Coronary heart disease is the leading cause of death and disability in the U.S., but recent advances have not led to declines in case fatality rates for women. The current review highlights gender-specific issues in ischemic heart disease (IHD) presentation, evaluation, and outcomes with a Special focus on the results derived from the National Institutes of Health-National Heart, Lung, and Blood institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. In the second part of this review, we will assess new evidence on gender-based differences in vascular wall or metabolic alterations, atherosclerotic plaque deposition, and functional expression on worsening outcomes of women. Additionally, innovative cardiovascular imaging techniques will be discussed. Finally, we identify critical areas of further inquiry needed to advance this new gender-specific IHD understanding into improved outcomes for women.

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 <= 4.7 to > 9.9 METs (p = 0.009); 67% of the events occurred in women scoring <= 4.7 METs (p = 0.003). Event rates were similar by exercise and DASI MET values. In women with DASI-estimated METs <= 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.

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 p I 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.

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 (CFVRado). 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 >= 50%. Women with a CFVRado < 2.5 (n = 98) had mean DASI of 1.5 +/- 13.6, compared to women (n = 92) with CFVRado >= 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. CFVRado of >= 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 CFVRado. 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.

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 a (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 >= 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).

Background - We previously reported that 20% of women with chest pain but without obstructive coronary artery disease ( CAD) had stress-induced reduction in myocardial phosphocreatine - adenosine triphosphate ratio by phosphorus-31 nuclear magnetic resonance spectroscopy ( abnormal MRS), consistent with myocardial ischemia. The prognostic implications of these findings are unknown.Methods and Results - Women referred for coronary angiography for suspected myocardial ischemia underwent MRS handgrip stress testing and follow-up evaluation. These included ( 1) n = 60 with no CAD/normal MRS, (2) n = 14 with no CAD/ abnormal MRS, and ( 3) n = 352 a reference group with CAD. Cardiovascular events were death, myocardial infarction, heart failure, stroke, other vascular events, and hospitalization for unstable angina. Cumulative freedom from events at 3 years was 87%, 57%, and 52% for women with no CAD/ normal MRS, no CAD/ abnormal MRS, and CAD, respectively ( P < 0.01). After adjusting for CAD and cardiac risk factors, a phosphocreatine - adenosine triphosphate ratio decrease of 1% increased the risk of a cardiovascular event by 4% ( P = 0.02). The higher event rate in women with no CAD/ abnormal MRS was primarily due to hospitalization for unstable angina, which is associated with repeat catheterization and higher healthcare costs.Conclusions - Among women without CAD, abnormal MRS consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catheterization, and greater treatment costs. Further evaluation into the underlying pathophysiology and possible treatment options for women with evidence of myocardial ischemia but without CAD is indicated.

OBJECTIVES This study was designed to investigate the relationship between hemoglobin level (Hgb) and adverse cardiovascular outcomes in women with suspected ischemia.BACKGROUND Low Hgb levels correlate with increased cardiovascular morbidity and mortality in patients presenting with acute myocardial infarction (MI) or congestive heart failure (CHF). However, the prognostic significance of Hgb in women with suspected ischemia is unclear.METHODS As part of the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE), we prospectively studied 936 women referred for coronary angiography to evaluate suspected ischemia. We compared Hgb levels with cardiovascular risk factors, core lab interpreted angiograms, inflammatory markers, and adverse cardiovascular outcomes.RESULTS Of women enrolled, 864 (mean age 58.4 +/- 11.6 years) had complete Hgb, angiogram, and follow-up (mean 3.3 +/- 1.7 years) data. The mean Hgb was 12.9 g/dl (range 7.7 to 16.4 g/dl) and 184 women (21%) were anemic (Hgb <12 g/dl). Anemic women had higher creatinine and were more likely to be nonwhite and have a history of diabetes, hypertension, and CHF (p < 0.05). However, we found no difference in EF or severity of coronary artery disease. Anemic women had a higher risk of death from any cause (10.3% vs. 5.4%; p = 0.02) and total adverse outcomes (26% vs. 16%, p < 0.01). In a multivariable model, decreasing Hgb was associated with significantly higher risk of adverse outcomes (hazard ratio = 1.20, p = 0.002). Also, anemic women had shorter survival time free of adverse outcome (p < 0.001).CONCLUSIONS Our findings extend previous reports, linking lower hemoglobin levels with higher risk for adverse cardiovascular outcomes, to women evaluated for suspected ischemia in the absence of acute MI or CHF. (C) 2004 by the American College of Cardiology Foundation.

Purpose: We analyzed the impact of hormone replacement therapy (HRT) on psychological factors in white and black women. We hypothesized that both groups of women would have fewer symptoms of depression and lower hostility scores associated with HRT use. Methods: The cohort included 463 postmenopausal 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 ischemia. The psychosocial indices included the Beck Depression Inventory (BDI) and the Cook Medley Hostility questionnaire measuring cynicism, hostility, and aggression. Results: There were no differences by race in use, duration, and type of HRT or presence of menopausal symptoms. There were differences by race in baseline psychological measurements, with black women exhibiting higher BDI scores and higher total Cook Medley scores (p = 0.03) than white women. Use of HRT was consistently associated with better psychological health in white women, with fewer symptoms of depression and lower aggression and cynicism scores (p < 0.04). Black women with menopausal symptoms who used HRT had significantly lower hostility (p < 0.01) and cynicism scores (p < 0.05) than black women who did not use HRT. The presence of menopausal symptoms and hysterectomy status were sig nificant independent predictors of HRT use for both white and black women (p < 0.05). Conclusions: We observed racial differences in associations between HRT use and psychological health. Within the white but not the black HRT users, there were fewer symptoms of depression and lower aggression and cynicism scores.

BACKGROUND:Recently revised American College of Cardiology/American Heart Association guidelines have suggested that exercise test scores be used in decisions concerning patients with suspected coronary artery disease (CAD). Pretest and exercise test scores derived for use in women without known CAD have not been tested in women with a low prevalence of CAD.METHODS:Within the Women's Ischemia Syndrome Evaluation (WISE) study, we evaluated 563 women undergoing coronary angiography for suspected myocardial ischemia. The prevalence of angiographic CAD was 26%. Overall, 189 women underwent treadmill exercise testing. Prognostic end points included death, myocardial infarction, stroke, and revascularization.RESULTS:Each score stratified women into 3 probability groups (P <.001) according to the prevalence of coronary disease: Pretest: low 20/164 (12%), intermediate 53/245 (22%), high 75/154 (49%); Exercise test: low 11/83 (13%), intermediate 22/74 (30%), high 17/32 (53%). However, the Duke score did not stratify as well: low 7/46 (15%), intermediate 36/126 (29%), high 6/17 (35%); P =.44. When pretest and exercise scores were considered together, the best stratification with the exercise test score was in the intermediate pretest group (P <.03). The Duke score did not stratify this group at all (P =.98). Pretest and exercise test scores also stratified women according to prognostic end points: pretest--low 7/164 (4.3%), intermediate 28/245 (11.4%), high 27/154 (17.5%), P <.01; exercise test--low 4/83 (4.8%) and intermediate-high 17/106 (16%), P =.014.CONCLUSION:Both pretest and exercise test scores performed better than the Duke score in stratifying women with a low prevalence of angiographic CAD. The exercise test score appears useful in women with an intermediate pretest score, consistent with American College of Cardiology/American Heart Association guidelines.

BACKGROUND:Coronary vascular dysfunction has been linked to atherosclerosis and adverse cardiovascular outcomes in men, but these relationships have not been firmly established in women.METHODS AND RESULTS:As part of the Women's Ischemia Syndrome Evaluation (WISE) sponsored by the National Heart, Lung, and Blood Institute, 163 women referred for clinically indicated coronary angiography underwent coronary reactivity assessment with quantitative coronary angiography and intracoronary Doppler flow before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin and were then followed up for clinical outcomes. History of hypertension was present in 61%, dyslipidemia in 54%, diabetes in 26%, and current tobacco use in 21% of women enrolled. Seventy-five percent had no or only mild epicardial coronary artery disease (CAD). Over a median follow-up of 48 months, events occurred in 58 women. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area (DeltaCSA) in response to acetylcholine (P=0.0006) and nitroglycerin (P=0.04). In addition, women with abnormal coronary dilator response to acetylcholine had less time free from cardiovascular events (P=0.004). In multivariable analysis, after controlling for age, hypertension, diabetes, dyslipidemia, tobacco use, and CAD severity, %DeltaCSA with acetylcholine (P=0.001) independently predicted events. When the outcome was restricted to only death, myocardial infarction, congestive heart failure, and stroke, %DeltaCSA with acetylcholine remained a significant predictor (P=0.006).CONCLUSIONS:In women in this study, impaired coronary vasomotor response to acetylcholine was independently linked to adverse cardiovascular outcomes regardless of CAD severity.

Context Individual contributions of obesity and physical fitness (physical activity and functional capacity) to risk of coronary heart disease in women remain unclear.Objective To investigate the relationships of measures of obesity (body mass index [BMI], waist circumference, waist-hip ratio, and waist-height ratio) and physical fitness (self-reported Duke Activity Status Index [DASI] and Postmenopausal Estrogen-Progestin Intervention questionnaire [PEPI-Q] scores) with coronary artery disease (CAD) risk factors, angiographic CAD, and adverse cardiovascular (CV) events in women evaluated for suspected myocardial ischemia.Design, Setting, and Participants The National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) is a multicenter prospective cohort study. From 1996-2000, 936 women were enrolled at 4 US academic medical centers at the time of clinically indicated coronary angiography and then assessed (mean follow-up, 3.9 [SD, 1.8] years) for adverse outcomes.Main Outcome Measures Prevalence of obstructive CAD (any angiographic stenosis greater than or equal to50%) and incidence of adverse CV events (all-cause death or hospitalization for nonfatal myocardial infarction, stroke, congestive heart failure, unstable angina, or other vascular events) during follow-up.Results Of 906 women (mean age, 58 [SD, 12] years) with complete data, 19% were of nonwhite race, 76% were overweight (BMI greater than or equal to25), 70% had low functional capacity (DASI scores <25, equivalent to <= 7 metabolic equivalents [METs]), and 39% had obstructive CAD. During follow-up, 337 (38%) women had a first adverse event, 118 (13%) had a major adverse event, and 68 (8%) died. Overweight women were more likely than normal weight women to have CAD risk factors, but neither BMI nor abdominal obesity measures were significantly associated with obstructive CAD or adverse CV events after adjusting for other risk factors (P=.05 to .88). Conversely, women with lower DASI scores were significantly more likely to have CAD risk factors and obstructive CAD (44% vs 26%, P<.001) at baseline, and each 1-MET increase in DASI score was independently associated with an 8% (hazard ratio, 0.92; 95% confidence interval, 0.85-0.99; P=.02) decrease in risk of major adverse CV events during follow-up.Conclusions Among women undergoing coronary angiography for suspected ischemia, higher self-reported physical fitness scores were independently associated with fewer CAD risk factors, less angiographic CAD, and lower risk for adverse CV events. Measures of obesity were not independently associated with these outcomes.