found to increase risk of recurrent AMI at 1-year follow-up in younger patients, independent of biological 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?.
      Women who present with obstructive CAD are generally older than men and have a higher cardiovascular risk factor burden, with diabetes and smoking disproportionately affecting the risk of obstructive CAD in women, as well as an increased mortality.
      • Manfrini O.
      • Yoon J.
      • Mvd Schaar
      • et al.
      Sex differences in modifiable risk factors and severity of coronary artery disease.
      Women presenting with STEMI due to obstructive CAD experience longer door-to-balloon delays,
      • Roswell R.O.
      • Kunkes J.
      • Chen A.Y.
      • et al.
      impact of sex and contact-to-device time on clinical outcomes in acute ST-segment elevation myocardial infarction—findings from the National Cardiovascular Data Registry.
      which might be improving over time.
      • Udell J.A.
      • Fonarow G.C.
      Sustained sex-based treatment differences in acute coronary syndrome care: insights from the American Heart Association Get With The Guidelines Coronary Artery Disease Registry.
      Prehospital STEMI diagnosis systems, including automated systems, might attenuate this sex gap,
      • Pacheco C.
      • Boivin-Proulx L.A.
      • Bastiany A.
      • et al.
      Impact of STEMI diagnosis and catheterization laboratory activation systems on sex and age-based differences in treatment delay.
      but confirmatory studies are needed. Importantly, findings from a recent single-centre study suggest that a systems-based approach to STEMI care might reduce sex disparities and improve care and outcomes in women.
      • Huded C.P.
      • Johnson M.
      • Kravitz K.
      • et al.
      4-Step protocol for disparities in STEMI care and outcomes in women.
      Recent data from Alberta, Canada, show that women are at higher risk of in-hospital mortality and of HF and mortality in the 5 years after their myocardial infarction.
      • Ezekowitz J.A.
      • Savu A.
      • Welsh R.C.
      • McAlister F.A.
      • Goodman S.G.
      • Kaul P.
      Is there a sex gap in surviving an acute coronary syndrome or subsequent development of heart failure?.
      Women are less likely to achieve key quality indicators after AMI, and are less often discharged after a cardiac event with an optimal medical regimen, even when age and renal function are considered.
      • Wilkinson C.
      • Bebb O.
      • Dondo T.B.
      • et al.
      Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study.

      Nonobstructive CAD

      Plaque erosion is more frequently diagnosed in women.
      • Pacheco Claudio C.
      • Quesada O.
      • Pepine C.J.
      • Noel Bairey Merz C.
      Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease).
      ,
      • Pasupathy S.
      • Air T.
      • Dreyer R.P.
      • Tavella R.
      • Beltrame J.F.
      Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.
      Women exhibit positive remodelling, which results in concealment of atherosclerosis and fewer lumen-occluding lesions.
      • Bairey Merz C.N.
      • Shaw L.J.
      • Reis S.E.
      • et al.
      Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study: part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease.
      ,
      • Pacheco Claudio C.
      • Quesada O.
      • Pepine C.J.
      • Noel Bairey Merz C.
      Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease).
      IVUS in women enrolled in the Women’s Ischemia Syndrome Evaluation (WISE) cohort identified coronary atherosclerosis with positive remodelling in 73/92 (79%) of women with no obstructive CAD.
      • Khuddus M.A.
      • Pepine C.J.
      • Handberg E.M.
      • et al.
      An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: a substudy from the National Heart, Lung and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE).
      Total plaque burden is associated with adverse cardiovascular events in women.
      • Sharaf B.
      • Wood T.
      • Shaw L.
      • et al.
      Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) angiographic core laboratory.
      Overall burden of calcification measured using the Coronary Artery Calcification score is a marker of cardiovascular risk, with scores > 300 predicting higher risk of events in women.
      • Kelkar A.A.
      • Schultz W.M.
      • Khosa F.
      • et al.
      Long-term prognosis after coronary artery calcium scoring among low-intermediate risk women and men.
      These findings underline the importance of accurately diagnosing the pathophysiologic mechanism of IHD in women; differentiation of atherosclerotic CAD, obstructive or nonobstructive, and/or CMD, is important to improve risk stratification and treatment of IHD in women.

      HF

      HF is the second leading CVD-related cause of hospitalization and third leading CVD-related cause of death among Canadian women.
      • Jaffer S.
      • Foulds H.J.A.
      • Parry M.
      • et al.
      The Canadian Women’s Heart Health Alliance ATLAS on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 2: scope of the problem.
      Age-standardized prevalence of HF according to sex is presented in Figure 2.
      Although the lifetime risk of developing HF is 1 in 5 for female and male individuals, risk factors including previous AMI, hypertension, and diabetes differ in their importance according to sex, and some risk factors—hypertensive disorders of pregnancy, gestational diabetes, peripartum cardiomyopathy (PPCM), and early menopause—are unique to women.
      • Lawson C.A.
      • Zaccardi F.
      • Squire I.
      • et al.
      Risk factors for heart failure.
      ,
      • Sullivan K.
      • Doumouras B.S.
      • Santema B.T.
      • et al.
      Sex-specific differences in heart failure: pathophysiology, risk factors, management, and outcomes.
      It is not yet known whether the increased risk for HF in women (compared with men) post-AMI is because women present at an older age, with higher prevalence of diabetes/renal dysfunction, experience delays in diagnosis and treatment for AMI, or due to an inherent feature of IHD in women.
      • Regitz-Zagrosek V.
      • Oertelt-Prigione S.
      • et al.
      EUGenMed Cardiovascular Clinical Study Group
      Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes.
      HF in women manifests more commonly as HF with preserved left ventricular (LV) ejection fraction ([LVEF] ≥ 50%; HFpEF) rather than HF with reduced LVEF (LVEF < 50%; HFrEF).
      • Lam C.S.P.
      • Arnott C.
      • Beale A.L.
      • et al.
      Sex differences in heart failure.
      In the Swedish HF Registry (SwedeHF), which included 42,937 patients with HF, 55% of those with HFpEF were women, compared with only 29% of those with HFrEF.
      • Stolfo D.
      • Uijl A.
      • Vedin O.
      • et al.
      Sex-based differences in heart failure across the ejection fraction spectrum: phenotyping, and prognostic and therapeutic implications.
      Although a large proportion of women who develop HF (more often HFrEF) have CAD, the risk factors for progression from CAD to HF have not been well investigated. In women in the Heart and Estrogen/Progestin Replacement Study (HERS), diabetes was the strongest predictor of HF, especially in the setting of concomitant renal insufficiency or morbid obesity.
      • Hulley S.
      • Grady D.
      • Bush T.
      • et al.
      Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
      Patients presenting with symptoms suggestive of HF (edema, fatigue, and dyspnea) should undergo a clinical history and physical exam.
      • Roalfe A.K.
      • Mant J.
      • Doust J.A.
      • et al.
      Development and initial validation of a simple clinical decision tool to predict the presence of heart failure in primary care: the MICE (Male, Infarction, Crepitations, Edema) rule.
      • McKee P.A.
      • Castelli W.P.
      • McNamara P.M.
      • Kannel W.B.
      The natural history of congestive heart failure: the Framingham study.
      • Kelder J.C.
      • Cramer M.J.
      • van Wijngaarden J.
      • et al.
      The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure.
      In the 2017 comprehensive update of the Canadian Cardiovascular Society (CCS) guidelines for management of HF, Ezekowitz et al. noted that atypical presentations (cognitive impairment, delirium, nausea, abdominal discomfort, oliguria, anorexia, and cyanosis) should also be recognized, particularly when evaluating women.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
      Transthoracic echocardiography is the imaging modality of choice in a patient suspected of having HF. Assessment should include LVEF, LV mass, presence of valvular disease, and markers of diastolic dysfunction. It is important to note that there are normative gender-based values for echocardiographic measures of chamber volumes.
      • Lang R.M.
      • Badano L.P.
      • Mor-Avi V.
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

      HFrEF

      HFrEF, defined as an LVEF ≤ 40%,
      • Sullivan K.
      • Doumouras B.S.
      • Santema B.T.
      • et al.
      Sex-specific differences in heart failure: pathophysiology, risk factors, management, and outcomes.
      accounts for approximately half of all cases of HF.
      • Shah K.S.
      • Xu H.
      • Matsouaka R.A.
      • et al.
      Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes.
      In an American midwestern epidemiologic study conducted more than a decade ago, the age- and sex- adjusted incidence of HF had decreased over the decade by 37% (95% confidence interval [CI], −30% to −44%), more so for HFrEF (−45%; 95% CI, −33% to −55%) than HFpEF (−28%; 95% CI, −13% to −40%).
      • Gerber Y.
      • Weston S.A.
      • Redfield M.M.
      • et al.
      A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010.
      It is estimated that women account for 40% and men 60% of patients with HFrEF
      • Regitz-Zagrosek V.
      Unsettled issues and future directions for research on cardiovascular diseases in women.
      ; overall, women are approximately 65% less likely to develop HFrEF than men.
      • Eisenberg E.
      • Palo K.E.D.
      • Piña I.L.
      Sex differences in heart failure.
      Women with HFrEF live longer with the condition than men, likely because of sex-related differences in etiology. Although prevalence of diabetes is similar, women with HFrEF are more often obese and have a higher prevalence of hypertension, valvular heart disease (VHD), and nonischemic cardiomyopathy than men.
      • Eisenberg E.
      • Palo K.E.D.
      • Piña I.L.
      Sex differences in heart failure.
      ,
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      Women with HFrEF are less likely than men to smoke cigarettes or drink alcohol, and less likely to have preexisting cardiovascular comorbidities such as CAD, atrial fibrillation (AF), AMI, or stroke.
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      HFrEF-related rehospitalizations are less common in women (8.48 events per 100 person-years [95% CI, 7.89- 9.11] for women vs 11.40 events per 100 person-years [95% CI, 11.04- 11.79] for men), with an age-adjusted incident rate ratio of 0.69 (95% CI, 0.61-0.79).
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      Additionally, lower odds of in-hospital death has been independently associated with female sex (odds ratio, 0.88; 95% CI, 0.87-0.89).
      • Spall H.G.C.V.
      • Hill A.D.
      • Fu L.
      • Ross H.J.
      • Fowler R.A.
      Temporal trends and sex differences in intensity of healthcare at the end of life in adults with heart failure.

      Implantable cardioverter defibrillator/cardiac resynchronization therapy

      In current guidelines, similar recommendations for implantable cardiac device (ICD) therapy apply to women and men with HFrEF despite many differences established in subgroup analysis. The annual rate of sudden cardiac death in women is approximately half of that in men, and substudies of many large randomized controlled trials have consistently shown up to a 50% lower appropriate ICD shock rate in women, compared with men.
      • Santangeli P.
      • Pelargonio G.
      • Russo A.D.
      • et al.
      Gender differences in clinical outcome and primary prevention defibrillator benefit in patients with severe left ventricular dysfunction: a systematic review and meta-analysis.
      ,
      • Zabarovskaja S.
      • Gadler F.
      • Braunschweig F.
      • et al.
      Women have better long-term prognosis than men after cardiac resynchronization therapy.
      Women have a higher adverse event rate post-ICD implantation.
      • Moore K.
      • Ganesan A.
      • Labrosciano C.
      • et al.
      Sex differences in acute complications of cardiac implantable electronic devices: implications for patient safety.
      Sex-specific prospective studies on which patients will benefit from ICD implantation are ongoing.
      Women are less likely than men to receive cardiac resynchronization therapy (CRT) and less likely to undergo CRT with defibrillator (CRT-D) implantation.
      • Sullivan K.
      • Doumouras B.S.
      • Santema B.T.
      • et al.
      Sex-specific differences in heart failure: pathophysiology, risk factors, management, and outcomes.
      ,
      • Chatterjee N.A.
      • Borgquist R.
      • Chang Y.
      • et al.
      Increasing sex differences in the use of cardiac resynchronization therapy with or without implantable cardioverter-defibrillator.
      Slightly improved survival outcomes with CRT have been observed in women, compared with men.
      • Randolph T.C.
      • Hellkamp A.S.
      • Zeitler E.P.
      • et al.
      Utilization of cardiac resynchronization therapy in eligible patients hospitalized for heart failure and its association with patient outcomes.
      Despite the greater benefit, women are less likely to receive device counselling than men, which might partly explain sex differences in CRT implantation.
      • Randolph T.C.
      • Hellkamp A.S.
      • Zeitler E.P.
      • et al.
      Utilization of cardiac resynchronization therapy in eligible patients hospitalized for heart failure and its association with patient outcomes.
      In a retrospective study of New York Heart Association functional class III-IV patients (49.5% female) with left bundle branch block and nonischemic cardiomyopathy, women were more likely to experience a treatment response to CRT compared with men (84% and 58%, respectively).
      • Varma N.
      • Manne M.
      • Nguyen D.
      • He J.
      • Niebauer M.
      • Tchou P.
      Probability and magnitude of response to cardiac resynchronization therapy according to QRS duration and gender in nonischemic cardiomyopathy and LBBB.
      Response rate was high in women regardless of QRS duration, whereas men had greater benefit with QRS ≥ 150 ms. In a meta-analysis of 3 CRT-D vs ICD trials, CRT-D led to greater reductions in HF events and death in women with a left bundle branch block QRS of 130-149 ms. Benefits were observed for both sexes at QRS > 150 ms.
      • Zusterzeel R.
      • Selzman K.A.
      • Sanders W.E.
      • et al.
      Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patient-level data.
      Current guideline recommendations are identical for women and men; however, sex-specific indications for CRT-D on the basis of QRS duration might be warranted.

      Heart transplantation

      Women undergo heart transplantation less frequently than men.
      • Hickey K.T.
      • Doering L.V.
      • Chen B.
      • et al.
      Clinical and gender differences in heart transplant recipients in the NEW HEART study.
      Reasons might include: (1) fewer women listed for transplant; (2) more women die while waiting for transplant; (3) less aggressive HF treatment in women; and (4) increased sensitization in women limiting the transplant donor pool.
      • Kenchaiah S.
      • Vasan R.
      Heart failure in women – insights from the Framingham Heart study.
      • Frankenstein L.
      • Clark A.L.
      • Ribeiro J.P.
      Influence of sex on treatment and outcome in chronic heart failure.
      • Joseph S.M.
      Closing the sex gap in advanced heart failure: reality or illusion?.
      • Hsich E.M.
      • Starling R.C.
      • Blackstone E.H.
      • et al.
      Does the UNOS Heart Transplant Allocation System favor men over women?.
      After receiving the transplant, women are more likely to experience moderate or severe allograft rejection resulting in acute rejection and hospitalization.
      • Hickey K.T.
      • Doering L.V.
      • Chen B.
      • et al.
      Clinical and gender differences in heart transplant recipients in the NEW HEART study.
      Fewer women have a LV assist device before transplantation; this might be because, historically, larger ventricular assist devices not thought to be ideal for implantation in women, and this trend might change with the new smaller devices.
      • Miller L.W.
      • Guglin M.
      Patient selection for ventricular assist devices: a moving target.

      End of life care

      In-hospital health care utilization is lower among women than men with HFrEF and HFpEF in the final months of life.
      • Spall H.G.C.V.
      • Hill A.D.
      • Fu L.
      • Ross H.J.
      • Fowler R.A.
      Temporal trends and sex differences in intensity of healthcare at the end of life in adults with heart failure.
      Specifically, a lower proportion of women than men with HF presented to emergency departments, were hospitalized in the final month, and were admitted to the intensive care unit in the final month of life. Fewer women than men are mechanically ventilated, receive cardiac catheterization or coronary revascularization, and hemodialysis in the final month of life and female sex is an independent predictor of death outside a hospital setting.
      • Spall H.G.C.V.
      • Hill A.D.
      • Fu L.
      • Ross H.J.
      • Fowler R.A.
      Temporal trends and sex differences in intensity of healthcare at the end of life in adults with heart failure.

      Clinical outcomes

      In a large multicentre international study, including more than 15,000 participants (one-fifth women), and a participating Canadian site, women with HFrEF had better survival and lower hospitalization rates than men.
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      ,
      • Bozkurt B.
      • Khalaf S.
      Heart failure in women.
      The 5-year mortality rate for patients with HFrEF is 75.3%, which is comparable with the rate for HFpEF of 75.7%.
      • Shah K.S.
      • Xu H.
      • Matsouaka R.A.
      • et al.
      Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes.
      Compared with men, women have significantly lower rates of cardiovascular death (age-adjusted hazard ratio [aHR], 0.70; 95% CI, 0.69-0.81), first hospitalization for HF (aHR, 0.80; 95% CI, 0.72-0.89), sudden death (aHR, 0.65; 95% CI, 0.56-0.76), and pump failure death (aHR, 0.67; 95% CI, 0.55-0.82).
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      Additionally, women with HFrEF have lower rates of noncardiovascular death (aHR, 0.66; 95% CI, 0.52-0.83), all-cause death (aHR, 0.68; 95% CI, 0.62-0.74), and fatal/nonfatal myocardial infarction (aHR, 0.79; 95% CI, 0.63-1.00), compared with males.
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      Events of fatal/nonfatal stroke appear to be more common among women than men with HFrEF (aHR, 1.22; 95% CI, 0.99-1.50).
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      This might be because of the lower rate of anticoagulation in the setting of AF and higher prevalence of hypertension experienced in women vs men.
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      The odds of AF in women with HFrEF appears to be lower than that of men (adjusted odds ratio, 0.69; 95% CI, 0.64-0.75).
      • Sartipy U.
      • Dahlström U.
      • Fu M.
      • Lund L.H.
      Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction.
      However, women with AF report more severe symptoms, worse quality of life, and increased risk of complications (ie, mortality, stroke, myocardial infarction) than men.
      • Ko D.
      • Rahman F.
      • Schnabel R.B.
      • Yin X.
      • Benjamin E.J.
      • Christophersen I.E.
      Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis.
      Despite fewer recurrent events and better survival rates, women with HFrEF often report a greater prevalence of anxiety and depression; more severe symptoms affect their psychological and physical health with associated lower quality of life, and reduced 6-minute walk distance, compared with men.
      • Dewan P.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Differential impact of heart failure with reduced ejection fraction on men and women.
      ,
      • Blumer V.
      • Greene S.J.
      • Wu A.
      • et al.
      Sex differences in clinical course and patient-reported outcomes among patients hospitalized for heart failure.
      • Mentzer G.
      • Hsich E.M.
      Heart failure with reduced ejection fraction in women: epidemiology, outcomes, and treatment.
      • Stewart G.C.
      • Cascino T.
      • Richards B.
      • et al.
      Ambulatory advanced heart failure in women: a report from the REVIVAL Registry.

      Representation in clinical trials

      Relative to men, women have pharmacokinetic differences such as lower oral drug absorption rate, larger distribution for lipophilic drugs, smaller distribution for hydrophilic drugs, and differences in metabolic activity due to menopause, which mighty affect the female response to HFrEF drugs.
      • Eisenberg E.
      • Palo K.E.D.
      • Piña I.L.
      Sex differences in heart failure.
      Sex-specific HFrEF guidelines for medical management are lacking because of the under-representation of women in HF trials.
      • Sullivan K.
      • Doumouras B.S.
      • Santema B.T.
      • et al.
      Sex-specific differences in heart failure: pathophysiology, risk factors, management, and outcomes.
      ,
      • Whitelaw S.
      • Sullivan K.
      • Eliya Y.
      • et al.
      Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review.
      Women are recruited into clinical trials at disproportionately lower rates than the HFrEF prevalence.
      • Eisenberg E.
      • Palo K.E.D.
      • Piña I.L.
      Sex differences in heart failure.
      For example, female enrollment in β-blocker trials, angiotensin receptor blocker trials, aldosterone antagonist or mineralocorticoid receptor antagonist trials, hydralazine or isosorbide dinitrate trials, angiotensin receptor-neprilysin inhibitor trials, and ivabradine trials ranges from 0% to 29%.
      • Mentzer G.
      • Hsich E.M.
      Heart failure with reduced ejection fraction in women: epidemiology, outcomes, and treatment.
      The under-representation of women in HFrEF trials limits the generalizability of results and limits statistical power required to test for sex as an effect modifier of treatments.
      • Whitelaw S.
      • Sullivan K.
      • Eliya Y.
      • et al.
      Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review.
      ,
      • Van Spall H.G.
      • Toren A.
      • Kiss A.
      • Fowler R.A.
      Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.
      Factors independently associated with underenrollment relative to female:male disease distribution include trial leadership by men and sex-specific eligibility criteria, a majority of which are not justified in the context of their individual clinical trials.

      HFpEF

      Women with HFpEF are responsible for > 30% of HF cases in women in Canada.
      • Bhatia R.S.
      • Tu J.V.
      • Lee D.S.
      • et al.
      Outcome of heart failure with preserved ejection fraction in a population-based study.
      The most common risk factors for HFpEF include older age, obesity, hypertension, smoking, diabetes, VHD, and AF.
      • Lee M.P.
      • Glynn R.J.
      • Schneeweiss S.
      • et al.
      Risk factors for heart failure with preserved or reduced ejection fraction among Medicare beneficiaries: application of competing risks analysis and gradient boosted model.
      Long-term prognosis after HFpEF onset is poor; however, women have better survival than men overall.
      • Eisenberg E.
      • Palo K.E.D.
      • Piña I.L.
      Sex differences in heart failure.
      The cause of death in patients with HFpEF is often noncardiac, often associated with older age and comorbidities. The CCS guidelines emphasize that management should include identification and treatment of underlying etiologies and comorbid conditions that might exacerbate HF.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
      There are few randomized clinical trials to guide pharmacological therapy for HFpEF treatment. Although trial results have not consistently been stratified according to sex, treatment efficacy remains to be confirmed in women; however, the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF), a trial of angiotensin-neprilysin inhibition in patients with HFpEF, was associated with lower rates of the composite primary outcome of death or HF hospitalizations specifically in women.
      • McMurray J.J.V.
      • Jackson A.M.
      • Lam C.S.P.
      • et al.
      Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction.

      VHD

      VHD affects 0.6% of the general population and its prevalence increases with age, affecting 5%-10% of adults older than the age of 65 years, with a slight majority being men.
      • Andell P.
      • Li X.
      • Martinsson A.
      • et al.
      Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study.
      Approximately 6% (n = 1995) of CVD-related deaths and 4.6% (n = 6126) of CVD-related hospitalizations among Canadian women are due to VHD.
      • Jaffer S.
      • Foulds H.J.A.
      • Parry M.
      • et al.
      The Canadian Women’s Heart Health Alliance ATLAS on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 2: scope of the problem.
      ,
      • Canadian Women’s Heart Health Alliance
      Data Table: Number of Deaths, by Province, Diagnosis, and Age Category for Females in Canada in 2019.
      The most common VHD is aortic stenosis (55%) followed by mitral regurgitation (28%).
      • Andell P.
      • Li X.
      • Martinsson A.
      • et al.
      Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study.
      Most (93%) of the VHD were diagnosed in women older than 52 years of age. VHD hospitalizations were frequently complicated by hypertension (46%) and diabetes (26%). Despite women representing 47.5% of patients with VHD, most studies on VHD pathophysiology include a large proportion of men or male animals. Nevertheless, distinct characteristics of valve lesions and therapies in women are emerging.

      Aortic stenosis

      Women reach the same hemodynamic severity of aortic stenosis as men with a lower amount of aortic valve calcification, even after accounting for aortic annulus size.
      • Aggarwal S.R.
      • Clavel M.A.
      • Messika-Zeitoun D.
      • et al.
      Sex differences in aortic valve calcification measured by multidetector computed tomography in aortic stenosis.
      When analyzing explanted aortic valves from matched patients who received surgery for severe aortic stenosis, valves explanted from women had less calcification and more fibrosis compared with valves from men. Interestingly, in young women with stenotic bicuspid aortic valves, the quantity of calcium can be minimal and does not represent the severity of the stenosis.
      • Voisine M.
      • Hervault M.
      • Shen M.
      • et al.
      Age, sex, and valve phenotype differences in fibro-calcific remodeling of calcified aortic valve.
      These sex-specific valve lesions might be explained by the effect of sex hormones on aortic calcification/fibrosis. Indeed, androgens have been shown to induce the calcification pathway of smooth muscle cells via the androgen receptor,
      • Zhu D.
      • Hadoke P.W.
      • Wu J.
      • et al.
      Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification.
      whereas estrogen seems to inhibit valvular interstitial cells, but only in female cells.
      • Masjedi S.
      • Lei Y.
      • Patel J.
      • Ferdous Z.
      Sex-related differences in matrix remodeling and early osteogenic markers in aortic valvular interstitial cells.
      Thus, aortic valve lesions might also be linked to sex specificity at the cellular level. In normal swine aortic valves, 183 genes were identified as significantly different; females exhibited extracellular matrix remodelling genes, and males displayed more calcification/osteoblastic pathway genes.
      • McCoy C.M.
      • Nicholas D.Q.
      • Masters K.S.
      Sex-related differences in gene expression by porcine aortic valvular interstitial cells.
      These observations led to 2 hypotheses in the sex-specific aortic stenosis pathophysiology: disease development is sex-specific from the beginning with fibrosis in women and calcification in men, or both sexes have a common fibrotic pathway at the initiation of the disease and due to androgens, but calcification becomes preponderant in men.
      • Hervault M.
      • Clavel M.A.
      Sex-related differences in calcific aortic valve stenosis: pathophysiology, epidemiology, etiology, diagnosis, presentation, and outcomes.
      VHD should not be considered just as valvular disease; the effect on the ventricles must also be considered. Interestingly, ventricular remodelling is sex-specific and in aortic stenosis, women will most often present with concentric remodelling/hypertrophy, which can lead to paradoxical low flow aortic stenosis (ie, HFpEF associated with aortic stenosis).
      • Tribouilloy C.
      • Bohbot Y.
      • Rusinaru D.
      • et al.
      Excess mortality and undertreatment of women with severe aortic stenosis.
      Moreover, for a given level of aortic stenosis, women present with more myocardial fibrosis,
      • Tastet L.
      • Kwiecinski J.
      • Pibarot P.
      • et al.
      Sex-related differences in the extent of myocardial fibrosis in patients with aortic valve stenosis.
      which might explain the deleterious effect of concentric hypertrophy in women compared with men.
      • Capoulade R.
      • Clavel M.A.
      • Le Ven F.
      • et al.

      Mitral valve disease

      Women are more likely to present with rheumatic mitral VHD than men, despite an overall decrease in recent decades of this condition in industrialized countries.
      • Andell P.
      • Li X.
      • Martinsson A.
      • et al.
      Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study.
      ,
      • Vakamudi S.
      • Jellis C.
      • Mick S.
      • et al.
      Sex differences in the etiology of surgical mitral valve disease.
      This might be linked to differences in fibrotic valve remodelling modulated by the effects of androgens and estrogen; however, further mechanistic studies are warranted.
      • Andell P.
      • Li X.
      • Martinsson A.
      • et al.
      Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study.
      Mitral valve prolapse involving both leaflets is diagnosed more frequently in women, who present with thicker leaflets, representative of a generalized myxomatous degenerative process. Women less often present with flail leaflets, a phenomenon thought to be related to X chromosome-linked genetic determination of mitral valve prolapse properties.
      • Avierinos J.F.
      • Inamo J.
      • Grigioni F.
      • Gersh B.
      • Shub C.
      • Enriquez-Sarano M.
      Sex differences in morphology and outcomes of mitral valve prolapse.
      Posterior leaflet prolapse, which is associated with a more successful surgical repair, is less frequent in women, and thus their postoperative outcomes are poorer compared with men.
      • Avierinos J.F.
      • Inamo J.
      • Grigioni F.
      • Gersh B.
      • Shub C.
      • Enriquez-Sarano M.
      Sex differences in morphology and outcomes of mitral valve prolapse.
      Similarly, in the presence of severe mitral regurgitation, delays in surgical intervention, and associated poorer outcomes can occur due to failure to index LV enlargement to the smaller body size of women.
      • McNeely C.
      • Vassileva C.
      Mitral valve surgery in women.
      Sudden cardiac death associated with mitral valve prolapse is more frequent in women with bileaflet prolapse, mitral annular disjunction, and frequent and repetitive premature ventricular contractions.
      • Han H.C.
      • Ha F.J.
      • Teh A.W.
      • et al.
      Mitral valve prolapse and sudden cardiac death: a systematic review.
      ,
      • Hourdain J.
      • Clavel M.A.
      • Deharo J.C.
      • et al.
      Common phenotype in patients with mitral valve prolapse who experienced sudden cardiac death.
      Mitral annulus calcification develops more often and more extensively in women and could lead rarely to degenerative mitral stenosis or regurgitation. Despite being mostly without hemodynamic consequences, severe mitral annular calcification might have important consequences for surgical and catheter-based therapeutic interventions.
      • Abramowitz Y.
      • Jilaihawi H.
      • Chakravarty T.
      • Mack M.J.
      • Makkar R.R.
      Mitral annulus calcification.

      Tricuspid and pulmonic valve disease

      Despite being rare, isolated tricuspid regurgitation is more prevalent in women than in men. In-hospital mortality after surgical repair is high (approximately 9%), but comparable for both sexes.
      • Chandrashekar P.
      • Fender E.A.
      • Zack C.J.
      • et al.
      Sex-stratified analysis of national trends and outcomes in isolated tricuspid valve surgery.

      Cardiomyopathies

      Takotsubo or stress cardiomyopathy

      Takotsubo syndrome, also known as stress cardiomyopathy, apical ballooning syndrome or, in the lay literature, “broken heart syndrome,” is characterized by chest pain, HF symptoms ranging from dyspnea to cardiogenic shock, elevated serum troponin levels, and electrocardiogram changes, in the absence of acute obstructive CAD, and often occurs in response to an emotional or physical trigger.
      • Ghadri J.R.
      • Wittstein I.S.
      • Prasad A.
      • et al.
      International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology.
      Nearly 90% of patients affected are postmenopausal women.
      • Ghadri J.R.
      • Wittstein I.S.
      • Prasad A.
      • et al.
      International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology.
      Proposed pathophysiological mechanisms involve excess catecholamine stimulation of the myocardium, possibly associated with acute multivessel epicardial coronary artery spasm, and not infrequently observed, acute LV outflow tract obstruction.
      • Ghadri J.R.
      • Wittstein I.S.
      • Prasad A.
      • et al.
      International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology.
      ,
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical features and outcomes of Takotsubo (stress) cardiomyopathy.
      Although atypical patterns exist, characteristic findings include transient LV dysfunction with akinesis of the apical and mid ventricular wall segments, and hypercontractility of the basal segments.
      • Ghadri J.R.
      • Wittstein I.S.
      • Prasad A.
      • et al.
      International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology.
      ,
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical features and outcomes of Takotsubo (stress) cardiomyopathy.
      Patients diagnosed with this condition are at higher risk of in-hospital complications, including acute HF (12%-45%), AF (5%-15%), malignant arrhythmias (3%-10%), LV thrombus (2%-3%), cardiac arrest (4%-6%), ventricular rupture (< 1%), and death (1%-5%).
      • Ghadri J.R.
      • Wittstein I.S.
      • Prasad A.
      • et al.
      International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology.
      ,
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical features and outcomes of Takotsubo (stress) cardiomyopathy.
      Risk of recurrence is estimated to be between 5% and 22% over 10 years, and might be reduced by the administration of angiotensin converting enzyme inhibitors or β-blockers.
      • Ghadri J.R.
      • Wittstein I.S.
      • Prasad A.
      • et al.
      International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology.
      ,
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical features and outcomes of Takotsubo (stress) cardiomyopathy.
      The mean age at presentation for patients with stress-induced cardiomyopathy is older than for SCAD (67 years vs 48 years, respectively); however, the age ranges do overlap and it is important to note that stress-induced cardiomyopathy and SCAD might have similar clinical presentation characteristics. Both diagnoses require coronary angiography with careful examination of the coronary appearance; additional investigations including optical coherence tomography might be required to differentiate SCAD.

      Dilated cardiomyopathy

      Dilated cardiomyopathy (DCM) has numerous genetic or acquired origins,
      • Fatkin D.
      • Huttner I.G.
      • Kovacic J.C.
      • Seidman J.G.
      • Seidman C.E.
      Precision medicine in the management of dilated cardiomyopathy: JACC State-of-the-Art Review.
      which result in myocardial dysfunction leading to systolic dysfunction and clinical HF. DCM is less frequently diagnosed in women,
      • Fairweather D.
      • Cooper L.T.
      • Blauwet L.A.
      Sex and gender differences in myocarditis and dilated cardiomyopathy.
      who are less often diagnosed with HFrEF. Up to 30% of cases of DCM have a familial basis, and sex differences in phenotype are likely due to genetic variations, including gene mutations, differences in penetrance, and modifier genes. Mutations such as the troponin TA171S and TTN mutations have been associated with sex differences in phenotype of DCM.
      • Fairweather D.
      • Cooper L.T.
      • Blauwet L.A.
      Sex and gender differences in myocarditis and dilated cardiomyopathy.

      PPCM

      PPCM is a cause of HF affecting women toward the end of pregnancy or in the postpartum period. Diagnosis is on the basis of women presenting with signs and symptoms of HF, including systolic LV dysfunction, and an LVEF < 45%, in the absence of other causes of HF.
      • Regitz-Zagrosek V.
      • Roos-Hesselink J.W.
      • Bauersachs J.
      • et al.
      2018 ESC guidelines for the management of cardiovascular diseases during pregnancy.
      Risk factors for developing PPCM include multiparity, twin pregnancies, African American ethnicity, and advanced maternal age.
      • Regitz-Zagrosek V.
      • Roos-Hesselink J.W.
      • Bauersachs J.
      • et al.
      2018 ESC guidelines for the management of cardiovascular diseases during pregnancy.
      Concomitant preeclampsia increases the risk of adverse events in women with PPCM, namely the risk of clinical HF and pulmonary embolism.
      • Malhamé I.
      • Dayan N.
      • Moura C.S.
      • Samuel M.
      • Vinet E.
      • Pilote L.
      Peripartum cardiomyopathy with co-incident preeclampsia: a cohort study of clinical risk factors and outcomes among commercially insured women.
      Indigenous women in Canada presenting with PPCM have lower ejection fraction and greater LV dilatation on diagnosis.
      • Liu S.
      • Zuberi S.A.
      • Malik A.A.
      • et al.
      Peripartum cardiomyopathy characteristics and outcomes in Canadian Aboriginal and non-Aboriginal women.
      A protein resulting from cleavage of the lactation hormone prolactin, 16-kilodalton, has anti-angiogenic properties, and has been linked to myocyte damage and HF in animal models.
      • Tremblay-Gravel M.
      • Marquis-Gravel G.
      • Avram R.
      • et al.
      The effect of bromocriptine on left ventricular functional recovery in peripartum cardiomyopathy: insights from the BRO-HF retrospective cohort study.
      Higher LV end diastolic diameter, low LVEF on presentation, and African American ethnicity have been associated with poor LV recovery.
      • McNamara D.M.
      • Elkayam U.
      • Alharethi R.
      • et al.
      Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (Investigations of Pregnancy-Associated Cardiomyopathy).
      In addition to standard HF goal-directed medical therapy, bromocriptine, an antagonist of prolactin production in the anterior hypothalamus, might be useful in improving LVEF and clinical outcomes at follow-up.
      • Regitz-Zagrosek V.
      • Roos-Hesselink J.W.
      • Bauersachs J.
      • et al.
      2018 ESC guidelines for the management of cardiovascular diseases during pregnancy.
      ,
      • Tremblay-Gravel M.
      • Marquis-Gravel G.
      • Avram R.
      • et al.
      The effect of bromocriptine on left ventricular functional recovery in peripartum cardiomyopathy: insights from the BRO-HF retrospective cohort study.
      Anticoagulation is recommended in conjunction with bromocriptine, and might be considered in women with PPCM and very low LVEF.
      • Regitz-Zagrosek V.
      • Roos-Hesselink J.W.
      • Bauersachs J.
      • et al.
      2018 ESC guidelines for the management of cardiovascular diseases during pregnancy.
      Pregnancy after a diagnosis of PPCM should be avoided in women with any residual LV impairment (LVEF ≤ 50%-55%).
      • Regitz-Zagrosek V.
      • Roos-Hesselink J.W.
      • Bauersachs J.
      • et al.
      2018 ESC guidelines for the management of cardiovascular diseases during pregnancy.
      Some data suggest a possible genetic link between PPCM and DCM. Cardiologic screening of family members of women diagnosed with PPCM have identified first-degree relatives with DCM and vice-versa.
      • Fairweather D.
      • Cooper L.T.
      • Blauwet L.A.
      Sex and gender differences in myocarditis and dilated cardiomyopathy.

      Myocarditis

      Myocarditis is an inflammatory disease of the muscle cells of the myocardium, with or without necrosis.
      • Fairweather D.
      • Cooper L.T.
      • Blauwet L.A.
      Sex and gender differences in myocarditis and dilated cardiomyopathy.
      ,
      • Fung G.
      • Luo H.
      • Qiu Y.
      • Yang D.
      • McManus B.
      It can be acute, subacute, or chronic, and can involve focal or diffuse areas of the myocardium.
      • Fung G.
      • Luo H.
      • Qiu Y.
      • Yang D.
      • McManus B.
      In Canada and other developed countries, viral infections are the leading cause of myocarditis.
      • Fairweather D.
      • Cooper L.T.
      • Blauwet L.A.
      Sex and gender differences in myocarditis and dilated cardiomyopathy.
      Presentation of myocarditis ranges from asymptomatic states with vague symptoms to severe chest pain, cardiogenic shock, and arrhythmias.
      • Fung G.
      • Luo H.
      • Qiu Y.
      • Yang D.
      • McManus B.
      Despite myocarditis being more common in men, there are sex differences.
      • Fairweather D.
      • Cooper L.T.
      • Blauwet L.A.
      Sex and gender differences in myocarditis and dilated cardiomyopathy.
      Women are able to clear infections and repair damage without high levels of inflammation and without long-lasting damage.
      • Huber S.A.
      Coxsackievirus B3-induced myocarditis: infection of females during the estrus phase of the ovarian cycle leads to activation of T regulatory cells.
      However, similar to atherosclerosis, the mechanisms by which women develop myocarditis that subsequently leads to HF is different than in men.
      • Huber S.A.
      Coxsackievirus B3-induced myocarditis: infection of females during the estrus phase of the ovarian cycle leads to activation of T regulatory cells.
      Women might be more susceptible to certain types of myocarditis, such as autoimmune myocarditis caused by immune-complex deposition in the heart, which might be promoted by estrogen.
      • Fairweather D.
      • Petri M.A.
      • Coronado M.J.
      • Cooper L.T.
      Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis.

      Restrictive/infiltrative cardiomyopathies

      Characterized by diastolic dysfunction in a nondilated ventricle, restrictive cardiomyopathy is caused by either infiltrative diseases, storage diseases, or various systemic diseases.
      • Seward J.B.
      • Tajik A.J.
      Primary cardiomyopathies: classification, pathophysiology, clinical recognition and management.
      Infiltrative diseases are caused by a build-up of a substance in the myocardium and include amyloidosis, sarcoidosis, hereditary hemochromatosis, and primary hyperoxaluria.
      • Muchtar E.
      • Blauwet L.A.
      • Gertz M.A.
      Restrictive cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy.
      Storage diseases are congenital abnormalities in metabolism and include Anderson-Fabry disease.
      • Muchtar E.
      • Blauwet L.A.
      • Gertz M.A.
      Restrictive cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy.
      Systemic diseases including scleroderma, which has an overall female-to-male ratio of 3:1 and whose incidence is highest in women of childbearing age,
      • Shufelt C.L.
      • Pacheco C.
      • Tweet M.S.
      • Miller V.M.
      Sex-specific physiology and cardiovascular disease.
      can also lead to restrictive cardiomyopathy.
      • Muchtar E.
      • Blauwet L.A.
      • Gertz M.A.
      Restrictive cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy.
      Anderson-Fabry disease is a rare X-linked lysosomal storage disorder resulting from a deficiency of α-galactosidase A activity.
      • Deegan P.B.
      • Baehner A.F.
      • Romero M.Á.B.
      • Hughes D.A.
      • Kampmann C.
      • Beck M.
      Natural history of Fabry disease in females in the Fabry Outcome Survey.
      It is a multisystem disorder in which the substrate globotriaosylceramide is stored within many tissues such as vascular endothelium, renal glomeruli and tubules, dorsal root ganglia, cardiac myocytes, conducting tissue and valves, cornea, and skin.
      • Deegan P.B.
      • Baehner A.F.
      • Romero M.Á.B.
      • Hughes D.A.
      • Kampmann C.
      • Beck M.
      Natural history of Fabry disease in females in the Fabry Outcome Survey.
      Cardiac involvement, including LV hypertrophy, occurs in more than half of heterozygous female patients.
      • Deegan P.B.
      • Baehner A.F.
      • Romero M.Á.B.
      • Hughes D.A.
      • Kampmann C.
      • Beck M.
      Natural history of Fabry disease in females in the Fabry Outcome Survey.
      In contrast to men, who develop symptomatic manifestations of disease in the first to second decades of life, most symptoms of Anderson-Fabry in women develop in the third and fourth decades of life, or even later, with Fabry disease accounting for up to 12% of late-onset hypertrophic cardiomyopathy in women.
      • Chimenti C.
      • Pieroni M.
      • Morgante E.
      • et al.
      Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy.
      There often is a significant further delay between symptom onset and diagnosis in women.
      • Deegan P.B.
      • Baehner A.F.
      • Romero M.Á.B.
      • Hughes D.A.
      • Kampmann C.
      • Beck M.
      Natural history of Fabry disease in females in the Fabry Outcome Survey.
      One possible explanation for this delay is skewed X chromosome inactivation.
      • Lyon M.F.
      X-chromosome inactivation: a repeat hypothesis.
      Early in embryonic development, 1 of the 2 X chromosomes in each somatic cell becomes inactivated, which results in patchy and variable expression of the defective gene, resulting in the variable degree of disease severity and its delayed onset relative to men.
      • Lyon M.F.
      X-chromosome inactivation: a repeat hypothesis.
      Women develop fibrosis before evident hypertrophy, causing loss of myocardial function despite normal LV wall thickness, emphasizing the need for tissue characterization using cardiac magnetic resonance imaging; strain imaging with echocardiography might also have an emerging role.
      • Niemann M.
      • Herrmann S.
      • Hu K.
      • et al.
      Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment.
      Because women do often have some expression of α-galactosidase A, diagnosis using enzyme testing is not possible, and genetic diagnosis must be done if there is clinical suspicion. Plasma lyso-Gb3 represents a potential primary screening biomarker sensitive and specific for identifying Fabry disease in women and men, with more studies needed.
      • Maruyama H.
      • Miyata K.
      • Mikame M.
      • et al.
      Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.
      ,
      • Maruyama H.
      • Miyata K.
      • Mikame M.
      • et al.
      Correction: effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

      Sarcoidosis

      Cardiac sarcoidosis might be more common in women. A Finnish cohort study reported 65% of cardiac sarcoidosis cases to be in women, but recent data are lacking.
      • Kandolin R.
      • Lehtonen J.
      • Airaksinen J.
      • et al.
      Cardiac sarcoidosis.
      The exact mechanism for sarcoidosis is unclear, but is characterized by the development and accumulation of granulomas.
      • Iannuzzi M.C.
      • Rybicki B.A.
      • Teirstein A.S.
      Sarcoidosis.
      Granulomas usually develop to restrict pathogens, reduce inflammation, and protect surrounding tissue.
      • Iannuzzi M.C.
      • Rybicki B.A.
      • Teirstein A.S.
      Sarcoidosis.
      Granulomas are small, centrally organized collections of macrophages and epithelioid cells encircled by lymphocytes.
      • Iannuzzi M.C.
      • Rybicki B.A.
      • Teirstein A.S.
      Sarcoidosis.
      Because of the presence of chronic cytokine response, macrophages differentiate into epithelioid cells, develop secretory and bactericidal capacity, reduce phagocytic capacity, and fuse to form multinucleated giant cells.
      • Iannuzzi M.C.
      • Rybicki B.A.
      • Teirstein A.S.
      Sarcoidosis.
      As they mature, fibroblasts and collagen encase the granulomas into a ball-like cluster of cells, causing sclerosis and altering organ architecture and function.
      • Iannuzzi M.C.
      • Rybicki B.A.
      • Teirstein A.S.
      Sarcoidosis.

      Hypertrophic cardiomyopathy

      Despite being an autosomal dominant genetic disorder, hypertrophic cardiomyopathy is more often diagnosed in men, potentially because of the under-recognition of the condition in women.
      • Siontis K.C.
      • Ommen S.R.
      • Geske J.B.
      Sex, survival, and cardiomyopathy: differences between men and women with hypertrophic cardiomyopathy.
      Contemporary cohorts have shown that symptomatic HF is more frequent in women with hypertrophic cardiomyopathy, who are twice as likely to progress to advanced HF and 3 times more likely to experience HFpEF.
      • Rowin E.J.
      • Maron M.S.
      • Wells S.
      • Patel P.P.
      • Koethe B.C.
      • Maron B.J.
      Impact of sex on clinical course and survival in the contemporary treatment era for hypertrophic cardiomyopathy.
      Consequently, a higher proportion of women undergo myectomy and alcohol septal ablation.
      • Rowin E.J.
      • Maron M.S.
      • Wells S.
      • Patel P.P.
      • Koethe B.C.
      • Maron B.J.
      Impact of sex on clinical course and survival in the contemporary treatment era for hypertrophic cardiomyopathy.
      Age-adjusted mortality is similar for men and women, with similar rates of sudden cardiac death and appropriate reference for primary prevention ICD.
      • Rowin E.J.
      • Maron M.S.
      • Wells S.
      • Patel P.P.
      • Koethe B.C.
      • Maron B.J.
      Impact of sex on clinical course and survival in the contemporary treatment era for hypertrophic cardiomyopathy.

      Arrhythmia

      Arrhythmias are the fourth leading CVD-related cause of death among Canadian women, resulting in > 2600 deaths per year.
      • Canadian Women’s Heart Health Alliance
      Data Table: Number of Deaths, by Province, Diagnosis, and Age Category for Females in Canada in 2019.
      Arrhythmias are a leading cause of annual emergency department visits and CVD-related hospitalizations for Canadian women.
      • Jaffer S.
      • Foulds H.J.A.
      • Parry M.
      • et al.
      The Canadian Women’s Heart Health Alliance ATLAS on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 2: scope of the problem.
      More than 74% of cases of arrhythmia are due to AF,
      • Canadian Women’s Heart Health Alliance
      Data Table: Number of Deaths, by Province, Diagnosis, and Age Category for Females in Canada in 2019.
      the most common sustained arrhythmia in clinical practice. Its prevalence is 1%-2% in the general population and is expected to double in the next 50 years. Up to age 75 years, AF is more commonly found in men
      • Ganjehei L.
      • Massumi A.
      • Nazeri A.
      • Razavi M.
      Cardiac arrhythmias in women.
      ; however, after age 75 years, almost 60% of people with AF are women, with concomitant higher rates of mortality.
      • Ganjehei L.
      • Massumi A.
      • Nazeri A.
      • Razavi M.
      Cardiac arrhythmias in women.
      Women with AF have a higher risk of stroke and all-cause mortality, greater symptom burden, and worse quality of life, including poorer functional outcomes.
      • Andrade J.G.
      • Aguilar M.
      • Atzema C.
      • et al.
      The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.
      ,
      • Andrade J.G.
      • Deyell M.W.
      • Lee A.Y.K.
      • Macle L.
      Sex differences in atrial fibrillation.
      Women with AF suffer larger strokes and have greater admission rates to long-term care.
      • Ganjehei L.
      • Massumi A.
      • Nazeri A.
      • Razavi M.
      Cardiac arrhythmias in women.
      • Andrade J.G.
      • Aguilar M.
      • Atzema C.
      • et al.
      The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.
      • Andrade J.G.
      • Deyell M.W.
      • Lee A.Y.K.
      • Macle L.
      Sex differences in atrial fibrillation.
      AF is typically associated with obesity and VHD in women, and with CAD in men.
      • Andrade J.G.
      • Aguilar M.
      • Atzema C.
      • et al.
      The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.
      • Andrade J.G.
      • Deyell M.W.
      • Lee A.Y.K.
      • Macle L.
      Sex differences in atrial fibrillation.
      • Volgman A.S.
      • Manankil M.F.
      • Mookherjee D.
      • Trohman R.G.
      Women with atrial fibrillation: greater risk, less attention.
      Women tend to be more symptomatic with AF and have higher recurrence rates,
      • Ganjehei L.
      • Massumi A.
      • Nazeri A.
      • Razavi M.
      Cardiac arrhythmias in women.
      ,
      • Andrade J.G.
      • Deyell M.W.
      • Lee A.Y.K.
      • Macle L.
      Sex differences in atrial fibrillation.
      and women with paroxysmal AF tend to have faster and longer heart rate responses compared with men.
      • Forleo G.B.
      • Tondo C.
      • De Luca L.
      • et al.
      Gender-related differences in catheter ablation of atrial fibrillation.
      In South Asian women, AF is less prevalent despite a high burden of traditional risk factors such as hypertension and CAD.
      • Jaffer S.
      • Foulds H.J.A.
      • Parry M.
      • et al.
      The Canadian Women’s Heart Health Alliance ATLAS on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 2: scope of the problem.
      ,
      • Gillott R.G.
      • Willan K.
      • Kain K.
      • Sivananthan U.M.
      • Tayebjee M.H.
      South Asian ethnicity is associated with a lower prevalence of atrial fibrillation despite greater prevalence of established risk factors: a population-based study in Bradford Metropolitan District.
      ,
      • Potluri R.
      • Bainey K.
      • Bhatt D.
      • et al.
      42Atrialfibrillation and long -termsurvival in South Asians :insights from the UK ACALM registry.
      It has been hypothesized that genetic predisposition for South Asian women to have smaller left atrial volume size protects against the development of reentrant circuits and atrial fibrosis, thereby reducing structural and electrical remodelling.
      • Andrade J.G.
      • Deyell M.W.
      • Lee A.Y.K.
      • Macle L.
      Sex differences in atrial fibrillation.
      ,
      • Gillott R.G.
      • Willan K.
      • Kain K.
      • Sivananthan U.M.
      • Tayebjee M.H.
      South Asian ethnicity is associated with a lower prevalence of atrial fibrillation despite greater prevalence of established risk factors: a population-based study in Bradford Metropolitan District.
      ,
      • Odening K.E.
      • Deiß S.
      • Dilling-Boer D.
      • et al.
      Mechanisms of sex differences in atrial fibrillation: role of hormones and differences in electrophysiology, structure, function, and remodelling.
      ,
      • O’Neill J.
      • Swoboda P.P.
      • Plein S.
      • Tayebjee M.H.
      Left atrial size and function in a South Asian population and their potential influence on the risk of atrial fibrillation.
      No ethnic or sex-specific differences in direct oral anticoagulation therapy efficacy has been determined although there is a significant reduction in major and nonmajor bleeding in female patients receiving direct oral anticoagulation therapy.
      • Andrade J.G.
      • Aguilar M.
      • Atzema C.
      • et al.
      The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.
      ,
      • Chiang C.E.
      • Wang K.L.
      • Lin S.J.
      Asian strategy for stroke prevention in atrial fibrillation.
      ,
      • Goto S.
      • Zhu J.
      • Liu L.
      • et al.
      Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.
      Symptom control in women with AF remains suboptimal in women compared with men, who experience symptoms more frequently and have poorer quality of life pre- and postablation.
      • Yao R.J.R.
      • Macle L.
      • Deyell M.W.
      • et al.
      Impact of female sex on clinical presentation and ablation outcomes in the CIRCA-DOSE study.
      Registry data show that women are less likely to undergo electrical cardioversion in clinical practice,
      • Schnabel R.B.
      • Pecen L.
      • Ojeda F.M.
      • et al.
      Gender differences in clinical presentation and 1-year outcomes in atrial fibrillation.
      but more likely to be treated with pharmacological cardioversion. Female patients with AF are less likely to undergo ablation therapy, despite obtaining similar symptom relief, reduction in AF burden, and outcomes similar to those of men after ablation therapy.
      • Yao R.J.R.
      • Macle L.
      • Deyell M.W.
      • et al.
      Impact of female sex on clinical presentation and ablation outcomes in the CIRCA-DOSE study.
      Women are at a higher rate of complications after catheter ablation for AF, including phrenic nerve injury, although this difference is not statistically significant (3.5% in men vs 7.0% in women; P = 0.18).
      • Yao R.J.R.
      • Macle L.
      • Deyell M.W.
      • et al.
      Impact of female sex on clinical presentation and ablation outcomes in the CIRCA-DOSE study.
      Women have a longer length of systole and a longer QT segment, compared with men.
      • Prince S.A.
      • Reed J.L.
      • McFetridge C.
      • Tremblay M.S.
      • Reid R.D.
      Correlates of sedentary behaviour in adults: a systematic review.
      ,
      • Lombard W.P.
      • Cope O.M.
      Effect of pulse rate on the length of the systoles and diastoles of the normal human heart in the standing position.
      It is believed sex differences in arrhythmias are related to sex hormones and their influence on cardiac electrophysiology.
      • Ganjehei L.
      • Massumi A.
      • Nazeri A.
      • Razavi M.
      Cardiac arrhythmias in women.
      Women’s longer QT segments are thought to occur in the absence of testosterone, which suppresses the inward movement of calcium into cell membranes and enhances inward-rectifying potassium currents, thereby causing a net positive potential to the membrane, and shorter QTc intervals in men.
      • Jonsson M.K.B.
      • Vos M.A.
      • Duker G.
      • Demolombe S.
      • van Veen T.A.B.
      Gender disparity in cardiac electrophysiology: implications for cardiac safety pharmacology.
      Although progesterone might have an effect similar to that of testosterone, estrogen prolongs the QT interval.
      • Ganjehei L.
      • Massumi A.
      • Nazeri A.
      • Razavi M.
      Cardiac arrhythmias in women.
      ,
      • Andrade J.G.
      • Aguilar M.
      • Atzema C.
      • et al.
      The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.
      ,
      • Nakagawa M.
      • Ooie T.
      • Takahashi N.
      • et al.
      Influence of menstrual cycle on QT interval dynamics.
      The normally occurring increase in progesterone and the decrease in estrogen levels during a normal menstrual cycle correspond to an increased frequency, symptomatic burden, and duration of supraventricular tachycardia (SVT) in women.
      • Rosano G.M.C.
      • Leonardo F.
      • Rosano G.M.C.
      • et al.
      Cyclical variation in paroxysmal supraventricular tachycardia in women.
      Sick sinus syndrome, SVT, atrioventricular nodal reentry tachycardia (AVNRT), and postural orthostatic tachycardia syndrome are also more common in women.
      • Porter M.J.
      • Morton J.B.
      • Denman R.
      • et al.
      Influence of age and gender on the mechanism of supraventricular tachycardia.
      The most common type of SVT in women is AVNRT. In a study on the sex-related differences in patients undergoing catheter ablation of AVNRT, women were twice as likely to have AVNRT, and were significantly younger at onset compared with men.
      • Suenari K.
      • Hu Y.F.
      • Tsao H.M.
      • et al.
      Gender differences in the clinical characteristics and atrioventricular nodal conduction properties in patients with atrioventricular nodal reentrant tachycardia.
      Pregnancy is a proarrhythmic state and the risk of SVT increases with pregnancy, especially in women with a history of Wolff-Parkinson-White.
      • Widerhorn J.
      • Widerhorn A.L.M.
      • Rahimtoola S.H.
      • Elkayam U.
      WPW syndrome during pregnancy: increased incidence of supraventricular arrhythmias.

      Vascular arterial disease

      Aortic aneurysms

      Thoracic aortic aneurysm (TAA) is more prevalent in men, who account for nearly 70% of those with thoracic aortic dissections.
      • Nienaber C.A.
      • Fattori R.
      • Mehta R.H.
      • et al.
      Gender-related differences in acute aortic dissection.
      However, women with TAA have faster aneurysm expansion,
      • Cheung K.
      • Boodhwani M.
      • Chan K.L.
      • Beauchesne L.
      • Dick A.
      • Coutinho T.
      Thoracic aortic aneurysm growth: role of sex and aneurysm etiology.
      are 3 times more likely to dissect
      • Juvonen T.
      • Ergin M.A.
      • Galla J.D.
      • et al.
      Prospective study of the natural history of thoracic aortic aneurysms.
      (especially at smaller aneurysm sizes),
      • Pape L.A.
      • Tsai T.T.
      • Isselbacher E.M.
      • et al.
      Aortic diameter ≥ 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD).
      and are 40% more likely to die
      • Nienaber C.A.
      • Fattori R.
      • Mehta R.H.
      • et al.
      Gender-related differences in acute aortic dissection.
      than men with TAA.
      • Cheung K.
      • Boodhwani M.
      • Chan K.L.
      • Beauchesne L.
      • Dick A.
      • Coutinho T.
      Thoracic aortic aneurysm growth: role of sex and aneurysm etiology.
      ,
      • Pape L.A.
      • Tsai T.T.
      • Isselbacher E.M.
      • et al.
      Aortic diameter ≥ 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD).
      Evidence from the Canadian Thoracic Aortic Collaborative identified that after aortic surgical repair women experience higher risk of mortality (81%) and stroke (90%), compared with their male counterparts.
      • Chung J.
      • Stevens L.M.
      • Ouzounian M.
      • et al.
      Sex-related differences in patients undergoing thoracic aortic surgery: evidence from the Canadian Thoracic Aortic Collaborative.
      Prevalence of abdominal aortic aneurysm (AAA) is also higher in men,
      • Singh K.
      • Bønaa K.H.
      • Jacobsen B.K.
      • Bjørk L.
      • Solberg S.
      Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study. The Tromsø Study.
      but AAA-related outcomes are far worse in women. Current smoking yields twice the risk of AAA for women compared with men.
      • Carter J.L.
      • Morris D.R.
      • Sherliker P.
      • et al.
      Sex-specific associations of vascular risk factors with abdominal aortic aneurysm: findings from 1.5 million women and 0.8 million men in the United States and United Kingdom [erratum in: 2020;9:e014559].
      Women with AAA also experience twice as fast aneurysm growth,
      • Mofidi R.
      • Goldie V.J.
      • Kelman J.
      • Dawson A.R.W.
      • Murie J.A.
      • Chalmers R.T.A.
      Influence of sex on expansion rate of abdominal aortic aneurysms.
      and up to 4 times higher risk of AAA rupture
      • Sweeting M.J.
      • Thompson S.G.
      • Brown L.C.
      Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms.
      despite having smaller aneurysm sizes, compared with men. Women are less likely than men to be referred for AAA repair,
      • Dillavou E.D.
      • Muluk S.C.
      • Makaroun M.S.
      A decade of change in abdominal aortic aneurysm repair in the United States: have we improved outcomes equally between men and women?.
      and more likely to experience surgical complications post repair.
      • Wisniowski B.
      • Barnes M.
      • Jenkins J.
      • Boyne N.
      • Kruger A.
      • Walker P.J.
      Predictors of outcome after elective endovascular abdominal aortic aneurysm repair and external validation of a risk prediction model.
      ,
      • Lo R.C.
      • Bensley R.P.
      • Hamdan A.D.
      • Wyers M.
      • Adams J.E.
      • Schermerhorn M.L.
      Gender differences in abdominal aortic aneurysm presentation, repair, and mortality in the Vascular Study Group of New England.
      Thus, although women appear to be “naturally protected” against thoracic aortic disease, for women who go on to develop the condition this might be a signal that their aortas harbor a greater burden of wall pathology, and/or are exposed to greater hemodynamic challenges—all of which might contribute to worse aorta-related outcomes in women.
      A potential explanation for these sex differences lies in hormonal, molecular, and hemodynamic differences between women and men. Aortic stiffness (a robust marker of aortic health and arterial aging) correlates better with TAA expansion in women compared with men.
      • Boczar K.E.
      • Cheung K.
      • Boodhwani M.
      • et al.
      Sex differences in thoracic aortic aneurysm growth: role of aortic stiffness.
      In a study of TAA specimens obtained during elective repair, higher levels of matrix metalloproteinase (MMP)-2 and MMP-9 (enzymes capable of degrading and remodelling the arterial wall) and decreased expression of the inhibitory enzymes TIMP metallopeptidase inhibitor 1 and -2 were found in women, compared with men.
      • Sokolis D.P.
      • Iliopoulos D.C.
      Impaired mechanics and matrix metalloproteinases/inhibitors expression in female ascending thoracic aortic aneurysms.
      This impairment of aortic wall homeostasis, resulting in enhanced extracellular matrix degradation, led to a higher aortic elastic modulus, increased aortic stiffness, and decreased aortic strength in women. This suggests that women with TAA have greater insults to aortic health and structure than men, potentially explaining women’s faster aneurysm expansion and worse TAA-related outcomes. For AAA, evidence supports a role for estrogen in modulating inflammation and MMP activity, resulting in a protective effect on aortic matrix remodelling.
      • Crowther M.
      • Goodall S.
      • Jones J.L.
      • Bell P.R.
      • Thompson M.M.
      Increased matrix metalloproteinase 2 expression in vascular smooth muscle cells cultured from abdominal aortic aneurysms.
      ,
      • Wu X.F.
      • Zhang J.
      • Paskauskas S.
      • Xin S.J.
      • Duan Z.Q.
      The role of estrogen in the formation of experimental abdominal aortic aneurysm.
      The amount of estrogen receptor α in the aortic wall is inversely associated with MMP activity and AAA expansion.
      • Yeap B.B.
      • Hyde Z.
      • Norman P.E.
      • Chubb S.A.P.
      • Golledge J.
      Associations of total testosterone, sex hormone-binding globulin, calculated free testosterone, and luteinizing hormone with prevalence of abdominal aortic aneurysm in older men.
      These findings help explain the lower prevalence of AAA among reproductive-age women, while highlighting links between loss of estrogen and worse AAA outcomes in older, postmenopausal women.
      Despite worse TAA-related outcomes in women, guidelines do not propose sex-specific approaches for this condition. The CCS position statement on the management of thoracic aortic disease
      • Boodhwani M.
      • Andelfinger G.
      • Leipsic J.
      • et al.
      Canadian Cardiovascular Society position statement on the management of thoracic aortic disease.
      recommends indexing TAA size to body surface area in shorter individuals and women, and surgery should be contemplated when the TAA size exceeds 2.75 cm/m2. However, it remains unclear whether simple indexation will eliminate the sex differences in TAA complications and outcomes among those undergoing regular surveillance. The Society of Vascular Surgery recommends elective AAA repair in women when the aneurysm reaches between 50 and 54 mm,
      • Chaikof E.L.
      • Dalman R.L.
      • Eskandari M.K.
      • et al.
      The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm.
      which is smaller than the 55 mm cutoff for men. Although AAA ultrasound screening recommendations are available, studies for AAA screening have notoriously under-represented women, undermining the evidence to guide screening practices in women.
      • Kapila V.
      • Jetty P.
      • Wooster D.
      • Vucemilo V.
      • Dubois L.
      2018 Screening for abdominal aortic aneurysms in Canada: review and position statement from the Canadian Society of Vascular Surgery.
      The CCS, Canadian Society of Vascular Surgery, and Society of Vascular Surgery recommend screening women for AAA if they have smoked, have heart disease, have a family history of AAA, and are between the ages of 65 and 80 years.
      • Boodhwani M.
      • Andelfinger G.
      • Leipsic J.
      • et al.
      Canadian Cardiovascular Society position statement on the management of thoracic aortic disease.

      Atherosclerotic lower extremity arterial disease (“peripheral arterial disease”)

      Similar to other atherosclerotic vascular diseases, peripheral arterial disease (PAD) tends to develop 1-2 decades later in women, compared with men.
      • Nguyen L.
      • Liles D.R.
      • Lin P.H.
      • Bush R.L.
      Hormone replacement therapy and peripheral vascular disease in women.
      After menopause, rates of PAD are at least similar, and possibly higher, in women than men.
      • Pollak A.W.
      PAD in women: the ischemic continuum.
      Risk factors for PAD are similar for both sexes, except that hypertensive disorders of pregnancy increase future risk of PAD by threefold
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      ; and diabetes appears to be more ominous for women, tripling the risk of occlusive vascular mortality.
      Prospective Studies Collaboration and Asia Pacific Cohort Studies Collaboration
      Sex-specific relevance of diabetes to occlusive vascular and other mortality: a collaborative meta-analysis of individual data from 980793adults from 68 prospective studies.
      Women with PAD are more likely than men to be asymptomatic or have atypical leg symptoms.
      • Higgins P.
      • Higgins A.
      Epidemiology of peripheral arterial disease in women.
      Conversely, when disease is clinically manifest, women have more complex disease,
      • Ortmann J.
      • Nüesch E.
      • Traupe T.
      • Diehm N.
      • Baumgartner I.
      Gender is an independent risk factor for distribution pattern and lesion morphology in chronic critical limb ischemia.
      have greater functional impairment,
      • McDermott M.M.
      • Greenland P.
      • Liu K.
      • et al.
      Sex differences in peripheral arterial disease: leg symptoms and physical functioning.
      and, perhaps partially as a result, are 4 times more likely to be depressed
      • Smolderen K.G.
      • Spertus J.A.
      • Vriens P.W.
      • Kranendonk S.
      • Nooren M.
      • Denollet J.
      Younger women with symptomatic peripheral arterial disease are at increased risk of depressive symptoms.
      than men. Although it has been reported that women have slightly lower ankle-brachial index than men, this is not expected to affect diagnostic accuracy.
      • Aboyans V.
      • Criqui M.H.
      • McClelland R.L.
      • et al.
      Intrinsic contribution of gender and ethnicity to normal ankle-brachial index values: the Multi-Ethnic Study of Atherosclerosis (MESA).
      The sensitivity and specificity of advanced anatomical imaging techniques do not appear to be different for men and women.
      • Aboyans V.
      • Criqui M.H.
      • McClelland R.L.
      • et al.
      Intrinsic contribution of gender and ethnicity to normal ankle-brachial index values: the Multi-Ethnic Study of Atherosclerosis (MESA).
      Sex differences have been reported in response to treatment and outcomes in PAD. Although walking rehabilitation is an integral component of claudication treatment, women with diabetes and PAD have a worse functional response to rehabilitation than men with diabetes.
      • Gardner A.W.
      • Parker D.E.
      • Montgomery P.S.
      • Blevins S.M.
      Diabetic women are poor responders to exercise rehabilitation in the treatment of claudication.
      However, other studies and clinical trials that have evaluated walking rehabilitation in patients with PAD either failed to recruit women or to report results according to sex, limiting our ability to draw conclusions about its overall efficacy in women. Women are less likely than men to be referred for elective lower extremity revascularization; however, they are more likely to be admitted emergently for PAD-related complications.
      • Egorova N.
      • Vouyouka A.G.
      • Quin J.
      • et al.
      Analysis of gender-related differences in lower extremity peripheral arterial disease.
      Women tend to be older and have more advanced disease at the time of surgical revascularization. Postprocedurally, women are more likely to have a bleeding complication and have longer hospital stays.
      • Egorova N.
      • Vouyouka A.G.
      • Quin J.
      • et al.
      Analysis of gender-related differences in lower extremity peripheral arterial disease.
      ,
      • Lo R.C.
      • Bensley R.P.
      • Dahlberg S.E.
      • et al.
      Presentation, treatment, and outcome differences between men and women undergoing revascularization or amputation for lower extremity peripheral arterial disease.
      Postoperatively, women have a 31% higher 30-day mortality, 56% higher risk of early graft thrombosis, 64% higher risk of embolization, 7% higher risk of amputation, 21% higher risk of cardiac events, and 35% higher risk of stroke than men.
      • Wang J.
      • He Y.
      • Shu C.
      • Zhao J.
      • Dubois L.
      The effect of gender on outcomes after lower extremity revascularization.
      Outside of the postoperative period, non-PAD outcomes are worse in women, because they are 15% more likely to suffer AMI, compared with men.
      • Hussain M.A.
      • Lindsay T.F.
      • Mamdani M.
      • Wang X.
      • Verma S.
      • Al-Omran M.
      Sex differences in the outcomes of peripheral arterial disease: a population-based cohort study.
      Despite disease prevalence that is at least as high as men’s and worse outcomes, women remain under-represented in PAD studies. Women constitute < 35% of participants in PAD research; and 22% of participants in randomized trials of arterial revascularization.
      • Hoel A.W.
      • Kayssi A.
      • Brahmanandam S.
      • Belkin M.
      • Conte M.S.
      • Nguyen L.L.
      Under-representation of women and ethnic minorities in vascular surgery randomized controlled trials.
      As a result, present guidelines about PAD do not specifically address PAD in women.

      Vascular cognitive impairment, dementia, and stroke

      Stroke

      Stroke is a major cause of all adult disability worldwide,
      • Barker-Collo S.
      • Bennett D.A.
      • Krishnamurthi R.V.
      • et al.
      Sex differences in stroke incidence, prevalence, mortality and disability-adjusted life years: results from the Global Burden of Disease Study 2013.
      and is the second leading cause of CVD-related mortality in women in Canada, resulting in approximately 7000 deaths annually.
      • McMurray J.J.V.
      • Jackson A.M.
      • Lam C.S.P.
      • et al.
      Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction.
      Stroke is a major driver of emergency room visits for Canadian women, responsible for more than 25,000, or 22% of CVD-related encounters in primarily women of postmenopausal age (89%), with 57% of visits resulting in an admission to inpatient care.
      • Jaffer S.
      • Foulds H.J.A.
      • Parry M.
      • et al.
      The Canadian Women’s Heart Health Alliance ATLAS on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 2: scope of the problem.
      Just under 20% (n > 25,000) of CVD-related hospitalizations among Canadian women are due to stroke. The age-standardized occurrence rates of stroke according to sex are presented in Figure 2, and age-standardized mortality rates for stroke according to sex in Figure 3.
      Although the overall incidence of stroke is higher in men, incidence in women rises sharply after age 75 years to rates exceeding those observed in men.
      GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      Because of the increased life expectancy of women, the lifetime risk of stroke is higher in women compared with men.
      GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      Women are disproportionately affected by stroke, demonstrating higher age-specific mortality after age 75 years,
      • Reeves M.J.
      • Bushnell C.D.
      • Howard G.
      • et al.
      Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes.
      greater stroke severity
      • Phan H.T.
      • Reeves M.J.
      • Blizzard C.L.
      • et al.
      Sex differences in severity of stroke in the INSTRUCT study: a meta-analysis of individual participant data.
      (although this disparity might be confounded by older age at onset and premorbid functional status
      • Renoux C.
      • Coulombe J.
      • Li L.
      • et al.
      Confounding by pre-morbid functional status in studies of apparent sex differences in severity and outcome of stroke.
      ), an increased likelihood of stroke-related disability,
      • Gall S.L.
      • Tran P.L.
      • Martin K.
      • Blizzard L.
      • Srikanth V.
      Sex differences in long-term outcomes after stroke: functional outcomes, handicap, and quality of life.
      reduced quality of life after stroke,
      • Bushnell C.D.
      • Reeves M.J.
      • Zhao X.
      • et al.
      Sex differences in quality of life after ischemic stroke.
      increased levels of post-stroke depression,
      • Guiraud V.
      • Gallarda T.
      • Calvet D.
      • et al.
      Depression predictors within six months of ischemic stroke: the DEPRESS study.
      and higher rates of institutionalization compared with male stroke survivors.
      • Reeves M.J.
      • Bushnell C.D.
      • Howard G.
      • et al.
      Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes.
      Although major vascular risk factors (eg, hypercholesterolemia, smoking, IHD, diabetes) are more prevalent among men who present with stroke, hypertension and AF are more frequent among female stroke patients.
      • Haast R.A.
      • Gustafson D.R.
      • Kiliaan A.J.
      Sex differences in stroke.
      AF is a major preventable cause of stroke,
      • Go A.S.
      • Hylek E.M.
      • Phillips K.A.
      • et al.
      Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study.
      independently increasing stroke risk by fivefold
      • Wolf P.A.
      • Abbott R.D.
      • Kannel W.B.
      Atrial fibrillation as an independent risk factor for stroke: the Framingham study.
      and accounting for more than 20% of all acute ischemic strokes.
      • Hughes M.
      • Lip G.Y.
      Guideline Development Group
      National Clinical Guideline for Management of Atrial Fibrillation in Primary and Secondary Care, National Institute for Health and Clinical Excellence. Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data.
      Although they have a lower prevalence of AF, because of aging, women have a comparable lifetime risk.
      • Andrade J.G.
      • Deyell M.W.
      • Lee A.Y.K.
      • Macle L.
      Sex differences in atrial fibrillation.
      Early population-based studies and clinical trials showed an increased risk of stroke for women with AF, especially after age 75 years,
      • Fang M.C.
      • Singer D.E.
      • Chang Y.
      • et al.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study.
      ,
      • Hart R.G.
      • Pearce L.A.
      • McBride R.
      • Rothbart R.M.
      • Asinger R.W.
      Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators.
      and a more recent meta-analysis of more than 4 million participants reported a twofold increase in the pooled relative risk of stroke associated with AF in women vs men (Relative risk = 1.99; 95% CI, 1.46-2.71).
      • Emdin C.A.
      • Wong C.X.
      • Hsiao A.J.
      • et al.
      Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies.
      On the basis of these associations, female sex was included as a risk factor in the Congestive Heart Failure, Hypertension, Age (≥75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female) (CHA2DS2-VASc) score for stroke risk stratification
      • Lip G.Y.
      • Nieuwlaat R.
      • Pisters R.
      • Lane D.A.
      • Crijns H.J.
      Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation.
      and clinical guidelines for stroke prevention and the management of AF.
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ,
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
      However, recent work suggests that this excess risk might be more dependent on age and the presence of comorbid risk factors
      • Mikkelsen A.P.
      • Lindhardsen J.
      • Lip G.Y.
      • Gislason G.H.
      • Torp-Pedersen C.
      • Olesen J.B.
      Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study.
      and a reanalysis of the prognostic value of female sex for stroke risk in AF patients identified sex as a “risk modifier,” rather than independent risk factor.
      • Nielsen P.B.
      • Skjoth F.
      • Overvad T.F.
      • Larsen T.B.
      • Lip G.Y.H.
      Female sex is a risk modifier rather than a risk factor for stroke in atrial fibrillation: should we use a CHA2DS2-VA score rather than CHA2DS2-VASc?.
      Women have several unique risk factors that make them vulnerable to stroke across the lifespan, particularly during pregnancy and postmenopausal aging. A recent meta-analysis (n > 10 million) of sex-specific stroke risk factors showed that hypertensive disorders of pregnancy, including gestational hypertension, preeclampsia, and eclampsia increase relative stroke risk by 81% and stroke mortality by 54%
      • Poorthuis M.H.
      • Algra A.M.
      • Algra A.
      • Kappelle L.J.
      • Klijn C.J.
      Female- and male-specific risk factors for stroke: a systematic review and meta-analysis.
      and stroke risks were increased among women with oophorectomy, preterm delivery, and stillbirth.
      • Poorthuis M.H.
      • Algra A.M.
      • Algra A.
      • Kappelle L.J.
      • Klijn C.J.
      Female- and male-specific risk factors for stroke: a systematic review and meta-analysis.
      Endothelial dysfunction and disruption of the blood brain barrier play a central role in cerebral injury related to preeclampsia/eclampsia, as suggested by the presence of microangiopathic hemolysis and subcortical edema in the occipital lobes in 28 women who underwent cerebral magnetic resonance imaging.
      • Schwartz R.B.
      • Feske S.K.
      • Polak J.F.
      • et al.
      Preeclampsia-eclampsia: clinical and neuroradiographic correlates and insights into the pathogenesis of hypertensive encephalopathy.
      Estrogen, particularly 17b-estradiol, has multiple potential protective effects associated with enhanced endothelial nitric oxide synthesis and production, vasodilating prostanoids, and endothelium-derived hyperpolarizing factor, all of which promote tissue perfusion during and after a cerebral artery occlusion.
      • Haast R.A.
      • Gustafson D.R.
      • Kiliaan A.J.
      Sex differences in stroke.
      Other protective effects of estrogen might include reduced oxidative stress, increased neuro- and angiogenesis and the suppression of atherogenesis,
      • Liu M.
      • Kelley M.H.
      • Herson P.S.
      • Hurn P.D.
      Neuroprotection of sex steroids.
      potentially contributing to increases in stroke risk associated with estrogen reductions at menopause. Differences in genetic factors and differential activation of apoptotic cell-cell signalling pathways and neuroinflammatory and immune responses might contribute to sex differences in stroke risk.
      • Spychala M.S.
      • Honarpisheh P.
      • McCullough L.D.
      Sex differences in neuroinflammation and neuroprotection in ischemic stroke.
      Although some evidence of sex differences in acute stroke management exists, these findings are inconsistent and many studies did not account for treatment confounds such as age, stroke severity, and pre-stroke functional status.
      • Bushnell C.
      • Howard V.J.
      • Lisabeth L.
      • et al.
      Sex differences in the evaluation and treatment of acute ischaemic stroke.
      ,
      • Appelros P.
      • Stegmayr B.
      • Terent A.
      A review on sex differences in stroke treatment and outcome.
      Despite this variability, there remains consistent evidence that women might experience greater prehospital delays and longer door-to-imaging times,
      • Bushnell C.
      • Howard V.J.
      • Lisabeth L.
      • et al.
      Sex differences in the evaluation and treatment of acute ischaemic stroke.
      undergo fewer lipid investigations,
      • Appelros P.
      • Stegmayr B.
      • Terent A.
      A review on sex differences in stroke treatment and outcome.
      and have reduced access to some preventive medications, including antiplatelet and anticoagulation therapy.
      • Appelros P.
      • Stegmayr B.
      • Terent A.
      A review on sex differences in stroke treatment and outcome.
      However, although some registries have shown that women with AF are less likely to receive oral anticoagulation after stroke,
      • Thompson L.E.
      • Maddox T.M.
      • Lei L.
      • et al.
      Sex differences in the use of oral anticoagulants for atrial fibrillation: a report from the National Cardiovascular Data Registry (NCDR ®) PINNACLE Registry.
      others report no differences,
      • Mazurek M.
      • Huisman M.V.
      • Rothman K.J.
      • et al.
      Gender differences in antithrombotic treatment for newly diagnosed atrial fibrillation: the GLORIA-AF Registry Program.
      highlighting the need for more sex-stratified studies of treatment and outcomes post-stroke.

      Vascular cognitive impairment and dementia

      Two-thirds of the > 5 million Americans living with dementia due to Alzheimer disease are women.
      • Snyder H.M.
      • Asthana S.
      • Bain L.
      • et al.
      Sex biology contributions to vulnerability to Alzheimer’s disease: a think tank convened by the Women’s Alzheimer’s Research Initiative.
      Several population-based studies report comparable rates of incident dementia among men and women until age 80, at which point incidence increases dramatically among women and significantly reduces quality of life.
      • Snyder H.M.
      • Asthana S.
      • Bain L.
      • et al.
      Sex biology contributions to vulnerability to Alzheimer’s disease: a think tank convened by the Women’s Alzheimer’s Research Initiative.
      Although there is much less evidence characterizing sex differences and mechanisms of vascular cognitive impairment (VCI) and dementia than stroke, female sex has been shown to be an independent predictor of pre-stroke dementia.
      • Pendlebury S.T.
      • Rothwell P.M.
      Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis.
      Potential mechanisms of sex differences in the development of cognitive decline include genetic, neurochemical, and vascular risk factors.
      • Snyder H.M.
      • Asthana S.
      • Bain L.
      • et al.
      Sex biology contributions to vulnerability to Alzheimer’s disease: a think tank convened by the Women’s Alzheimer’s Research Initiative.
      Specifically, women with the apolipoprotein E genotype show higher age-specific odds of developing dementia and are more likely to convert from mild cognitive impairment to dementia.
      • Snyder H.M.
      • Asthana S.
      • Bain L.
      • et al.
      Sex biology contributions to vulnerability to Alzheimer’s disease: a think tank convened by the Women’s Alzheimer’s Research Initiative.
      Although midlife hypertension is more common in men, the onset of midlife hypertension is predictive of increased dementia risk in women only.
      • Gilsanz P.
      • Mayeda E.R.
      • Glymour M.M.
      • et al.
      Female sex, early-onset hypertension, and risk of dementia.
      At menopause, reductions in estrogen might reduce neuroprotective effects and increase vulnerability to cognitive decline, and metabolic factors (eg, changes in glucose metabolism and insulin signalling) might also contribute to dementia risk.
      • Snyder H.M.
      • Asthana S.
      • Bain L.
      • et al.
      Sex biology contributions to vulnerability to Alzheimer’s disease: a think tank convened by the Women’s Alzheimer’s Research Initiative.
      Although there are limited available treatment options for VCI and dementia, future work on sex-specific vascular contributions to dementia risk and related biological pathways is urgently needed to identify potentially viable therapeutic targets for VCI and dementia.

      Conclusions

      Sex- and gender-unique differences in CVD affect symptom presentation, underlying pathophysiology, and clinical outcomes. These differences must be understood when evaluating women to determine optimal CVD management and improve patient outcomes. With a few notable exceptions in which women predominate in CVD manifestations, such as SCAD and stress-induced cardiomyopathy, there is a paucity of sex-disaggregated data to guide management and guideline development. Evaluation of women with cardiovascular disorders must be done through this sex- and gender-specific lens. Efforts must be made to increase enrollment of women into clinical trials, to build a solid evidence base for guideline-directed management.

      Acknowledgements

      The authors gratefully acknowledge Lisa Comber for her coordination of this effort. 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 chapter illustration. This chapter has been submitted on behalf of the Canadian Women’s Heart Health Alliance (CWHHA), a pan-Canadian network of >90 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

      University of Ottawa Heart Institute Foundation.

      Disclosures

      S.L.M. is a member of the Novo Nordisk steering committee for the Semaglutide Cardiovascular Outcomes Trial in Patients With T2D clinical trial and has served on advisory boards for Lantheus Medical Imaging. C.P. has received conference moderating fees from Pfizer and has served on advisory boards for KYE pharmaceuticals. The remaining authors have no conflicts of interest to disclose.

      References

        • Public Health Agency of Canada
        Report from the Canadian Chronic Disease Surveillance System: Heart Disease in Canada, 2018.
        Public Health Agency of Canada, Ottawa, Ontario2018
        • Statistics Canada
        Table 1-1. Deaths and mortality rate, by selected grouped causes, sex and geography - Canada.
        (Available at:)
        • Go A.S.
        • Mozaffarian D.
        • Roger V.L.
        • et al.
        Heart disease and stroke statistics--2013 update: a report from the American Heart Association.
        Circulation. 2013; 127: e6-e245
        • Murabito J.M.
        • Evans J.C.
        • Larson M.G.
        • Levy D.
        Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation.
        Circulation. 1993; 88: 2548-2555
        • Brush Jr., J.E.
        • Krumholz H.M.
        • Greene E.J.
        • Dreyer R.P.
        Sex differences in symptom phenotypes among patients with acute myocardial infarction.
        Circ Cardiovasc Qual Outcomes. 2020; 13e005948
        • Khan N.A.
        • Daskalopoulou S.S.
        • Karp I.
        • et al.
        Sex differences in prodromal symptoms in acute coronary syndrome in patients aged 55yearsor younger.
        Heart. 2017; 103: 863-869
        • Lichtman J.H.
        • Leifheit E.C.
        • Safdar B.
        • et al.
        Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction.
        Circulation. 2018; 137: 781-790
        • Canto J.G.
        • Canto E.A.
        • Goldberg R.J.
        Time to standardize and broaden the criteria of acute coronary syndrome symptom presentations in women.
        Can J Cardiol. 2014; 30: 721-728
        • Kirchberger I.
        • Heier M.
        • Wende R.
        • von Scheidt W.
        • Meisinger C.
        The patient’s interpretation of myocardial infarction symptoms and its role in the decision process to seek treatment: the MONICA/KORA Myocardial Infarction Registry.
        Clin Res Cardiol. 2012; 101: 909-916
        • Pepine C.J.
        • Ferdinand K.C.
        • Shaw L.J.
        • et al.
        Emergence of nonobstructive coronary artery disease: a woman’s problem and need for change in definition on angiography.
        J Am Coll Cardiol. 2015; 66: 1918-1933
        • Mozaffarian D.
        • Benjamin E.J.
        • Go A.S.
        • et al.
        Heart disease and stroke statistics--2015 update: a report from the American Heart Association.
        Circulation. 2015; 131: e29-e322
        • Tisminetzky M.
        • Gurwitz J.H.
        • Miozzo R.
        • et al.
        Age differences in the chief complaint associated with a first acute myocardial infarction and patient’s care-seeking behavior.
        Am J Med. 2020; 133: e501-e507
        • Mirzaei S.
        • Steffen A.
        • Vuckovic K.
        • et al.
        The association between symptom onset characteristics and prehospital delay in women and men with acute coronary syndrome.
        Eur J Cardiovasc Nurs. 2020; 19: 142-154
        • Canto J.G.
        • Rogers W.J.
        • Goldberg R.J.
        • et al.
        Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality.
        JAMA. 2012; 307: 813-822
        • Pelletier R.
        • Choi J.
        • Winters N.
        • et al.
        Sex differences in clinical outcomes after premature acute coronary syndrome.
        Can J Cardiol. 2016; 32: 1447-1453
        • Mehta L.S.
        • Beckie T.M.
        • DeVon H.A.
        • et al.
        Acute myocardial infarction in women: a scientific statement from the American Heart Association.
        Circulation. 2016; 133: 916-947
        • Spatz E.S.
        • Curry L.A.
        • Masoudi F.A.
        • et al.
        The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) classification system: a taxonomy for young women with acute myocardial infarction.
        Circulation. 2015; 132: 1710-1718
        • Shaw L.J.
        • Bairey Merz C.N.
        • Pepine C.J.
        • et al.
        Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study: part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies.
        J Am Coll Cardiol. 2006; 47: S4-S20
        • Bairey Merz C.N.
        • Shaw L.J.
        • Reis S.E.
        • et al.
        Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study: part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease.
        J Am Coll Cardiol. 2006; 47: S21-S29
        • Bairey Merz C.N.
        • Pepine C.J.
        • Walsh M.N.
        • Fleg J.L.
        Ischemia and No Obstructive Coronary Artery Disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
        Circulation. 2017; 135: 1075-1092
        • Pacheco Claudio C.
        • Quesada O.
        • Pepine C.J.
        • Noel Bairey Merz C.
        Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease).
        Clin Cardiol. 2018; 41: 185-193
        • AlBadri A.
        • Bairey Merz C.N.
        • Johnson B.D.
        • et al.
        Impact of abnormal coronary reactivity on long-term clinical outcomes in women.
        J Am Coll Cardiol. 2019; 73: 684-693
        • Kunadian V.
        • Chieffo A.
        • Camici P.G.
        • et al.
        An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
        Eur Heart J. 2020; 41: 3504-3520
        • Ford T.J.
        • Stanley B.
        • Good R.
        • et al.
        Stratified medical therapy using invasive coronary function testing in angina: the CorMicA Trial.
        J Am Coll Cardiol. 2018; 72: 2841-2855
        • Handberg E.M.
        • Merz C.N.B.
        • Cooper-Dehoff R.M.
        • et al.
        Rationale and design of the Women’s Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial.
        Am Heart J. 2021; 237: 90-103
        • Rodriguez Ziccardi M.
        • Hatcher J.D.
        Prinzmetal Angina. StatPearls. Treasure Island.
        StatPearls Publishing, Florida2019
        • Beltrame J.F.
        • Crea F.
        • Kaski J.C.
        • et al.
        International standardization of diagnostic criteria for vasospastic angina.
        Eur Heart J. 2017; 38: 2565-2568
        • Bory M.
        • Pierron F.
        • Panagides D.
        • Bonnet J.L.
        • Yvorra S.
        • Desfossez L.
        Coronary artery spasm in patients with normal or near normal coronary arteries. Long-term follow-up of 277 patients.
        Eur Heart J. 1996; 17: 1015-1021
        • Pasupathy S.
        • Air T.
        • Dreyer R.P.
        • Tavella R.
        • Beltrame J.F.
        Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.
        Circulation. 2015; 131: 861-870
        • Reynolds H.R.
        • Maehara A.
        • Kwong R.Y.
        • et al.
        Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women.
        Circulation. 2021; 143: 624-640
        • Tamis-Holland J.E.
        • Jneid H.
        • Reynolds H.R.
        • et al.
        Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association.
        Circulation. 2019; 139: e891-e908
        • Saw J.
        • Starovoytov A.
        • Humphries K.
        • et al.
        Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes.
        Eur Heart J. 2019; 40: 1188-1197
        • Saw J.
        • Aymong E.
        • Sedlak T.
        • et al.
        Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes.
        Circ Cardiovasc Interv. 2014; 7: 645-655
        • Hayes S.N.
        • Kim E.S.H.
        • Saw J.
        • et al.
        Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
        Circulation. 2018; 137: e523-e557
        • Saw J.
        • Poulter R.
        • Fung A.
        • Wood D.
        • Hamburger J.
        • Buller C.E.
        Spontaneous coronary artery dissection in patients with fibromuscular dysplasia: a case series.
        Circ Cardiovasc Interv. 2012; 5: 134-137
        • Tweet M.S.
        • Kok S.N.
        • Hayes S.N.
        Spontaneous coronary artery dissection in women: what is known and what is yet to be understood.
        Clin Cardiol. 2018; 41: 203-210
        • Alfonso F.
        • Paulo M.
        • Lennie V.
        • et al.
        Spontaneous coronary artery dissection: long-term follow-up of a large series of patients prospectively managed with a “conservative” therapeutic strategy.
        ACC Cardiovasc Interv. 2012; 5: 1062-1070
        • Hayes S.N.
        • Tweet M.S.
        • Adlam D.
        • et al.
        Spontaneous coronary artery dissection: JACC State-of-the-Art Review.
        J Am Coll Cardiol. 2020; 76: 961-984
        • Saw J.
        • Humphries K.
        • Aymong E.
        • et al.
        Spontaneous coronary artery dissection: clinical outcomes and risk of recurrence.
        J Am Coll Cardiol. 2017; 70: 1148-1158
        • Kok S.N.
        • Hayes S.N.
        • Cutrer F.M.
        • et al.
        Prevalence and clinical factors of migraine in patients with spontaneous coronary artery dissection.
        J Am Heart Assoc. 2018; 7e010140
        • Liang J.J.
        • Tweet M.S.
        • Hayes S.E.
        • Gulati R.
        • Hayes S.N.
        Prevalence and predictors of depression and anxiety among survivors of myocardial infarction due to spontaneous coronary artery dissection.
        J Cardiopulm Rehabil Prev. 2014; 34: 138-142
        • Norris C.M.
        • Yip C.Y.Y.
        • Nerenberg K.A.
        • et al.
        State of the science in women’s cardiovascular disease: a Canadian perspective on the influence of sex and gender.
        J Am Heart Assoc. 2020; 9e015634
        • Shufelt C.L.
        • Pacheco C.
        • Tweet M.S.
        • Miller V.M.
        Sex-specific physiology and cardiovascular disease.
        Adv Exp Med Biol. 2018; 1065: 433-454
        • Falk E.
        • Nakano M.
        • Bentzon J.F.
        • Finn A.V.
        • Virmani R.
        Update on acute coronary syndromes: the pathologists’ view.
        Eur Heart J. 2013; 34: 719-728
        • Ouyang P.
        • Michos E.D.
        • Karas R.H.
        Hormone replacement therapy and the cardiovascular system lessons learned and unanswered questions.
        J Am Coll Cardiol. 2006; 47: 1741-1753
        • Pelletier R.
        • Khan N.A.
        • Cox J.
        • et al.
        Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
        J Am Coll Cardiol. 2016; 67: 127-135
        • Manfrini O.
        • Yoon J.
        • Mvd Schaar
        • et al.
        Sex differences in modifiable risk factors and severity of coronary artery disease.
        J Am Heart Assoc. 2020; 9e017235
        • Roswell R.O.
        • Kunkes J.
        • Chen A.Y.
        • et al.
        impact of sex and contact-to-device time on clinical outcomes in acute ST-segment elevation myocardial infarction—findings from the National Cardiovascular Data Registry.
        J Am Heart Assoc. 2017; 6e004521
        • Udell J.A.
        • Fonarow G.C.
        Sustained sex-based treatment differences in acute coronary syndrome care: insights from the American Heart Association Get With The Guidelines Coronary Artery Disease Registry.
        Clin Cardiol. 2018; 41: 758-768
        • Pacheco C.
        • Boivin-Proulx L.A.
        • Bastiany A.
        • et al.
        Impact of STEMI diagnosis and catheterization laboratory activation systems on sex and age-based differences in treatment delay.
        CJC Open. 2021; 3: 723-732
        • Huded C.P.
        • Johnson M.
        • Kravitz K.
        • et al.
        4-Step protocol for disparities in STEMI care and outcomes in women.
        J Am Coll Cardiol. 2018; 71: 2122-2132
        • Ezekowitz J.A.
        • Savu A.
        • Welsh R.C.
        • McAlister F.A.
        • Goodman S.G.
        • Kaul P.
        Is there a sex gap in surviving an acute coronary syndrome or subsequent development of heart failure?.
        Circulation. 2020; 142: 2231-2239
        • Wilkinson C.
        • Bebb O.
        • Dondo T.B.
        • et al.
        Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study.
        Heart. 2019; 105: 516-523
        • Khuddus M.A.
        • Pepine C.J.
        • Handberg E.M.
        • et al.
        An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: a substudy from the National Heart, Lung and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE).
        J Interv Cardiol. 2010; 23: 511-519
        • Sharaf B.
        • Wood T.
        • Shaw L.
        • et al.
        Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) angiographic core laboratory.
        Am Heart J. 2013; 166: 134-141
        • Kelkar A.A.
        • Schultz W.M.
        • Khosa F.
        • et al.
        Long-term prognosis after coronary artery calcium scoring among low-intermediate risk women and men.
        Circ Cardiovasc Imaging. 2016; 9e003742
        • Jaffer S.
        • Foulds H.J.A.
        • Parry M.
        • et al.
        The Canadian Women’s Heart Health Alliance ATLAS on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 2: scope of the problem.
        CJC Open. 2021; 3: 1-11
        • Lawson C.A.
        • Zaccardi F.
        • Squire I.
        • et al.
        Risk factors for heart failure.
        Circ Heart Fail. 2020; 13e006472
        • Sullivan K.
        • Doumouras B.S.
        • Santema B.T.
        • et al.
        Sex-specific differences in heart failure: pathophysiology, risk factors, management, and outcomes.
        Can J Cardiol. 2021; 37: 560-571
        • Regitz-Zagrosek V.
        • Oertelt-Prigione S.
        • et al.
        • EUGenMed Cardiovascular Clinical Study Group
        Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes.
        Eur Heart J. 2015; 37: 24-34
        • Lam C.S.P.
        • Arnott C.
        • Beale A.L.
        • et al.
        Sex differences in heart failure.
        Eur Heart J. 2019; 40 (68c): 3859
        • Stolfo D.
        • Uijl A.
        • Vedin O.
        • et al.
        Sex-based differences in heart failure across the ejection fraction spectrum: phenotyping, and prognostic and therapeutic implications.
        JACC Heart Fail. 2019; 7: 505-515
        • Hulley S.
        • Grady D.
        • Bush T.
        • et al.
        Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
        JAMA. 1998; 280: 605-613
        • Roalfe A.K.
        • Mant J.
        • Doust J.A.
        • et al.
        Development and initial validation of a simple clinical decision tool to predict the presence of heart failure in primary care: the MICE (Male, Infarction, Crepitations, Edema) rule.
        Eur J Heart Fail. 2012; 14: 1000-1008
        • McKee P.A.
        • Castelli W.P.
        • McNamara P.M.
        • Kannel W.B.
        The natural history of congestive heart failure: the Framingham study.
        N Engl J Med. 1971; 285: 1441-1446
        • Kelder J.C.
        • Cramer M.J.
        • van Wijngaarden J.
        • et al.
        The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure.
        Circulation. 2011; 124: 2865-2873
        • Ezekowitz J.A.
        • O’Meara E.
        • McDonald M.A.
        • et al.
        2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
        Can J Cardiol. 2017; 33: 1342-1433
        • Lang R.M.
        • Badano L.P.
        • Mor-Avi V.
        • et al.
        Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
        J Am Soc Echocardiogr. 2015; 28 (e14): 1-39
        • Shah K.S.
        • Xu H.
        • Matsouaka R.A.
        • et al.
        Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes.
        J Am Coll Cardiol. 2017; 70: 2476-2486
        • Gerber Y.
        • Weston S.A.
        • Redfield M.M.
        • et al.
        A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010.
        JAMA Intern Med. 2015; 175: 996-1004
        • Regitz-Zagrosek V.
        Unsettled issues and future directions for research on cardiovascular diseases in women.
        Korean Circ J. 2018; 48: 792-812
        • Eisenberg E.
        • Palo K.E.D.
        • Piña I.L.
        Sex differences in heart failure.
        Clin Cardiol. 2018; 41: 211-216
        • Dewan P.
        • Rørth R.
        • Jhund P.S.
        • et al.
        Differential impact of heart failure with reduced ejection fraction on men and women.
        J Am Coll Cardiol. 2019; 73: 29-40
        • Spall H.G.C.V.
        • Hill A.D.
        • Fu L.
        • Ross H.J.
        • Fowler R.A.
        Temporal trends and sex differences in intensity of healthcare at the end of life in adults with heart failure.
        J Am Heart Assoc. 2021; 10e018495
        • Santangeli P.
        • Pelargonio G.
        • Russo A.D.
        • et al.
        Gender differences in clinical outcome and primary prevention defibrillator benefit in patients with severe left ventricular dysfunction: a systematic review and meta-analysis.
        Heart Rhythm. 2010; 7: 876-882
        • Zabarovskaja S.
        • Gadler F.
        • Braunschweig F.
        • et al.
        Women have better long-term prognosis than men after cardiac resynchronization therapy.
        Europace. 2012; 14: 1148-1155
        • Moore K.
        • Ganesan A.
        • Labrosciano C.
        • et al.
        Sex differences in acute complications of cardiac implantable electronic devices: implications for patient safety.
        J Am Heart Assoc. 2019; 8e010869
        • Chatterjee N.A.
        • Borgquist R.
        • Chang Y.
        • et al.
        Increasing sex differences in the use of cardiac resynchronization therapy with or without implantable cardioverter-defibrillator.
        Eur Heart J. 2017; 38: 1485-1494
        • Randolph T.C.
        • Hellkamp A.S.
        • Zeitler E.P.
        • et al.
        Utilization of cardiac resynchronization therapy in eligible patients hospitalized for heart failure and its association with patient outcomes.
        Am Heart J. 2017; 189: 48-58
        • Varma N.
        • Manne M.
        • Nguyen D.
        • He J.
        • Niebauer M.
        • Tchou P.
        Probability and magnitude of response to cardiac resynchronization therapy according to QRS duration and gender in nonischemic cardiomyopathy and LBBB.
        Heart Rhythm. 2014; 11: 1139-1147
        • Zusterzeel R.
        • Selzman K.A.
        • Sanders W.E.
        • et al.
        Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patient-level data.
        JAMA Intern Med. 2014; 174: 1340-1348
        • Hickey K.T.
        • Doering L.V.
        • Chen B.
        • et al.
        Clinical and gender differences in heart transplant recipients in the NEW HEART study.
        Eur J Cardiovasc Nurs. 2017; 16: 222-229
        • Kenchaiah S.
        • Vasan R.
        Heart failure in women – insights from the Framingham Heart study.
        Cardiovasc Drugs Ther. 2015; 29: 377-390
        • Frankenstein L.
        • Clark A.L.
        • Ribeiro J.P.
        Influence of sex on treatment and outcome in chronic heart failure.
        Cardiovasc Ther. 2012; 30: 182-192
        • Joseph S.M.
        Closing the sex gap in advanced heart failure: reality or illusion?.
        J Card Fail. 2015; 21: 561-563
        • Hsich E.M.
        • Starling R.C.
        • Blackstone E.H.
        • et al.
        Does the UNOS Heart Transplant Allocation System favor men over women?.
        JACC Heart Fail. 2014; 2: 347-355
        • Miller L.W.
        • Guglin M.
        Patient selection for ventricular assist devices: a moving target.
        J Am Coll Cardiol. 2013; 61: 1209-1221
        • Bozkurt B.
        • Khalaf S.
        Heart failure in women.
        Methodist Debakey Cardiovasc J. 2017; 13: 216-223
        • Sartipy U.
        • Dahlström U.
        • Fu M.
        • Lund L.H.
        Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction.
        JACC Heart Fail. 2017; 5: 565-574
        • Ko D.
        • Rahman F.
        • Schnabel R.B.
        • Yin X.
        • Benjamin E.J.
        • Christophersen I.E.
        Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis.
        Nat Rev Cardiol. 2016; 13: 321-332
        • Blumer V.
        • Greene S.J.
        • Wu A.
        • et al.
        Sex differences in clinical course and patient-reported outcomes among patients hospitalized for heart failure.
        JACC Heart Fail. 2021; 9: 336-345
        • Mentzer G.
        • Hsich E.M.
        Heart failure with reduced ejection fraction in women: epidemiology, outcomes, and treatment.
        Heart Fail Clin. 2019; 15: 19-27