Review Article

Chest Pain in Women: Gender- and Sex-based Differences in the Presentation and Diagnosis of Heart Disease

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.
Information image
Average (ratings)
No ratings
Your rating

Abstract

Ischemic heart disease is a major cause of morbidity and mortality in the US, affecting both men and women significantly. The presentation of chest pain is largely similar in female and male patients, but additional non-chest pain symptoms can confound timely diagnosis in women. Management, diagnostic evaluation, and clinical outcomes for patients admitted with chest pain differ significantly between men and women, and understanding of these discrepancies is limited. The objective of this review is to familiarize readers with gender- and sex-specific differences in the presentation, diagnosis, and management of chest pain.

Disclosure:The authors have no conflicts of interest to declare.

Received:

Accepted:

Published online:

Correspondence Details:Mariem A Sawan, Department of Medicine, Division of Cardiology, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322. E: mariem.sawan@emory.edu

Open Access:

This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Gender and Sex Terminology

The term sex refers to biological constructs including genetic, anatomical, and hormonal characteristics. When referring to sex-related differences, we have used the categorization of male versus female. The term gender reflects social constructs, including roles, behaviors, and identities. When referring to gender-related differences, we have used the categorization of men versus women. For the purpose of this review, we have generally maintained the terminology used in the original articles referenced, but recognize that these terms may have been interchanged inappropriately in the referenced literature.

Chest pain is one of the most common reasons for emergency department visits.1 The term is used by patients to describe an uncomfortable sensation in the anterior chest. Chest pain that raises concern for myocardial ischemia is often reported as pressure, tightness, squeezing, or heaviness, and is occasionally associated with nausea, diaphoresis, or shortness of breath. Patients may also report pain or discomfort in an area other than the chest, including the shoulder, arm, neck, jaw, or upper abdomen.

The characteristic symptoms induced by myocardial ischemia have been historically described as typical versus atypical. Recently, the ACC/AHA Joint Committee on Clinical Data Standards defined chest pain and acute MI (AMI). The committee has discouraged the use of the term atypical, which can be used to describe both non-cardiac and cardiac symptoms that are not representative of myocardial ischemia.1 Instead, the multi-society committee has recommended the following terminology to describe chest pain: cardiac; possible cardiac; and non-cardiac.2

Presentation of Chest Pain in Women

Character, Timing, Location, and Associated Factors

Women with ischemic heart disease have a higher risk of dying of acute AMI than similarly aged men.3–5 Differences in symptom presentation among women is thought to play a role in treatment delays despite the burden of cardiovascular disease (CVD) in this population.

Figure 1: Chest Pain in Women

Article image

Most women present with traditional chest pain symptoms of pain, pressure, tightness, or discomfort.6–10 However, they are more likely than men to report a greater number of associated symptoms such as weakness and/or pain in the back, shoulder, or neck (Figure 1).10 Therefore, the patient’s complaint of several non-chest pain symptoms may influence the clinician’s decision to evaluate her ischemic heart disease, especially if chest pain is not the primary complaint at the time of presentation.11

The delays in diagnosis of acute coronary syndrome (ACS) in women illustrate the importance of thoughtful communication to health professionals and the public about not classifying symptoms in women as atypical and viewing symptoms in men as the gold standard.12

Most Common Risk Factors

Traditional CVD risk factors are similar in men and women, although prevalence and risk factors for chest pain differ by sex and gender.13

Risk factors, including diabetes, hypertension, dyslipidemia, obesity, smoking, and physical inactivity, are either more prevalent or have greater effects in women compared to men.14 Young women who present with ACS are more likely to smoke and have a history of diabetes, metabolic syndrome, hypertension, or chronic kidney disease than young men.15,16 Women who experience MI often present with higher rates of chronic obstructive pulmonary disease, congestive heart failure, elevated inflammatory markers, and poor mental health compared to men.16

Women have specific non-traditional cardiovascular risk factors because of their genetic and hormonal predisposition. They are at greater risk of developing autoimmune disorders than men, which may increase their risk of cardiovascular events.12 Patients with autoimmune disorders can develop endothelial damage and atherosclerosis over time, and autoimmune-related symptoms may overlap with clinical symptoms of CVD.17

Pregnancy itself poses risks to the cardiovascular health of women because of comorbidities that can develop during gestation, such as gestational diabetes, gestational hypertension, and pre-eclampsia.12,18 Those with a history of adverse pregnancy outcomes are at risk of accelerated atherosclerosis and premature coronary artery disease (CAD).18

Women diagnosed with polycystic ovary syndrome (PCOS) may have dysregulation of hormones, including increased aldosterone (which can lead to an increase in blood pressure), a fall in estrogen, and increased androgens.17 Decreases in estrogen in women may lead to a loss of endothelium-derived nitric oxide, impairing vasodilation.19 Raised androgens may be related to insulin resistance and increases in visceral fat, although relationships to CV outcomes are ill defined.19

Most Common Diagnoses

Cardiovascular

Compared to men, women with chest pain are more likely to be diagnosed with coronary vasospasm, MI with non-obstructive coronary arteries (MINOCA), ischemia with non-obstructive coronary arteries (INOCA), spontaneous coronary artery dissection (SCAD), and takotsubo cardiomyopathy.20

Coronary vasospasm can be induced at the level of the epicardial coronary arteries or in the microvascular circulation of the heart.20 Coronary vasospasm is associated with MINOCA, defined as AMI without coronary artery obstruction on angiography.21 INOCA is defined by objective myocardial ischemia via abnormal EKG, imaging tests, or biomarker evidence, with <50% stenosis in the epicardial vessels.22 MINOCA and INOCA can be driven by vascular dysfunction and vasospasm in epicardial arteries or at the level of the cardiac microcirculation. Vascular dysfunction can lead to a supplydemand mismatch, leading to ischemia or infarction.22

SCAD is a dissection of an epicardial coronary artery not caused by atherosclerosis or trauma and accounts for about 35% of ACS in women.23 Notably, women make up 87–95% of SCAD cases and, while the exact mechanism is unknown, sex hormones may contribute to development of this condition.24

Women are less likely than men to have obstructive multivessel disease; however, this should not preclude this diagnosis from being thoroughly explored.23

Non-cardiovascular

Misdiagnosis of cardiac causes as non-cardiac in etiology seems to be more prevalent in women. Women themselves are likely to attribute their symptoms to a non-cardiac cause (particularly acid reflux and anxiety), which may contribute to delayed clinical presentation.25

Care-seeking behaviors of younger men and women hospitalized for AMI were described in the VIRGO study.10 VIRGO researchers found that women were more likely to have their symptoms initially attributed to a non-cardiac condition (53% versus 37%; p<0.001) by their provider, including acid reflux, stress and anxiety, muscle pain, asthma, diabetes, fatigue, or gastroenteritis.

Non-cardiac causes of chest pain that must be evaluated in women include pulmonary embolism, gastrointestinal disruptions such as esophagitis and peptic ulcer disease, pneumonia, pneumothorax, and costochondritis (Figure 1).2

Differences in Evaluation of Chest Pain in Women

Hospital and Intensive Care Admission

Women admitted to hospital after presentation with chest pain to an emergency department or ambulatory care facility experience sex- and gender-based differences in evaluation, hospital admission rates and management of their chest pain (Table 1).

Outcomes of Women Presenting with Chest Pain

Article image

A cohort analysis reviewing 54,134 patients presenting to an Alberta emergency department found that women presenting with stable angina, unstable angina, AMI, or chest pain were significantly more likely to be discharged than men.26 In 2010, a prospective German study of 1,249 patients similarly found that women presenting with chest pain were significantly less likely to be admitted to the hospital than men (2.9% versus 6.6%; p<0.01).27,28 Data from the BEACON trial further confirmed that women with suspected ACS were admitted to hospitals at significantly lower rates than men (33% versus 42%; p=0.04).29

The known lower incidence of obstructive CAD in women may contribute to this admission behavior; however, women found to have obstructive CAD have significantly higher mortality rates (RR 1.75; 95% CI [1.48–2.07]).30 Therefore, although less prevalent, there should be a high index of suspicion and appropriate evaluation for obstructive CAD in women, which may require increased rates of admission for further assessment.

In addition to differences in hospital admission rates, women experience lower rates of observation unit admission and delays in hospital admission, and are less likely to be transferred to an intensive care unit. A Swedish retrospective chart review of 2,393 patients found that women experienced a delay in hospital admission of 36 minutes on average compared to men, and men were three times as likely to be admitted to a coronary care unit.31 Other research, carried out in young adults, also found significantly decreased rates of hospital admission and rates of observation unit admission in women compared to men (p=0.026 and p<0.001, respectively).32

Diagnostic Testing and Imaging Studies:

Gender-specific differences also exist regarding diagnostic testing for women who seek care for acute chest pain. Given that women have worse outcomes after an AMI than men, it is important to evaluate cardiac causes of chest pain early and efficiently.33 However, significant disparities are present in performing early noninvasive testing.

In 2008, a study of 7,068 patients in the emergency department found that, over a span of 5 years (1995–2000), African-American women had a significant lower rates of chest radiography use over time (70.5–58.1%; p<0.05) compared to non-African-American women (76.1–77.4%). Non-African-American women had significantly less cardiac monitoring (53.1 to 42.1%, p<0.05) than non-African-American men (52.3–53.1%).34 These discrepancies were thought to be related to differences in insurance, provider bias, and atypical presentations of chest pain in certain groups.

Regarding patients with stable angina, women are also less likely to undergo a functional ischemia assessment than men, and, in women under 50 years of age, cardiac troponin (cTn) testing is ordered less frequently than in men (OR 0.78; 95% CI [0.70–0.87]).35,36

Gender-specific differences may be present in performing invasive cardiac testing and treatment, although studies have drawn varied conclusions.

In a large study of 7,272 patients presenting to an emergency department with chest pain, of those with cardiac troponin levels in the >99th percentile, women underwent 16% fewer diagnostic cardiac catheterizations than men (p<0.001).37 However, it should be noted that women were 11% less likely to be diagnosed with MI after catheterization.37

Post-hoc analysis of the CURE trial showed that women undergo in-hospital cardiac angiography less frequently than men (25.4% versus 29.5%; p=0.0001), and women also undergo post-discharge angiography less frequently (14% versus 16%; p=0.006).38

There are several plausible reasons for these differences in invasive testing rates, and various potential factors have been studied. Gender bias in invasive testing is likely to be not solely explained by differences in presentation, history, or clinical course.39 The disparity in cardiac catheterization does not appear to be related to physician sex.40 Women have also been shown to refuse invasive cardiac procedures at higher rates than men, which is likely to be one of many contributing factors to the disparities in observed invasive testing rates.41

Sex-specific physiologic differences have been implicated in the differing results of certain diagnostic tests. Clinicians should be aware of these sex-specific differences when performing and interpreting diagnostic results. Factors such as menopausal status and exercise capacity have been shown to affect the prevalence of CAD, EKG findings, and the accuracy of pharmacologic stress testing.42 Women are more likely to have elevated levels of brain natriuretic peptide and are less likely to have elevated levels of troponin when experiencing chest pain.43

Hospital Stay and Follow-up

Women hospitalized for cardiac chest pain have been shown to require longer inpatient stays and have different readmission patterns.

A study investigating patients who received inpatient phase I cardiac rehabilitation after AMI found that women had significantly more days of hospitalization, spent more time in the intensive care unit, and had a 4% higher 1-year mortality rate.44

In patients who undergo percutaneous coronary intervention for an ACS, being a woman has been shown to be an independent risk factor for 30-day readmission (13.0% women versus 9.6% men; p<0.0001).45

Another study has shown that young women (aged <65 years) have 30-day readmission rates that are nearly twice as high as those for men after acute an MI, and the reason for this is likely to be secondary to be non-cardiac causes.46

Further studies are needed to investigate sex- and gender-specific differences in hospitalizations for all-cause chest pain.

Cost and Economic Impact of Misdiagnosis in Women

Healthcare costs associated with heart disease in the US are greater than $200 billion annually.47 Given sex differences in the prevalence of atherosclerotic heart disease and usage of physician resources, women continue to face a high economic burden for all-cause chest pain.

In the 2006 National Institutes of Health-sponsored WISE study of 883 women, 5-year costs of $32,000 and $53,000 were associated with non-obstructive and three-vessel CAD, respectively. The predicted lifetime cost for an individual woman with recurrent, refractory chest pain without obstructive coronary disease has been estimated to be more than $750,000. The cost for women with obstructive disease was estimated to be roughly $1,000,000.48

Gender discrepancies that exist in the initial evaluation of chest pain contribute to further work-up and cost. A Spanish study of 41,828 women concluded that, upon initial evaluation, the diagnosis of AMI was underestimated in women presenting with chest pain leading to late and missed diagnosis, further elevating diagnostic costs.49

Future studies are also needed to comprehensively evaluate the differences between the cost of chest pain in men and women, as well as the economic impact of chest pain misdiagnosis in women.

Differences in Outcomes

Mortality and Morbidity

Women, especially those who are younger (aged <60–65 years), are commonly perceived to be protected from heart disease, and to have a higher likelihood of benign etiologies of chest pain. Oversimplification of this concept and overgeneralization regarding biological sex differences such as delayed atherosclerotic disease and stress manifestations lead to inappropriate dismissal and under-diagnosis of serious etiologies of chest pain in younger women.

This is exacerbated by the use of the dichotomous terms of typical/atypical chest pain as indicators of risk for cardiovascular events in women. We attempt below to dissect the factors contributing to differential outcomes of chest pain as an indicator of CVD in women, as well as the impact of worse cardiovascular outcomes on women’s mental health, which in itself is a predictor of cardiovascular health.

Hospitalization for chest pain is more often a predictor of CVD and mortality in men than women. In a study in Norway,women were less likely to have a cardiovascular diagnosis 1 year after discharge from the hospital with unexplained chest pain, and had lower mortality compared to men.50

Atherosclerotic burden is lower in women presenting with chest pain. In a study of patients with stable chest pain who underwent coronary CT angiography, women had a higher prevalence of atypical chest pain but lower overall CAD and all-cause mortality than men.51

Chest pain in patients with non-obstructive CAD can be due to etiologies that are more difficult to diagnose and treat because of difficulty in diagnosis and a lack of appropriate interventional and pharmacological therapies. This leads to higher morbidity rates, which disproportionately affect women, especially at younger ages. These etiologies include microvascular dysfunction leading to MINOCA, vascular spasm, and endothelial dysfunction.52 In particular, takotsubo cardiomyopathy is seen more often in menopausal than pre-menopausal women, but younger women with takotsubo syndrome have worse outcomes.53 Other non-atherosclerotic etiologies with worse outcomes in the acute setting that are more prevalent in younger women include SCAD.24

When chest pain is due to cardiovascular causes, women have worse outcomes even with prompt diagnosis. In a study of patients presenting with chest pain and stratified by cTn levels, women with cTn levels above the 99th percentile, which triggered a rapid cardiac evaluation, had higher 1-year rates of major adverse cardiovascular events than men. This was attributed to their lower use of appropriate medications and higher burden of comorbidities.37 In 2006, a study found that in patients without obstructive CAD on angiography, women with persistent chest pain at least 1 year after the procedure had more than double the rate of cardiovascular events compared to men.54

In the acute setting, outcomes of chest pain are also worse for women. In a retrospective study of all adults (over 50,000 patients) presenting to three emergency departments with chest pain over a 5-year period in Melbourne, Australia, women had a 35% higher likelihood of dying in the emergency department compared to men. Even though less likely to be admitted, women were also 36% more likely to die in the hospital if admitted.55

Age is an important factor in the disparities of outcomes between women and men, as these differences may become less pronounced in older populations. In a large observational study of patients diagnosed with MI, women aged >65 years were more likely to present with chest pain than younger women, and the difference in in-hospital mortality between men and women was attenuated by this age.9 Older women have had more favorable outcomes whereas younger women had higher mortality following AMI outside the acute setting after the initial 28-day period.56,57

The absence of chest pain on presentation with MI is a predictor of mortality risk for both sexes, but more strongly for women.58 Delay in diagnosis and treatment may not fully explain the higher morbidity after MI in women, since women also experience higher bleeding complications from procedures or drug therapies, and higher rates of developing mechanical complications such as heart failure.

Impact on Mental Health

The prevalence of depression after MI, a known adverse prognostic factor following ACS, and anxiety are higher in women compared to men.59 Following adverse cardiovascular events such as MI, women survivors aged <50 years old are also more susceptible to subsequent ischemia induced by psychosocial stress.60 Women with atherosclerotic CVD report poorer interaction with providers, and perception of health and quality of life compared to men.61

Mechanisms of Differences in Presentation and Outcomes

Bias and Impact of Physician Sex on Testing and Outcomes

Delayed presentation and delayed care have been studied as causes of worse outcomes in women presenting with chest pain (Table 2). This is evident in the acute setting, with fewer women receiving higher urgency triage in the emergency department, although pre-hospital delay in presentation is also a contributing factor.55,62

Mechanisms of Sex-based Differences

Article image

Physician–patient sex concordance results in better patient-reported quality of life.61 Female patients post-MI treated by male physicians were found to have an increased mortality risk in a retrospective study of Florida hospital admissions over two decades; this risk was mitigated by male physicians practicing alongside female colleagues or exposure to a female population, but other studies showed no influence.63,64

Bias in Studies

Inclusion of women in CVD studies of the last decade is improving for younger women (aged <55 years) and certain disease populations, but is still lacking.65 This extends to trials evaluating cardiovascular drugs.66 This limitation in existing studies severely limits the generalizability of the data and restricts its clinical applicability.

Neurohormonal Mechanisms

Pain perception differs by sex, and studies suggest a higher sensitivity to somatic pain as well as a higher prevalence of psychosomatic pain perception in women, either independently or comorbid with psychiatric disorders such as depression and anxiety. This may contribute to the lower prevalence of heart disease in women presenting with chest pain, but the awareness of this difference can contribute to underdiagnosis and undertreatment of CVD in women with this symptom.

Sex and gender differences in pain perception and etiology have been attributed to a variety of causes, including psychosocial, genetic, neurohormonal, and experiential.67

Psychiatric conditions known to be CVD risk factors, such as depression and anxiety, are more prevalent in women, especially at a younger age, and are disproportionately over-represented in young women as both causes and outcomes of acute cardiovascular events.68,69 Psychosocial stress can also be causative of cardiovascular events.

There are known sex disparities in response to stress and its impact on adverse cardiovascular outcomes. In a study of the association of inflammatory response to stress with adverse cardiovascular events, increased circulating biomarkers in response to a stressful event (a speech task) in patients with stable coronary heart disease was a predictor of major adverse cardiovascular events in women but not in men.70

Mental stress-induced myocardial ischemia by perfusion imaging is also more prevalent in younger women than men, with the difference attenuating by 50 years of age.71 Mental-stress induced myocardial ischemia is more predictive of adverse cardiovascular outcomes in men than women, perhaps due to less precise imaging in women owing to artifacts from breast tissue.72 The differential response to stress in women could also underlie the higher prevalence of stress-related cardiomyopathy or takotsubo syndrome in older women, although its prevalence is increasing across age groups.73

Hormonal mechanisms affect presentation and outcomes of chest pain indirectly as modulators of pain perception, and directly via known cardiovascular effects. Estrogen is a known vasodilator with well-known direct effects on the cardiac muscle and vasculature, as well as metabolic functions directly associated with cardiovascular risk. It exerts its effects at the cellular level via upregulation of signaling pathways that enhance cardioprotection and reduce ischemia-reperfusion injury, as well as at the systemic metabolism level, where it has a favorable effect on lipid profiles and insulin sensitivity, and is protective against cardiac hypertrophy.74

Estrogen increases sensitivity to somatic pain, and estrogen antagonism can provide analgesia.75,76 This may contribute to the higher prevalence of non-cardiac symptoms in younger female patients with cardiovascular chest pain.

Indirect evidence for the cardioprotective role of estrogen includes accelerated cardiovascular risk during menopause, and higher cardiovascular risk being associated with earlier menopause.77 Men with estrogen receptor mutations also have a higher CVD risk and earlier onset of disease.78,79 However, menopausal hormone therapies were shown several decades ago in clinical trials to be of no benefit in reducing atherosclerotic coronary disease, while increasing thromboembolic adverse events.80 Newer studies show a safer profile with early use after menopause with lower cardiovascular risk, but menopausal hormone therapy is not recommended for primary prevention.81

Genetic Studies

Genetic effects may in part underlie the response to stress and pain perception, as well as encode direct cardiovascular risk factors.76,82 Genetic effects can manifest as polymorphisms of genes that increase risk preferentially in women (e.g. apolipoprotein E [APOE]), mutations on the X chromosome, or epigenetic alterations due to environmental or hormonal factors.82 However, the X chromosome is commonly excluded from genome-wide association study analyses due to variability in X-inactivation and the difference in number between men and women.82,83

Genes on the Y chromosome are involved in several pathways relevant to chest pain and cardiovascular outcomes. Polymorphisms on the Y chromosome are associated with hypertension, which is more prevalent in men and is a significant risk factor for ischemic heart disease, as well as innate immune activation, increasing risk of inflammation-induced atherosclerosis in men compared to women.84,85

Conclusion

Despite having more cardiovascular risk factors on average compared to men, women are underdiagnosed when presenting with chest pain, largely due to misclassification, misinformation, and underrepresentation in clinical trials.

The novelty of this review is in its extensive comparison of observed clinical differences in men versus women alongside contemporary theories behind these discrepancies, from subjective societal biases and misinformation to objective genetic and hormonal mechanisms under exploration.

Women experience worse outcomes and more mental health strain than men. Genetic and hormonal differences between men and women alone do not sufficiently explain the discrepancies in chest pain evaluation by sex and gender, and healthcare provider bias may play a large role in this disparity. Therefore, it is imperative that the medical community redefine the presentation of chest pain to reflect an accurate clinical picture inclusive of women, addressing their unique and predominant risk factors and their patterns of clinical presentation.

References

  1. Anderson HVS, Masri SC, Abdallah MS, et al. 2022 ACC/AHA key data elements and definitions for chest pain and acute myocardial infarction: a report of the American Heart Association/American College of Cardiology joint committee on clinical data standards. Circ Cardiovasc Qual Outcomes 2022;15:e000112. 
    Crossref | PubMed
  2. Gulati M, Levy PD, Mukherjee D, et al. AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation 2021;144:e368–454. 
    Crossref | PubMed
  3. Gupta A, Wang Y, Spertus JA, et al. Trends in acute myocardial infarction in young patients and differences by sex and race, 2001 to 2010. J Am Coll Cardiol 2014;64:337–45. 
    Crossref | PubMed
  4. Vaccarino V, Parsons L, Every NR, et al. Sex-based differences in early mortality after myocardial infarction. National registry of myocardial infarction 2 participants. N Engl J Med 1999;341:217–25. 
    Crossref | PubMed
  5. Vaccarino V, Parsons L, Peterson ED, et al. Sex differences in mortality after acute myocardial infarction: changes from 1994 to 2006. Arch Intern Med 2009;169:1767–74. 
    Crossref | PubMed
  6. Milner KA, Funk M, Richards S, et al. Symptom predictors of acute coronary syndromes in younger and older patients. Nurs Res 2001;50:233–41. 
    Crossref | PubMed
  7. Milner KA, Funk M, Richards S, et al. Gender differences in symptom presentation associated with coronary heart disease. Am J Cardiol 1999;84:396–9. 
    Crossref | PubMed
  8. Khan NA, Daskalopoulou SS, Karp I, et al. Sex differences in acute coronary syndrome symptom presentation in young patients. JAMA Intern Med 2013;173:1863–71. 
    Crossref | PubMed
  9. Canto JG, Rogers WJ, Goldberg RJ, et al. Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA 2012;307:813–22. 
    Crossref | PubMed
  10. Lichtman JH, Leifheit EC, Safdar B, 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). Circulation 2018;137:781–90. 
    Crossref | PubMed
  11. Hemal K, Pagidipati NJ, Coles A, et al. Sex differences in demographics, risk factors, presentation, and noninvasive testing in stable outpatients with suspected coronary artery disease: insights from the PROMISE Trial. JACC Cardiovasc Imaging 2016;9:337–46. 
    Crossref | PubMed
  12. Wenger NK, Lloyd-Jones DM, Elkind MSV, et al. Call to action for cardiovascular disease in women: epidemiology, awareness, access, and delivery of equitable health care: a presidential advisory from the American Heart Association. Circulation 2022;145:e1059–71. 
    Crossref | PubMed
  13. Bello N, Mosca L. Epidemiology of coronary heart disease in women. Prog Cardiovasc Dis 2004;46:287–95. 
    Crossref | PubMed
  14. Garcia M, Mulvagh SL, Merz CN, et al. Cardiovascular disease in women: clinical perspectives. Circ Res 2016;118:1273–93. 
    Crossref | PubMed
  15. Wenger NK. Coronary heart disease: the female heart is vulnerable. Prog Cardiovasc Dis 2003;46:199–229. 
    Crossref | PubMed
  16. Wada H, Miyauchi K, Daida H. Gender differences in the clinical features and outcomes of patients with coronary artery disease. Expert Rev Cardiovasc Ther 2019;17:127–33. 
    Crossref | PubMed
  17. Mulvagh SL, Mullen KA, Nerenberg KA, et al. Sex- and gender-unique disparities: CVD across the lifespan of a woman. CJC Open 2022;4:115–32. 
    Crossref | PubMed
  18. Chandrasekhar J, Gill A, Mehran R. Acute myocardial infarction in young women: current perspectives. Int J Womens Health 2018;10:267–84. 
    Crossref | PubMed
  19. Pandurevic S, Macut D, Fanelli F, et al. Biomediators in polycystic ovary syndrome and cardiovascular risk. Biomolecules 2021;111350. 
    Crossref | PubMed
  20. Bullock-Palmer RP, Shaw LJ, Gulati M. Emerging misunderstood presentations of cardiovascular disease in young women. Clin Cardiol 2019;42:476–83. 
    Crossref | PubMed
  21. Herling de Oliveira LL, Correia VM, Nicz PFG, et al. MINOCA: one size fits all? Probably not – a review of etiology, investigation, and treatment. J Clin Med 2022;11:5497. 
    Crossref | PubMed
  22. Mehta PK, Huang J, Levit RD, et al. Ischemia and no obstructive coronary arteries (INOCA): a narrative review. Atherosclerosis 2022;363:8–21. 
    Crossref | PubMed
  23. Madan N, Gajo E, Sanghani RM, Volgman AS. Sex-based considerations in the evaluation of chest pain and management of obstructive coronary artery disease. Curr Atheroscler Rep 2020;22:39. 
    Crossref | PubMed
  24. Hayes SN, Tweet MS, Adlam D, et al. Spontaneous coronary artery dissection: JACC state-of-the-art review. J Am Coll Cardiol 2020;76:961–84. 
    Crossref | PubMed
  25. Parry M, Van Spall HGC, Mullen KA, et al. Sex- and gender-specific diagnosis and treatment. CJC Open 2022;4:589–608. 
    Crossref | PubMed
  26. Kaul P, Chang WC, Westerhout CM, et al. Differences in admission rates and outcomes between men and women presenting to emergency departments with coronary syndromes. CMAJ 2007;177:1193–9. 
    Crossref | PubMed
  27. Karlson BW, Herlitz J. Hospitalisations, infarct development, and mortality in patients with chest pain and a normal admission electrocardiogram in relation to gender. Coron Artery Dis 1996;7:231–7
    PubMed
  28. Bosner S, Haasenritter J, Becker A, et al. Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule. CMAJ 2010;182:1295–300. 
    Crossref | PubMed
  29. Arslan M, Schaap J, Moelker A, et al. Coronary CT angiography for suspected acute coronary syndrome: sex-associated differences. Neth Heart J 2021;29:518–24. 
    Crossref | PubMed
  30. Manfrini O, Yoon J, van der Schaar M, et al. Sex differences in modifiable risk factors and severity of coronary artery disease. J Am Heart Assoc 2020;9:e017235. 
    Crossref | PubMed
  31. Ravn-Fischer A, Karlsson T, Santos M, et al. Inequalities in the early treatment of women and men with acute chest pain? Am J Emerg Med 2012;30:1515–21. 
    Crossref | PubMed
  32. Banco D, Chang J, Talmor N, et al. Sex and race differences in the evaluation and treatment of young adults presenting to the emergency department with chest pain. J Am Heart Assoc 2022;11:e024199. 
    Crossref | PubMed
  33. DeFilippis EM, Collins BL, Singh A, et al. Women who experience a myocardial infarction at a young age have worse outcomes compared with men: the Mass General Brigham Young–MI registry. Eur Heart J 2020;41:4127–37. 
    Crossref | PubMed
  34. Pezzin LE, Keyl PM, Green GB. Disparities in the emergency department evaluation of chest pain patients. Acad Emerg Med 2007;14:149–56. 
    Crossref | PubMed
  35. Maas AH, Appelman YE. Gender differences in coronary heart disease. Neth Heart J 2010;18:598–602. 
    Crossref | PubMed
  36. Humphries KH, Gao M, Lee MK, et al. Sex differences in cardiac troponin testing in patients presenting to the emergency department with chest pain. J Womens Health (Larchmt) 2018;27:1327–34. 
    Crossref | PubMed
  37. Humphries KH, Lee MK, Izadnegahdar M, et al. Sex differences in diagnoses, treatment, and outcomes for emergency department patients with chest pain and elevated cardiac troponin. Acad Emerg Med 2018;25:413–24. 
    Crossref | PubMed
  38. Anand SS, Xie CC, Mehta S, et al. Differences in the management and prognosis of women and men who suffer from acute coronary syndromes. J Am Coll Cardiol 2005;46:1845–51. 
    Crossref | PubMed
  39. Chang AM, Mumma B, Sease KL, et al. Gender bias in cardiovascular testing persists after adjustment for presenting characteristics and cardiac risk. Acad Emerg Med 2007;14:599–605. 
    Crossref | PubMed
  40. Rathore SS, Chen J, Wang Y, et al. Sex differences in cardiac catheterization: the role of physician gender. JAMA 2001;286:2849–56. 
    Crossref | PubMed
  41. Takakuwa KM, Shofer FS, Limkakeng AT Jr, Hollander JE. Preferences for cardiac tests and procedures may partially explain sex but not race disparities. Am J Emerg Med 2008;26:545–50. 
    Crossref | PubMed
  42. Keteepe-Arachi T, Sharma S. Cardiovascular disease in women: understanding symptoms and risk factors. Eur Cardiol 2017;12:10–3. 
    Crossref | PubMed
  43. Motiwala SR, Sarma A, Januzzi JL, O’Donoghue ML. Biomarkers in ACS and heart failure: should men and women be interpreted differently? Clin Chem 2014;60:35–43. 
    Crossref | PubMed
  44. Lin WC, Ho CH, Tung LC, et al. Differences between women and men in phase I cardiac rehabilitation after acute myocardial infarction: a nationwide population-based analysis. Medicine (Baltimpre) 2016;95:e2494. 
    Crossref | PubMed
  45. Lam L, Ahn HJ, Okajima K, et al. Gender differences in the rate of 30-day readmissions after percutaneous coronary intervention for acute coronary syndrome. Womens Health Issues 2019;29:17–22. 
    Crossref | PubMed
  46. Dreyer RP, Ranasinghe I, Wang Y, et al. Sex differences in the rate, timing, and principal diagnoses of 30-day readmissions in younger patients with acute myocardial infarction. Circulation 2015;132:158–66. 
    Crossref | PubMed
  47. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics – 2022 update: a report from the American Heart Association. Circulation 2022;145:e153–639. 
    Crossref | PubMed
  48. Shaw LJ, Merz CN, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health–National Heart, Lung, and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation. Circulation 2006;114:894–904. 
    Crossref | PubMed
  49. Martinez-Nadal G, Miro O, Matas A, et al. An analysis based on sex gender in the chest pain unit of an emergency department during the last 12 years. Eur Heart J Acute Cardiovasc Care 2021;10(Suppl 1):zuab020.122. 
    Crossref.
  50. Egeland GM, Akerkar R, Kvale R, et al. Hospitalised patients with unexplained chest pain: incidence and prognosis. J Intern Med 2019;286:562–72. 
    Crossref | PubMed
  51. Sharma SP, Manintveld OC, Budde RPJ, et al. Gender differences in patients with stable chest pain. Am J Cardiol 2022;171:84–90. 
    Crossref | PubMed
  52. Shamsi F, Hasan KY, Hashmani S, et al. Clinical overview of myocardial infarction without obstructive coronary artey disease (MINOCA). J Saudi Heart Assoc 2021;33:9–10. 
    Crossref | PubMed
  53. Cammann VL, Szawan KA, Stahli BE, et al. Age-related variations in takotsubo syndrome. J Am Coll Cardiol 2020;75:1869–77. 
    Crossref | PubMed
  54. Johnson BD, Shaw LJ, Pepine CJ, et al. Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored Women’s Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J 2006;27:1408–15. 
    Crossref | PubMed
  55. Mnatzaganian G, Hiller JE, Braitberg G, et al. Sex disparities in the assessment and outcomes of chest pain presentations in emergency departments. Heart 2020;106:111–8. 
    Crossref | PubMed
  56. Koek HL, de Bruin A, Gast F, et al. Short- and long-term prognosis after acute myocardial infarction in men versus women. Am J Cardiol 2006;98:993–9. 
    Crossref | PubMed
  57. Song PS, Kim MJ, Seong SW, et al. Gender differences in all-cause mortality after acute myocardial infarction: evidence for a gender–age interaction. J Clin Med 2022;11:541. 
    Crossref | PubMed
  58. Mehta LS, Beckie TM, Devon HA, et al. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation 2016;133:916–47. 
    Crossref | PubMed
  59. Liblik K, Mulvagh SL, Hindmarch CCT, et al. Depression and anxiety following acute myocardial infarction in women. Trends Cardiovasc Med 2022;32:341–7. 
    Crossref | PubMed
  60. Vaccarino V, Shah AJ, Rooks C, et al. Sex differences in mental stress-induced myocardial ischemia in young survivors of an acute myocardial infarction. Psychosom Med 2014;76:171–80. 
    Crossref | PubMed
  61. Okunrintemi V, Valero-Elizondo J, Patrick B, et al. Gender differences in patient-reported outcomes among adults with atherosclerotic cardiovascular disease. J Am Heart Assoc 2018;7:e010498. 
    Crossref | PubMed
  62. Bugiardini R, Ricci B, Cenko E, et al. Delayed care and mortality among women and men with myocardial infarction. J Am Heart Assoc 2017;6:e005968. 
    Crossref | PubMed
  63. Greenwood BN, Carnahan S, Huang L. Patient–physician gender concordance and increased mortality among female heart attack patients. Proc Natl Acad Sci U S A 2018;115:8569–74. 
    Crossref | PubMed
  64. Lau ES, Hayes SN, Volgman AS, et al. Does patient-physician gender concordance influence patient perceptions or outcomes? J Am Coll Cardiol 2021;77:1135–8. 
    Crossref | PubMed
  65. Jin X, Chandramouli C, Allocco B, et al. Women’s participation in cardiovascular clinical trials from 2010 to 2017. Circulation 2020;141:540–8. 
    Crossref | PubMed
  66. Scott PE, Unger EF, Jenkins MR, et al. Participation of women in clinical trials supporting FDA approval of cardiovascular drugs. J Am Coll Cardiol 2018;71:1960–9. 
    Crossref | PubMed
  67. Mehta PK, Wei J, Shufelt C, et al. Gender-related differences in chest pain syndromes in the frontiers in CV medicine special issue: sex and gender in CV medicine. Front Cardiovasc Med 2021;8:744788. 
    Crossref | PubMed
  68. Mallik S, Spertus JA, Reid KJ, et al. Depressive symptoms after acute myocardial infarction: evidence for highest rates in younger women. Arch Intern Med 2006;166:876–83. 
    Crossref | PubMed
  69. Nabi H, Hall M, Koskenvuo M, et al. Psychological and somatic symptoms of anxiety and risk of coronary heart disease: the health and social support prospective cohort study. Biol Psychiatry 2010;67:378–85. 
    Crossref | PubMed
  70. Sullivan S, Young A, Hammadah M, et al. Sex differences in the inflammatory response to stress and risk of adverse cardiovascular outcomes among patients with coronary heart disease. Brain Behav Immun 2020;90:294–302. 
    Crossref | PubMed
  71. Vaccarino V, Wilmot K, Al Mheid I, et al. Sex differences in mental stress-induced myocardial ischemia in patients with coronary heart disease. J Am Heart Assoc 2016;5:e003630. 
    Crossref | PubMed
  72. Vaccarino V, Almuwaqqat Z, Kim JH, et al. Association of mental stress-induced myocardial ischemia with cardiovascular events in patients with coronary heart disease. JAMA 2021;326:1818–28. 
    Crossref | PubMed
  73. Pattisapu VK, Hao H, Liu Y, et al. Sex- and age-based temporal trends in takotsubo syndrome incidence in the United States. J Am Heart Assoc 2021;10:e019583. 
    Crossref | PubMed
  74. Murphy E. Estrogen signaling and cardiovascular disease. Circ Res 2011;109:687–96. 
    Crossref | PubMed
  75. Paller CJ, Campbell CM, Edwards RR, Dobs AS. Sex-based differences in pain perception and treatment. Pain Med 2009;10:289–99. 
    Crossref | PubMed
  76. Mogil JS. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci 2012;13:859–66. 
    Crossref | PubMed
  77. El Khoudary SR, Aggarwal B, Beckie TM, et al. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation 2020;142:e506–32. 
    Crossref | PubMed
  78. Shearman AM, Cupples LA, Demissie S, et al. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA 2003;290:2263–70. 
    Crossref | PubMed
  79. Sudhir K, Chou TM, Chatterjee K, et al. Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation 1997;96:3774–7. 
    Crossref | PubMed
  80. Mosca L, Collins P, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499–503. 
    Crossref | PubMed
  81. US Preventive Services Task Force. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force recommendation statement. JAMA 2017;318:2224–33. 
    Crossref | PubMed
  82. Kavousi M, Bielak LF, Peyser PA. Genetic research and women’s heart disease: a primer. Curr Atheroscler Rep 2016;18:67. 
    Crossref | PubMed
  83. Winham SJ, De Andrade M, Miller VM. Genetics of cardiovascular disease: importance of sex and ethnicity. Atherosclerosis 2015;241:219–28. 
    Crossref | PubMed
  84. Charchar FJ, Tomaszewski M, Padmanabhan S, et al. The Y chromosome effect on blood pressure in two European populations. Hypertension 2002;39:353–6. 
    Crossref | PubMed
  85. Khan SI, Andrews KL, Jennings GL, et al. Y chromosome, hypertension and cardiovascular disease: is inflammation the answer? Int J Mol Sci 2019;20:2892. 
    Crossref | PubMed