A middle-aged woman is experiencing episodes of chest pain and fatigue. Although stress test results are positive for ischemia, coronary angiography reveals open arteries. What next step would you take?
A 42-year-old woman complains of recurrent episodes of chest pain and fatigue. Although stress test results are positive for ischemia, coronary angiography reveals open arteries. What next step would you take? Until recently, this patient might have been reassured that her symptoms were not related to heart disease. She almost certainly would not have been referred for further cardiologic evaluation. Yet it is possible that this woman's symptoms represent microvascular disease and that she is at increased risk for future coronary events.
The evaluation of ischemic heart disease (IHD) in women poses a unique challenge because obstructive coronary artery disease (CAD) is less common in women than in men. About half of women referred to cardiologists for suspected ischemia because of chest pain or debilitating symptoms do not have obstructive heart disease, but some of these women may be at risk for IHD because of coronary microvascular dysfunction.1,2 Traditional management approaches that focus on detection of a critical stenosis often fail to identify these women. A key question for clinicians who care for women is how to detect and manage myocardial ischemia in the absence of significant obstructive CAD.
The recent Women's Ischemic Syndrome Evaluation (WISE) study summarizes results of trials supported by the National Heart, Lung, and Blood Institute that focus on the pathophysiology of IHD in women and sex differences in risk factors, symptom evaluation, and diagnostic strategies.3 Understanding the implications of these differences is crucial to optimal management of heart disease in women.
WOMEN AND HEART DISEASE: THE CHALLENGE
Heart disease remains the leading cause of death in the United States. Despite advances in treatment that have reduced mortality, prevalence has risen because of increased numbers of survivors of myocardial infarction (MI), revascularization procedures, and heart failure.4 In addition, the incidence of IHD is rising among younger persons because of growing rates of obesity, hypertension, sedentary lifestyle, and the metabolic syndrome.
Although overall coronary death rates have dropped in recent decades, most of the improvements have been in men. Cardiovascular disease now kills more women than men. This is not simply because women live longer than men: IHD is the leading killer of women at all ages.4 Since 1984, more than 250,000 women have died annually of CAD, and this number is expected to grow as the population ages.5 In 2000, 60,000 more women than men died of IHD.5 Although heart disease generally strikes women at older ages than men, once women have IHD, their outcomes are worse than men's despite their lower rate of angiographic disease and higher rate of preserved left ventricular function. Some experts believe that IHD, rather than a man's disease, might well be relabeled "a woman's affliction."4
The burden of heart disease and of suboptimal management in women is in part related to our poor understanding of sex-specific pathophysiologic differences in the presentation and prognosis of IHD and the lack of comprehensive diagnostic and treatment guidelines that take these differences into account.
MICROVASCULAR DISEASE: AN OVERVIEW
The WISE study, which began in 1996, included 936 women who underwent angiography because of chest discomfort or other symptoms of myocardial ischemia. The average age of participants was 58 years; however, one fourth were younger and premenopausal. The angiograms found that only one third of the women had blockages in their coronary arteries. (In men with similar symptoms, three quarters or more would have had severe blockages.) Another third had no blockages but did have diminished blood flow to the heart, most likely a result of microvascular disease. The risk of a major adverse event (death, MI, stroke, or heart failure) in these women was 10% after 4 years.
Women with symptoms of ischemia, such as recurrent chest pain, and signs of ischemia on noninvasive stress testing in the setting of open coronary arteries on angiography may have coronary microvascular disease. Microvascular disease refers to diffuse plaque deposition in smaller coronary arteries (arterioles) that does not show up on angiography because the arteries are too small. These vessels lose their ability to dilate and increase blood flow to the heart, not because of plaque buildup but because of remodeling as a response to injury from cholesterol deposits: the muscles in the arterioles thicken and the walls may stiffen and begin to close in, although the lumen remains the same. This leads to ischemia and the risk of heart failure and MI.
Microvascular disease primarily affects younger women; the prevalence of obstructive coronary disease increases dramatically after age 60 years. In men and older women, rupture of the collagen cap may cause sudden death; in younger women, the acute cardiac event is more likely to be precipitated by plaque erosion.
Unique risk factors for IHD in women may include hormonal and metabolic alterations. These conditions may promote an inflammatory milieu that produces cardiovascular symptoms and ischemia without obstructive CAD.6 Inflammation, coupled with a clustering of risk factors that accompany the loss of estrogen during menopause, may be associated with endothelial dysfunction, a loss of arterial compliance, and microvascular dysfunction. Endothelial dysfunction is a key pathophysiologic element in vascular disease. But women are also likely to have non-endothelial-dependent microvascular dysfunction, particularly in the early stages of IHD.6
In younger women, specific risk factors for IHD include smoking and endogenous estrogen deficiency attributable to a central disruption of ovarian function.4
In older women, a primary risk factor is obesity, which is associated with increased frequency of insulin resistance, dyslipidemia, diabetes, and hypertension. In postmenopausal women, the clustering of obesity, hypertension, and dyslipidemia may be related to nonspecific metabolic differences exacerbated by hormonal imbalance.4 The so-called metabolic syndrome is one link between obesity and cardiovascular disease.
In women, a diagnosis of metabolic syndrome is made if 3 of the following are present4:
Because traditional risk factors underestimate the risk of IHD in women, research is under way to identify novel risk markers. These include inflammatory markers, such as elevated levels of high sensitivity C-reactive protein; retinal artery narrowing; and coronary calcification.
Women with acute coronary syndromes may present with atypical symptoms, including fatigue and sleep disturbance. They may also present with such "typical" symptoms as chest pain or discomfort, dyspnea, diaphoresis, and arm or shoulder pain. In 60% of cases, the initial presentation of IHD in women is acute MI or sudden cardiac death.7
Nonobstructive disease. Most women with IHD and no signs of obstruction have functional rather than structural abnormalities of the coronary circulation that adversely affect their quality of life. Symptoms include atypical or typical chest pain, dyspnea, vascular dysfunction, and diminished functional capacity.4 Such women may be at considerable risk for a cardiac event.
Obstructive disease. Women with obstructive disease tend to be older than men with similar blockages and to have worse symptoms, including more chest pain and disability. They are also more likely to have hypertension, dyslipidemia, and diabetes. Heart failure is more likely to develop in these women than in their male counterparts.
The second most common presentation of obstructive coronary disease in women (after acute MI or sudden cardiac death) is atypical symptoms, including fatigue, dyspnea, and atypical chest pain.7
Self-reported functional capacity. Functional capacity is one of the strongest and most consistent estimators of cardiac prognosis in both men and women.8 Most women with myocardial ischemia have impaired functional capacity. The Duke Activity Status Index (DASI) is a simple questionnaire that correlates with a woman's capabilities to perform adequate levels of exercise stress testing (Table).9 In the WISE study, lower self-reported physical fitness scores were associated with a higher prevalence of CAD risk factors and angiographic CAD at baseline, as well as a higher risk of adverse events during intermediate-term follow-up.10
The DASI may be particularly helpful as a pretest risk assessment tool for women who cannot perform maximal levels of exercise stress, including those who are obese or elderly or who have a significant comorbidity. The DASI may also be used before exercise stress testing in symptomatic, functionally impaired women to help identify those who might benefit from pharmacologic as opposed to exercise stress testing.9
Imaging. Imaging is recommended for those at intermediate risk for CAD.11 The high prevalence of nonobstructive CAD and single-vessel disease in women results in decreased diagnostic accuracy and higher false-positive rates for noninvasive testing.11 However, although traditional stress testing may not detect CAD in women who do not have a significant coronary stenosis, stress echocardiography and stress myocardial perfusion single photon emission CT (SPECT) imaging may be used for risk assessment, as these modalities are highly accurate for near-term prognosis.4 Nevertheless, the accuracy and limitations of stress testing in women remain an area of significant confusion.11
Exercise electrocardiography is recommended for women with relatively normal ECG findings who are capable of performing moderate to high levels of exercise. However, only a minority of women who are referred for IHD evaluation meet this requirement. Exercise electrocardiography will not confirm a diagnosis of heart disease in women who perform submaximal levels of exercise with no inducible ischemia.4 Women incapable of maximal exercise testing are candidates for pharmacologic stress testing.
SPECT is the most commonly used modality for women who present with chest pain; it is highly accurate for both diagnosis and prognosis in the evaluation of symptomatic women with an intermediate to high risk of IHD. However, the accuracy of SPECT imaging is diminished in women with limited exercise capacity; pharmacologic stress testing (usually with adenosine or dipyridamole) is recommended for these women.11
Stress echocardiography with exercise or dobutamine is an effective and highly accurate noninvasive means of detecting IHD and risk-stratifying symptomatic women with an intermediate to high pretest likelihood of CAD.11 It can provide information about the presence of left ventricular systolic or diastolic dysfunction, valvular heart disease, and the extent of infarction and stress-induced ischemia. Stress echocardiographic techniques are also used for near-term prognosis.4
Cardiovascular magnetic resonanceassessment and invasive coronary vasomotor testing, although not in wide use, may identify early myocardial ischemia, especially in women who do not have obstructive CAD.12
The results of the WISE study may lead to a revised clinical approach that is based on a clearer understanding of the differences in pathophysiology and manifestations of heart disease in women. Findings from the study thus far have important implications for clinical practice.
History. Women with IHD may not exhibit the traditional symptoms of substernal chest pain or pressure, but may instead report dyspnea or fatigue. The fact that symptoms are of new onset is more clinically significant than their exact location. In addition, women are more likely to report the presence of symptoms during daily activities and times of emotional stress than during exercise.1
Determine whether a patient has the metabolic syndrome. This clustering of risk markers is associated with an elevated risk of cardiovascular events and death.
Management. Because microvascular ischemia often coexists with endothelial dysfunction, aggressive medical therapy is warranted to improve endothelial function, atherosclerosis, and established risk factors. Recommended agents include lipid-lowering drugs, angiotensin-converting enzyme inhibitors, and aspirin.1 Aggressively control all modifiable risk factors in both normal-weight and overweight women to prevent development of the metabolic syndrome. Exercise, smoking cessation, weight loss, and control of hypertension are critical components of management.
REFERENCES:1. Lerman A, Sopko G. Women and cardiovascular disease: clinical implica- tions from the Women's Ischemia Syndrome Evaluation (WISE) Study. Are we smarter? J Am Coll Cardiol. 2006;47(suppl 3):S59-S62.
2. Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001; 141:735-741.
3. Challenging exisiting paradigms in ischemic heart disease: The NHLBI- sponsored Women's Ischemia Syndrome Evaluation (WISE). J Am Coll Cardiol. 2006;47(suppl 3):S1-S71.
4. Shaw LJ, Bairey Merz CN, Pepine CJ, et al. Insights from the NLHBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol. 2006;47(suppl 3):S4-S20.
5. American Heart Association. Heart Disease and Stroke Statistics: 2004 Update. Available at: http://americanheart.org/downloadable/heart/ 1072969766940HSStats2004Update.pdf.
6. Pepine CJ. Ischemic heart disease in women. J Am Coll Cardiol. 2006;47 (suppl 3):S1-S3.
7. Bairey Merz C, Shaw LJ, Reis SE, et al; WISE Investigators. Insights from the NLHBI-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(suppl 3):S21-S29.
8. Gibbons RJ, Balady GJ, Bricker JT, et al; American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Committee to Update the 1997 Exercise Testing Guidelines. ACC/AHA 2002 guidelines 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;40:1531-1540.
9. Shaw LJ, Olson MB, Kip K, et al. The value of estimated functional capacity in estimating outcome: results from the NHBLI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. J Am Coll Cardiol. 2006;47(suppl 3):S36-S43.
10. Wessel TR, Arant CB, Olson MB, et al. Relationship of physical fitness vs body mass index with coronary artery disease and cardiovascular events in women. JAMA. 2004;292:1179-1187.
11. Mieres JH, Shaw LJ, Arai A, et al; Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: Consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation. 2005;111:682-696.
12. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med. 2002;346:1948-1953.
13. Hlatky MA, Boineau RE, Higginbotham MB, et al. A brief self-administered questionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol. 1989;64:651-654.