Diagnostic Approach to Defining CAD in Women

I. Coronary Artery Disease in Women: What every physician needs to know.

CAD remains the leading cause of death of U.S. women, claiming the lives of almost 200,000 in 2007.

The 26.9% decline in coronary deaths seen in women since 1999, may be credited in part to a combination of reduction and treatment of major coronary risk factors, as well as the application of evidence-based treatments for established CAD.

Therefore, early identification of women at risk for CAD is crucial, especially given that sudden cardiac death is often the first manifestation of CAD in a high proportion of women (52%), compared with men (42%).

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Like men, most women often experience typical symptoms of CAD, but there are sex specific differences in both how women present with acute coronary syndromes and the symptoms they report.

Women present more commonly with unstable angina than with ST elevation MI; they have a higher mortality than men.

Younger women appear to have less plaque rupture leading to ST elevation MI, and more plaque erosion resulting in unstable angina. In autopsy studies, women have less evidence of obstructive disease until the seventh decade of life.

Two thirds of women have fatal MI without recognized prodromal symptoms as their initial presentation of CAD.

There is evidence that there are gender differences in pain perception, and this may contribute to the lack of specificity of typical anginal symptoms in women.

Contributing to the challenge in diagnosing CAD in women is the variability in the reporting of chest pain as the predominant symptom in women who present with CAD.

Notable recent findings relevant to the practicing clinician include:

The shift in focus from diagnostic accuracy in detecting CAD to risk assessment as a means to guiding therapy in women with symptoms suggestive of ischemic heart disease (IHD).

Cases with observed paradoxical sex differences in which women with symptoms suggestive of IHD and documented ischemia on noninvasive imaging have less anatomic obstructive CAD but yet worse prognosis compared with age-matched men.

The term ischemic heart disease is proposed in lieu of CAD or CHD to reflect the spectrum of coronary atherosclerosis in women to include: (1) obstructive CAD, (2) dysfunction of the coronary microvasculature and endothelium, and (3) plaque erosion/distal microembolization.

Recently reviewed data demonstrated that symptomatic women with angiographically normal or nonobstructive coronary stenoses have increased rates of myocardial infarction (MI), stroke, hospitalization for congestive heart failure, and cardiac mortality compared with a similarly matched cohort of patients without symptoms.

The evolving evidence that “at-risk” women may have a high burden of atherosclerosis as evidenced by diffuse coronary atherosclerosis more often than focal lesions makes noninvasive evaluation increasingly challenging.

Women have a higher atherosclerotic burden, are more symptomatic, and have a worse clinical outcome; they have a lower prevalence of obstructive coronary disease than men.

As the pathophysiology of heart disease in women is a spectrum, the clinician must consider a unique evaluation approach that in some case will extend beyond the detection of epicardial stenosis to include evaluation of the atherosclerotic burden, as well as an evaluation of coronary reactivity of the microvasculature and endothelium.

Clinicians must evaluate risk factors, symptoms, and baseline ECG in women with risk factors for IHD to establish their pretest likelihood of disease. Next, an assessment of the patient’s functional capacity is important to assess prognosis, but also to appropriately choose the best noninvasive stress testing modality.

II. Diagnostic Confirmation: Are you sure your patient has Coronary Artery Disease?

Diagnostic confirmation of obstructive coronary artery disease

Q waves on EKG correlating to the area of previous infarction
Segmental wall motion abnormalities seen in the territory of myocardial infarction
Direct visualization of atherosclerosis of the coronary arteries by angiography, intravascular ultrasound (IVUS), or
The gold-standard for the diagnosis of CAD is invasive coronary angiography.

Diagnostic confirmation of nonobstructive coronary artery disease

Direct visualization of atherosclerosis of the coronary arteries by angiography, intravascular ultrasound (IVUS) or
The gold-standard for the diagnosis of CAD is invasive coronary angiography.

A. History Part I: Pattern Recognition

Signs and symptoms of a patient with coronary artery disease or ischemia

Chest pain on exertion or angina (typically pressure in quality with potential radiation to the jaw and left arm)
Dyspnea on exertion
Diaphoresis
Decreased exercise capacity
Multiple cardiac risk factors (hypercholesterolemia, diabetes, age, postmenopausal state, hypertension, tobacco use, sedentary lifestyle, obesity, family history of premature atherosclerosis)
Elevated high-sensitivity C-reactive protein
Abnormal EKG findings (Q waves to indicate prior infarction, ST depressions, or elevations to suggest active ischemia)

B. History Part 2: Prevalence

CAD is manifest earlier in the lives of men
Threshold onset delayed 10 years in women
Disease prevalence increased postmenopause (average age = 51 years)
Later menopause associated with longer overall survival
Life expectancy – menopause > age 55 = 2.0 years longer vs. menopause < age 40
Age-adjusted mortality reduced 2% with each increasing year of age at menopause
Net effect = later menopause increased lifespan

National Center for Health Statistics

2 of 3 U.S. women have at least 1 coronary risk factor
High-risk factor prevalence middle-age and elderly women
Only 11% of women low risk
>80% midlife women (age 40 to 60) have ≥1 risk factors
31% 2 risk factors
17% ≥ 3 risk factors

Increase in CAD prevalence

Hypoestrogenemia in young women – CAD risk factor
7.4-fold increased risk of CAD
Defined = Estradiol <184 pmol/L, follicle-stimulating hormone (FSH) <10 IU/L, and luteinizing hormone (LH) <10 IU/L
Approximately 10% to 25% of women
Polycystic ovary syndrome (PCOS) approximately 10% of women: increased risk of type 2 diabetes

Women who have had pregnancy complications are at increased risk of CVD

Preeclampsia
Gestational diabetes during pregnancy
Birth of a preterm infant or an infant who is small for gestational age

Bleeding in the third trimester

Increased risk with vascular diseases

Lupus and rheumatoid arthritis

C. History Part 3: Competing diagnoses that can mimic Coronary Artery Disease

Differential diagnosis for patients presenting with signs and symptoms suggestive of CAD, including pneumonia, pneumothorax, pulmonary embolism, pleurisy. Diagnosis made based on history of symptoms and predisposing risk factors often accompanied by appropriate radiologic testing.

1. Pulmonary diseases

2. Gastrointestinal diseases

3. Other Cardiovascular diseases

4. Musculoskeletal conditions

5. Psychological conditions

Panic attack and other anxiety disorders, hypochondria, somatization disorders and clinical depression.

A careful history, assessment of risk factors for these conditions and evaluate laboratory data, and the ECG will help distinguish these conditions: costochondritis, fibromyalgia, skin conditions (herpes zoster), radiculopathies. Careful history, physical examination and risk factor assessment can help distinguish these conditions. Aortic dissection, pericarditis, and other forms of pericardial disease, valvular heart disease, and myocarditis.

Careful history, physical examination, ECG, and selective radiographic studies are used to distinguish these conditions, including hiatal hernia, peptic ulcer disease, gastroesophageal reflux (GERD), other forms of dyspepsia, and pancreatic and gall bladder disease. Diagnosis requires careful history for predisposing risks for GI disease, and description of pain, including those things that exacerbate and relieve symptoms. Sometimes appropriate laboratory studies and radiographic examinations are also required.

D. Physical Examination Findings

Although clinical history is most important in patients with suspected coronary artery disease, there are some physical examination findings that can help confirm disease presence.

The physical examination is important both for the evaluation of patients with coronary artery disease and to help distinguish other clinical disease states that may mimic this condition. Vital signs may be either normal or show a derangement in both heart rate (HR) (bradycardia or tachycardia, as well as irregular rhythm) and BP (elevated or reduced). Elevated temperature may be a clue to an infectious cause of the presentation.

Lung examination may reveal or exclude a pulmonary cause for this presentation (wheezes, egophony, absent or asymmetric breath sounds). Examination of the chest wall may reveal a musculoskeletal cause and careful abdominal examination may lead to a GI etiology.

Careful cardiac examination is critical. Often the presentation of CAD reveals no specific cardiac abnormalities, although ischemia may present with heart murmurs, S3, or S4 gallops, derangements in heart rate and rhythm. The examination can also distinguish other cardiac causes with the presence of absence of pericardial friction rubs, muffled heart sounds, or murmurs suggestive of chronic valvular heart disease (aortic stenosis).

E. What diagnostic tests should be performed?

Clinical suspicion should lead directly to the appropriate laboratory evaluation and the appropriate noninvasive imaging test. (See Figure 1, which illustrates an appropriate algorithm for the clinician to follow.)

Algorithm for the evaluation of symptomatic women at risk for CAD.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Laboratory evaluation

Routine laboratory evaluation should be done on all patients being evaluated for potential coronary artery disease (basic metabolic profile, TSH, complete blood count, liver function tests).
Most importantly, however, a fasting lipid profile (total cholesterol, HDL, LDL, triglycerides [TG] ), and screening for diabetes must be performed to assess for primary cardiac risk factors.

Determine lipoprotein levels – obtain complete lipoprotein profile after 9- to 12-hour fast.

ATP III classification of LDL, total, and HDL cholesterol (mg/dL)

LDL cholesterol – primary target of therapy

<100 Optimal
100-129 Near Optimal/Above Optimal
130-159 Borderline High
160-189 High
190 Very high

Total cholesterol

<200 Desirable
200-239 Borderline high
240 High

HDL cholesterol

The American Diabetes Association recommends a fasting glucose or a different test, the hemoglobin A_1c (A_1c) to diagnose diabetes, but says that testing should be done twice, at different times, preferably with the same test in order to confirm a diagnosis of diabetes.

<40 Low
60 High

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Multiple noninvasive imaging modalities are available to assess for coronary artery disease in women.

Exercise stress testing

Exercise stress testing is the most commonly used method of diagnosing IHD in women and is the initial noninvasive study of choice.
As per the American College of Cardiology/American Heart Association guidelines, nonimaging treadmill exercise stress testing continues to be an appropriate first line testing symptomatic women who are (1) deemed intermediate risk for IHD, (2) have a normal resting 12-lead ECG, and (3) are capable of maximal exercise.
The accuracy for detecting obstructive CAD is dependent on the magnitude, morphology, and duration of the ECG changes. Marked ST segment changes (i.e., ≥2 mm horizontal or downsloping ST depression at low workloads and persisting into recovery) are more sensitive markers for epicardial disease in women.

Stress echocardiography

Contemporary stress echocardiography using exercise or dobutamine can be used to identify stress-induced ischemia based on the development of regional wall motion abnormalities in the area of a decrease in myocardial blood flow.
The role of stress echocardiography in symptomatic women at risk for ischemic heart disease has been well established.
The added imaging information provided by stress-echocardiography provides improved diagnostic and prognostic accuracy in women at risk for CAD compared to clinical variables and data from exercise treadmill testing.
A unique benefit of stress echocardiography for evaluating at-risk women is the absence of radiation exposure when compared to other noninvasive imaging techniques (e.g., SPECT, cardiac CT, coronary artery calcium scoring).
Incremental data (i.e., valvular function pericardial abnormalities) provided from a complete echocardiogram may also reveal an alternative explanation for symptoms of dyspnea or chest pain.

Myocardial perfusion imaging with SPECT

Myocardial perfusion imaging with single photon emission tomography (SPECT) with ECG gating (MPI) provides quantitative information on myocardial perfusion, regional and global left ventricular function, and end-systolic and end diastolic volumes.
The commonly seen limitations of traditional MPI techniques including photon attenuation due to breast attenuation artifact and limited spatial resolution where minor perfusion defects may go undetected in smaller hearts, are less problematic with the addition of electrocardiographic gating, attenuation correction protocols, use of prone imaging, and use of the higher-energy radioisotope technetium.
An important advantage of MPI is the ability to use pharmacologic stress for at-risk patients who are unable to exercise or achieve an acceptable maximum heart rate with exercise.
A large body of evidence supports the excellent prognostic accuracy of exercise and pharmacologic stress MPI in both men and women with the size and severity of defects directly linked to the risk of cardiac events, (death or myocardial infarction) even independent of gender.
Based on the available evidence, stress MPI is recommended for symptomatic women with an intermediate to high pretest likelihood of CAD with an abnormal, equivocal, or nondiagnostic baseline ECG.
Pharmacologic stress is recommended for symptomatic women with normal or abnormal baseline ECG who are unable to exercise or unable to achieve maximum predicted target heart rate with exercise.

Coronary artery calcium scoring and computed tomographic angiography

Multislice computed tomography scanning with coronary artery calcium (CAC) scoring and computed tomographic angiography (CTA) allows for a noninvasive anatomic identification and quantification of obstructive and nonobstructive CAD.
CTA allows for a noninvasive evaluation of the coronary arteries with high diagnostic accuracy for obstructive epicardial CAD.
CAC detection adds incremental prognostic value to traditional cardiac risk factors for coronary artery disease.
CAC scoring is highly sensitive for the presence of obstructive CAD (≥ 50% stenosis) and provides an estimate of the total calcified atherosclerotic plaque burden, thereby correlating to a patient’s cardiac risk.
Sex-specific analysis of the role of CAC in evaluating symptomatic women at risk for coronary disease reveals a high negative predictive value when correlated with invasive coronary angiography.

Myocardial perfusion imaging with positron emission (PET)

MPI with PET is a robust nuclear medicine imaging technique, and with its superior spatial resolution improves on the diagnostic and prognostic accuracy for detecting epicardial CAD in both men and women.
Given the spectrum of IHD in women, an enhanced value to PET is the ability to calculate absolute blood flow in all areas of the coronary tree, assess wall motion at peak hyperemia with vasodilator stress, and evaluate coronary flow reserve, thereby interrogating the coronary microvasculature and endothelium.
The capacity to quantify myocardial perfusion provides an added advantage over SPECT for evaluating multi-vessel CAD.
Vasodilatory stress MPI with PET using nuclear tracer 82Rb allows for integrated photon attenuation correction and enhanced image quality, a notable advantage over SPECT when evaluating CAD in obese women.
The use of the isotope 82Rb PET is additionally beneficial in women due to the ability to accurately quantify absolute values of regional and global myocardial blood flow to assess microvascular disease (flow reserve).
Contemporary integrated hybrid PET/CT offers an opportunity to assess the presence and magnitude of subclinical atherosclerotic disease burden and to further investigate myocardial blood flow as a marker of endothelial function and atherosclerotic disease activity, which is of paramount importance in female patients.

Cardiac magnetic resonance imaging

Cardiac magnetic resonance (CMR) imaging is emerging as an important imaging modality for the diagnosis of CAD in women.
CMR perfusion has the unique ability to evaluate subendocardial ischemia, assess left and right ventricular function, and provide a detailed anatomic evaluation of both the myocardium, as well as of the peripheral vasculature.
The specific advantages to the use of CMR imaging for the evaluation of women with suspected CAD is its excellent soft tissue characterization, three-dimensionality, superior temporal and spatial resolution, and lack of ionizing radiation.
Dobutamine CMR has been studied to identify flow limiting coronary artery stenoses in women.
CMR with vasodilator stress (dipyridamole or adenosine) has also been used to detect myocardial ischemia through first-pass perfusion imaging.

III. Management.

Assess for any instability to exclude the possibility of an unstable or accelerated pattern. This is determined through careful history, ECG findings (particularly changes in ECG), and results of noninvasive testing.
Determine the need to define the coronary anatomy with cardiac catheterization and coronary angiography. This is based on the presentation, results of noninvasive testing, and any other data that may suggest benefit from assessing the possibility of benefit from an invasive strategy.
Assessment of risk factors, particularly those that are modifiable ( HTN, DM, hyperlipidemia, tobacco use, obesity, and inactivity). Determine appropriate therapeutic modalities (both nonpharmacologic and pharmacologic).
Provide education to patient and family regarding the recommended treatment options, including side effects, opportunities to minimize the likelihood of major adverse CV events) and the nature of scheduled follow-up and need to contact medical personnel for any changes in symptoms. Determine the need to screen family members.

A. Immediate management.

Immediate management will be required for those individuals who present in an unstable manner on the initial presentation of CAD. These therapies will often include hospitalization, antiplatelet and anticoagulant agents, and other medications, including acute beta blocker therapy. Acute presentations may require treatment for arrhythmia or arrhythmia prevention along with treatment for heart failure.

Interventional treatments may be beneficial for this population, including acute cardiac catheterization, such as the placement of a right heart catheter, mechanical ventilation and echocardiography to assess the extent of acute ischemic damage, and for the presence of mechanical complications.

B. Physical Examination Tips to Guide Management

For chronic stable CAD, physical examination is used to monitor the effect of medications and to evaluate for the presence of side effects (vital signs including heart rate and blood pressure). Examination findings of acute ischemia, including S3 or S4 gallops, new or changing heart murmurs, or pulmonary peripheral findings of heart failure should be noted.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Lab testing should be performed for patients with diabetes and should include both fasting glucose and assessment of hemoglobin A_1C levels. Patients with hyperlipidemia on statin therapy will have monitoring of the lipid panel (to confirm that the appropriate dosing is used to obtain lipid results “at goal” based on CV risk profile and to exclude important side effects of these medications).

Patients on antiplatelet and/or anticoagulants should be tested for anemia and thrombocytopenia along with regular evaluations of stool for occult GI blood loss. Those on anticoagulants should be monitored appropriately based on the agent used.

Certain medications with require other forms of lab testing. Those taking ACE I should have their renal function and potassium checked. Diuretics used for heart failure will require monitoring of electrolyte levels and renal function.

D. Long-term management.

The prognosis in women with obstructive CAD and nonobstructive CAD are worse than their male counterparts. Women have worse in-hospital mortality and greater short-term mortality with more frequent complications of reinfarction. Long-term management must take this into consideration and include:

Life-style modification – Each patient should receive therapeutic lifestyle counseling to encourage adherence to a low cholesterol diet, an exercise routine to promote weight loss, and cessation of smoking.

Optimal medical therapy – Unless contraindicated, each patient should be on a statin to achieve an optimal cholesterol profile, beta-blocker, and angiotensin-converting enzyme inhibitor to achieve optimal blood pressure and heart rate, and a daily antiplatelet agent (ASA and Plavix when indicated).

Close clinical follow-up – Patient should be followed closely for change or progression of symptoms and to confirm medical adherence.

E. Common Pitfalls and Side-Effects of Management

Women with symptoms and nonobstructive disease are at intermediate risk for cardiac events: (death and MI). Cardiac imaging is useful to investigate the other elements implicated in the spectrum of IHD in women—the coronary and noncoronary atherosclerotic burden and methods to detect dysfunction of the coronary endothelium, flow reserve, and microvasculature, as these factors have increasingly significant implications for diagnosis, prognosis, and treatment.
For the symptomatic woman with a positive stress test and evidence of nonobstructive disease on coronary angiography, additional diagnostic testing may be warranted.
Expanding our focus from the detection of flow-limiting CAD lesions, cardiac imaging techniques with cardiac CT, positron emission tomography (PET), and CMR are emerging imaging techniques to investigate other contributors implicated in the spectrum of IHD in women—the coronary and noncoronary atherosclerotic burden. Also, other methods are being used with increasing frequency to detect dysfunction of the coronary endothelium and microvasculature.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Optimal medical therapy with medical compliance

Optimal medical therapy and medication compliance is extremely important to prevent progression of disease and hospital readmissions.
Patients with coronary artery disease are optimally on at least four medications (aspirin, beta-blocker, statin, angiotensin-converting enzyme).
Recent research including the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial demonstrated that women with CAD and chronic stable angina drive an equal benefit from intensive, long-term medical therapy. However, women have been notoriously undertreated with less intensive use of indicated medical therapy.
The Cooperative Cardiovascular Project showed that women received less medical treatment after MI, including 5% that received fewer prescriptions of aspirin at discharge.

Close clinical follow-up

Women must be closely followed clinically as an outpatient to:

Confirm optimal medical therapy with goal blood pressure and laboratory results
Assess for any change or progression of anginal symptoms

B. What's the Evidence for specific management and treatment recommendations?

Evaluation of ischemic heart disease in at risk women with symptoms

History: symptoms, risk factors

Evaluate pretest risk of ischemic heart disease

Select the appropriate test for diagnosis and risk assessment.

Provides extent & severity of inducible ischemia: Stress echo/nuclear: (SPECT and PET)

Documents the extent and severity of obstructive and non-obstructive CAD: Cardiac CT: calcium, stenosis and plaque

Excellent safety – minimal radiation burden : Stress echo, stress CMR and state of the art techniques: nuclear and CT

Provides information on functional capabilities: (Duke Activity Status Index: DASI) and stress ECG treadmill

References:

Roger, VL, Go, AS, Lloyd-Jones, DM, Benjamin, EJ. “Heart disease and stroke statistics—2012 update: a report from the American Heart Association”. Circulation. vol. 125. 2012. pp. e2-e220.

Mosca, L, Benjamin, EJ, Berra, K. “Effectiveness-based guidelines for the prevention of cardiovascular disease in women – 2011 update: a guideline from the American Heart Association”. Circulation. vol. 123. 2011. pp. 1243-62.

Shaw, LJ, Bugiardini, R, Merz, CN. “Women and ischemic heart disease: evolving knowledge”. J Am Coll Cardiol. vol. 54. 2009. pp. 1561-75. (In this state-of-the-art paper, the authors discuss an expanded spectrum of etiologies involved in IHD in women. Dysfunction of the microvasculature is implicated as a cause of symptoms and worse prognosis in the absence of obstructive disease. An additional leading culprit is abnormal reactivity in the small heart arteries leading to poor blood flow [ischemia] to the heart muscle.)

Bairey Merz, CN, Shaw, LJ, Reis, SE. “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. vol. 47. 2006. pp. S21-9.

Shaw, LJ, Shaw, RE, Radford, M. “ACC-National Cardiovascular Data Registry: Sex and ethnic differences in the prevalence of significant and severe coronary artery disease in the ACC-National Cardiovascular Data Registry”. Circulation. vol. 110. 2004. pp. SIII800

Mieres, JH, Shaw, LJ, Arai, A. “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. vol. 111. 2005. pp. 682-96.

Shaw, LJ, Mieres, JH, Hendel, RH. “Comparative effectiveness of exercise electrocardiography with or without myocardial perfusion single photon emission computed tomography in women with suspected coronary artery disease: results from the What Is the Optimal Method for Ischemia Evaluation in Women (WOMEN) Trial”. Circulation.. vol. 124. 2011. pp. 1239-49. (The only prospective randomized study in 824 women with an intermediate risk for CAD randomized to the stress ECG or stress MI, demonstrated that women with very good functional capacity (i.e., can complete 8METs on the treadmill ) are at low risk for major cardiac events and can be evaluated for symptoms of ischemic heart disease with the stress ECG as the first test.)

Gulati, M, Cooper-DeHoff, RM, McClure, C. “Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project”. Arch Intern Med. vol. 169. 2009. pp. 843-50. (This study reports on cardiovascular events [MI, death, stroke, heart failure] between the symptomatic cohort of women from the WISE study and the asymptomatic cohort of women from the St. James WTH Project. Women with symptoms and signs suggestive of ischemia but without obstructive CAD are at elevated risk for cardiovascular events compared with asymptomatic community-based women.)

Kohli, P, Gulati, M. “Exercise stress testing in women: going back to the basics”. Circulation.. vol. 122. 2010. pp. 2570-80. (Comprehensive review of the role of stress testing in the evaluation of women at risk for ischemic heart disease.)

Vavas, E, Hong, SN, Henry, S, Rosen, SE, Mieres, JH. “Imaging Tests, Provocative Tests, Including Exercise Testing in Women with Suspected Coronary Artery Disease”. Curr Cardiovasc Risk Rep. vol. 6. 2012 Oct. pp. 469-78. (Review of noninvasive testing for symptomatic women with suspected ischemic disease.)

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