Identifying and managing chest pain in women Andrew R. Wyant, MD; DeShana Collett, PhD, PA-C

ABSTRACT Heart disease continues to be the leading cause of death in women in the United States. Sex disparities remain despite research highlighting the unique aspects of managing women with ischemic heart disease. Increased mortality in women may be related to the critical differences in the clinical presentation of ischemic heart disease between the sexes. Sex-related differences in the pathophysiology of ischemic heart disease also influence diagnostic testing and management. This article reviews the differences in diagnosis and management between men and women with ischemic heart disease. Keywords: ischemia, cardiovascular disease, women, health disparities, chest pain, ischemic heart disease

Heart disease is the leading cause of mortality and morbidity in women.1 Ischemic heart disease is the greatest single cause of death among women in the Western world.2 Ischemic heart disease represents a spectrum of heart diseases, including acute coronary syndromes (ACS), coronary artery disease (CAD), and stable and unstable angina. Significant and specific differences exist in women with ischemic heart disease when compared with men. Despite these known differences, sex disparities in ischemic heart disease exist in several key objective and measurable variables.3,4 Important differences between the sexes include the prevalence of ischemic heart disease, mortality following major cardiac events, clinical response to traditional treatments, unique diagnostics, and clinical presentation. These sex differences are likely secondary to several important pathophysiology mechanisms leading to the development of CAD and medical conditions distinct to women. These sex-unique mechanisms have translated clinically into perplexing symptomatology and therapeutic uncertainty for clinicians managing women with chest pain. Conditions unique to women result in accelerated progression to ischemic heart disease: hypertensive disorders of pregnancy, polycystic ovarian synAndrew R. Wyant is an assistant professor and DeShana Collett is a didactic and clinical faculty instructor in the PA program at the University of Kentucky’s College of Health Sciences. The authors have disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000458859.76773.2c Copyright © 2015 American Academy of Physician Assistants


drome, hypoestrogenemia, and hormone replacement therapy, among many others.5 These conditions along with altered coronary artery anatomy, plaque remodeling, and the variant signs and symptoms associated with chest pain syndromes specific to women result in measurable sex disparities. As a result, women with ischemic heart disease may be treated differently than men, and have higher overall mortality and rates of complications compared with men.6 Managing ischemic heart disease in women is challenging for clinicians in many settings, including primary care, emergency medicine, gynecology, and cardiology. Women have greater symptom burden, more adverse outcomes, increased functional disability, and higher healthcare costs compared with men with ischemic heart disease.7 Researchers are still uncertain about the fundamental mechanisms responsible for coronary ischemia Volume 28 • Number 1 • January 2015

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Identifying and managing chest pain in women

Key points Heart disease is the leading cause of death in women in the United States. Increased mortality in women may be related to critical differences in the clinical presentation of ischemic heart disease between the sexes. Sex-related differences in the pathophysiology of ischemic heart disease also influence diagnostic testing and management.

in women.3 Clinicians who understand the differences in the pathophysiology, symptomatology, diagnostic testing, and treatment for ischemic heart disease in women can provide prompt, appropriate care for women with chest pain. EPIDEMIOLOGY Cardiovascular disease (CVD), the leading global cause of mortality, causes 17.1 million deaths worldwide annually, including more than 597,000 in the United States.8,9 Ischemic heart disease (ACS or sudden cardiac death) accounts for almost half of total CVD mortality. In years past, women were thought to be at low risk for ischemic heart disease compared with men. However, statistics reveal that heart disease is the leading cause of death in women in the United States, accounting for more than 290,000 deaths in 2010—a greater burden of disease for women than all cancers combined.8 Generally, overall mortality for ischemic heart disease in the United States has declined due to improved prevention and intervention; however, the mortality in women (especially those under age 55 years) has not seen the equivalent decline.4 Surprisingly, mortality has risen among young women with ischemic heart disease.4 Despite a higher prevalence of ischemic heart disease in men, mortality in women has been greater than in men since 1984.8 Coupled with a higher disease-specific mortality from ischemic heart disease, women also have higher 30-day mortality after hospitalization for a coronary event (6.1% versus 2.9%).4 The growing prevalence of ischemic heart disease in women has been attributed by some to expanding disproportionate cumulative effects of obesity, metabolic syndrome, and diabetes over age-matched men.10 Although women typically present with CAD about 10 years later than men, prevalence rises quickly after onset of menopause, with comparable burden of heart disease seen in men and women by their 60s.2 Despite lower rates of visualized CAD, women have poorer clinical outcomes than men because compared with men, their coronary arteries are smaller in diameter, and women with ischemic heart disease have higher incidences than men of endothelial dysfunction, microvascular dysfunction, and distal microemboli.3 Research literature is inconclusive on the reasons for these differences. JAAPA Journal of the American Academy of Physician Assistants

PATHOPHYSIOLOGY Each year in the United States, more women than men undergo diagnostic workup and hospitalization for ischemic heart disease.11 However, diagnostic left heart catheterization on symptomatic women reveals lower rates of obstructive epicardial coronary disease than in men.10 Of this symptomatic cohort, the prevalence of obstructive coronary disease was lower in women across all age groups compared with men. Although women had a lower extent of obstructive findings overall, they were more likely to have angina and experienced less relief of cardiac symptoms with typical treatment than did men with similar amounts of epicardial obstruction. These paradoxical sex differences point to divergent disease-producing mechanisms, perhaps a different disease requiring another approach. Distinct pathologic mechanisms are thought to be responsible for the variant and unfavorable clinical outcomes in women with ischemic heart disease. Women also have physiologic variation to cardiovascular abnormalities compared with men: for example, after a myocardial infarction (MI), more women than men develop heart failure despite normal ejection fraction. Women have a higher prevalence of diastolic heart failure.1 Following coronary artery bypass grafting (CABG) surgery, women have higher incidences of heart failure, postoperative acute MI, and renal failure, as well as higher postoperative mortality (7% versus 4%). The prevalence of obstructive coronary disease, defined as greater than 50% stenosis, is markedly less prominent in women with ischemic heart disease (specifically, ACS or sudden death). This paradoxical finding was found across all age groups, so another mechanism must be found to explain ischemic heart disease in women. Plaque formation with subsequent narrowing of epicardial coronary arteries has driven diagnostic strategies, pharmacologic treatments, and invasive interventions. Obstructive coronary disease is far less prevalent than would be expected in women with cardiac disease, which TABLE 1.

Sex-based pathologic findings in women with ischemic heart disease8,10,11,14

• Decreased angiographic coronary artery critical stenosis despite symptomatic CAD • Persistent chest symptoms despite typical therapy • Smaller coronary arteries • Increased role of inflammation in coronary vasculopathy • Higher incidence relative to age-matched men of ¡ Microvascular coronary atherosclerosis ¡ Endothelial dysfunction ¡ Diffuse CAD ¡ Microvascular spasm and smooth muscle dysfunction ¡ Altered vessel remodeling and fibrosis

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may explain the different pathology and variant presentations (Table 1). Women generally have smaller coronary arteries and less-developed collateral circulation, resulting in diminished oxygen supply to the myocardium during increased demand (exercise or exertion).12 Smaller coronary artery diameter also contributes to less success with CABG surgery or revascularization procedures.13 Women treated for ischemic heart disease without critical stenosis (greater than 50% stenosis) of coronary arteries typically have persistent symptoms despite traditional treatment. Recalcitrant symptoms and abnormal stress test results in these women have been attributed to endothelial dysfunction and/or microvascular disease. Endothelial dysfunction is prevalent in states of higher inflammation, as seen with the loss of estrogen in perimenopause, and is associated with risk factors such as hypertension, dyslipidemia, and autoimmune disorders. Chronic endothelial dysfunction along with a loss of arterial compliance and dysfunction in the microvasculature combine to diminish myocardial blood flow.7 An autopsy series revealed greater frequency of distal microvascular embolization, and higher likelihood of plaque erosion in women than in men. In general, the disease process of ischemic heart disease in women is characterized by: • larger symptom burden and greater disability with fewer obstructive coronary lesions in epicardial vessels • chest pain symptoms and disability that do not correlate with degree of coronary stenosis • high rates of adverse outcomes after acute MI, particularly in women under age 55 years. TABLE 2.

CLINICAL PRESENTATION Women typically present with ischemic heart disease a decade later than men on average, and tend to have a greater burden of risk factors than men at acute presentation. Signs and symptoms of ACS in women are often atypical and variant, characteristically following a more insidious course than in men. Vague and/or atypical symptoms with ongoing or evolving ACS may contribute to less forceful diagnostic workups and potential delays in treatment. Nearly half of women experiencing acute MI report no chest pain at all. Further, most women (64%) who die suddenly from CAD do not manifest classic warning signs.14 Studies show that shortness of breath (dyspnea) was the most common symptom during MI or cardiac ischemia.15 Frequent atypical presenting ACS symptoms are fatigue, nausea, weakness, palpitations, or mid-back pain.10 Other symptoms characteristic in women with ACS include sharp or pleuritic chest discomfort, dyspnea, neck or throat pain or a feeling of choking, shoulder pain, isolated arm pain, anxiety, dyspepsia/heartburn, or burning sensation in the chest (Table 2). Clinicians must keep a high index of suspicion for ischemic heart disease in all women presenting with atypical symptoms in order to prevent missing acute MI and angina. Women under age 60 years are particularly likely to present with MI without chest pain and have unrecognized MI. Women under age 55 years were most likely to be discharged from the ED with missed diagnosis of ACS than any other sex or age group.4 Classic findings of chest pressure, diaphoresis, typical radiation of pain with nausea and vomiting, or exertional chest pain are common in men

Clinical factors, presentation, and diagnostic evaluation of women with ischemic heart disease

Clinical factor



Typically 10 or more years older than men who present with ischemic heart disease

Neck pain

ST-segment depression (initial ECG)

Greater risk factor burden than men

Throat pain

Elevated BNP is common

Abdominal obesity (waist/hip ratio of >0.9)

Sharp chest pain or atypical pain

Less likely than men to have elevated myonecrosis markers (CPK-MB)

Diabetes or metabolic syndrome

Burning chest pain or gastroesophageal reflux disease

Diminished accuracy for noninvasive testing (stress ECG) compared with men

Low HDL (3.2 mg/dL


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Identifying and managing chest pain in women

but should not be expected when evaluating women. Atypical symptomatology in women appears to cross the spectrum of CAD: stable angina, unstable angina, ACS, and evolving infarction. DIAGNOSTIC EVALUATION Because women have worse prognosis and poorer interventional outcomes after acute MI, compared with men, astute and timely diagnosis and appropriate evidencebased risk stratification are key.14 Before choosing diagnostic tests, determine the patient’s pretest probability of CAD (based on age, sex, and symptoms) according to the American College of Cardiology/AHA guideline on exercise testing.16 The underlying pathology responsible for ischemic heart disease also determines diagnostic testing strategies. Generally, tests that identify stenotic lesions have lower specificity than those that identify demonstrable or functional ischemic burden. Functional testing also is more specific than anatomical testing in women. Therapeutic decision making is directed by the extent and severity of inducible ischemia (Table 2). Diagnostic evaluation for acute MI includes 12-lead ECG and cardiac biomarkers. Women have been shown to more likely have evidence of ST-segment depression on their initial presenting ECG, and elevated concentrations of brain natriuretic peptide (BNP), which may indicate myocardial damage. However, women are less likely than men to have elevated markers for myonecrosis (troponin, CPKMB).17 Diagnostic tests include: • Exercise ECG/stress test. Compared with men, women are more likely to have false-positive results from traditional exercise stress testing.2 This finding is secondary to the lower prevalence of obstructive CAD in women.18 Provocative ECG-stress testing has a high false-positive rate in women when used without corresponding imaging modalities. However, exercise capacity does have predictive value; studies have demonstrated that women who cannot exercise beyond 5 METS on the Bruce Protocol have a threefold increased risk for death.19 • Stress echocardiography. Detection of wall motion abnormalities under stress of exercise or dobutamine is directly related to a diminished regional myocardial blood flow. No sex bias has been reported with stress echocardiography. The mean sensitivity is 81% to 89% with a specificity of 86% and overall accuracy of 84% for accurately detecting ischemic heart disease.14 • Myocardial perfusion imaging. Single-photon emission CT uses nuclear imaging to diagnose and risk-stratify women with ischemic heart disease and its effects. Myocardial perfusion imaging evaluates heart muscle perfusion, as well as left ventricular function and volumes. Postexercise (stress) imaging with myocardial perfusion imaging reveals wall motion defects, estimates left ventricular function, and localizes ischemia without sex JAAPA Journal of the American Academy of Physician Assistants

bias. Myocardial perfusion imaging bias-adjusted sensitivity and specificity are reported at 87% and 91%, respectively.14 • Coronary artery calcium (CAC) with CT. CAC is a marker of coronary atherosclerosis burden. Although a high CAC (more than 100-400) is not perfectly correlated with obstructive CAD, the clinical usefulness of CAC-scoring with CT in women lies in this test’s near 100% negative predictive value.20 This predictive value makes CAC-CT an excellent diagnostic test for stratifying asymptomatic women and predicting prognosis beyond more traditional risk factors. Low CAC scores are predictive of a low adverse reaction risk; high calcium scores are associated with less likelihood of event-free survival. The evidence points toward a trend of using imagingbased stress testing as opposed to traditional exercise stress ECG, and testing that evaluates functional ischemic burden rather than anatomic stenosis.14 The WISE trial found that 50% of women undergoing testing for ischemia do not have obstructive CAD—cholesterol plaques are diffuse rather than focal-stenotic in many women. Thus, coronary angiography reveals normal coronary vasculature as angiography reveals a luminogram, not assessing fatty plaques in a diffuse pattern and not evaluating endothelial dysfunction or microvascular disease. Again, the pathologic mechanisms responsible for ischemic heart disease in women must dictate diagnostic and testing strategies. Another imperative dynamic in managing ischemic heart disease and chest pain in women revolves around risk stratification, and risk factor modification. RISK STRATIFICATION AND MODIFICATION Asking about risk factors for ischemic heart disease should be part of cardiovascular preventive maintenance screening for women age 20 years and older. Nonmodifiable risk factors include: • older age. Risk doubles every 10 years after age 55 years, making age one of the strongest predictors of the development of ischemic heart disease. • family history of premature cardiovascular disease, defined as being diagnosed when younger than age 55 years in men or younger than age 65 years in women. • black race.21 Modifiable risk factors include tobacco use, hypertension, dyslipidemia, diabetes, obesity, sedentary lifestyle, psychosocial aspects, and menopausal state. Women with diabetes are at three times the risk of ischemic heart disease than women without diabetes.22 In 2013, the American College of Cardiology and the American Heart Association in collaboration with the National Heart, Lung and Blood Institute released updated guidelines and recommendations for risk stratification based on the 10-year risk and lifetime risk of CVD. These recommendations provide a more adequate

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assessment of risk than the Framingham risk assessment, which covers the risk of cardiovascular disease over a 10-year period and excludes differences associated with sex and ethnicity.23 RISK REDUCTION The new guidelines highlight three modifiable risk factors that can significantly affect patients’ risk of developing CVD: hypertension, dyslipidemia, and diabetes. Clinicians should counsel patients about these risks and prescribe lifestyle modifications in diet, physical activity, and weight management. Moderate exercise is recommended three to four times per week for a minimum of 40 minutes each time. Patients should reduce their intake of saturated and trans fats and sodium. Patients who need to lose weight should reduce their caloric intake, increase physical activity, meet with a weight loss interventionist, and if appropriate, consider bariatric surgery.24 Treatment should be individually tailored to patient risk and may include aggressive pharmacologic treatment of dyslipidemia.25

8. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation. 2010;121(7):e46-e215. 9. World Heart Federation. State of the heart: cardiovascular disease report. 2010. publications/reports/state-of-the-heart-cvd-report. Accessed October 9, 2014. 10. Hu FB, Stampfer MJ, Manson JE, et al. Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women. New Engl J Med. 2000;343(8):530-537. 11. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115(5):e69-e171. 12. Matyal R. Newly appreciated pathophysiology of ischemic heart disease in women mandates changes in perioperative management: a core review. Anesth Analg. 2008;107(1):37-50. 13. Caños DA, Mintz GS, Berzingi CO, et al. Clinical, angiographic, and intravascular ultrasound characteristics of early saphenous vein graft failure. J Am Coll Cardiol. 2004;44(1):53-56. 14. Makaryus AN, Shaw LJ, Mieres JH. Diagnostic strategies for heart disease in women: an update on imaging techniques for optimal management. Cardiol Rev. 2007;15(6):279-287. 15. Fox AA. Pro: newly appreciated pathophysiology of ischemic heart disease in women mandates changes in perioperative management. Anesth Analg. 2008;107(1):29-32.

CONCLUSION CVD is the leading cause of mortality in women. Unique pathogenic mechanisms, hormonal differences, and conditions distinct to women translate into altered clinical presentation, diagnostics, and outcomes when compared with men. The gap defined by many studies is representative of a sex disparity. Increased understanding and awareness about these important and tangible differences in diagnostic and management strategies should increase the quality of care for women presenting with cardiac disease. JAAPA

16. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to Update the 1997 exercise testing guidelines). J Am Coll Cardiol. 2002;40(8):1531-1540.


19. Kohli P, Gulati M. Exercise stress testing in women: going back to the basics. Circulation. 2010;122(24):2570-2580.

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17. Mega JL, Hochman JS, Scirica BM, et al. Clinical features and outcomes of women with unstable ischemic heart disease: observations from metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromes-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36). Circulation. 2010;121(16):1809-1817. 18. Lerman A, Sopko G. Women and cardiovascular heart disease: clinical implications from the Women’s Ischemia Syndrome Evaluation (WISE) study. Are we smarter? J Am Coll Cardiol. 2006;47(3 suppl):S59-S62.

20. Haberl R, Becker A, Leber A, et al. Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1,764 patients. J Am Coll Cardiol. 2001;37(2):451-457.

3. Merz CN, Shaw LJ. Stable angina in women: lessons from the National Heart, Lung and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation. J Cardiovasc Med. 2011;12(2): 85-87.

21. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA Guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 suppl 2):S49-S73.

4. Levit RD, Reynolds HR, Hochman JS. Cardiovascular disease in young women: a population at risk. Cardiol Rev. 2011;19(2): 60-65.

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5. Pepine CJ, Kerensky RA, Lambert CR, et al. Some thoughts on the vasculopathy of women with ischemic heart disease. J Am Coll Cardiol. 2006;47(3 suppl):S30-S35.

23. Sibley C, Blumenthal RS, Merz CN, Mosca L. Limitations of current cardiovascular disease risk assessment strategies in women. J Womens Health. 2006;15(1):54-56.

6. Vaccarino V. Ischemic heart disease in women: many questions, few facts. Circ Cardiovasc Qual Outcomes. 2010;3(2):111-115.

24. American College of Cardiology and American Heart Association. 2013 ASCVD Risk Estimator. ASCVD-Risk-Estimator. Accessed October 7, 2014.

7. Bairey Merz CN, Shaw LJ, Reis SE. Insights From the NHLBISponsored 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(3 suppl):S21-S29.


25. American College of Cardiology and American Heart Association. Summary of major recommendations for the treatment of blood cholesterol to reduce ASCVD risk in adults. http://tools. recommendations. Accessed October 7, 2014. Volume 28 • Number 1 • January 2015

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Identifying and managing chest pain in women.

Heart disease continues to be the leading cause of death in women in the United States. Sex disparities remain despite research highlighting the uniqu...
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