Clinical features and diagnosis of coronary heart disease in women

INTRODUCTION — There are significant differences between men and women in the epidemiology, diagnosis, treatment, and prognosis of coronary heart disease (CHD). These should be taken into account in the care of women with known or suspected disease.

The clinical features and diagnosis of CHD in women will be reviewed here. The management of CHD in women in general and specific information regarding young women are discussed separately. (See "Management of coronary heart disease in women" and "Coronary artery disease and myocardial infarction in young people".)

Myocardial infarction (MI) associated with nonobstructive coronary artery disease is discussed separately. Ischemia due to nonobstructive coronary artery disease, including microvascular angina and vasospasm, is discussed separately.

●(See "Myocardial infarction or ischemia with no obstructive coronary atherosclerosis".)

●(See "Microvascular angina: Angina pectoris with normal coronary arteries".)

●(See "Vasospastic angina".)

EPIDEMIOLOGY — Cardiovascular disease, including coronary heart disease (CHD), is the most common cause of death and disability in women in the United States [1,2]. Although there has been a reduction in the death rate from CHD since 1980, it accounted for 22 percent of all-cause mortality in women in 2013 [3]. Between the ages of 45 and 64, one in nine women develop symptoms of some form of cardiovascular disease. After age 65, the ratio climbs to one in three women, according to the National Center for Health Statistics. Additional epidemiologic information and issues related to prognosis are found elsewhere. (See "Overview of established risk factors for cardiovascular disease" and "Prognosis after myocardial infarction".)

CLINICAL PRESENTATION — The initial presentation of coronary heart disease (CHD) in women and men is more often than not similar. It may be a stable pattern of chest pain (stable angina), an acute coronary syndrome, heart failure (HF), or sudden cardiac death (SCD). Rarely, there are no symptoms and the initial presentation is an abnormal cardiac test such as an electrocardiogram or echocardiogram ordered for another reason.

This section will discuss how female sex may lead to presentation and diagnosis that differs somewhat from those in men. The broad discussions of presentations and diagnosis of CHD are found elsewhere. (See "Diagnosis of acute myocardial infarction", section on 'Definitions' and "Cardiac evaluation of the survivor of sudden cardiac arrest", section on 'Initial evaluation' and "Chronic coronary syndrome: Overview of care", section on 'Introduction'.)

Women may not identify their initial symptoms as an expression of heart disease and therefore may not seek medical advice promptly. In addition, practitioners may not evaluate symptoms that represent myocardial ischemia as early in women [4,5]. (See "Overview of atherosclerotic cardiovascular risk factors in females".)

Women with CHD are generally about 10 years older than men at the time of presentation and carry a greater burden of risk factors [6-8]. However, women younger than age 45 years also develop CHD [9].

Symptoms of ischemia — While differences between women and men in the description of ischemic symptoms have been identified [10], we believe that there are more similarities than differences [11,12].

Chest pain is the most common anginal symptom in both sexes and is described similarly with regard to quality of pain (heaviness, pressure), pattern of radiation, and many associated symptoms (fatigue, nausea, etc). Indeed, in an analysis of the PROMISE trial, women presenting in the outpatient setting were as likely as men to report chest pain as their primary symptom, and were more likely to describe the pain as "crushing/pressure/squeezing/tightness" [13]. In a study of 109 women and 128 men with suspected coronary artery disease (CAD) with or without angina and at least one prior abnormal cardiac test result who underwent coronary arteriography, the rates of the use of the following descriptors of chest pain were similar between women and men who were found to have obstructive CAD: "chest pain" (84 versus 82 percent), "pressure" (58 versus 54 percent), and "tightness" (58 versus 43 percent) [10]. Similar findings have been noted in other studies [14,15], while older studies based on patients undergoing testing suggest that women may have more atypical pain [16].

One potential important factor in the interpretation of symptoms, and in particular chest pain, in women is the greater likelihood of their being induced by rest, sleep, and mental stress, in addition to or instead of physical exertion [17].

Myocardial infarction — The clinical presentation of MI in men and women can be similar; however, women are more likely than men to present without chest pain. This may contribute to underdiagnosis and a higher frequency of complications in women.

●Classic presentation – The classic syndrome of MI (eg, substernal or left-sided chest pain with radiation to neck or jaw) is the most common form of presentation for women. A prospective cohort study evaluated over 790 women and over 1600 men who presented to an emergency department within 12 hours of the onset of acute chest pain (MI was diagnosed in 20 percent of patients) [18]. Thirty-four predefined chest pain characteristics were reported with similar frequency in women and men, including the subpopulation of individuals who were diagnosed with MI.

●Absent chest pain in a higher proportion – During an MI, women are more likely than men to present without chest pain. Most [18-20] but not all [21] studies support this point [22], and the reported relative frequencies vary widely, perhaps as a function of study design. In a study of over one million women and men in the National Registry of Myocardial Infarction (United States), the proportion of MI patients who presented without chest pain was higher for women than men (42 versus 30.7 percent) [20]. A separate a prospective cohort study of 1015 patients being evaluated for acute coronary syndrome showed that 19 percent of women presented without chest pain versus 14 percent of men [23]. In this study, patients without chest pain reported fewer symptoms overall. In another report of over 500 women with acute MI, chest pain was absent in 43 percent of women; prodromal chest pain was absent in 70 percent of women [19]. (See 'Symptoms of ischemia' above.).

●Unrecognized MI in younger women – A large percentage of MI in women may go unrecognized. In a study of over 90,000 people, the prevalence of unrecognized MI was shown to be higher in women than men (30 versus 16 percent) [24].

Younger women may be at even higher risk of unrecognized MI [25]. Among 13,000 women from Iceland, the incidence of MI on electrocardiogram increased from 1.3 to 60 per 1000 persons from ages 35 to 75 years; the proportion that was unrecognized was higher in the younger versus older women (41 versus 24 percent) [25]. Even when younger women (age <55 years) present with chest pain during an MI, medical providers are less likely to accurately identify the pain as cardiac than they would for a similarly aged man [26].

To what extent the relatively lower likelihood and inaccurate diagnosis of cardiac chest pain in women lead to the relatively high prevalence of unrecognized MI [25], observed delays in MI diagnosis and treatment [27-29], and higher in-hospital mortality for women with MI leading to cardiogenic shock [30] is uncertain.

SEQUELAE

Hospitalizations — Young females with acute myocardial infarction experience more adverse outcomes than males in the year after discharge. Coronary-related hospitalizations were most common, but noncardiac hospitalizations showed the most significant sex disparity. Among 2979 patients <55 years of age with acute myocardial infarction, at least one hospitalization occurred among 905 patients (30.4 percent) in the year after discharge. The leading causes of hospitalization were coronary related. Furthermore, a sex difference was present for coronary-related hospitalizations in females versus males (incidence rate per 1000 person-years 171.8 versus 117.8; subdistribution hazard ratio [SHR] 1.33; 95% CI 1.04-1.70) and noncardiac hospitalizations (incidence rates per 1000 person-years 145.8 versus 69.6; SHR 1.51; 95% CI 1.13-2.07).

Specific causes of coronary-related hospitalizations in females versus males are summarized as follows:

●Acute MI – 30.9 versus 25.3 (incidence rate ratio or IRR 1.22 [0.75 to 2.05])

●Stable/unstable angina – (135.2 versus 89.3; IRR 1.51 [1.17 to 1.97])

●Other cardiac/stroke – (58.8 versus 53.8 [40.8 to 71]; IRR 1.09 [0.78 to 1.56])

●Heart failure – (25.7 versus 16.8 [10.3 to 27.4]; IRR 1.53 [0.86 to 2.88])

Although reasons underlying these findings are not certain, women are less likely to return to work [31] or be referred to enroll and to adhere to cardiac rehabilitation programs post-acute MI [32-34].

Heart failure — Women with CHD more frequently have or develop symptomatic HF than men [35,36]. This appears to be due at least in part to a greater frequency of diastolic dysfunction [36]. Why this might occur is not known, but it is postulated to be related to a greater prevalence of hypertensive heart disease and hypertrophy in women. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)

Risk factors for HF in women with CHD were examined in an analysis from the HERS trial of 2391 women with established coronary disease who had no HF at baseline [37]. At a mean of six years, 237 women (10 percent) developed HF. Significant risk factors included the following:

●Diabetes mellitus

●Atrial fibrillation

●MI

●Renal dysfunction (creatinine clearance <40 mL/min)

●Hypertension (systolic blood pressure >120 mmHg)

●Current smoking

●Obesity (body mass index >35 kg/m²)

●Left bundle branch block on electrocardiogram

●Left ventricular hypertrophy on electrocardiogram

Diabetes was the variable associated with the greatest increase in HF risk (adjusted hazard ratio 3.1). Women with diabetes and at least three other risk factors had an annual HF incidence of 8.2 percent.

Sudden cardiac death — A 38-year follow-up from the Framingham Heart study evaluated the incidence of SCD in women compared with men (see "Overview of sudden cardiac arrest and sudden cardiac death") [38]. The following findings were noted:

●Women had a lower SCD rate than men at all ages and at any level of multivariate risk; the risk of sudden death among women with CHD was one-half that of men with CHD and accounted for a smaller proportion of coronary deaths (37 versus 56 percent).

●A higher fraction of sudden deaths in women occurred in the absence of prior overt CHD (63 versus 44 percent in men). (See "Pathophysiology and etiology of sudden cardiac arrest".)

●The presence of HF increased overall mortality and the incidence of SCD; however, among patients with HF, the absolute risk in women was only one-third that of men.

Cardiogenic shock — Women having acute MI complicated by cardiogenic shock may have a higher in-hospital mortality than men.

In a United States registry of over 17,000 patients with acute MI complicated by cardiogenic shock, 37 percent of patients were women [30]. Women had higher risks of in-hospital mortality (odds ratio [OR] 1.10 95% CI 1.02-1.19) and major bleeding (OR 1.23, 95% CI 1.12-1.34). Among patients ≥65 years of age, women did not have a higher adjusted mortality risk (56 versus 51 percent; adjusted hazard ratio [HR] 0.98, 95% CI 0.88-1.09) or heart failure hospitalization (61 versus 55 percent; adjusted HR 1.01, 95%CI 0.91-1.12) compared with men. Long-term outcomes for patients <65 years of age were not available in this study.

It is uncertain why women had a worse prognosis than men in this study. One reason might be that women were less likely than men to undergo diagnostic angiography (85 versus 91 percent) or to receive mechanical circulatory support (25 versus 34 percent) [30].

DIAGNOSIS — Coronary heart disease, also referred to as stable ischemic heart disease (SIHD), is present when a patient has one or more symptoms, signs, or complications from an inadequate supply of blood to the myocardium. Many patients can be given the diagnosis based on a classic history of angina pectoris in the presence of one or more risk factors for atherosclerotic cardiovascular disease. (See "Overview of established risk factors for cardiovascular disease", section on 'Established risk factors for atherosclerotic CVD'.)

When first evaluated for possible SIHD, patients should receive a thorough physical examination in addition to a complete history. An electrocardiogram should be performed in all patients. However, most patients will require diagnostic testing, discussed below, either to secure the diagnosis or to evaluate the extent of disease. (See "Chronic coronary syndrome: Overview of care".)

DIAGNOSTIC APPROACH — The initial evaluation of a woman presenting with chest pain or other ischemic symptom and suspected coronary heart disease (CHD) is similar to that for men and often includes some form of noninvasive testing. However, most data suggest that women are not referred as often as men for appropriate diagnostic and/or therapeutic procedures, despite similar clinical conditions [39-45].

The specific approach depends on whether the presentation is felt to be stable or unstable. (See "Stress testing for the diagnosis of obstructive coronary heart disease".)

Stable patients — Similar to men, the most common presentation of stable disease is chest pain. Women who present with episodic chest pain should be evaluated for CHD.

Our approach is generally in accordance with the 2012 American College of Cardiology/American Heart Association guideline for the diagnosis and management of patients with stable ischemic heart disease, which was not changed in the 2014 focused update [46-48]. This guideline does not specify separate diagnostic approaches for women and men.

The first step in securing the diagnosis is to gauge the likelihood based on the character of the presenting symptoms (eg, typical versus atypical angina) and the presence or absence of coronary risk factors. The risk assessment must be sex specific because the risk factors themselves, as well as their relative importance, may differ between women and men. In particular, hormonal status, diabetes, smoking, and a family history of premature CHD appear to be more important in women. Of note, the American Heart Association guidelines for primary prevention in women suggest that using a lifetime likelihood of CHD is preferred in women, rather than a more conventional 10-year Framingham risk calculation, as the latter often underestimates risk [49]. (See "Overview of atherosclerotic cardiovascular risk factors in females".)

Risk assessment tools can be used in women who present with symptoms suggestive of CHD. However, these tools, such as the Framingham Risk Estimation tool, may underestimate risk in women with a family history of early heart disease. For this reason, alternative scores, such as the Reynolds Risk Score, have been developed specifically for use in women [50]. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

If the risk assessment process discussed above suggests that CHD is possible (intermediate risk or higher), we usually perform a noninvasive test to secure the diagnosis. Local expertise and test availability should dictate noninvasive test selection, in part because there is a lack of clearly identifiable difference in accuracy among them. The exact choice of test will depend on a variety of clinical factors such as patient risk, ability to exercise, body habitus, prior test information for comparison, renal function, and non-clinical factors such as local test availability and expertise. Either anatomic testing with coronary computed tomography angiography (CCTA) or functional stress testing are appropriate diagnostic tests among stable chest pain patients at intermediate or high risk of CAD [51]. (See "Exercise ECG testing: Performing the test and interpreting the ECG results" and "Stress testing for the diagnosis of obstructive coronary heart disease" and "Clinical use of coronary computed tomographic angiography", section on 'As an alternative to functional stress testing'.)

If a functional test is chosen as the initial test, the results will determine whether additional testing is necessary:

●If the stress was adequate (maximal) and the test was negative, no further evaluation is necessary. Other diagnoses should be considered. (See "Outpatient evaluation of the adult with chest pain".)

●Coronary angiography may be appropriate as the next test for patients with a strongly positive exercise test. (See 'Role of coronary angiography' below.)

●In women with a nondiagnostic functional test, additional noninvasive tests providing anatomic information may help rule in or out the diagnosis:

•Coronary angiography with cardiac computed tomography. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".)

•Coronary artery calcium scoring. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)

Each noninvasive test is imperfect in its ability to accurately diagnose CHD (see individual topic reviews). The following points need to be kept in mind when considering a noninvasive test in women:

●Treadmill exercise testing has a higher false-positive rate (regarding the diagnosis of obstructive, epicardial atherosclerotic coronary artery disease) in women [52]. This is in part due to a lower CHD prevalence in women in the populations studied (Bayesian factors). Women are also more likely to have ischemia without obstructive coronary artery disease due to microvascular angina, which is not usually diagnosed by stress testing. (See "Microvascular angina: Angina pectoris with normal coronary arteries".)

The diagnostic accuracy in women is also lower due to older age at presentation with the attendant higher frequency of comorbidities and lower exercise capacity [4]. Other explanations for the sex-related differences have included hormonal medication and autonomic influences [4]. Nevertheless, exercise stress provides valuable information regarding reproducibility of symptoms, exercise capacity and longevity, and is the preferred mode of stress in women, with or without imaging. Of note, women have a lower functional capacity than men, usually achieving a maximal workload that is 2 METs less than men.

●The sensitivity and specificity of these tests are suboptimal. In a meta-analysis that evaluated 19 studies of women who underwent exercise ECG testing (five exercise thallium imaging and three exercise echocardiography) and coronary angiography, the sensitivity and specificity for CHD with exercise ECG stress testing, exercise thallium testing, and exercise echocardiography were 61 and 70 percent, 78 and 64 percent, and 86 and 79 percent, respectively [53]. These values are similar to those in men for stress echocardiography and nuclear imaging, but lower for stress ECG.

●None of the stress tests is without sources of artifact. All require adequate stress for optimal accuracy, whether pharmacologic or exercise. Thus, a negative exercise test in a patient with poor exercise tolerance may be inconclusive.

●Radiation exposure from CCTA and radionuclide tests has not been convincingly shown to be harmful, but it is best avoided in young women, as breast tissue is included in the radiation field. (See "Radiation dose and risk of malignancy from cardiovascular imaging".)

●CCTA may provide greater prognostic information than functional stress testing in women presenting to clinic with stable symptoms suggesting ischemia. Men, on the other hand, appear to derive similar prognostic values from both test types [54].

Unstable patients — For all patients who present with possible acute coronary syndrome (ACS), an ECG (to be repeated) and serial high sensitivity troponins should be obtained as soon as possible. (See "Diagnosis of acute myocardial infarction", section on 'Definitions'.)

A more complete discussion of the diagnostic approach to women and men with suspected ACS is found elsewhere. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Clinical presentation' and "Evaluation of emergency department patients with chest pain at low or intermediate risk for acute coronary syndrome", section on 'Initial evaluation'.)

The optimal approach to the role of additional testing, such as diagnostic coronary angiography and the accurate assessment of risk in women with a non-ST elevation ACS may differ from that in men. This was suggested by an analysis from TACTICS-TIMI 18, which found that women were more likely to have elevations of high sensitivity C-reactive protein (hs-CRP) and brain natriuretic peptide (BNP), and less likely to have elevations of troponins than men, despite similar levels of risk [55]. Further, when a multimarker approach incorporating hs-CRP, BNP, and troponins was used, women with any positive marker benefited from an invasive strategy, while those with no positive markers benefited from a conservative strategy. In contrast, men benefited from an invasive strategy when there was biomarker positivity, but there was no difference in benefit according to strategy if biomarkers were negative.

The vast majority of cardiac biomarkers have similar diagnostic and prognostic value in women and men, with the exception of high-sensitivity cardiac troponin [56]. Troponin levels at baseline are lower in women than in men, and sex-specific cut-offs using a high-sensitivity assay may improve detection of MI [57]. One study demonstrated that high sensitivity troponin I assay using sex-specific diagnostic thresholds, compared with contemporary sensitive troponin I assay with a single threshold, significantly increased the diagnosis of MI in women (from 11 to 22 percent, p<0.001), but had less of an effect in men (19 to 21 percent, p = 0.002) [58]. Only women identified using the high sensitivity assay with sex-specific thresholds had the highest risk of death or recurrent MI, suggesting that these women may yield the greatest benefit from reclassification and treatment for acute MI.

Early exercise testing in women after a non-ST elevation ACS can be useful in those who have not had a coronary angiogram for establishing the presence of coronary disease and for risk stratification and prognosis. The majority of patients who have undergone coronary angiography do not need further risk assessment, although testing may be indicated once the acute phase of ACS is resolved to evaluate the possible significance of lesions in vessels other than the infarct related artery.

If testing is indicated, findings on the exercise test that independently predict future cardiac events are low maximal workload, the number of leads with ≥0.1 mV ST segment depression, and maximal rate-pressure product [59-61]. (See "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes".)

High-risk patients have at least two of these three criteria, intermediate-risk patients have one criterion, and low-risk patients lack all three criteria [61]. However, as noted above, women have a high percentage of false-positive exercise tests, which might make the test less reliable [52]. This issue was addressed in a study of 395 women with unstable angina entered into the FRISC trial who were followed for six months [61]. Based upon the exercise test results, low-, intermediate-, and high-risk groups were identified with event rates of cardiac death or MI of 1, 9, and 19 percent, respectively. The results were the same as those observed for 778 men in the trial.

A number of studies have documented gender-based differences in utilization rates of coronary angiography and revascularization, even among those with an acute MI [40,62-67]. These differences may reflect physicians' failure to refer women with positive exercise tests for subsequent testing [68], leading to a poorer outcome [69]. In a meta-analysis of patients with ST-elevation MI world-wide, women were less likely to receive primary percutaneous coronary intervention (59.5 versus 68.2 percent) and had longer door-to-balloon time (4.9 min) than men [70].

Other studies have not found a difference in catheterization rates between men and women [71-74]. However, closer examination of these reports reveals an over-referral of low-risk men (based upon clinical risk stratification) [71], and a near equal rate of catheterization following MI when the procedure was performed for the treatment (not diagnosis) of CHD [72]. In a review of over 3000 patients (33 percent women) who underwent exercise radionuclide imaging, referral rates for men and women were comparable when stratified by the amount of abnormally perfused myocardium detected [74]. However, among patients with an abnormal scan, the subsequent cardiac event rate was higher for women than men (17.5 versus 6.3 percent), indicating that women were under-referred for comparable degrees of risk.

Role of coronary angiography — The indications for diagnostic cardiac catheterization and coronary angiography are similar for women and men. Recommendations for invasive testing are found elsewhere. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization" and "Overview of the acute management of ST-elevation myocardial infarction".)

In stable patients, the prevalence of significant coronary disease found at the time of angiography is lower in women than men presenting with chest pain [35,75,76]. The magnitude of this difference was illustrated in a report of 886 patients referred for angiographic evaluation of presumed angina, 23 percent of whom were women [75]. Normal coronary arteries were much more common in women (41 versus 8 percent in men).

A higher rate of absence of significant coronary stenoses has also been noted in women with a non-ST elevation ACS (unstable angina or non-ST elevation MI). In different clinical trials, 12 to 14 percent of such patients have, on coronary angiography, either normal vessels or no vessels with ≥50 to 60 percent stenosis. This appears to be more common in women (17 versus 9 percent in men in one trial) [77,78]. Possible mechanisms for the absence of significant coronary disease in these patients include rapid clot lysis, vasospasm, and coronary microvascular disease. (See "Acute coronary syndrome: Terminology and classification", section on 'Absence of significant coronary disease'.)

Diagnostic coronary angiography may detect a cause of chest pain not attributable to atherosclerotic coronary artery disease:

●Cardiac syndrome X or coronary microvascular disease: Myocardial ischemia and/or coronary microvascular dysfunction is present in 20 to 50 percent of women with chest pain and normal coronary arteries [79-83]. (See "Microvascular angina: Angina pectoris with normal coronary arteries".)

●Stress-induced cardiomyopathy: An uncommon cause of an ACS, usually ST-elevation MI, occurring in the absence of critical coronary artery disease is stress-induced cardiomyopathy, also called transient left ventricular apical ballooning, takotsubo cardiomyopathy, and broken heart syndrome. This disorder is typically precipitated by intense psychologic stress and primarily occurs in postmenopausal women. This topic is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)

●Spontaneous coronary artery dissection (SCAD): In the general population, SCAD is a rare cause of acute MI. However, in young women, it may account for up to a quarter of cases [84]. SCAD is discussed in detail separately. (See "Spontaneous coronary artery dissection".)

●Coronary vasospasm: On occasion, the diagnosis of clinically important coronary vasospasm can be made at the time of coronary angiography. (See "Vasospastic angina", section on 'Diagnostic criteria'.)

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SUMMARY AND RECOMMENDATIONS

●Background – Obstructive coronary heart disease (CHD) is present when a patient has one or more symptoms, signs, or complications from an inadequate supply of blood to the myocardium. Important differences between women and men in the presentation of obstructive CHD may make it more difficult to establish the diagnosis in women (see 'Clinical presentation' above):

•Presentation at later ages – Women generally present about 10 years later than men and with a greater CHD risk-factor burden.

•CHD presentations in men and women – More similarities exist in how women and men present with CHD than differences. Chest pain is the most common anginal symptom in women and men; however, the likelihood of presenting without chest pain is greater in women. Also, women are more likely than men to have chest pain induced by rest, sleep, and mental stress.

•Underdiagnosis of myocardial infarction (MI) in women – Women are less likely than men to have chest pain diagnosed as cardiac during an MI. Women face a delay in diagnosis of acute coronary syndrome (ACS), particularly at younger ages or in patients with diabetes. (See 'Myocardial infarction' above.)

●Complications – In-hospital mortality and other complications may be higher in younger women than men with MI.

●Diagnosis of CHD in women – The process of establishing the diagnosis of CHD in women is similar to that in men, but there are also some notable differences.

•Stress testing – Exercise stress testing without imaging has a higher false-positive rate (for the diagnosis of obstructive coronary artery disease) in women, while stress testing with imaging appears to have similar accuracy. (See 'Stable patients' above.)

•Coronary computed tomography angiography (CCTA) – This can be used as initial testing of patients with stable chest pain and may have superior diagnostic performance in women compared with functional testing.