Weight cycling and cardiovascular outcome in women with suspected ischemia: A report from the NHLBI-sponsored WISE Study.

BACKGROUND: We previously reported in a cross-sectional analysis an adverse relationship between weight cycling and HDL-cholesterol but not angiographic obstructive coronary artery disease (CAD) among women undergoing coronary angiography for suspected ischemia in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE). We now examine the relationship between weight cycling and prospective adverse cardiovascular outcome in this group. METHODS: 795 women enrolled between 1996-2001 in the WISE undergoing coronary angiography for evaluation of suspected ischemia and followed for a median of 6.0 years (interquartile range = 3.4 years). Adverse outcome was defined as a composite of all-cause death, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure. Weight cycling was defined as the intentional loss of at least 10 lbs. (4.5 kgs.) at least three times during the women's lifetime. RESULTS: Women (n = 224) who reported a history of weight cycling were younger; more often white and better educated compared those without this history. At baseline, women with a weight cycling history had lower HDL-C values, higher body mass index, larger waist circumferences and higher values for fasting blood sugar, but no difference in obstructive CAD prevalence or severity. There was an inverse relationship between weight cycling and adverse composite cardiovascular outcome, whereby fewer of women with a history of weight cycling experienced an adverse outcome as compared to non-cyclers (21% vs 29%, respectively, p = 0.03). CONCLUSIONS: Despite an adverse association with HDL-cholesterol in women undergoing coronary angiography for suspected ischemia, weight cycling was associated with a lower adverse outcome rate in women with suspected ischemia.

Left Ventricular Energy Model Predicts Adverse Events in Women With Suspected Myocardial Ischemia: Results From The NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVES: To assess the prognostic value of a left ventricular energy-model in women with suspected myocardial ischemia. BACKGROUND: The prognostic value of internal energy utilization (IEU) of the left ventricle in women with suspected myocardial ischemia is unknown. METHODS: Women (n=227, mean age 59±12 years, range 31-86), with symptoms of myocardial ischemia, underwent myocardial perfusion imaging (MPI) assessment for regional perfusion defects along with measurement of ventricular volumes separately by gated Single Photon Emission Computed Tomography (SPECT) (n= 207) and magnetic resonance imaging (MRI) (n=203). During follow-up (40±17 months), time to first major adverse cardiovascular event (MACE, death, myocardial infarction or hospitalization for congestive heart failure) was analyzed using MRI and gated SPECT variables. RESULTS: Adverse events occurred in 31 (14%). Multivariable Cox models were formed for each modality: IEU and wall thickness by MRI (Chi-squared 34, p<0.005) and IEU and systolic blood pressure by gated SEPCT (Chi-squared 34, p<0.005). The models remained predictive after adjustment for age, disease history and Framingham risk score. For each Cox model, patients were categorized as high-risk if the model hazard was positive and not high-risk otherwise. Kaplan-Meier analysis of time to MACE was performed for high-risk vs. not high-risk for MR (log rank 25.3, p<0.001) and gated SEPCT (log rank 18.2, p<001) models. CONCLUSIONS: Among women with suspected myocardial ischemia a high internal energy utilization has higher prognostic value than either a low EF or the presence of a myocardial perfusion defect assessed using two independent modalities of MR or gated SPECT.

Exercise intensity self-regulation using the OMNI scale in children with cystic fibrosis.

Prescribing exercise at intensities that improve fitness is difficult in children with cystic fibrosis (CF) due to ventilatory limitations and fluctuating health status. Our aim was to determine if children with CF could regulate the intensity of cycle ergometer and treadmill exercise using target ratings of perceived exertion (RPE) derived from the Children's OMNI Scale. We examined prescription congruence (similar oxygen consumption [VO2] and heart rate [HR] for target RPE) and intensity discrimination (different VO2 and HR for different RPEs), from cycle to cycle and cycle to treadmill. Subjects were 24 children (12 male, 12 female), aged 10-17 years with varying disease severity. Each child participated in one orientation, one estimation trial (graded maximal exercise test), and two production trials (cycle and treadmill, alternating between RPE 4 and 7). At RPE 4, congruence was evident for both VO2 and HR on the treadmill. On the cycle at RPE 4, VO2 was significantly higher only in the first production trial, although HRs tended to be higher in the production trials than the estimation trial. Prescription congruence was also supported at RPE 7, with no significant differences in VO2 or HR between estimation and production trials on cycle or treadmill. Results fully supported intensity discrimination, with significant differences between VO2 and HR at RPE 4 and 7 (P < 0.0001). Children with CF appear capable of using the OMNI Scale to regulate cycle and treadmill exercise intensity. Training using this methodology has the potential to promote fitness in children with CF of varying severity.

Prognostic value of global MR myocardial perfusion imaging in women with suspected myocardial ischemia and no obstructive coronary disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.

OBJECTIVES: The purpose of this study was to assess the prognostic value of global magnetic resonance (MR) myocardial perfusion imaging (MPI) in women with suspected myocardial ischemia and no obstructive (stenosis <50%) coronary artery disease (CAD). BACKGROUND: The prognostic value of global MR-MPI in women without obstructive CAD remains unknown. METHODS: Women (n = 100, mean age 57 ± 11 years, age range 31 to 76 years), with symptoms of myocardial ischemia and with no obstructive CAD, as assessed by coronary angiography, underwent MR-MPI and standard functional assessment. During follow-up (34 ± 16 months), time to first adverse event (death, myocardial infarction, or hospitalization for worsening anginal symptoms) was analyzed using global MPI and left ventricular ejection fraction (EF) data. RESULTS: Adverse events occurred in 23 (23%) women. Using univariable Cox proportional hazards regression modeling, variables found to be predictive of adverse events were global MR-MPI average uptake slope (p < 0.05), the ratio of MR-MPI peak signal amplitude to uptake slope (p < 0.05), and EF (p < 0.05). Two multivariable Cox models were formed, 1 using variables that were performance site dependent: ratio of MR-MPI peak amplitude to uptake slope together with EF (chi square: 13, p < 0.005); and a model using variables that were performance site independent: MR-MPI slope and EF (chi square: 12, p < 0.005). Each of the 2 multivariable models remained predictive of adverse events after adjustment for age, disease history, and Framingham risk score. For each of the Cox models, patients were categorized as high risk if they were in the upper quartile of the model and as not high risk otherwise. Kaplan-Meier analysis of time to event was performed for high risk versus not high risk for site-dependent (log rank: 15.2, p < 0.001) and site-independent (log rank: 13.0, p < 001) models. CONCLUSIONS: Among women with suspected myocardial ischemia and no obstructive CAD, MR-MPI-determined global measurements of normalized uptake slope and peak signal uptake, together with global functional assessment of EF, appear to predict prognosis.

A randomized controlled trial of low-dose hormone therapy on myocardial ischemia in postmenopausal women with no obstructive coronary artery disease: results from the National Institutes of Health/National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Compared with men, women have more evidence of myocardial ischemia with no obstructive coronary artery disease. Although low endogenous estrogen levels are associated with endothelial dysfunction, the role of low-dose hormone therapy has not been fully evaluated. We postulate that a 12-week duration of low-dose hormone replacement therapy is associated with myocardial ischemia and endothelial dysfunction. METHODS AND RESULTS: Using a multicenter, randomized, placebo-controlled design, subjects were randomized to receive either 1 mg norethindrone/10 microg ethinyl estradiol or placebo for 12 weeks. Chest pain and menopausal symptoms, cardiac magnetic resonance spectroscopy, brachial artery reactivity, exercise stress testing, and psychosocial questionnaires were evaluated at baseline and exit. Recruitment was closed prematurely because of failure to recruit after publication of the Women's Health Initiative hormone trial. Of the 35 women who completed the study, there was less frequent chest pain in the treatment group compared with the placebo group (P = .02) at exit. Women taking 1 mg norethindrone/10 microg ethinyl estradiol also had significantly fewer hot flashes/night sweats (P = .003), less avoidance of intimacy (P = .05), and borderline differences in sexual desire and vaginal dryness (P = .06). There were no differences in magnetic resonance spectroscopy, brachial artery reactivity, compliance, or reported adverse events between the groups. CONCLUSIONS: These data suggest that low-dose hormone therapy improved chest pain symptoms, menopausal symptoms, and quality of life, but did not improve ischemia or endothelial dysfunction. Given that it was not possible to enroll the prespecified sample size, these results should not be considered definitive.

Self-rated versus objective health indicators as predictors of major cardiovascular events: the NHLBI-sponsored Women's Ischemia Syndrome Evaluation.

OBJECTIVE: To determine the association between self-rated health and major cardiovascular events in a sample of women with suspected myocardial ischemia. Previous studies showed that self-rated health is a predictor of objective health outcomes, such as mortality. METHOD: At baseline, 900 women rated their health on a 5-point scale ranging from poor to excellent as part of a protocol that included quantitative coronary angiography, cardiovascular disease (CVD) risk factor assessment, cardiac symptoms, psychotropic medication use, and functional impairment. Participants were followed for a maximum of 9 years (median, 5.9 years) to determine the prevalence of major CVD events (myocardial infarction, heart failure, stroke, and CVD-related death). RESULTS: A total of 354 (39.3% of sample) participants reported their health as either poor or fair. After adjusting for demographic factors, CVD risk factors, and coronary artery disease severity, women who rated their health as poor (hazard ratio, 2.1 [1.1-4.2]) or fair (hazard ratio, 2.0 [1.2-3.6]) experienced significantly shorter times to major CVD events compared with women who rated their health as excellent or very good. Further adjustment for functional impairment, however, attenuated the self-rated health relationships with major CVD events. CONCLUSIONS: Among women with suspected myocardial ischemia, self-rated health predicted major CVD events independent of demographic factors, CVD risk factors, and angiogram-defined disease severity. However, functional impairment seemed to explain much of the self-rated health association. These results support the clinical utility of self-rated health scores in women and encourage a multidimensional approach to conceptualizing these measures.

Multimarker approach predicts adverse cardiovascular events in women evaluated for suspected ischemia: results from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND: Inflammatory marker and hemoglobin levels (eg biomarkers) considered separately, predict adverse events in selected populations. HYPOTHESIS: A multiple biomarker approach predicts adverse events in women referred for evaluation of ischemia. METHODS: We investigated associations between biomarkers (high sensitivity C-reactive protein, interleukin-6, serum amyloid-A, and hemoglobin levels) with adverse outcomes in women referred for coronary angiography for suspected ischemia in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE). RESULTS: Among 595 women (mean age 58 years, ejection fraction [EF] 65%, majority without coronary stenosis >or= 50%) followed for 3.6 +/- 1.8 years (mean +/- SD), those without abnormal markers had fewer events (11.6%) compared to those with 1 (18.4%), 2 (20.9%), or 3 (37%) abnormal markers (p < 0.001 for trend). Women without abnormal markers had fewer deaths (1.6%) than women with 1 (6.1%), 2 (9.1%), or 3 (17%) abnormal markers (p < 0.001 for trend). Adding low hemoglobin was associated with higher adverse event and all-cause mortality rates. In multivariate analysis, as the number of abnormal biomarkers increased risk increased. Women with 3 or 4 abnormal biomarkers were approximately 10-20 times more likely to die (p < 0.05). Biomarkers added to the predictive information provided by the Framingham Risk Score. CONCLUSIONS: Among women undergoing coronary angiography for suspected ischemia, a multibiomarker approach predicted adverse events. Biomarkers added prognostic information beyond that obtained from traditional risk factors.

The joint impact of smoking and exercise capacity on clinical outcomes among women with suspected myocardial ischemia: the WISE study.

BACKGROUND: Although extensive research has been conducted on both smoking and low exercise capacity alone, few studies have examined the joint impact or interaction of these two risk factors. We examined the joint and interactive effects of smoking and self-reported exercise capacity on subsequent clinical events (heart failure, myocardial infarction [MI], stroke, and cardiovascular-related mortality) among women with suspected myocardial ischemia. METHODS: At baseline (1996-1999), 789 women completed angiographic testing of coronary artery disease (CAD) severity and provided self-report information about their smoking history and exercise capacity as well as demographic and other risk factor data. Incidence of clinical events among the women was tracked for a median of 5.9 years; this analysis was conducted in 2008. RESULTS: In an adjusted survival analysis, women with a positive smoking history and self-reported low exercise capacity had the greatest risk of experiencing a clinical event (HR = 7.7, 95% CI 2.3, 25.5), followed by women with a positive smoking history and self-reported high exercise capacity (HR = 6.9, 95% CI 2.0, 24.6) and those with a negative smoking history and self-reported low exercise capacity (HR = 4.9, 95% CI 1.5, 15.8), relative to women with a negative smoking history and self-reported high exercise capacity. Additional analyses revealed a significant interaction between smoking history and exercise capacity, such that (1) women with a positive smoking history did not experience an additional significantly greater risk due to low exercise capacity, unlike those with a negative smoking history, and (2) all women experienced a significantly greater risk due to a positive smoking history regardless of their exercise capacity. CONCLUSIONS: Among women with suspected myocardial ischemia, the combined protective health effects of self-reported high exercise capacity and a negative smoking history remained significant after controlling for preexisting CAD severity and other established risk factors. These findings highlight the importance of studying behavioral risk factors in combination.

Depression and cardiovascular health care costs among women with suspected myocardial ischemia: prospective results from the WISE (Women's Ischemia Syndrome Evaluation) Study.

OBJECTIVES: This study evaluated 3 novel questions in a prospective clinical cohort of women undergoing evaluation for suspected myocardial ischemia: 1) What is the relationship between depression and cardiovascular costs? 2) Does the relationship vary by definition of depression? 3) Do depression-cost relationship patterns differ among women with versus without coronary artery disease (CAD)? BACKGROUND: Comorbid depression has been linked to higher medical costs in previous studies of cardiovascular patients. METHODS: A total of 868 women presenting with suspected myocardial ischemia completed an extensive baseline examination including cardiovascular risk factor assessment and coronary angiogram. Depression was defined by: 1) current use of antidepressants; 2) a reported history of depression treatment; and 3) Beck Depression Inventory scores. Direct (hospitalizations, office visits, procedures, and medications) and indirect (out-of-pocket, lost productivity, and travel) costs were collected through 5 years of follow-up to estimate cardiovascular costs. RESULTS: Using the study criteria, 17% to 45% of the women studied met study depression criteria. Depressed women showed adjusted annual cardiovascular costs $1,550 to $3,300 higher than nondepressed groups (r = 0.08 to 0.12, p < 0.05). Depression-cost relationships also varied by CAD status, with stronger associations present among women without evidence of significant CAD. CONCLUSIONS: Depression was associated with 15% to 53% increases in 5-year cardiovascular costs, and cost differences were present using 3 definitions of depression. The results reinforce the importance of assessing depression in clinical populations and support the hypothesis that improved management of depression in women with suspected myocardial ischemia could reduce medical costs.

Social networks and incident stroke among women with suspected myocardial ischemia.

OBJECTIVE: To describe the prospective relationship between social networks and nonfatal stroke events in a sample of women with suspected myocardial ischemia. Social networks are an independent predictor of all-cause and cardiovascular mortality, but their relationship with stroke events in at-risk populations is largely unknown. METHOD: A total of 629 women (mean age = 59.6 +/- 11.6 years) were evaluated at baseline for cardiovascular disease risk factors as part of a protocol including coronary angiography; the subjects were followed over a median 5.9 years to track the incidence of cardiovascular events including stroke. Participants also completed the Social Network Index (SNI), measuring the presence/absence of 12 types of common social relationships. RESULTS: Stroke events occurred among 5.1% of the sample over follow-up. More isolated women were older and less educated, with higher rates of smoking and hypertension, and increased use of cardiovascular medications. Women with smaller social networks were also more likely to show elevations (scores of > or =10) on the Beck Depression Inventory (54% versus 41%, respectively; p = .003). Relative to women with higher SNI scores, Cox regression results indicated that more isolated women experienced strokes at greater than twice the rate of those with more social relationships after adjusting for covariates (hazard ratio = 2.7; 95% Confidence Interval = 1.1-6.7). CONCLUSIONS: Smaller social networks are a robust predictor of stroke in at-risk women, and the magnitude of the association rivals that of conventional risk factors.

Lipid-lowering medication use and aggression scores in women: a report from the NHLBI-sponsored WISE study.

AIM: The aim of this study was to examine the association between the use of lipid-lowering medication and aggressive responding, hostility, cynicism, and depression scores in women undergoing coronary angiography. METHODS: The cohort included 498 women from the National Heart, Lung and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. WISE is a four-center study of women with chest pain who underwent quantitative coronary angiography for suspected myocardial ischemia. The psychosocial indices included the Cook Medley Hostility questionnaire, measuring aggression, hostility, and cynicism, and the Beck Depression Inventory (BDI). RESULTS: Compared to those not on lipid-lowering medication, women receiving lipid-lowering pharmacotherapy were older (62 vs. 55 years, p < 0.001) and had more hypertension, dyslipidemia, diabetes, and coronary artery disease (CAD, defined as > or =50% stenoses in at least one epicardial artery) (all p < 0.003). Women on lipid-lowering medication had higher aggressive responding scores than those not on medication, 3.0 +/- 1.8 vs. 2.7 +/- 1.7, respectively (age-adjusted p < 0.003). This association persisted after adjustment for coronary risk factors, education, and extent of angiographic disease (CAD) (p < 0.005), and after exclusion of women using psychotropic medications (p < 0.001). Hostility, cynicism, and depression scores did not differ by medication use.

Depression, the metabolic syndrome and cardiovascular risk.

BACKGROUND: The relationship between depression and the metabolic syndrome is unclear, and whether metabolic syndrome explains the association between depression and cardiovascular disease (CVD) risk is unknown. METHODS: We studied 652 women who received coronary angiography as part of the Women's Ischemia Syndrome Evaluation (WISE) study and completed the Beck Depression Inventory (BDI). Women who had both elevated depressive symptoms (BDI > or =10) and a previous diagnosis of depression were considered at highest risk, whereas those with one of the two conditions represented an intermediate group. The metabolic syndrome was defined according to the ATP-III criteria. The main outcome was incidence of adverse CVD events (hospitalizations for myocardial infarction, stroke, congestive heart failure, and CVD-related mortality) over a median follow-up of 5.9 years. RESULTS: After adjusting for demographic factors, lifestyle and functional status, both depression categories were associated with about 60% increased odds for metabolic syndrome compared with no depression (p = .03). The number of metabolic syndrome risk factors increased gradually across the three depression categories (p = .003). During follow-up, 104 women (15.9%) experienced CVD events. In multivariable analysis, women with both elevated symptoms and a previous diagnosis of depression had 2.6 times higher risk of CVD. When metabolic syndrome was added to the model, the risk associated with depression only decreased by 7%, and both depression and metabolic syndrome remained significant predictors of CVD. CONCLUSIONS: In women with suspected coronary artery disease, the metabolic syndrome is independently associated with depression but explains only a small portion of the association between depression and incident CVD.

Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Altered coronary reactivity is frequent in women with findings of myocardial ischemia without significant obstructive disease. This suggests a defect in coronary microvascular function. The adenosine-related component of this altered reactivity has been described in male and mixed gender populations, while the factors influencing this component of coronary reactivity in symptomatic women have received limited attention. Accordingly, the relationship between adenosine-related microvascular coronary reactivity and risk factors in symptomatic women evaluated for suspected ischemia remains uncertain. HYPOTHESIS: Abnormal coronary microvascular reactivity to adenosine is predicted by atherosclerosis risk factors in women. METHODS: As part of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated the relationship between risk factors and coronary microvascular reactivity as flow velocity reserve to intracoronary adenosine (CFVR(Ado)) in 210 women referred for angiography to evaluate suspected ischemia. RESULTS: Univariate analyses identified associations between CFVR(Ado) and multiple risk conditions; however, after adjusting for age, none remained significant. The best multivariable model using combinations of risk conditions to predict CFVR(Ado) yielded an R2 of only 0.18. CONCLUSIONS: Among women with suspected ischemia, risk factors account for <20% of observed variability in CFVR(Ado). Therefore, other as yet unidentified factors must primarily account for coronary microvascular reactivity to adenosine.

Obesity distribution and reproductive hormone levels in women: a report from the NHLBI-sponsored WISE Study.

PURPOSE: Relationships between body weight and disease are not straightforward. Central obesity appears to be a relatively greater cardiovascular risk factor than generalized obesity. The purpose of this study was to evaluate body mass index (BMI) and waist circumference and the association of obesity distribution with blood estrogen levels (estradiol, bioavailable estradiol, and estrone). METHODS: The study cohort consisted of 207 postmenopausal women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) undergoing angiography for evaluation of suspected ischemia. RESULTS: Both BMI and waist circumference were positively associated with all three blood estrogen levels (p < 0.01), with the highest estrogen levels found in the obese women with large waists (p < 0.01). Results from regression analyses confirmed significant associations of BMI and waist circumference with the estrogen levels. CONCLUSIONS: These results demonstrate differing relationships between blood estrogen levels and obesity distribution in a cohort of postmenopausal women with chest pain undergoing coronary angiography. The differing levels by general and central obesity may help explain in part observed epidemiological relationships between obesity and disease.

Depression symptom severity and reported treatment history in the prediction of cardiac risk in women with suspected myocardial ischemia: The NHLBI-sponsored WISE study.

BACKGROUND: Depression is associated with clinical events and premature mortality among patients with established coronary artery disease (CAD). Typically, however, studies in this area focus only on baseline symptom severity and lack any data concerning symptom duration or symptom history. OBJECTIVES: To describe and compare the relationships between 2 measures of depression-assessed in the form of depression symptom severity and reported treatment history-with atherosclerosis risk factors and major clinical events in a sample of women with suspected myocardial ischemia. DESIGN: Follow-up study of women who completed a diagnostic CAD protocol, including cardiac symptoms, coronary angiography, ischemic testing, and assessments of depression symptom severity and reported treatment history. SETTING: The Women's Ischemia Syndrome Evaluation (WISE), a National Heart, Lung, and Blood Institute (NHLBI)-sponsored multicenter study assessing cardiovascular function using state-of-the-art techniques in women referred for coronary angiography to evaluate chest pain or suspected myocardial ischemia. PARTICIPANTS: Five hundred five women (mean age, 53.4 years) enrolled in WISE and followed up for a mean of 4.9 years. MAIN OUTCOME MEASURES: Incidence of cardiac events, including myocardial infarction, stroke, and heart failure, and total mortality. RESULTS: Relative to those with no or less stable depression symptoms, women with elevated depression symptoms and a reported treatment history showed higher rates of smoking, hypertension, and poorer education and an increased incidence of death and cardiac events (multivariate-adjusted risk ratio, 3.1; 95% confidence interval, 1.5-6.3; P = .001). CONCLUSIONS: Among women with suspected myocardial ischemia, a combination of depressive symptom severity and treatment history was a strong predictor of an elevated CAD risk profile and increased risk of cardiac events compared with those without depression or with only 1 of the 2 measured depression markers. These findings reinforce the importance of assessing mental health factors in women at elevated CAD risk. Focusing only on baseline depression symptom severity may provide an incomplete picture of CAD risk.

The value of estimated functional capacity in estimating outcome: results from the NHBLI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVES: Our objective was to determine the prognostic value of estimated metabolic equivalents (METs) based on self-reported functional capacity by the Duke Activity Status Index (DASI) in symptomatic women. BACKGROUND: Functional capacity is an important component affecting the predictive value of exercise testing, yet current guidelines offer limited assistance regarding identification of functional impairment and choice of pharmacologic stress testing. METHODS: A total of 914 women underwent clinically indicated coronary angiography and completed the 12-item DASI questionnaire; a subgroup of 251 women also underwent exercise testing. Cox proportional hazards modeling was used to estimate five-year death or myocardial infarction by DASI scores. In a secondary analysis, additional events included unstable angina, heart failure, or stroke at five years. RESULTS: Average DASI-estimated functional capacity was 5.7 +/- 4.2 METs and, for exercising women, 6.0 +/- 2.6 METs. In the 914 women, event-free survival ranged from 83% to 95% in subgroups with < or =4.7 to >9.9 METs (p = 0.009); 67% of the events occurred in women scoring < or =4.7 METs (p = 0.003). Event rates were similar by exercise and DASI MET values. In women with DASI-estimated METs < or =4.7 (n = 75), ischemia occurred less (39% vs. 64%, p < 0.0001), and exercise testing results were more often indeterminate (<85% predicted maximum heart rate = 37% vs. 6%, p = 0.001) as compared to women achieving >4.7 METs. CONCLUSIONS: Among women with suspected myocardial ischemia, functional impairment estimated by the DASI correlates with indeterminate exercise test results and is associated with an adverse prognosis. Use of the DASI before exercise testing can risk stratify symptomatic women and may improve the identification of higher-risk, functionally impaired subjects that would benefit from pharmacologic stress imaging and targeted risk management.

Impaired coronary vascular reactivity and functional capacity in women: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVES: We investigated the relationship between coronary vascular reactivity and functional capacity as assessed from the Duke Activity Status Index (DASI) in a cohort of women evaluated for suspected ischemia. BACKGROUND: Reduced functional capacity and impaired vascular reactivity are associated with poor prognosis, but an association between vascular reactivity and functional capacity is unknown. METHODS: A total of 190 women enrolled in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE) study had baseline clinical assessment and coronary artery flow velocity response to adenosine (CFVR(ado)). We compared these results with self-reported DASI metabolic equivalents (METs). RESULTS: Mean age was 55 +/- 11 years (range 21 to 83 years), and only 18% had coronary stenosis > or =50%. Women with a CFVR(ado) <2.5 (n = 98) had mean DASI of 15.1 +/- 13.6, compared to women (n = 92) with CFVR(ado) > or =2.5, whose mean DASI was 21.0 +/- 15.2 (p = 0.004). This relationship was maintained after adjusting for age and presence of coronary artery disease. CFVR(ado) of > or =2.5 was associated with a DASI of >20 (odds ratio 3.03, 95% confidence interval 1.56 to 5.90, p = 0.001). CONCLUSIONS: Women with reduced CFVR(ado) were significantly more likely to have reduced functional capacity. Impairment in coronary vascular function and reduced levels of activity may both play a role in the poorer prognosis observed in the WISE study women; however, the relationship between the two is still unclear.

Hypertension, menopause, and coronary artery disease risk in the Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVES: We evaluated whether the relationship between hypertension, other cardiac risk factors, and coronary artery disease (CAD) is modulated by menopausal status and/or age. BACKGROUND: The relative contribution of age versus menopausal status in the development of CAD in women remains unclear. METHODS: We compared systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and traditional cardiac risk factors for CAD in premenopausal (n = 123) and postmenopausal (n = 482) women undergoing coronary angiography for suspected ischemia. To assess the relative contribution of age versus menopausal status, we fit a hypertension-menopausal status interaction term and adjusted for age. RESULTS: There were similar relationships with regard to traditional coronary risk factors and angiographic CAD in premenopausal versus postmenopausal women, with few exceptions. Twenty percent of premenopausal women had angiographic CAD versus 31% of postmenopausal women (p = 0.02). Premenopausal women had lower mean (standard deviation) SBP (132 [25] vs. 139 [20] mm Hg; p < 0.0001) and lower PP (54 [18] vs. 62 [18] mm Hg; p < 0.0001) compared to postmenopausal women; however, multivariable analyses revealed that SBP was a risk factor for CAD in premenopausal (p = 0.002) but not postmenopausal women (p = 0.13), and regression slopes were significantly different (p = 0.04). This interaction effect remained after age adjustment, suggesting independent risk contribution from both age and menopausal status. A similar slope difference was observed for PP (p = 0.03) but not for DBP. CONCLUSIONS: Among women undergoing angiography for suspected ischemia, elevated SBP and PP are potent risk factors in premenopausal women. The results suggest that identification of hypertension in premenopausal women dictates additional CAD risk factor assessment and management.

Anger, hostility, and cardiac symptoms in women with suspected coronary artery disease: the Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVE: To determine the relationship of anger and hostility to angiographic coronary artery disease (CAD), symptoms, and functional status among women with suspected CAD. METHODS: Data were collected from 636 women with suspected CAD referred for diagnostic angiography in the Women's Ischemia Syndrome Evaluation (WISE) Study. CAD was assessed as angiographic presence/absence of disease (> or =50% stenosis in any epicardial coronary artery). Hostility/anger, angina, symptoms, and functional status were assessed by the Cook-Medley Hostility Inventory, Spielberger Anger Expression Scale, cardiovascular symptom history, and the Duke Activity Status Index. RESULTS: Logistic regression revealed that anger-out (i.e., aggressive behavior in response to angry feelings) was independently associated with the presence/absence of angiographic CAD (OR = 1.09, CI 1.01-1.17). Anger and hostility were higher among women reporting increased cardiovascular symptoms. In women without angiographic CAD, those with nonanginal cardiac symptoms had the highest anger-out, anger expression, hostile affect, and aggressive responding scores, and those with typical angina reported the lowest functional status. Among women with CAD, functional status was lowest in women with atypical angina. CONCLUSIONS: Among women with suspected CAD, anger-out scores were associated with the presence of angiographic CAD. Anger/hostility traits were associated with increased symptoms, particularly with nonanginal chest pain in women without angiographic CAD. Relationships among psychosocial factors, cardiac symptoms, and angiographic CAD are potentially important in the management of women with suspected CAD.

Global inflammation predicts cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study.

BACKGROUND: Measurement of C-reactive protein (CRP), a marker of inflammation, is recommended to improve cardiovascular disease (CVD) risk stratification. However, no studies have collectively evaluated how inflammatory markers cluster empirically and relate to angiographic coronary artery disease and CVD events. METHODS: From the WISE study, 580 women with fasting plasma samples of inflammatory markers (interleukin [IL]-6, IL-18, tumor necrosis factor alpha, transforming growth factor beta, CRP, serum amyloid A [SAA], and intercellular adhesion molecules) were analyzed over a median of 4.7 years follow-up. All women were referred for coronary angiography (1996-2000) to evaluate suspected myocardial ischemia. RESULTS: In factor analysis, a "proinflammation" factor (cluster) loaded on IL-6, CRP, and SAA (r = 0.63-0.87); a "proinflammation and anti-inflammation" cluster loaded on IL-18 and tumor necrosis factor alpha (r = 0.72, 0.77); and an "immunosuppressive" factor loaded singly on transforming growth factor beta (r = 0.96). No cluster was independently associated with angiographic coronary artery disease. However, quartile increases of the "proinflammation" cluster (IL-6, CRP, and SAA) yielded death rates of 2.6%, 7.2%, 13.1%, 26.6%, respectively (P < .0001). Women with > or = 2 of 3 proinflammation markers in the upper quartile had an adjusted relative risk of death of 4.21 (95% CI 1.91-9.25), a higher conferred risk than any single marker alone, all of which were roughly equally predictive. CONCLUSIONS: Although IL-6, CRP, and SAA all predict CVD risk in women, development of global measures of inflammation and simply counting the number of markers with high levels improve CVD risk stratification. In addition, results indicate that the adverse impact of inflammation may be largely through other mechanisms than promotion of atherogenesis (ie, destabilization of vulnerable plaques).