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Heart, Lung and Circulation

Sex Disparities in Myocardial Infarction: Biology or Bias?

Published:August 15, 2020DOI:https://doi.org/10.1016/j.hlc.2020.06.025
      Women have generally worse outcomes after myocardial infarction (MI) compared to men. The reasons for these disparities are multifactorial. At the beginning is the notion—widespread in the community and health care providers—that women are at low risk for MI. This can impact on primary prevention of cardiovascular disease in women, with lower use of preventative therapies and lifestyle counselling. It can also lead to delays in presentation in the event of an acute MI, both at the patient and health care provider level. This is of particular concern in the case of ST elevation MI (STEMI), where “time is muscle”. Even after first medical contact, women with acute MI experience delays to diagnosis with less timely reperfusion and percutaneous coronary intervention (PCI). Compared to men, women are less likely to undergo invasive diagnostic testing or PCI. After being diagnosed with a STEMI, women receive less guideline-directed medical therapy and potent antiplatelets than men. The consequences of these discrepancies are significant—with higher mortality, major cardiovascular events and bleeding after MI in women compared to men. We review the sex disparities in pathophysiology, risk factors, presentation, diagnosis, treatment, and outcomes for acute MI, to answer the question: are they due to biology or bias, or both?

      Keywords

      Introduction

      Ischaemic heart disease is the main cause of death across countries from all income groups [
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      • Francis D.P.
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      Mortality from ischemic heart disease.
      ]. In Australia, it caused 17,533 deaths in 2018, of which 41% were women [
      Australia’s leading causes of death, 2018 Australian Bureau of Statistics2018.
      ]. With a high number of premature deaths, this equates to a large number of potential years of life lost [
      Australia’s leading causes of death, 2018 Australian Bureau of Statistics2018.
      ]. Owing to advancements in medical therapy and device technology, mortality after acute myocardial infarction (MI) has been dramatically reduced over the past decade [
      Australia’s leading causes of death, 2018 Australian Bureau of Statistics2018.
      ]. Despite this improvement, there remain two important negative trends. First, recent data shows this decline has decelerated, particularly in younger females [
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      ]. Second, women throughout all age groups and ethnicities have worse outcomes after MI compared to men [
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      • Jones S.B.
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      • Shaw L.J.
      • Vaccarino V.
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      Age and sex differences in inhospital complication rates and mortality after percutaneous coronary intervention procedures: evidence from the NCDR((R)).
      ,
      • Pancholy S.B.
      • Shantha G.P.
      • Patel T.
      • Cheskin L.J.
      Sex differences in short-term and long-term all-cause mortality among patients with ST-segment elevation myocardial infarction treated by primary percutaneous intervention: a meta-analysis.
      ,
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      • Dreyer R.P.
      • Alexander K.P.
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      Sex-based differences in presentation, treatment, and complications among older adults hospitalized for acute myocardial infarction: the SILVER-AMI study.
      ]. The reasons for these disparities are multifactorial (displayed in Figure 1), but the question remains: Are these disparities due to sex (biology) or disparities in care (bias)?
      Figure thumbnail gr1
      Figure 1Cumulative Sex Differences in Myocardial Infarction: Biology and Bias.

      Pathogenesis and Pathophysiology

      Observational studies examining the pathogenesis of MI in women have yielded a number of biological differences when compared with men [
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      ]. In younger women, the culprit mechanism for an MI is more often plaque erosion compared with higher rates of plaque rupture in men and older women [
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      Differences in underlying culprit lesion morphology between men and women: an IVUS analysis from the ADAPT-DES study.
      ,
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      • Kelsey S.F.
      • Olson M.
      • 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.
      ]. Women with MI, particularly younger women, are more likely to have underlying spontaneous coronary artery dissection (SCAD). SCAD is reported to be responsible for approximately 1% of all women presenting with an MI [
      • Mahmoud A.N.
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      • Mentias A.
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      Trends of Incidence, clinical presentation, and in-hospital mortality among women with acute myocardial infarction with or without spontaneous coronary artery dissection: a population-based analysis.
      ], and is the cause for an MI in up to 25% of women younger than 60 years of age [
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      Nonatherosclerotic coronary artery disease in young women.
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      • Sheth T.
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      • Minhas K.
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      Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes.
      ]. Women also have more coronary microvascular dysfunction and impaired coronary flow reserve compared to men, both strongly associated with cardiovascular events [
      • Taqueti V.R.
      • Shaw L.J.
      • Cook N.R.
      • Murthy V.L.
      • Shah N.R.
      • Foster C.R.
      • et al.
      Excess cardiovascular risk in women relative to men referred for coronary angiography is associated with severely impaired coronary flow reserve, not obstructive disease.
      ]. Both play a role in myocardial infarction with non-obstructive coronary arteries (MINOCA] [
      • Opolski M.P.
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      • Debski A.
      • Knaapen P.
      • Schumacher S.P.
      • et al.
      Mechanisms of myocardial infarction in patients with nonobstructive coronary artery disease: results from the optical coherence tomography study.
      ,
      • Reynolds H.R.
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      • Iqbal S.N.
      • Slater J.N.
      • Mancini G.B.
      • Feit F.
      • et al.
      Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease.
      ]. MINOCA is reported in approximately 6–15% of all MIs [
      • 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 are disproportionally represented in this population and are almost five times as likely to have MINOCA in the setting of an MI, compared to men [
      • 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.
      ,
      • Safdar B.
      • Spatz E.S.
      • Dreyer R.P.
      • Beltrame J.F.
      • Lichtman J.H.
      • Spertus J.A.
      • et al.
      Presentation, clinical profile, and prognosis of young patients with myocardial infarction with nonobstructive coronary arteries (MINOCA): results from the VIRGO study.
      ], with numbers reported as high as 10% in ST elevation myocardial infarction (STEMI) [
      • Hochman J.S.
      • Tamis J.E.
      • Thompson T.D.
      • Weaver W.D.
      • White H.D.
      • Van de Werf F.
      • et al.
      Sex, clinical presentation, and outcome in patients with acute coronary syndromes. Global use of strategies to open occluded coronary arteries in acute coronary syndromes IIb investigators.
      ] to 15% in the setting of a non-ST elevation myocardial infarction (NSTEMI) [
      • Gehrie E.R.
      • Reynolds H.R.
      • Chen A.Y.
      • Neelon B.H.
      • Roe M.T.
      • Gibler W.B.
      • et al.
      Characterization and outcomes of women and men with non-ST-segment elevation myocardial infarction and nonobstructive coronary artery disease: results from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative.
      ]. Conversely, the MINOCA population consists of almost 50% women, whereas this is only 25% in the population with MI due to obstructive coronary artery disease. The MINOCA population is a heterogeneous population with the underlying pathology of MINOCA including coronary spasm, microvascular dysfunction, coronary embolism, plaque erosion, and coronary dissection. Despite the presence of non-obstructed coronary arteries, MINOCA patients have significantly worse outcomes compared to age-matched controls with a hazard ratio (HR) of 4.6 (95% CI 3.54–6.10) for cardiovascular events during a follow up of 2 years [
      • Williams M.J.A.
      • Barr P.R.
      • Lee M.
      • Poppe K.K.
      • Kerr A.J.
      Outcome after myocardial infarction without obstructive coronary artery disease.
      ]. Moreover, the recent Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) sub-study found mortality in MINOCA patients to be as high as in patients with coronary artery disease. Thus, the prognosis of MINOCA is not benign [
      • Safdar B.
      • Spatz E.S.
      • Dreyer R.P.
      • Beltrame J.F.
      • Lichtman J.H.
      • Spertus J.A.
      • et al.
      Presentation, clinical profile, and prognosis of young patients with myocardial infarction with nonobstructive coronary arteries (MINOCA): results from the VIRGO study.
      ]. The challenge in MINOCA patients is the lack of randomised controlled trials targeting management. Results from the Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry showed a benefit of statins and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but only a trend for β-blockers, and no benefit of dual antiplatelet agents in this patient group [
      • Lindahl B.
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      • Gard A.
      • et al.
      Medical therapy for secondary prevention and long-term outcome in patients with myocardial infarction with nonobstructive coronary artery disease.
      ].

      Risk Factors

      Traditional cardiovascular risk factors such as diabetes, smoking and hypertension are associated with an excess relative risk in women compared to men. Systemic hypertension in women confers 1.8 times the risk for MI compared to men; with smoking, the risk in women is two-fold, and in diabetes, almost three-fold that of men [
      • Millett E.R.C.
      • Peters S.A.E.
      • Woodward M.
      Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants.
      ]. Despite a decline of this association between risk factors and ischaemic heart disease (IHD) with age, the significantly higher relative risk in women compared to men remains [
      • Millett E.R.C.
      • Peters S.A.E.
      • Woodward M.
      Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants.
      ].
      Furthermore, women can have non-traditional risk factors which are specific to the female sex. These include early menopause and pregnancy-associated disorders, including preterm delivery, small-for-gestational age births, gestational diabetes, pregnancy-induced hypertension, preeclampsia and eclampsia. In particular, the hypertensive disorders of pregnancy lead to a markedly increased risk for cardiovascular events later in life, occurring at a younger age and persisting up to the age of 70 years [
      • Haug E.B.
      • Horn J.
      • Markovitz A.R.
      • Fraser A.
      • Klykken B.
      • Dalen H.
      • et al.
      Association of conventional cardiovascular risk factors with cardiovascular disease after hypertensive disorders of pregnancy: analysis of the Nord-Trondelag health study.
      ]. Elevated fasting blood glucose during pregnancy has an impact on cardiovascular disease risk, even in women who did not meet criteria for gestational diabetes [
      • Retnakaran R.
      • Shah B.R.
      Glucose screening in pregnancy and future risk of cardiovascular disease in women: a retrospective, population-based cohort study.
      ]. In addition, chronic inflammatory autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus, more prevalent in women, are all associated with premature coronary artery disease.
      Despite this increased risk, young women with coronary artery disease are 16% less likely than men to have health care providers talk with them about their disease and ways to modify the risk for an MI [
      • Leifheit-Limson E.C.
      • D'Onofrio G.
      • Daneshvar M.
      • Geda M.
      • Bueno H.
      • Spertus J.A.
      • et al.
      Sex differences in cardiac risk factors, perceived risk, and health care provider discussion of risk and risk modification among young patients with acute myocardial infarction: the VIRGO study.
      ].

      Presentation and Timing

      Significant delays in time to presentation and revascularisation of women with acute MI have been demonstrated in studies in Australia and globally [
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
      ,
      • D'Onofrio G.
      • Safdar B.
      • Lichtman J.H.
      • Strait K.M.
      • Dreyer R.P.
      • Geda M.
      • et al.
      Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction: results from the VIRGO study.
      ,
      • Sederholm Lawesson S.
      • Isaksson R.M.
      • Ericsson M.
      • Angerud K.
      • Thylen I.
      • SymTime Study G.
      Gender disparities in first medical contact and delay in ST-elevation myocardial infarction: a prospective multicentre Swedish survey study.
      ,
      • Khan E.
      • Brieger D.
      • Amerena J.
      • Atherton J.J.
      • Chew D.P.
      • Farshid A.
      • et al.
      Differences in management and outcomes for men and women with ST-elevation myocardial infarction.
      ]. The time delays are of critical importance in patients presenting with STEMI and can be divided into two categories. The first delay occurs from symptom onset until the patient seeks first medical contact (FMC). The second delay arises after FMC until definitive treatment is performed (i.e. primary percutaneous coronary intervention [PCI]); also called the ‘system’-delay.
      Reasons for delays from symptom onset to FMC are multifactorial [
      • Sederholm Lawesson S.
      • Isaksson R.M.
      • Ericsson M.
      • Angerud K.
      • Thylen I.
      • SymTime Study G.
      Gender disparities in first medical contact and delay in ST-elevation myocardial infarction: a prospective multicentre Swedish survey study.
      ,
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • Bao H.
      • Krumholz H.M.
      • Lorenze N.P.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      ,
      • Khan N.A.
      • Daskalopoulou S.S.
      • Karp I.
      • Eisenberg M.J.
      • Pelletier R.
      • Tsadok M.A.
      • et al.
      Sex differences in prodromal symptoms in acute coronary syndrome in patients aged 55 years or younger.
      ]: Women with MI experience a higher rate of associated symptoms such as shortness of breath, palpitations, nausea or pain irradiating into the arm, neck, between shoulder blades and the jaw [
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • Bao H.
      • Krumholz H.M.
      • Lorenze N.P.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      ]. Therefore, both patient and provider can misinterpret clinical signs of acute MI [
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • Bao H.
      • Krumholz H.M.
      • Lorenze N.P.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      ,
      • Kirchberger I.
      • Heier M.
      • Kuch B.
      • Wende R.
      • Meisinger C.
      Sex differences in patient-reported symptoms associated with myocardial infarction (from the population-based MONICA/KORA Myocardial Infarction Registry).
      ]. However, the VIRGO study showed that approximately 90% of young women also had chest pain symptoms upon presentation with STEMI, equal to those of younger men [
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • Bao H.
      • Krumholz H.M.
      • Lorenze N.P.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      ]. Interestingly, even in those women with typical symptoms, there was a longer delay in seeking care and less concern for potential cardiac issues, in both the women themselves, and their health care providers [
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • Bao H.
      • Krumholz H.M.
      • Lorenze N.P.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      ]. The misperception that only men suffer heart attacks remains strong in our society leading women to under-estimate their risk [
      • Hoare E.
      • Stavreski B.
      • Kingwell B.A.
      • Jennings G.L.
      Australian adults' behaviours, knowledge and perceptions of risk factors for heart disease: A cross-sectional study.
      ]. Research has demonstrated that women are more likely to have lower socioeconomic status compared to men and this is associated with poorer MI awareness and emergency presentation [
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • Bao H.
      • Krumholz H.M.
      • Lorenze N.P.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      ]. Finally, not only biological sex, but also gender roles have a significant impact [
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • Daskalopoulou S.S.
      • Eisenberg M.J.
      • Bacon S.L.
      • et al.
      Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      ]. Societal gender roles of women as primary care-givers can limit their own care-seeking behaviour, leading to less frequent presentation to an emergency department. In stark contrast is the finding that the presence of a female spouse reduces time to FMC for their male spouse suffering an acute MI [
      • Sederholm Lawesson S.
      • Isaksson R.M.
      • Ericsson M.
      • Angerud K.
      • Thylen I.
      • SymTime Study G.
      Gender disparities in first medical contact and delay in ST-elevation myocardial infarction: a prospective multicentre Swedish survey study.
      ].
      The second delay, from FMC to invasive treatment can be difficult to assess because of its multiple time components. It can be crudely divided into a prehospital time gap from FMC to arrival at the hospital, and door-to-balloon (DTB) time. Previous data have revealed that this is largely driven by prehospital delays [
      • Bugiardini R.
      • Ricci B.
      • Cenko E.
      • Vasiljevic Z.
      • Kedev S.
      • Davidovic G.
      • et al.
      Delayed Care and mortality among women and men with myocardial infarction.
      ]. The main reason is that health care providers are less likely to attribute women’s prodromal symptoms to heart disease compared to men [
      • Sederholm Lawesson S.
      • Isaksson R.M.
      • Ericsson M.
      • Angerud K.
      • Thylen I.
      • SymTime Study G.
      Gender disparities in first medical contact and delay in ST-elevation myocardial infarction: a prospective multicentre Swedish survey study.
      ,
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • Bao H.
      • Krumholz H.M.
      • Lorenze N.P.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      ,
      • Kirchberger I.
      • Heier M.
      • Kuch B.
      • Wende R.
      • Meisinger C.
      Sex differences in patient-reported symptoms associated with myocardial infarction (from the population-based MONICA/KORA Myocardial Infarction Registry).
      ]. This is despite the fact that in young patients with MI, 85% of men and women experience typical chest pain [
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • Bao H.
      • Krumholz H.M.
      • Lorenze N.P.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      ] and that the prevalence of prodromal symptoms is higher in women than men [
      • Khan N.A.
      • Daskalopoulou S.S.
      • Karp I.
      • Eisenberg M.J.
      • Pelletier R.
      • Tsadok M.A.
      • et al.
      Sex differences in prodromal symptoms in acute coronary syndrome in patients aged 55 years or younger.
      ]. Similar to symptoms at the time of the MI, prodromal symptoms can be more diffuse in women, such as arm weakness, sleep disturbances, coughing, headache and fatigue [
      • Khan N.A.
      • Daskalopoulou S.S.
      • Karp I.
      • Eisenberg M.J.
      • Pelletier R.
      • Tsadok M.A.
      • et al.
      Sex differences in prodromal symptoms in acute coronary syndrome in patients aged 55 years or younger.
      ]. However, the vast majority of women would still present with prodromal symptoms of chest pain [
      • Lichtman J.H.
      • Leifheit-Limson E.C.
      • Watanabe E.
      • Allen N.B.
      • Garavalia B.
      • Garavalia L.S.
      • et al.
      Symptom recognition and healthcare experiences of young women with acute myocardial infarction.
      ]. The interpretation of a STEMI-electrocardiograph (ECG) can be more challenging in women: The J-point elevation in healthy women is less compared to men, leading to less prominent ST elevation. Therefore, a STEMI can be more easily missed. This is reflected in practice guidelines, with only >1.5 mm of ST elevation required in leads V2–V3 in women, compared to >2 mm or 2.5 mm in men for the diagnosis of a STEMI [
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • Chaitman B.R.
      • Bax J.J.
      • Morrow D.A.
      • et al.
      Fourth universal definition of myocardial infarction (2018).
      ,
      • Ibanez B.
      • James S.
      • Agewall S.
      • Antunes M.J.
      • Bucciarelli-Ducci C.
      • Bueno H.
      • et al.
      2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
      ]. Women are more likely to have the right coronary artery as the culprit vessel, leading to potentially more subtle ECG findings then left anterior coronary artery occlusion, seen more commonly in men [
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
      ]. However, reperfusion delays in women exist even when adjusting for the presence of more subtle ECG characteristics [
      • Gupta A.
      • Barrabes J.A.
      • Strait K.
      • Bueno H.
      • Porta-Sanchez A.
      • Acosta-Velez J.G.
      • et al.
      Sex differences in timeliness of reperfusion in young patients with ST-segment-elevation myocardial infarction by initial electrocardiographic characteristics.
      ]. Importantly, female patients have longer delays regardless of the mode of transportation to the hospital and utilisation of pre-hospital ECG transmission, supporting the theory that delays often occur at the time of FMC [
      • Roswell R.O.
      • Kunkes J.
      • Chen A.Y.
      • Chiswell K.
      • Iqbal S.
      • Roe M.T.
      • 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.
      ]. Although less substantial, significant delays in DTB times exist as well in women [
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
      ]. Together with the ‘symptom-to-door’ time delay, these delays result in longer total ischaemic time of 30 minutes in women compared to men after adjustment for age and confounders (Figure 2) [
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
      ].
      Figure thumbnail gr2
      Figure 2Adjusted mean ischaemic time in female versus male Australian ST elevation myocardial infarction (STEMI) patients (n=3,883) [
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
      ].
      The adjusted mean symptom-to-door (STD) and door-to-balloon (DTB) time was 7.3 and 17.6 minutes longer, respectively in women compared to men giving a total 30-minute delay in the geometric mean ischaemic time [
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
      ].
      In patients with NSTEMI, conflicting results have been observed in the past when evaluating the benefit of timely PCI [
      • Hoedemaker N.P.G.
      • Damman P.
      • Woudstra P.
      • Hirsch A.
      • Windhausen F.
      • Tijssen J.G.P.
      • et al.
      Early invasive versus selective strategy for non-ST-segment elevation acute coronary syndrome: the ICTUS Trial.
      ,
      • Kofoed K.F.
      • Kelbaek H.
      • Hansen P.R.
      • Torp-Pedersen C.
      • Hofsten D.
      • Klovgaard L.
      • et al.
      Early versus standard care invasive examination and treatment of patients with non-ST-segment elevation acute coronary syndrome.
      ]. However, a recent randomised trial conducted in Italy showed that women with NSTEMI who were treated with early PCI benefitted with a three-fold lower in-hospital and 1-year mortality compared to women who underwent medical management [
      • De Carlo M.
      • Morici N.
      • Savonitto S.
      • Grassia V.
      • Sbarzaglia P.
      • Tamburrini P.
      • et al.
      Sex-related outcomes in elderly patients presenting with non-ST-segment elevation acute coronary syndrome: insights from the Italian elderly ACS study.
      ]. Importantly, 12.5% less women than men undergo timely revascularisation, significantly influencing their prognosis [
      • Wilkinson C.
      • Bebb O.
      • Dondo T.B.
      • Munyombwe T.
      • Casadei B.
      • Clarke S.
      • et al.
      Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study.
      ].

      Diagnosis

      Female sex has an impact on almost all tests and procedures required for the definitive diagnosis and treatment of acute MI. A significant sex discrepancy in troponin cut-offs has been noted using a high-sensitivity troponin assay [
      • Apple F.S.
      • Ler R.
      • Murakami M.M.
      Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population.
      ]. Consequentially, the Fourth Universal Definition of Myocardial Infarction publication has recommended lower cut-offs for sensitivity troponin assays in women with suspected MI, however it does not provide any cut-off values, since these are dependent on the specific troponin assay used [
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • Chaitman B.R.
      • Bax J.J.
      • Morrow D.A.
      • et al.
      Fourth universal definition of myocardial infarction (2018).
      ]. Global survey data showed that the practise of sex-dependent cut-off values has not been widely adopted.[
      • Anand A.
      • Shah A.S.V.
      • Beshiri A.
      • Jaffe A.S.
      • Mills N.L.
      Global adoption of high-sensitivity cardiac troponins and the universal definition of myocardial infarction.
      ] This is unfortunate, given that retrospective analyses demonstrate that the use of sex-specific troponin cut-offs doubled the percentage of women diagnosed with an MI and this diagnosis identified those at higher risk of reinfarction or death [
      • Shah A.S.
      • Griffiths M.
      • Lee K.K.
      • McAllister D.A.
      • Hunter A.L.
      • Ferry A.V.
      • et al.
      High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study.
      ]. The use of sex-specific thresholds identified five times more additional women than men with MI [
      • Lee K.K.
      • Ferry A.V.
      • Anand A.
      • Strachan F.E.
      • Chapman A.R.
      • Kimenai D.M.
      • et al.
      Sex-specific thresholds of high-sensitivity troponin in patients with suspected acute coronary syndrome.
      ]. Even though the new troponin cut-off led additional women being diagnosed with an MI, women overall were still half as likely to undergo invasive testing and treatment, compared to men [
      • Lee K.K.
      • Ferry A.V.
      • Anand A.
      • Strachan F.E.
      • Chapman A.R.
      • Kimenai D.M.
      • et al.
      Sex-specific thresholds of high-sensitivity troponin in patients with suspected acute coronary syndrome.
      ]. This difference persisted in both patients with classical Type-1 MI (i.e. atherosclerotic plaque disruption and subsequent thrombosis leading to significant narrowing or occlusion of the coronary artery) or Type-2 MI (i.e. pre-existing narrowing of the coronary artery with new mismatch between oxygen supply and demand) [
      • Lee K.K.
      • Ferry A.V.
      • Anand A.
      • Strachan F.E.
      • Chapman A.R.
      • Kimenai D.M.
      • et al.
      Sex-specific thresholds of high-sensitivity troponin in patients with suspected acute coronary syndrome.
      ]. The differences are particularly important since women and men reclassified to the diagnosis of an MI were at the same risk for death and reinfarction at one year as those originally classified as MI [
      • Lee K.K.
      • Ferry A.V.
      • Anand A.
      • Strachan F.E.
      • Chapman A.R.
      • Kimenai D.M.
      • et al.
      Sex-specific thresholds of high-sensitivity troponin in patients with suspected acute coronary syndrome.
      ]. Recently, two large registry studies, the Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) [
      • Alabas O.A.
      • Gale C.P.
      • Hall M.
      • Rutherford M.J.
      • Szummer K.
      • Lawesson S.S.
      • et al.
      Sex differences in treatments, relative survival, and excess mortality following acute myocardial infarction: national cohort study using the SWEDEHEART Registry.
      ] and the Myocardial Ischaemic National Audit Project (MINAP, conducted in England and Wales) [
      • Wilkinson C.
      • Bebb O.
      • Dondo T.B.
      • Munyombwe T.
      • Casadei B.
      • Clarke S.
      • et al.
      Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study.
      ,
      • Wilkinson C.
      • Weston C.
      • Timmis A.
      • Quinn T.
      • Keys A.
      • Gale C.P.
      The Myocardial Ischaemia National Audit Project (MINAP).
      ] confirmed Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events (CONCORDANCE) [
      • Khan E.
      • Brieger D.
      • Amerena J.
      • Atherton J.J.
      • Chew D.P.
      • Farshid A.
      • et al.
      Differences in management and outcomes for men and women with ST-elevation myocardial infarction.
      ] study results, by demonstrating women with MI undergo less invasive testing, less percutaneous revascularisation, and less timely PCI, compared to men. The reasons for the lower adherence to guideline-directed diagnosis and treatment in women are multifactorial and not well defined, however. One factor seems to be the underestimation of risk by the health care professionals. Another is the perceived higher risk of bleeding in women undergoing invasive testing and treatment compared to men. Despite awareness campaigns, the underutilisation of an invasive strategy in women with MI has not improved: women are still 15% less likely to undergo an invasive strategy compared to men, even when adjusted for patient-related factors [
      • Hansen K.W.
      • Soerensen R.
      • Madsen M.
      • Madsen J.K.
      • Jensen J.S.
      • von Kappelgaard L.M.
      • et al.
      Developments in the invasive diagnostic-therapeutic cascade of women and men with acute coronary syndromes from 2005 to 2011: a nationwide cohort study.
      ]. Importantly, omitting diagnostic steps—despite clear guidelines in the setting of a known MI—leads to uncertainties about the diagnosis, again resulting in the undertreatment of women.

      Management and Post MI Care

      A model for optimal care in patients presenting with a MI has recently been developed by the European Society of Cardiology (ESC) with quality indicators corresponding to short- and long-term mortality [
      • Schiele F.
      • Gale C.P.
      • Bonnefoy E.
      • Capuano F.
      • Claeys M.J.
      • Danchin N.
      • et al.
      Quality indicators for acute myocardial infarction: A position paper of the Acute Cardiovascular Care Association.
      ]. Women were significantly less likely to attain 13 of the 16 suggested quality indicators. The areas where women fell short were the indicators of timely diagnostic angiogram and PCI, for both NSTEMI and STEMI [
      • Wilkinson C.
      • Bebb O.
      • Dondo T.B.
      • Munyombwe T.
      • Casadei B.
      • Clarke S.
      • et al.
      Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study.
      ,
      • Sarma A.A.
      • Braunwald E.
      • Cannon C.P.
      • Guo J.
      • Im K.
      • Antman E.M.
      • et al.
      Outcomes of women compared with men after non-ST-segment elevation acute coronary syndromes.
      ,
      • Gupta T.
      • Kolte D.
      • Khera S.
      • Agarwal N.
      • Villablanca P.A.
      • Goel K.
      • et al.
      Contemporary sex-based differences by age in presenting characteristics, use of an early invasive strategy, and inhospital mortality in patients with non-ST-Segment-elevation myocardial infarction in the United States.
      ] Women also underwent less invasive treatment than men [
      • D'Onofrio G.
      • Safdar B.
      • Lichtman J.H.
      • Strait K.M.
      • Dreyer R.P.
      • Geda M.
      • et al.
      Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction: results from the VIRGO study.
      ], despite equal benefits conferred between the sexes from PCI [
      • Stefanini G.G.
      • Kalesan B.
      • Pilgrim T.
      • Raber L.
      • Onuma Y.
      • Silber S.
      • et al.
      Impact of sex on clinical and angiographic outcomes among patients undergoing revascularization with drug-eluting stents.
      ]. This has been explained by the lower diagnostic yield and the higher rates of MINOCA, SCAD and Tako-Tsubo cardiomyopathy in women [
      • Hansen K.W.
      • Soerensen R.
      • Madsen M.
      • Madsen J.K.
      • Jensen J.S.
      • von Kappelgaard L.M.
      • et al.
      Developments in the invasive diagnostic-therapeutic cascade of women and men with acute coronary syndromes from 2005 to 2011: a nationwide cohort study.
      ], and the larger proportion of women who present for treatment after significant delays, thus missing the window of opportunity for revascularisation [
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
      ,
      • D'Onofrio G.
      • Safdar B.
      • Lichtman J.H.
      • Strait K.M.
      • Dreyer R.P.
      • Geda M.
      • et al.
      Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction: results from the VIRGO study.
      ]. In women who do undergo angiography and PCI, the procedure is performed less often via radial arterial access compared to men [
      • Feldman D.N.
      • Swaminathan R.V.
      • Kaltenbach L.A.
      • Baklanov D.V.
      • Kim L.K.
      • Wong S.C.
      • et al.
      Adoption of radial access and comparison of outcomes to femoral access in percutaneous coronary intervention: an updated report from the national cardiovascular data registry (2007-2012).
      ,
      • Asrar Ul Haq M.
      • Tsay I.M.
      • Dinh D.T.
      • Brennan A.
      • Clark D.
      • Cox N.
      • et al.
      Prevalence and outcomes of trans-radial access for percutaneous coronary intervention in contemporary practise.
      ]. This is despite the fact that radial access has been shown to significantly reduce major bleeding, a benefit which is greater in women than men [
      • Gargiulo G.
      • Ariotti S.
      • Vranckx P.
      • Leonardi S.
      • Frigoli E.
      • Ciociano N.
      • et al.
      Impact of sex on comparative outcomes of radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: data from the randomized MATRIX-access trial.
      ]. The difference is particularly seen in STEMI patients and radial access is therefore endorsed by both the European and American guidelines for both female and male patients [
      • Ibanez B.
      • James S.
      • Agewall S.
      • Antunes M.J.
      • Bucciarelli-Ducci C.
      • Bueno H.
      • et al.
      2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
      ,
      • Mason P.J.
      • Shah B.
      • Tamis-Holland J.E.
      • Bittl J.A.
      • Cohen M.G.
      • Safirstein J.
      • et al.
      An update on radial artery access and best practices for transradial coronary angiography and intervention in acute coronary syndrome: a scientific statement from the American Heart Association.
      ]. However, Australian data demonstrate persistently lower radial access use in women compared to men [
      • Stehli J.
      • Zaman S.
      • Martin C.
      • Brennan A.
      • Lefkovits J.
      • Dinh D.
      • et al.
      Impact of gender on radial access use and bleeding risk in patients presenting with acute coronary syndromes to Victorian hospitals.
      ].
      Registry data show that compared to men, women with MI are less often prescribed potent P2Y12 inhibitors [
      • Sherwood M.W.
      • Wiviott S.D.
      • Peng S.A.
      • Roe M.T.
      • Delemos J.
      • Peterson E.D.
      • et al.
      Early clopidogrel versus prasugrel use among contemporary STEMI and NSTEMI patients in the US: insights from the National Cardiovascular Data Registry.
      ,
      • Cenko E.
      • van der Schaar M.
      • Yoon J.
      • Manfrini O.
      • Vasiljevic Z.
      • Vavlukis M.
      • et al.
      Sex-related differences in heart failure after ST-segment elevation myocardial infarction.
      ], despite a proven mortality reduction with ticagrelor [
      • Bonaca M.P.
      • Bhatt D.L.
      • Cohen M.
      • Steg P.G.
      • Storey R.F.
      • Jensen E.C.
      • et al.
      Long-term use of ticagrelor in patients with prior myocardial infarction.
      ]. Women also have a lower rate of adherence to antiplatelet therapy [
      • Yu J.
      • Baber U.
      • Mastoris I.
      • Dangas G.
      • Sartori S.
      • Steg P.G.
      • et al.
      Sex-based differences in cessation of dual-antiplatelet therapy following percutaneous coronary intervention with stents.
      ]. The reasons for the difference in compliance are thought to be that women have more drug-related side effects such as dyspnoea and bleeding, both leading to early antiplatelet cessation [
      • Yu J.
      • Baber U.
      • Mastoris I.
      • Dangas G.
      • Sartori S.
      • Steg P.G.
      • et al.
      Sex-based differences in cessation of dual-antiplatelet therapy following percutaneous coronary intervention with stents.
      ,
      • Zanchin T.
      • Temperli F.
      • Karagiannis A.
      • Zanchin C.
      • Rasanen M.
      • Koskinas K.C.
      • et al.
      Frequency, reasons, and impact of premature ticagrelor discontinuation in patients undergoing coronary revascularization in routine clinical practice: results from the Bern Percutaneous Coronary Intervention Registry.
      ]. Importantly, the results of a large meta-analysis revealed that increased bleeding with P2Y12 inhibitors was similar between sexes post MI [
      • Lau E.S.
      • Braunwald E.
      • Murphy S.A.
      • Wiviott S.D.
      • Bonaca M.P.
      • Husted S.
      • et al.
      Potent P2Y12 Inhibitors in men versus women: a collaborative meta-analysis of randomized trials.
      ]. A sub-analysis of the GLOBAL LEADERS trial came to a similar conclusion; increased bleeding events with P2Y12 inhibitors were mostly seen in women with stable coronary artery disease, but less so in women with MI [
      • Chichareon P.
      • Modolo R.
      • Kerkmeijer L.
      • Tomaniak M.
      • Kogame N.
      • Takahashi K.
      • et al.
      Association of sex with outcomes in patients undergoing percutaneous coronary intervention: a subgroup analysis of the GLOBAL LEADERS randomized clinical trial.
      ]. Crucially, even in older women with MI, P2Y12 inhibitors were reportedly safe and effective [
      • Lau E.S.
      • Braunwald E.
      • Murphy S.A.
      • Wiviott S.D.
      • Bonaca M.P.
      • Husted S.
      • et al.
      Potent P2Y12 Inhibitors in men versus women: a collaborative meta-analysis of randomized trials.
      ].
      The benefit of secondary prevention medical therapy post-MI is well established. And yet, women are less likely than men to receive optimal guideline-directed medical therapy (GDMT), including high dose statins, ACE inhibitors, ARBs and beta blockers, despite a higher burden of comorbidities [
      • Wilkinson C.
      • Bebb O.
      • Dondo T.B.
      • Munyombwe T.
      • Casadei B.
      • Clarke S.
      • et al.
      Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study.
      ,
      • Zhao M.
      • Vaartjes I.
      • Graham I.
      • Grobbee D.
      • Spiering W.
      • Klipstein-Grobusch K.
      • et al.
      Sex differences in risk factor management of coronary heart disease across three regions.
      ]. Importantly, younger women and women presenting with STEMI receive less GDMT than their male counterparts [
      • Redfors B.
      • Angeras O.
      • Ramunddal T.
      • Petursson P.
      • Haraldsson I.
      • Dworeck C.
      • et al.
      Trends in gender differences in cardiac care and outcome after acute myocardial infarction in western Sweden: a report from the Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART).
      ]. Furthermore, women with MINOCA are much less likely to receive secondary prevention medical therapy, despite proven benefits in this cohort [
      • Maddox T.M.
      • Ho P.M.
      • Roe M.
      • Dai D.
      • Tsai T.T.
      • Rumsfeld J.S.
      Utilization of secondary prevention therapies in patients with nonobstructive coronary artery disease identified during cardiac catheterization: insights from the National Cardiovascular Data Registry Cath-PCI Registry.
      ]. The reasons for lower GDMT use in women are poorly understood, with socio-economic factors and treatment non-adherence by women mooted as possible causes [
      • Nanna M.G.
      • Wang T.Y.
      • Xiang Q.
      • Goldberg A.C.
      • Robinson J.G.
      • Roger V.L.
      • et al.
      Sex differences in the use of statins in community practice.
      ]. However, less frequent prescription by treating doctors who underestimate women’s risk for recurrent events also plays a part [
      • Nanna M.G.
      • Wang T.Y.
      • Xiang Q.
      • Goldberg A.C.
      • Robinson J.G.
      • Roger V.L.
      • et al.
      Sex differences in the use of statins in community practice.
      ]. Following hospital discharge, further sex and gender discrepancies become evident. One notable example is that women are less likely to be referred to, or participate in a cardiac rehabilitation program than men [
      • Wilkinson C.
      • Bebb O.
      • Dondo T.B.
      • Munyombwe T.
      • Casadei B.
      • Clarke S.
      • et al.
      Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study.
      ,
      • Oosenbrug E.
      • Marinho R.P.
      • Zhang J.
      • Marzolini S.
      • Colella T.J.
      • Pakosh M.
      • et al.
      Sex differences in cardiac rehabilitation adherence: a meta-analysis.
      ,
      • Koh Y.
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • et al.
      Does sex predict quality of life after acute coronary syndromes: an Australian, state-wide, multicentre prospective cohort study.
      ]. despite its proven efficacy in reducing cardiac mortality for both sexes.

      Outcomes and Complications

      It is a matter of debate as to whether sex outcome disparities for women with MI are simply a function of their older average age and subsequent higher comorbidity burden, or to biological factors intrinsic to the female sex, conferring higher bleeding complications and differing treatment response. Due to the multiple differences in diagnosis and management of MI in women, teasing out which factors most affect outcomes is particularly challenging. In most adequately sized studies, differences in outcomes between women and men with STEMI remain despite adjustment for age, comorbidities, presentation delays and differences in treatment [
      • Venetsanos D.
      • Sederholm Lawesson S.
      • Alfredsson J.
      • Janzon M.
      • Cequier A.
      • Chettibi M.
      • et al.
      Association between gender and short-term outcome in patients with ST elevation myocardial infraction participating in the international, prospective, randomised Administration of Ticagrelor in the catheterisation Laboratory or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) trial: a prespecified analysis.
      ,
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • Roe M.
      • Granger C.B.
      • Armstrong P.W.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      ,
      • Bucholz E.M.
      • Normand S.L.
      • Wang Y.
      • Ma S.
      • Lin H.
      • Krumholz H.M.
      Life Expectancy and years of potential life lost after acute myocardial infarction by sex and race: a cohort-based study of Medicare beneficiaries.
      ]. Female sex remains an independent predictor of mortality in all age groups [
      • Venetsanos D.
      • Sederholm Lawesson S.
      • Alfredsson J.
      • Janzon M.
      • Cequier A.
      • Chettibi M.
      • et al.
      Association between gender and short-term outcome in patients with ST elevation myocardial infraction participating in the international, prospective, randomised Administration of Ticagrelor in the catheterisation Laboratory or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) trial: a prespecified analysis.
      ,
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • Roe M.
      • Granger C.B.
      • Armstrong P.W.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      ], including octagenarians [
      • Vicent L.
      • Ariza-Sole A.
      • Alegre O.
      • Sanchis J.
      • Lopez-Palop R.
      • Formiga F.
      • et al.
      Octogenarian women with acute coronary syndrome present frailty and readmissions more frequently than men.
      ]. Female patients lose on average 8% more expected life years after a STEMI than males do [
      • Bucholz E.M.
      • Normand S.L.
      • Wang Y.
      • Ma S.
      • Lin H.
      • Krumholz H.M.
      Life Expectancy and years of potential life lost after acute myocardial infarction by sex and race: a cohort-based study of Medicare beneficiaries.
      ]. However, the widest discrepancy between the sexes for life years lost is seen in younger patients (age <60 years) with STEMI [
      • Redfors B.
      • Angeras O.
      • Ramunddal T.
      • Petursson P.
      • Haraldsson I.
      • Dworeck C.
      • et al.
      Trends in gender differences in cardiac care and outcome after acute myocardial infarction in western Sweden: a report from the Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART).
      ,
      • Cenko E.
      • Yoon J.
      • Kedev S.
      • Stankovic G.
      • Vasiljevic Z.
      • Krljanac G.
      • et al.
      Sex differences in outcomes after STEMI: effect modification by treatment strategy and age.
      ]. Most concerning, in this younger group of patients mortality rates are rising, particularly in women [
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • Grines C.L.
      • Krumholz H.M.
      • Johnson M.N.
      • et al.
      Acute myocardial infarction in women: a scientific statement from the American Heart Association.
      ]. On a more positive note, recent studies have demonstrated that the excess mortality in women following STEMI can be significantly attenuated, simply by equal delivery of cardiovascular care [
      • Alabas O.A.
      • Gale C.P.
      • Hall M.
      • Rutherford M.J.
      • Szummer K.
      • Lawesson S.S.
      • et al.
      Sex differences in treatments, relative survival, and excess mortality following acute myocardial infarction: national cohort study using the SWEDEHEART Registry.
      ], based on STEMI check-lists and protocols [
      • Huded C.P.
      • Johnson M.
      • Kravitz K.
      • Menon V.
      • Abdallah M.
      • Gullett T.C.
      • et al.
      4-Step protocol for disparities in STEMI care and outcomes in women.
      ], or on ESC quality indicators [
      • Wilkinson C.
      • Bebb O.
      • Dondo T.B.
      • Munyombwe T.
      • Casadei B.
      • Clarke S.
      • et al.
      Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study.
      ].
      A strong interaction between sex and type of MI (STEMI versus NSTEMI) exists [
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • Roe M.
      • Granger C.B.
      • Armstrong P.W.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      ]. Stark sex-based differences in the STEMI cohort are observed, however, findings from studies of NSTEMI patients have been less consistent. A recent large meta-analysis of TIMI-trials revealed that women with NSTEMI were actually at lower risk of major adverse cardiovascular events (MACE) and death after adjustment for comorbidities and age [
      • Sarma A.A.
      • Braunwald E.
      • Cannon C.P.
      • Guo J.
      • Im K.
      • Antman E.M.
      • et al.
      Outcomes of women compared with men after non-ST-segment elevation acute coronary syndromes.
      ]. Several other studies have come to the same conclusion [
      • De Carlo M.
      • Morici N.
      • Savonitto S.
      • Grassia V.
      • Sbarzaglia P.
      • Tamburrini P.
      • et al.
      Sex-related outcomes in elderly patients presenting with non-ST-segment elevation acute coronary syndrome: insights from the Italian elderly ACS study.
      ,
      • Gupta T.
      • Kolte D.
      • Khera S.
      • Agarwal N.
      • Villablanca P.A.
      • Goel K.
      • et al.
      Contemporary sex-based differences by age in presenting characteristics, use of an early invasive strategy, and inhospital mortality in patients with non-ST-Segment-elevation myocardial infarction in the United States.
      ,
      • Redfors B.
      • Angeras O.
      • Ramunddal T.
      • Petursson P.
      • Haraldsson I.
      • Dworeck C.
      • et al.
      Trends in gender differences in cardiac care and outcome after acute myocardial infarction in western Sweden: a report from the Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART).
      ]. This is contradicted by another recent investigation demonstrating that despite propensity matching, women faced poorer outcomes than men, even when they were treated with an early invasive strategy [
      • Udell J.A.
      • Koh M.
      • Qiu F.
      • Austin P.C.
      • Wijeysundera H.C.
      • Bagai A.
      • et al.
      Outcomes of women and men with acute coronary syndrome treated with and without percutaneous coronary revascularization.
      ].
      Major bleeding is one of the main drivers of worse outcomes in women [
      • Yu J.
      • Baber U.
      • Mastoris I.
      • Dangas G.
      • Sartori S.
      • Steg P.G.
      • et al.
      Sex-based differences in cessation of dual-antiplatelet therapy following percutaneous coronary intervention with stents.
      ,
      • Ng V.G.
      • Baumbach A.
      • Grinfeld L.
      • Lincoff A.M.
      • Mehran R.
      • Stone G.W.
      • et al.
      Impact of bleeding and bivalirudin therapy on mortality risk in women undergoing percutaneous coronary intervention (from the REPLACE-2, ACUITY, and HORIZONS-AMI Trials).
      ]. Higher rates of bleeding in women compared to men occurs in patients presenting with both STEMI and NSTEMI, before and after PCI [
      • Nanna M.G.
      • Hajduk A.M.
      • Krumholz H.M.
      • Murphy T.E.
      • Dreyer R.P.
      • Alexander K.P.
      • et al.
      Sex-based differences in presentation, treatment, and complications among older adults hospitalized for acute myocardial infarction: the SILVER-AMI study.
      ]. One explanation proffered is the lower rate of radial access used in women. In the large, randomised Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial, women benefitted from radial access with a reduction in bleeding and MACE that was more pronounced than in men [
      • Gargiulo G.
      • Ariotti S.
      • Vranckx P.
      • Leonardi S.
      • Frigoli E.
      • Ciociano N.
      • et al.
      Impact of sex on comparative outcomes of radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: data from the randomized MATRIX-access trial.
      ]. However, nationally and globally, women continue to be treated using radial access less often than men [
      • Stehli J.
      • Zaman S.
      • Martin C.
      • Brennan A.
      • Lefkovits J.
      • Dinh D.
      • et al.
      Impact of gender on radial access use and bleeding risk in patients presenting with acute coronary syndromes to Victorian hospitals.
      ]. Another cause of excessive bleeding in women is medication use; thrombolytic agents lead to significantly higher rates of blood loss in women. This is likely due to more comorbidities and differing pharmacokinetics due to lower average body weight [
      • Weaver W.D.
      • White H.D.
      • Wilcox R.G.
      • Aylward P.E.
      • Morris D.
      • Guerci A.
      • et al.
      Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. GUSTO-I investigators.
      ]. In spite of proven benefit in reducing overall MACE, women experience more bleeding, including haemorrhagic stroke with P2Y12 inhibitor treatment, particularly in the first year after PCI [
      • Chichareon P.
      • Modolo R.
      • Kerkmeijer L.
      • Tomaniak M.
      • Kogame N.
      • Takahashi K.
      • et al.
      Association of sex with outcomes in patients undergoing percutaneous coronary intervention: a subgroup analysis of the GLOBAL LEADERS randomized clinical trial.
      ,
      • Venetsanos D.
      • Sederholm Lawesson S.
      • Alfredsson J.
      • Janzon M.
      • Cequier A.
      • Chettibi M.
      • et al.
      Association between gender and short-term outcome in patients with ST elevation myocardial infraction participating in the international, prospective, randomised Administration of Ticagrelor in the catheterisation Laboratory or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) trial: a prespecified analysis.
      ]. Bleeding often leads to cessation of antiplatelet therapy, potentially leading to further MACE.
      Another factor strongly influencing outcomes in women is new onset heart failure, which is more common in women compared to men following STEMI [
      • Cenko E.
      • van der Schaar M.
      • Yoon J.
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      • Vasiljevic Z.
      • Vavlukis M.
      • et al.
      Sex-related differences in heart failure after ST-segment elevation myocardial infarction.
      ]. Importantly, when women present with new onset heart failure after a STEMI, they have higher mortality than men, even after adjustment for comorbidities and treatment differences [
      • Cenko E.
      • van der Schaar M.
      • Yoon J.
      • Manfrini O.
      • Vasiljevic Z.
      • Vavlukis M.
      • et al.
      Sex-related differences in heart failure after ST-segment elevation myocardial infarction.
      ]. Additionally, women of all ages have a 26–29% higher hazard ratio of being hospitalised after an MI, even after adjustment for common, known confounders such as age. However, when further adjusting for psychological factors and baseline health status, the association was attenuated [
      • Dreyer R.P.
      • Dharmarajan K.
      • Kennedy K.F.
      • Jones P.G.
      • Vaccarino V.
      • Murugiah K.
      • et al.
      Sex differences in 1-year all-cause rehospitalization in patients after acute myocardial infarction: a prospective observational study.
      ].
      Female sex has been shown to be independently associated with reduced quality of life after a MI, including increased pain, anxiety and depression [
      • Koh Y.
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • et al.
      Does sex predict quality of life after acute coronary syndromes: an Australian, state-wide, multicentre prospective cohort study.
      ]. This is likely influenced by personality traits and social roles that are traditionally ascribed to women, or more specifically, to the female gender. The GENdEr and Sex determInantS of cardiovascular disease: From bench to beyond-Premature Acute Coronary SYndrome (Genesis Praxy) study concluded that event rates after MI were higher in female patients who displayed gender attributes commonly seen in women, such as having a high level of responsibility for caring for children or having a high number of hours per week spent doing housework, but also displaying a low level of confidence in stress management abilities [
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • Daskalopoulou S.S.
      • Eisenberg M.J.
      • Bacon S.L.
      • et al.
      Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      ]. In contrast, event rates were not different when only biological sex was considered. Consequentially, as women’s gender attributes remain commonplace in most societies, this increases the risk of MACE in young women with MI [
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • Daskalopoulou S.S.
      • Eisenberg M.J.
      • Bacon S.L.
      • et al.
      Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
      ]. This is compounded by the fact that women continue to be underrepresented in clinical MI trials, with participation to prevalence ratio of only 0.6, limiting sex-based analysis and insights [
      • Scott P.E.
      • Unger E.F.
      • Jenkins M.R.
      • Southworth M.R.
      • McDowell T.Y.
      • Geller R.J.
      • et al.
      Participation of women in clinical trials supporting FDA approval of cardiovascular drugs.
      ].

      Conclusion and Challenges

      In conclusion, sex disparities cannot be explained by either bias or biology alone and represent a complex construct of both of these, influencing each other in multiple ways. The question as to the relative contributions of biology versus bias to the disparate outcomes remains unanswered and will likely only become apparent once all bias is eliminated.
      In this context, three main challenges need to be addressed (outlined in Figure 3) [
      • Gulati M.
      Yentl's bikini: sex differences in STEMI.
      ]: First, we must increase both female patients’, nurses’, and doctors’ awareness of women’s risk of cardiovascular disease. Artificial intelligence and machine learning or check-list based approaches could help to reduce implicit bias originating from health care providers [
      • Gulati M.
      Yentl's bikini: sex differences in STEMI.
      ,
      • Johnson K.W.
      • Torres Soto J.
      • Glicksberg B.S.
      • Shameer K.
      • Miotto R.
      • Ali M.
      • et al.
      Artificial intelligence in cardiology.
      ]. Ongoing public campaigns are necessary to improve women’s awareness of their cardiovascular risk factors, warning signs for a heart attack, and knowledge of how and when to seek help. Empowering women to be their own advocates in the diagnosis of heart disease is crucial. Education of health care professionals should target sex differences in cardiovascular risk, the discrepancies in treatment and outcomes, and the potential role of bias in worsening and maintaining these. This includes promotion of sex-specific serum troponin level values, early invasive diagnostic testing with radial access, and appropriate secondary prevention. Second, more cardiovascular research is needed that is specific to women in order to attain a better understanding of all the factors that lead to comparatively poorer outcomes compared to men. This includes research into the underlying pathophysiology of MI in women and implementation of health services research that targets system delays. Finally, specific guidelines are needed to explicate the diagnostic steps and treatment recommendations suitable for women patients, so they can be implemented effectively into clinical practice.
      Figure thumbnail gr3
      Figure 3Ways to improve outcomes in women with MI, adapted from Gulati, JAHA 2019 [
      • Gulati M.
      Yentl's bikini: sex differences in STEMI.
      ].
      Abbreviations: STEMI, ST elevation myocardial infarction; MI, myocardial infarction.

      Funding

      This project did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

      Conflicts of Interest and Acknowledgements

      JS is supported by a Monash University scholarship and has received educational grants and holds stock in Medtronic and Abbott. SJD is proctor for Medtronic and his work is supported by a grant (1111170) from the National Health and Medical Research Council of Australia. SZ is supported by a fellowship (101993) from the National Heart Foundation of Australia. SZ has obtained research funding from Abbott Vascular, Biotronik Australia and Medtronic Australia and speaking honoraria from AstraZeneca. All other authors have no conflicts of interest.

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