Stable ischemic heart disease (SIHD) encumbers the broad definition of symptomatic patients with and without obstructive coronary artery disease (CAD).¹ This is a heterogeneous population that includes as many as 20 million patients evaluated and treated annually in the United States. Although the traditional definition of SIHD has focused on evaluation and management of patients with obstructive CAD, more recent discussions have included women and men with nonobstructive CAD, including those with coronary microvascular dysfunction as etiologic of symptoms.² The cornerstone for evaluation of patients with SIHD is demonstration of the extent and severity of ischemia and defining the burden of atherosclerotic CAD in order to focus anti-ischemic and preventive strategies of care. There is substantial evidence that women of diverse race and ethnicity receive lower rates of SIHD guideline diagnostic and management care (specifically, fewer diagnostic procedure and treatments) and higher rates of major adverse cardiac events (MACE), including a high rate of persistent chest pain, recurrent hospitalization, and related healthcare costs.^3,4 Indeed, a recent report from the Nationwide Inpatient Sample of young women (age <55 years) with an acute myocardial infarction revealed in-hospital mortality was nearly fivefold higher for women versus men.⁵ This report also noted an increase in hospitalization for acute myocardial infarction among young African American women with a greater burden of cardiovascular risk factors.

An impediment to early diagnosis and targeted treatment of women is their "atypical" (or non-male pattern) SIHD presentation profiles.^6,7 Moreover, MACE rates are higher among women in part related to a delayed SIHD diagnosis for women and non-Caucasian patients compared with their white male counterparts.⁸ The reason for this delay is multifactorial and appears to be due to sociocultural gender factors as well as atypical symptom profiles among women. Women's ischemic symptoms are more likely to be induced following emotionally stressful situations,¹⁴ which is consistent with the definition of "exertional angina." However, exertional angina is commonly interpreted as physical rather than emotional exertion, resulting in the more frequent recognition of symptoms in men compared with women. Women are also more likely to report epigastric pain, nausea, and back or jaw radiation.⁴ Subsequent to this "atypical" (female-pattern) presentation, women are less likely to be referred for stress testing and coronary angiography and are less often treated with anti-ischemic or risk-factor-modifying therapies.^4,6,7

During the diagnostic evaluation, women have higher rates of nonobstructive CAD with nearly half of symptomatic females with suspected ischemia having persistent or worsening symptoms at 1 year of follow-up.^2,9 Risk stratification based on the extent and severity of ischemia is similarly effective in women and men.^10,11 Coronary microvascular dysfunction is defined as symptoms, evidence of ischemia, absence of obstructive CAD, and limited coronary flow reserve (CFR).¹² Clearly, more research is needed in coronary microvascular dysfunction, in particular the relations between no CAD and nonobstructive CAD and the burden of reduced CFR in women.^12-14 Despite the paucity of evidence, reduced CFR measured directly invasively or on positron emission tomography or magnetic resonance imaging identifies risk and provides a means for targeting treatment. Existing intermediate outcome trials suggest benefit of angiotensin-converting enzyme and statin therapy; large outcome trials of these existing and novel treatment strategies are needed.¹⁵

The higher MACE rates in women are likely related to lower guideline-directed care patterns when compared with men.^16,17 Specifically, women are less likely than men to receive aspirin, lipid-lowering therapy, anti-ischemic therapies, and directed lifestyle modifications.^18,19 In addition, women are less likely to reach optimal blood pressure and lipid goals.¹⁹ Men and women show equal rates of hypertension prevalence overall, although rates are higher in women over 65 years of age.²⁰ Ethnic differences are seen; in 2011-2014, the prevalence of hypertension in African-American women over the age of 20 was 44.0% versus 28% in Caucasian women and 28.6% in Hispanic women.²¹

Postmenopausal women have higher rates of dyslipidemia, with higher levels of low-density lipoprotein and lower levels of high-density lipoprotein than age-matched men.²² The sequelae of untreated persistent symptoms and provocative ischemia without guideline-directed care is associated with more adverse clinical outcomes, including more discharges for angina and heart failure compared with men.^4,22 Of note, women with SIHD and nonobstructive CAD have an elevated hazard for coronary events compared with men with nonobstructive CAD.^7,23 Women of any ethnicity are at significantly higher risk of MACE within 2 years of presentation than men.^24,25

Research is needed to understand sex-related differences in the coronary microcirculation and related vasomotor abnormalities that appear to contribute to myocardial ischemia in the absence of obstructive CAD.² An urgent issue in women's cardiovascular health is the general perception that the pathobiology of SIHD in women is similar to that in men when, in fact, women and ethnic minorities have sufficiently different risk factor profiles, presentations, and clinical outcomes.²³ These data highlight the importance of diversity in sex- and ethnic-specific research. A greater understanding that cardiovascular disease in women and in patients of non-Caucasian ethnicity is not a single process should direct future research.

References

1. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44-e164.
2. Pepine CJ, Ferdinand KC, Shaw LJ, et al. Emergence of Nonobstructive Coronary Artery Disease: A Woman's Problem and Need for Change in Definition on Angiography. J Am Coll Cardiol 2015;66:1918-33.
3. 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.
4. Mieres JH, Gulati M, Bairey Merz N, et al. Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association. Circulation 2014;130:350-79.
5. 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.
6. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol 2009;54:1561-75.
7. Bairey Merz CN, Shaw LJ, Reis SE, et al. Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol 2006;47:S21-9.
8. 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.
9. 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.
10. Kay J, Dorbala S, Goyal A, et al. Influence of sex on risk stratification with stress myocardial perfusion Rb-82 positron emission tomography: Results from the PET (Positron Emission Tomography) Prognosis Multicenter Registry. J Am Coll Cardiol 2013;62:1866-76.
11. Baldassarre LA, Raman SV, Min JK, et al. Noninvasive Imaging to Evaluate Women With Stable Ischemic Heart Disease. JACC Cardiovasc Imaging 2016;9:421-35.
12. Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study. J Am Coll Cardiol 2010;55:2825-32.
13. Taqueti VR, Everett BM, Murthy VL, et al. Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease. Circulation 2015;131:528-35.
14. Murthy VL, Naya M, Taqueti VR, et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129:2518-27.
15. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Elsevier; 2011.
16. Daly C, Clemens F, Lopez Sendon JL, et al. Gender differences in the management and clinical outcome of stable angina. Circulation 2006;113:490-8.
17. Jneid H, Fonarow GC, Cannon CP, et al. Sex differences in medical care and early death after acute myocardial infarction. Circulation 2008;118:2803-10.
18. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation 2011;123:1243-62.
19. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115:1481-501.
20. Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief 2013:1-8.
21. Health, United States, 2015: With Special Feature on Racial and Ethnic Health Disparities (CDC website). May 2016. Available at: http://www.cdc.gov/nchs/data/hus/hus15.pdf#053. Accessed 5/26/2016.
22. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation 2011;123:e18-e209.
23. Shaw LJ, Shaw RE, Merz CN, et al. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology-National Cardiovascular Data Registry. Circulation 2008;117:1787-801.
24. Izadnegahdar M, Mackay M, Lee MK, et al. Sex and Ethnic Differences in Outcomes of Acute Coronary Syndrome and Stable Angina Patients With Obstructive Coronary Artery Disease. Circ Cardiovasc Qual Outcomes 2016;9:S26-35.
25. Norris CM, Ghali WA, Galbraith PD, et al. Women with coronary artery disease report worse health-related quality of life outcomes compared to men. Health Qual Life Outcomes 2004;2:21.

Keywords: Angina Pectoris, Blood Pressure, Coronary Angiography, Coronary Artery Disease, Dyslipidemias, Early Diagnosis, Health Care Costs, Heart Failure, Hospital Mortality, Hypertension, Inpatients, Life Style, Lipoproteins, HDL, Lipoproteins, LDL, Magnetic Resonance Imaging, Microcirculation, Myocardial Infarction, Myocardial Ischemia, Nausea, Physical Exertion, Positron-Emission Tomography, Postmenopause, Prevalence, Risk Factors, Angina, Stable

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