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Background: Previous Women's Ischemia Syndrome Evaluation (WISE) work demonstrated prior oral contraceptive (OC) use was associated with lower coronary artery disease (CAD) in women with suspected ischemia. The association of prior OC use with longer term all-cause and cardiovascular disease (CVD) mortality is unclear. Materials and Methods: WISE women undergoing coronary angiography for suspected ischemia (enrolled 1996–2001) with prior OC use history and 10-year follow-up data were analyzed. A blinded core laboratory assessed atherosclerotic CAD severity. Kaplan–Meier analyses evaluated prior OC use relative to all-cause and CVD mortality. Cox regression analyses adjusted for baseline differences. Mediation, interaction, and multicollinearity were analyzed. Results: Our 686 women had a mean age 62.5 ± 9.6 years, multiple cardiac risk factors, and 39% previously used OC. Prior OC users were younger, with less lipid-lowering medication use and lower atherosclerotic CAD severity scores (all p

Introduction: Association of serotonin transporter gene ( 5-HTTLPR) polymorphisms with adverse cardiovascular (CV) events in women with suspected ischemia has not yet been reported. We hypothesized an association of 5-HTTLPR polymorphisms with risk of adverse CV events in women with suspected ischemic heart disease (IHD) referred for coronary angiography enrolled in the Women’s Ischemia Syndrome Evaluation (WISE). Method: We studied clinical and angiographic data and DNA from a cohort of 437 Caucasian women enrolled in the WISE genotyped for the long (L) and short (S) variant of the 5-HTTLPR polymorphism. Women were followed yearly for adverse CV events (defined as first occurrence of all-cause death, myocardial infarction, stroke, or heart failure hospitalization) with data collected at WISE 10-year follow-up. Exploratory analyses compared outcomes between genotype groups. Results: A total of 437 women, with baseline, angiographic, and long-term follow-up data, were successfully genotyped. Their mean age was 58 ± 11 years and body mass index 29 ± 6; 54% had hypertension, 18% diabetes, 50% dyslipidemia, 20% depression history, and only 34% had obstructive CAD. At 8.9 years median follow-up, the SS genotype was associated with significantly increased risk of adverse CV event versus LL + LS (1.93, confidence interval [CI]: 1.03-3.61, P = .03). Results were not significant for all-cause death (hazard ratio: 1.63, CI: 0.91-2.93, P = .09). Conclusion: Among a cohort of Caucasian women with suspected IHD enrolled in the WISE, the SS homozygous genotype for the 5-HTTLPR polymorphism was associated with increased risk of adverse CV outcomes.

Contributory risk factors to premature coronary artery disease (CAD) in premenopausal women are poorly understood and data on this subset of women is lacking. There is growing evidence that the process of inflammation is a part of the atherosclerotic process. Mechanistic insights from animal work suggest that the profile of circulating cytokines reflects both endothelial integrity and the presence of immune and progenitor cells. Significant differences in pro- and anti-inflammatory cytokine concentrations between patients with and without CAD exist. Young women with obstructive CAD may experience differences in pro-inflammatory cytokines and the recruitment of reparative cells that secrete T-Helper (TH2 cytokines compared to women without CAD. Thus, cytokine balance may play a role in obstructive CAD in young women. In this pilot study we set out to identify an array of circulating inflammatory marker profiles which could be useful for the development of risk assessment and preventive strategies. We tested the hypothesis that an increase in serologic TH1 cytokines relative to TH2)/hematopoietic regulatory (HR) cytokines is related to premature coronary atherosclerosis in premenopausal women.

Background Recurrent hospitalization is prevalent in women with signs and symptoms of ischemia and no obstructive coronary artery disease. We hypothesized that rates of angina hospitalization might have changed over time, given advances in diagnostic and therapeutic approaches. Methods and Results We evaluated 551 women enrolled in the WISE (Women's Ischemia Syndrome Evaluation) study with no obstructive coronary artery disease (CAD) for a follow‐up period of 9.1 years. We analyzed angina hospitalization rates using the Kaplan‐Meier method. Univariate analysis and multivariable Cox proportional hazard models were developed for prediction of angina hospitalization in women with signs and symptoms of angina and no CAD. A total of 223 women had nonobstructive CAD (>20–50% P =0.03). Hypertension, dyslipidemia, nonobstructive CAD, use of nitrates, statins, and angiotensin‐converting enzyme inhibitors were univariate predictors of angina hospitalization. Adjusted multivariate hazard ratios for angina hospitalization were significant for use of nitrates 2.58 (1.80–3.69, P P =0.004), and angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers 1.81 (1.22–2.68, P =0.003). Conclusions Angina hospitalization rates continued at a relatively constant rate in all women with no obstructive CAD despite medical advances. Clinical trials aimed at reducing angina hospitalization rates and identifying the pathophysiological mechanisms contributing to angina symptoms in women with no CAD and women with no obstructive CAD.

Background Previous studies have reported an association between the timing of menarche and cardiovascular disease ( CVD ). However, emerging studies have not examined the timing of menarche in relation to role of estrogen over a lifetime and major adverse cardiac events ( MACE ). Methods and Results A total of 648 women without surgical menopause undergoing coronary angiography for suspected ischemia in the WISE (Women's Ischemia Syndrome Evaluation) study were evaluated at baseline and followed for 6 years (median) to assess major adverse CVD outcomes. MACE was defined as the first occurrence of all‐cause death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization. Age at menarche was self‐reported and categorized (≤10, 11, 12, 13, 14, ≥15 years) with age 12 as reference. Total estrogen time and supra–total estrogen time were calculated. Cox regression analysis was performed adjusting for CVD risk factors. Baseline age was 57.9 ± 12 years (mean ± SD ), body mass index was 29.5 ± 6.5 kg/m 2 , total estrogen time was 32.2 ± 8.9 years, and supra–total estrogen time was 41.4 ± 8.8 years. MACE occurred in 172 (27%), and its adjusted regression model was J‐shaped. Compared with women with menarche at age 12 years, the adjusted MACE hazard ratio for menarche at ≤10 years was 4.53 (95% CI 2.13‐9.63); and at ≥15 years risk for MACE was 2.58 (95% CI , 1.28‐5.21). Conclusions History of early or late menarche was associated with a higher risk for adverse CVD outcomes. These findings highlight age at menarche as a potential screening tool for women at risk of adverse CVD events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00000554.

Objective. In a separate, contemporary cohort, we sought to confirm findings of the original Women’s Ischemia Syndrome Evaluation (WISE). Background. The original WISE observed a high prevalence of both invasively determined coronary endothelial and coronary microvascular dysfunction (CMD) that predicted adverse events in follow-up. Methods. We comparatively studied the WISE-Coronary Vascular Dysfunction (CVD) cohort (2009-2011), with signs and symptoms of ischemia but without significant CAD, to the original WISE (1997-2001) cohort. CMD was defined as coronary flow reserve (CFR) ≤2.5, or endothelial dysfunction as epicardial coronary artery constriction to acetylcholine (ACH), or Results. In WISE (n=181) and WISE-CVD (n=235) women, mean age in both was 54 years, and 83% were white (WISE) vs 74% (WISE-CVD, p=0.04). Use of hormone replacement therapy was less frequent in WISE-CVD vs WISE (46% vs 57%, p=0.026) as was presence of hypertension (40% vs 52%, p=0.013), hyperlipidemia (20% vs 46%, p Conclusions. This study confirms prevalence of CMD in the contemporary WISE-CVD cohort similar to that of the original WISE cohort, despite a lower risk factor burden in WISE-CVD. Because these coronary functional abnormalities predict major adverse cardiac events, clinical trials of therapies targeting these abnormalities are indicated.

This paper evaluated long-term associations between psychosocial factors and premature mortality among women with suspected coronary artery disease (CAD). We tracked total mortality events over a median 9.3 years in a cohort of 517 women [baseline mean age = 58.3 (11.4) years]. Baseline evaluations included coronary angiography, psychosocial testing, and CAD risk factors. Measures included the Spielberger Trait Anxiety Scale, Beck Depression Inventory, self-rated health, and Social Network Index. Cox regression analysis was used to assess relationships. Covariates included age, CAD risk factors, and CAD severity. BDI scores (HR 1.09, 95 % CI 1.02–1.15), STAI scores (HR .86, 95 % CI .78–.93), and very good self-rated health (relative to the poor self-rated health group; HR .33, 95 % CI .12–.96) each independently predicted time to mortality outcomes in the combined model. SNI scores (HR .91, 95 % CI .81–1.06) and other self-rated health categories (i.e., fair, good, and excellent categories) were not significant mortality predictors after adjusting for other psychosocial factors. These results reinforce and extend prior psychosocial research in CAD populations.

Currently as many as one-half of women with suspected myocardial ischemia have no obstructive coronary artery disease (CAD), and abnormal coronary reactivity (CR) is commonly found.The authors prospectively investigated CR and longer-term adverse cardiovascular outcomes in women with and with no obstructive CAD in the National Heart, Lung, and Blood Institute-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.Women (n = 224) with signs and symptoms of ischemia underwent CR testing. Coronary flow reserve and coronary blood flow were obtained to test microvascular function, whereas epicardial CR was tested by coronary dilation response to intracoronary (IC) acetylcholine and IC nitroglycerin. All-cause mortality, major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke, and heart failure), and angina hospitalizations served as clinical outcomes over a median follow-up of 9.7 years.The authors identified 129 events during the follow-up period. Low coronary flow reserve was a predictor of increased MACE rate (hazard ratio [HR]: 1.06; 95% confidence interval [CI]: 1.01 to 1.12; p = 0.021), whereas low coronary blood flow was associated with increased risk of mortality (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.038) and MACE (HR: 1.11; 95% CI: 1.03 to 1.20; p = 0.006) after adjusting for cardiovascular risk factors. In addition, a decrease in cross-sectional area in response to IC acetylcholine was associated with higher hazard of angina hospitalization (HR: 1.05; 95% CI: 1.02 to 1.07; p 0.0001). There was no association between epicardial IC-nitroglycerin dilation and outcomes.On longer-term follow-up, impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of ischemia. Evaluation of CR abnormality can identify those at higher risk of adverse outcomes in the absence of significant CAD. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00000554).

Background: Information regarding the pathogenesis of ischemic heart disease (IHD) in women is limited. Sex-specific responses to atherosclerosis and coronary arterial remodelling in women versus men have been hypothesized, but limited study exists. Methods: Case-matched study of 174 women with suspected ischemia referred for coronary angiography: 87 with non-obstructive coronary artery disease (CAD) (no luminal diameter stenosis >20% in any coronary artery) and 87 age and ethnicity matched women with obstructive CAD. Groups were compared with regard to atheroma burden and coronary arterial remodelling assessed by coronary artery intravascular ultrasound (IVUS). Results: IVUS revealed more extensive atheroma with obstructive CAD vs. those without obstructive CAD, with greater percent atheroma volume (PAV) (36.1%±9.8% vs. 25.4%±9.1%, P

Observational studies have suggested that arterial distensibility decreases during menopause; however, its relationship with hormone therapy use remains controversial. We prospectively studied distensibility and hormone therapy use at different menopause stages.One hundred sixty-one women (aged between 42 and 61 y) without cardiovascular disease underwent carotid artery measurements by ultrasound to calculate distensibility index at baseline and 3 years later. Menopause stage was classified at each visit as premenopausal, perimenopausal, and postmenopausal. Across 3 years of prospective observation, women were classified as remaining premenopausal, remaining postmenopausal, or transitioning (defined as change from premenopausal to perimenopausal, from premenopausal to postmenopausal, from perimenopausal to perimenopausal, or from perimenopausal to postmenopausal).Distensibility declined across time at all menopause stages (P0.0001). Compared with postmenopausal women, premenopausal and transitioning/no hormone therapy women had more than twice the decline in distensibility index (P = 0.06 and P = 0.016, respectively), whereas transitioning/hormone therapy women did not differ in distensibility decline (P = 0.28). In a multivariate model, change in systolic blood pressure (P0.0001) and change in pulse pressure (P = 0.004) were independent predictors of distensibility index change and served as effect modulators. In an adjusted model, women in the premenopausal and transitioning/no hormone therapy groups had a significantly faster decline in distensibility index (P = 0.002 and P = 0.001, respectively) compared with postmenopausal women, whereas the transitioning/hormone therapy group did not (P = 0.21).These findings confirm that the menopausal transition is associated with reduced vascular compliance. Hormone therapy is associated with better arterial distensibility only during the menopausal transition. Additional prospective studies are needed to confirm these findings and to determine whether hormone therapy use beyond the menopausal transition is related to distensibility.

Objective In women, metabolic syndrome (MetS) is associated with higher risk of ischemic heart disease-related adverse outcomes versus individual components. We examined the relationship of MetS to subclinical coronary atherosclerosis. Methods Women (n = 100) undergoing coronary angiography for suspected ischemia but without obstructive coronary artery disease (CAD) underwent intravascular ultrasound (IVUS) of a segment of the left coronary artery. A core lab, masked to other findings, assessed IVUS measures and normalized volume measures to pull-back length. MetS [defined using ATPIII criteria (fasting glucose ≥ 100 mg/dl per revised NCEP guideline)] and its components were entered into multiple regression models to assess associations with IVUS measures. Results Detailed IVUS measurements were available in 87 women. Mean age was 54 ± 10 years, 36% had MetS, and 78% had atheroma. Comparing women with MetS versus without MetS, significant differences were observed for seven IVUS atherosclerosis measures, but were not significant after adjusting for the MetS components. Systolic blood pressure and waist circumference components remained independently positively associated with the IVUS measures after adjusting for age, diabetes, CAD family history, dyslipidemia, smoking, and hormone replacement. Conclusion In women with signs and symptoms of ischemia and no obstructive CAD, MetS is associated with coronary atherosclerosis presence and severity. However, these associations appear largely driven by components of waist circumference and systolic blood pressure versus MetS cluster. This supports the concept that MetS is a convenient clustering of risk factors rather than an independent risk predictor, and emphasizes that the critical factors for coronary atherosclerosis are potentially modifiable.

Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and adverse cardiovascular outcomes, but mechanisms are unclear. We hypothesized that mild CKD independently predicts adverse outcomes in women with symptoms and signs of ischemia.We categorized 876 women from the Women's Ischemia Syndrome Evaluation cohort according to estimated glomerular filtration rate (eGFR) (eGFR ≥90 mL/min per 1.73 m(2) [normal], 60-89 mL/min per 1.73 m(2) [mild CKD], ≤59 mL/min per 1.73 m(2) [severe CKD]). Time to death from all-cause and cardiovascular causes and major adverse outcomes were assessed by multivariate regression adjusted for baseline covariates.Obstructive coronary artery disease (CAD) was present only in few patients (39%). Even after adjusting for CAD severity, renal function remained a strong independent predictor of all-cause and cardiac mortality (P.001). Every 10-unit decrease in eGFR was associated with a 14% increased risk of all-cause mortality (adjusted hazard ratio [AHR] 1.14 [1.08-1.20], P.0001), 16% increased risk of cardiovascular mortality (AHR 1.16 [1.09-1.23], P.0001), and 9% increased risk of adverse cardiovascular events (AHR 1.09 [1.03-1.15], P = .002).Even mild CKD is a strong independent predictor of all-cause and cardiac mortality in women with symptoms/signs of ischemia, regardless of underlying obstructive CAD severity, underscoring the need to better understand the interactions between ischemic heart disease and CKD.

Introduction: Association of serotonin transporter gene ( 5-HTTLPR ) polymorphisms with adverse cardiovascular (CV) events in women with suspected ischemia has not yet been reported. We hypothesized an association of 5-HTTLPR polymorphisms with risk of adverse CV events in women with suspected ischemic heart disease (IHD) referred for coronary angiography enrolled in the Women’s Ischemia Syndrome Evaluation (WISE). Method: We studied clinical and angiographic data and DNA from a cohort of 437 Caucasian women enrolled in the WISE genotyped for the long (L) and short (S) variant of the 5-HTTLPR polymorphism. Women were followed yearly for adverse CV events (defined as first occurrence of all-cause death, myocardial infarction, stroke, or heart failure hospitalization) with data collected at WISE 10-year follow-up. Exploratory analyses compared outcomes between genotype groups. Results: A total of 437 women, with baseline, angiographic, and long-term follow-up data, were successfully genotyped. Their mean age was 58 ± 11 years and body mass index 29 ± 6; 54% had hypertension, 18% diabetes, 50% dyslipidemia, 20% depression history, and only 34% had obstructive CAD. At 8.9 years median follow-up, the SS genotype was associated with significantly increased risk of adverse CV event versus LL + LS (1.93, confidence interval [CI]: 1.03-3.61, P = .03). Results were not significant for all-cause death (hazard ratio: 1.63, CI: 0.91-2.93, P = .09). Conclusion: Among a cohort of Caucasian women with suspected IHD enrolled in the WISE, the SS homozygous genotype for the 5-HTTLPR polymorphism was associated with increased risk of adverse CV outcomes.

Background— The WISE study (Women’s Ischemia Syndrome Evaluation) was a prospective cohort study of 936 clinically stable symptomatic women who underwent coronary angiography to evaluate symptoms and signs of ischemia. Long-term mortality data for such women are limited. Methods and Results— Obstructive coronary artery disease (CAD) was defined as ≥50% stenosis on angiography by core laboratory. We conducted a National Death Index search to assess the mortality of women who were alive at their final WISE contact date. Death certificates were obtained. All deaths were adjudicated as cardiovascular or noncardiovascular by a panel of WISE cardiologists masked to angiographic data. Multivariate Cox proportional hazards regression was used to identify significant independent predictors of mortality. At baseline, mean age was 58±12 years; 176 (19%) were non-white, primarily black; 25% had a history of diabetes mellitus, 59% hypertension, 55% dyslipidemia, and 59% had a body mass index ≥30. During a median follow-up of 9.5 years (range, 0.2–11.5 years), a total of 184 (20%) died. Of these, 115 (62%) were cardiovascular deaths; 31% of all cardiovascular deaths occurred in women without obstructive CAD ( Conclusions— Among women referred for coronary angiography for signs and symptoms of ischemia, 1 in 5 died from predominantly cardiac pathogeneses within 9 years of angiographic evaluation. A majority of the factors contributing to the risk of death seem to be modifiable by existing therapies. Of note, 1 in 3 of the deaths in this cohort occurred in women without obstructive CAD, a condition often considered benign and without guideline-recommended treatments. Clinical trials are needed to provide treatment guidance for the group without obstructive CAD.

BackgroundSudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information onSCDamong women with and without obstructive coronary artery disease (CAD). We evaluatedSCDincidence in the WISE (Women's Ischemia Syndrome Evaluation) study.Methods and ResultsOverall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and asSCDor non‐SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% wereSCD. Mortality per 1000 person‐hours increased linearly withCADseverity (noCAD: 5.8; minimal: 15.9; obstructive: 38.6;PSCDwas similar acrossCADseverity: 40%, 58%, and 38% for no, minimal, and obstructiveCADsubgroups, respectively (Pvalue not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression (P=0.018) and longer corrected QT interval (P=0.023) were independentSCDpredictors in the entire cohort. Corrected QT interval was an independent predictor ofSCDin women without obstructiveCAD(P=0.033).ConclusionsSCDcontributes substantially to mortality in women with and without obstructiveCAD. Corrected QT interval is the single independentSCDrisk factor in women without obstructiveCAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women.

Wave reflections augment central aortic SBP and increase systolic pressure time integral (SPTI) thereby increasing left ventricular (LV) afterload and myocardial oxygen (MVO2) demand. When increased, such changes may contribute to myocardial ischemia and angina pectoris, especially when aortic diastolic time is decreased and myocardial perfusion pressure jeopardized. Accordingly, we examined pulse wave reflection characteristics and diastolic timing in a subgroup of women with chest pain (Women's Ischemia Syndrome Evaluation, WISE) and no obstructive coronary artery disease (CAD).Radial artery BP waveforms were recorded by applanation tonometry, and aortic BP waveforms derived. Data from WISE participants were compared with data from asymptomatic women (reference group) without chest pain matched for age, height, BMI, mean arterial BP, and heart rate.Compared with the reference group, WISE participants had higher aortic SBP and pulse BP and ejection duration. These differences were associated with increased augmentation index and reflected pressure wave systolic duration. These modifications in wave reflection characteristics were associated with increased SPTI and wasted LV energy (Ew) and a decrease in pulse pressure amplification, myocardial viability ratio, and diastolic pressure time fraction.WISE participants with no obstructive CAD have changes in systolic wave reflections and diastolic timing that increase LV afterload, MVO2 demand, and Ew with the potential to reduce coronary artery perfusion. These alterations in cardiovascular function contribute to an undesirable mismatch in the MVO2 supply/demand that promotes ischemia and chest pain and may contribute to, or increase the severity of, future adverse cardiovascular events.

Women presenting with signs and symptoms of myocardial ischemia frequently have no or nonobstructive coronary artery disease (CAD).This study aimed to investigate the associations between angiographic measures and longer-term clinical outcomes among women with signs and symptoms of ischemia referred for coronary angiography.A prospective cohort analysis of women referred for coronary angiography and enrolled in the National Heart, Lung, and Blood Institute-sponsored WISE was performed. An angiographic severity score was prospectively developed, assigning points for any stenosis weighted by stenosis severity, location, and collaterals and was then tested for prediction for adverse outcome in 917 women, over a median of 9.3 years.The study was conducted in referral centers.Women with signs and/or symptoms of myocardial ischemia referred for coronary angiography were consecutively consented and enrolled in a prospective study.Main outcomes included first occurrence of cardiovascular death or nonfatal myocardial infarction. Hospitalization for angina was a secondary outcome.Cardiovascular death or myocardial infarction at 10 years occurred in 6.7%, 12.8%, and 25.9% of women with no, nonobstructive, and obstructive CAD (P.0001), respectively. Cumulative 10-year cardiovascular death or myocardial infarction rates showed progressive, near-linear increases for each WISE CAD severity score range of 5, 5.1 to 10, 10.1 to 20, 20.1 to 50, and50. The optimal threshold in the WISE severity score classifications for predicting cardiovascular mortality was10 (eg, 5.0-10 vs 10.1-89), with both a sensitivity and specificity of 0.64 and an area under the curve of 0.64 (P = .02, 95% CI 0.59-0.68).Among women with signs and symptoms of ischemia, nonobstructive CAD is common and associated with adverse outcomes over the longer term. The new WISE angiographic score appears to be useful for risk prediction in this population.

Background The association between migraine headache and cardiovascular events has been inconsistent. This study determines the long-term risk of cardiovascular events among women with and without a history of migraine headache who were under evaluation for suspected myocardial ischemia in the Women's Ischemia Syndrome Evaluation (WISE). Methods The WISE is a National Heart, Lung and Blood Institute-sponsored prospective, multicenter study that aims to improve myocardial ischemia evaluation in women. A total of 936 women presenting with symptoms of myocardial ischemia underwent structured data collection and coronary angiography. Information pertaining to migraine headache was available in 917 women. All-cause mortality data were available on all women for a median of 9.5 years, and nonfatal cardiovascular event data were available on 888 women for a median of 6.5 years. Results A total of 224 (24.4%) women reported a history of migraine headache. Compared with women who did not report a history of migraine headache, women with a history of migraine headache had an increased adjusted risk of cardiovascular event (cardiovascular death, nonfatal myocardial infarction, heart failure, or stroke) (hazard ratio 1.83; 95% confidence interval, 1.22-2.75) at a median follow-up of 6.5 years. This result was driven mainly by a twofold increase in the risk of stroke (hazard ratio 2.33; 95% confidence interval, 1.16-4.68). Conclusion Among women being evaluated for ischemic heart disease, those reporting a history of migraine headache had increased risk of future cardiovascular events on long-term follow-up. This risk was primarily driven by a more-than twofold increase in the risk of stroke.

Studies have linked vasomotor symptoms (VMS) to markers of cardiovascular disease (CVD) risk, yet few have considered clinical cardiovascular events. Data suggest that associations may depend upon the age that symptoms occur. We examined associations between VMS and cardiovascular events and endothelial function, considering age of symptom onset.The Women's Ischemia Syndrome Evaluation enrolled women referred for coronary angiography for suspected myocardial ischemia. A total of 254 women aged more than 50 years, postmenopausal, with both ovaries, not taking hormone therapy underwent a baseline evaluation, were followed annually (median = 6.0 y), and the National Death Index was searched to ascertain CVD mortality (median = 9.3 y). A subset of participants underwent brachial artery ultrasound for flow-mediated dilation (FMD). Receiver-operating curve analysis was used to determine vasomotor symptom groups (symptoms beginning age 42 [early onset], beginning ≥42 [later onset], never) which were examined in relation to cardiovascular events and FMD in Cox proportional hazard and linear regression models.Women reporting early onset VMS (HR = 3.35, 95% CI = 1.23-7.86, P = 0.005) and women who never had VMS (HR = 2.17, 95% CI = 1.02-4.62, P = 0.05) had higher CVD mortality than women with later onset symptoms (multivariable models). Women with early onset VMS had lower FMD than women with later onset symptoms (b = -4.31, SE = 2.10, P = 0.04, multivariable).Women with signs and symptoms of ischemia who had VMS beginning early in midlife had higher CVD mortality and reduced endothelial function relative to women with later onset symptoms. Future research should evaluate the vascular phenotype of women with early midlife VMS.

Women with polycystic ovary syndrome (PCOS) have greater cardiac risk factor clustering but the link with mortality is incompletely described.To evaluate outcomes in 295 postmenopausal women enrolled in the National Institutes of Health-National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Women's Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS.A total of 25/295 (8%) women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia, defined as the top quartile of androstenedione (≥701 pg/mL), testosterone (≥30.9 ng/dL), or free testosterone (≥4.5 pg/mL). Cox proportional hazard model estimated death (n = 80).Women with clinical features of PCOS had an earlier menopause (p = 0.01), were more often smokers (p 0.04), and trended toward more angiographic coronary artery disease (CAD) (p = 0.07) than women without these features. Cumulative 10-year mortality was 28% for women with (n = 25) versus 27% without clinical features of PCOS (n = 270) (p = 0.85). PCOS was not a significant predictor (p = NS) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD.From this longer-term follow up of a relatively small cohort of postmenopausal women with suspected ischemia, the prevalence of PCOS is similar to the general population, and clinical features of PCOS are not associated with CAD or mortality. These findings question whether identification of clinical features of PCOS in postmenopausal women who already have known cardiovascular disease provides any additional opportunity for risk factor intervention.

Background We investigated the role of the renin-angiotensin system in women with signs and symptoms of ischemia without obstructive coronary artery disease (CAD). Although microvascular dysfunction has been suggested to explain this syndrome and recently was found to predict adverse outcomes, the mechanisms and treatments remain unclear. Methods In a substudy within the WISE, 78 women with microvascular dysfunction (coronary flow reserve [CFR] Results A total of 61 women completed the 16-week treatment period with repeat CFR measurements, and treatment was well tolerated. For the primary outcome, at 16 weeks, CFR improved more with ACE-I than placebo ( P P = .037) and CFR increase ( P = .008) both contributed. Conclusions Microvascular function improves with ACE-I therapy in women with signs and symptoms of ischemia without obstructive CAD. This improvement is associated with reduction in angina. The beneficial response of the coronary microvasculature was limited to women with lower baseline CFR values, suggesting that the renin-angiotensin system may be more involved among women with more severe microvascular defects.

Context: Dehydroepiandrosterone sulfate (DHEA-S), a major circulating sex steroid prohormone, declines with age. Low levels have been associated with increased cardiovascular disease (CVD) risk and all-cause mortality, although these results have not been consistently replicated, particularly in women. Objective: Our objective was to examine the association of circulating DHEA-S levels, CVD, and mortality risk among postmenopausal women with suspected myocardial ischemia. Design: In the Women’s Ischemia Syndrome Evaluation, 270 postmenopausal women underwent coronary angiography and blood hormone levels for suspected ischemia and were followed annually. The primary outcome of interest was CVD mortality; secondary analyses included all-cause mortality and nonfatal CVD events (myocardial infarction, stroke, and congestive heart failure) and angiographic obstructive coronary artery disease (CAD). Results: Women in the lowest DHEA-S tertile had higher CVD mortality (17% 6-yr mortality rate vs. 8%; log-rank P = 0.011), and all-cause mortality (21 vs. 10%; P = 0.011) compared with women with higher DHEA-S levels. The increased CVD mortality risk [hazard ratio (HR) = 2.55; 95% confidence interval (CI) = 1.19–5.45] remained unchanged after adjustment for multiple CVD risk factors (HR = 2.43; 95% CI = 1.06–5.56) but became nonsignificant when further adjusting for the presence or severity of angiographic obstructive CAD (HR = 1.99; 95% CI = 0.87–4.59). Results were similar for all-cause mortality. Lower DHEA-S levels were only marginally but not independently associated with obstructive CAD. Conclusions: Among postmenopausal women with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia, lower DHEA-S levels were linked with higher CVD mortality and all-cause mortality. Our study provides valuable feasibility data useful for future investigations and possible mechanistic pathways.

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 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 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.

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.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).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.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.

Objectives We investigated whether coronary microvascular dysfunction predicts major adverse outcomes during follow-up among women with signs and symptoms of ischemia. Background Altered coronary reactivity occurs frequently in women evaluated for suspected ischemia, and the endothelium-dependent component is linked with adverse outcomes. Possible links between endothelium-independent microvascular coronary reactivity and adverse outcomes remain uncertain. Methods As part of the National Heart, Lung and Blood Institute-sponsored WISE (Women9s Ischemia Syndrome Evaluation), we investigated relationships between major adverse outcomes and baseline coronary flow reserve (CFR) after intracoronary adenosine in 189 women referred to evaluate suspected ischemia. Results At a mean of 5.4 years, we observed significant associations between CFR and major adverse outcomes (death, nonfatal myocardial infarction, nonfatal stroke, or hospital stay for heart failure). An exploratory receiver-operator characteristic analysis identified CFR Conclusions Among women with suspected ischemia and atherosclerosis risk factors, coronary microvascular reactivity to adenosine significantly improves prediction of major adverse outcomes over angiographic CAD severity and CAD risk factors. These findings suggest that coronary microvessels represent novel targets for diagnostic and therapeutic strategies to predict and limit adverse outcomes in women. (Women9s Ischemia Syndrome Evaluation [WISE]; NCT00000554)

It has been suggested that both endogenous reproductive hormones and hormone therapy may play a protective role against coronary artery disease (CAD). However, recent clinical trials have failed to demonstrate the benefit of a variety of forms of hormone therapy. The observational data on the role of endogenous reproductive hormones, using surrogate measures such as number of birth, age at menarche, and age at menopause are inconsistent. In addition, the longer-term associations have not been evaluated. The aim of this study was to evaluate the relationships between detailed measurements of endogenous and exogenous estrogen exposure time with angiographic CAD and major adverse cardiovascular events.We assessed total estrogen exposure time, quantitative CAD by a core angiography laboratory, and prospectively measured major adverse cardiovascular events in 646 postmenopausal women undergoing coronary angiography for evaluation for suspected ischemia in the Women's Ischemia Syndrome Evaluation (WISE) study.Timing of postmenopausal exogenous hormone therapy (HT) use was associated with reduced CAD. Two summarized total estrogen time scores (TET and sTET) were not related to angiographic CAD after accounting for HT use. In addition, these scores were not related to cardiovascular events over a median of 6.0 years of follow-up.There was no independent relation of estrogen exposure time to angiographic CAD or major adverse cardiovascular events in a contemporary cohort of postmenopausal women evaluated for suspected ischemia. Our results suggest that the paradigm of estrogen protection from CAD in women may be more complex than estrogen exposure duration alone.

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 ≥ 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. Copyright © 2009 Wiley Periodicals, Inc.

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.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.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.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.

High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are important cardiovascular risk factors in women. The prognostic utility of the TG/HDL-C ratio, a marker for insulin resistance and small dense low-density lipoprotein particles, is unknown among high-risk women. Methods We studied 544 women without prior myocardial infarction or coronary revascularization, referred for clinically indicated coronary angiography and enrolled in the Women's Ischemia Syndrome Evaluation (WISE). Fasting lipid profiles and detailed demographic and clinical data were obtained at baseline. Multivariate Cox-proportional hazards models for all-cause mortality and cardiovascular events (death, myocardial infarction, heart failure, stroke) over a median follow-up of 6 years were constructed using log TG/HDL-C ratio as a predictor variable and accounting for traditional cardiovascular risk factors. Results Mean age was 57 ± 11 years; 84% were white, 55% hypertensive, 20% diabetic, 50% current or prior smokers. Triglyceride/HDL-C ranged from 0.3 to 18.4 (median 2.2, first quartile 0.35 to P P = .04). For cardiovascular events, the multivariate hazard ratio was 1.54 (95% CI 1.05-2.22, P = .03) when adjusted for demographic and clinical variables, but became nonsignificant when angiographic results were included. Conclusion Among women with suspected ischemia, the TG/HDL-C ratio is a powerful independent predictor of all-cause mortality and cardiovascular events.

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 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.

Context: Because androgens are obligatory precursors of estrogens, it is reasonable to assume that their serum concentrations would exhibit positive correlations. If so, then epidemiologic studies that examine the association between androgens and pathological processes should adjust the results for the independent effect of estrogens. Objective: The objective of the study was to examine the interrelationships among testosterone (T), androstenedione, estradiol (E2), estrone, and SHBG in postmenopausal women. Design: This was a cross-sectional study of women participating in the National Heart, Blood, and Lung Institute-sponsored Women’s Ischemia Syndrome Evaluation study. Setting: The study was conducted at four academic medical centers. Patients: A total of 284 postmenopausal women with chest pain symptoms or suspected myocardial ischemia. Main Outcome Measures: Post hoc analysis of the relationships among sex steroid hormones with insulin resistance, body mass index (BMI), and presence or absence of coronary artery disease as determined by coronary angiography. Results: BMI was significantly associated with insulin resistance, total E2, free E2, bioavailable E2, and free T. Highly significant correlations were found for total T, free T, and androstenedione with total E2, free E2, bioavailable E2, and estrone and persisted after adjustment for BMI and insulin resistance. A significant relationship was present between total and free T and the presence of coronary artery disease after adjustment for the effect of E2. Conclusions: Serum levels of androgens and estrogens track closely in postmenopausal women referred for coronary angiography for suspected myocardial ischemia. Epidemiological studies that relate sex steroid hormones to physiological or pathological processes need to control for the independent effect of both estrogens and androgens.

For women, who are more likely to live in poverty, defining the clinical and economic impact of socioeconomic factors may aid in defining redistributive policies to improve healthcare quality.The NIH-NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) enrolled 819 women referred for clinically indicated coronary angiography. This study's primary end point was to evaluate the independent contribution of socioeconomic factors on the estimation of time to cardiovascular death or myocardial infarction (MI) (n = 79) using Cox proportional hazards models. Secondary aims included an examination of cardiovascular costs and quality of life within socioeconomic subsets of women.In univariable models, socioeconomic factors associated with an elevated risk of cardiovascular death or MI included an annual household income$20,000 (p = 0.0001),9th grade education (p = 0.002), being African American, Hispanic, Asian, or American Indian (p = 0.016), on Medicaid, Medicare, or other public health insurance (p0.0001), unmarried (p = 0.001), unemployed or employed part-time (p0.0001), and working in a service job (p = 0.003). Of these socioeconomic factors, income (p = 0.006) remained a significant predictor of cardiovascular death or MI in risk-adjusted models that controlled for angiographic coronary disease, chest pain symptoms, and cardiac risk factors. Low-income women, with an annual household income$20,000, were more often uninsured or on public insurance (p0.0001) yet had the highest 5-year hospitalization and drug treatment costs (p0.0001). Only 17% of low-income women had prescription drug coverage (vs.or=50% of higher-income households, p0.0001), and 64% requiredor=2 anti-ischemic medications during follow-up (compared with 45% of those earningor=$50,000, p0.0001).Economic disadvantage prominently affects cardiovascular disease outcomes for women with chest pain symptoms. These results further support a profound intertwining between poverty and poor health. Cardiovascular disease management strategies should focus on policies that track unmet healthcare needs and worsening clinical status for low-income women.

Background: Women with polycystic ovary syndrome (PCOS) have a greater clustering of cardiac risk factors. However, the link between PCOS and cardiovascular (CV) disease is incompletely described. Objective: The aim of this analysis was to evaluate the risk of CV events in 390 postmenopausal women enrolled in the National Institutes of Health–National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Women’s Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS. Methods: A total of 104 women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia. Hyperandrogenemia was defined as the top quartile of androstenedione (≥701 pg/ml), testosterone (≥30.9 ng/dl), or free testosterone (≥4.5 pg/ml). Cox proportional hazard model was fit to estimate CV death or myocardial infarction (n = 55). Results: Women with clinical features of PCOS were more often diabetic (P < 0.0001), obese (P = 0.005), had the metabolic syndrome (P < 0.0001), and had more angiographic coronary artery disease (CAD) (P = 0.04) compared to women without clinical features of PCOS. Cumulative 5-yr CV event-free survival was 78.9% for women with clinical features of PCOS (n = 104) vs. 88.7% for women without clinical features of PCOS (n = 286) (P = 0.006). PCOS remained a significant predictor (P < 0.01) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD as covariates. Conclusion: Among postmenopausal women evaluated for suspected ischemia, clinical features of PCOS are associated with more angiographic CAD and worsening CV event-free survival. Identification of postmenopausal women with clinical features of PCOS may provide an opportunity for risk factor intervention for the prevention of CAD and CV events.

Objectives The purpose of this study was to examine prospectively whether inflammation explains the relationship between depression and cardiovascular disease (CVD). Background It is unclear whether inflammation is a mechanism linking depression to CVD. Methods We measured C-reactive protein (CRP) and interleukin (IL)-6 in 559 women with suspected coronary ischemia who completed the Beck Depression Inventory (BDI) at baseline and were followed over 5.9 years. We considered indicators of past and current depression to classify women into 3 groups: 1) depression, having both elevated depressive symptoms (BDI ≥10) and a previous diagnosis of depression requiring treatment; 2) possible depression, having either indicator but not both; and 3) no depression, having neither indicator of depression. The main outcome was incidence of CVD events (hospital stays for nonfatal myocardial infarction, stroke, congestive heart failure, and CVD-related mortality). Results Compared with women without depression, women with depression had a 70% higher CRP (p = 0.0008) and a 25% higher IL-6 (p = 0.04), whereas women with possible depression had 30% higher CRP (p = 0.02) and 28% higher IL-6 (p = 0.01). Depression was a significant predictor of CVD (hazard ratio 2.58, p = 0.0009), but possible depression was not (hazard ratio 1.12, p = 0.68). Adjustment for other patient factors did not substantially affect the results. Addition of CRP decreased the estimate for depression by 13% and addition of IL-6 decreased it by 4%. Both depression and inflammatory biomarkers remained independent predictors of outcome. Conclusions Despite their robust association with depression, inflammatory biomarkers explain only a small portion of the association between depression and CVD incidence.

Cardiac syndrome X (CSX) describes patients with angina-like chest pain, positive stress ischemia, and nonobstructive coronary angiograms. Microvascular angina (MVA) is an etiologic mechanism in women with cardiac symptoms and abnormal vascular dysfunction without obstructive coronary artery disease, although not all patients with MVA show detectable ischemia. CSX is more prevalent in women than men, with an average age in the mid-to-late 50s. Many additional cardiac and noncardiac mechanisms have been proposed for CSX over the past three decades. The uncertainty and inconsistency of data for determining diagnosis and causality along with the unusual response to traditional antianginal treatment hinder the development of effective treatment strategies. Many researchers believe that women with MVA do not have a benign prognosis and may be better classified as intermediate risk. Better understanding of the disease characteristics; its relation to traditional and novel risk factors, especially in women; identification of reliable, accurate diagnostic procedures; and a comprehensive preventive therapeutic approach are all important for optimizing management strategy for MVA and CSX.

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 (CFVRAdo) in 210 women referred for angiography to evaluate suspected ischemia. Results Univariate analyses identified associations between CFVRAdo and multiple risk conditions; however, after adjusting for age, none remained significant. The best multivariable model using combinations of risk conditions to predict CFVRAdo yielded an R2 of only 0.18. Conclusions Among women with suspected ischemia, risk factors account for

Background: Women frequently present with non-typical angina (NTA) making ischemia diagnosis and treatment challenging. We hypothesized that mortality would be higher in women with obstructive coronary artery disease (CAD) and NTA vs typical angina (TA). Methods: We studied 364 Women’s Ischemia Syndrome Evaluation (WISE) participants with signs and symptoms of ischemia and obstructive CAD, defined as ≥50% stenosis by WISE angiography core laboratory. TA was defined as sub-sternal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin, while NTA was defined as symptoms not meeting criteria for TA. Death was confirmed by National Death Index. Time to death was analyzed and plotted using Kaplan-Meier survival analyses. The analyses were adjusted by age using a Cox Proportional Hazards regression, and reported with a hazard ratio (HR) and 95% confidence interval (CI). Results: Overall, 249 (68%) NTA and 115 (32%) TA women had a mean age of 63 ± 12yrs and 21% were non-white. Women with NTA were more hypertensive (72% vs. 60%, p=0.03) and more often on angiotensin-converting enzyme inhibitor (37% vs 25%, p= 0.03) than women with TA. There was no difference in mean cholesterol level, CAD severity or body mass index between the two groups. Over a median of 8.8 years, 122 (34%) women died including 92 NTA and 30 TA (HR 1.5, 95% CI 1.006, 2.30) (Figure). Conclusions: Among WISE women with signs and symptoms of ischemia and obstructive CAD, NTA has a higher mortality compared to TA. These findings extend prior evidence that chest pain, including NTA, identifies higher risk in women with obstructive CAD. These data support intensive management and clinical follow up of women with obstructive CAD and NTA. Further evaluation regarding ischemic burden and treatment is ongoing to further understand the elevated NTA mortality.

Background— Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). Although traditional noninvasive stress imaging is often normal in CMD, cardiac MRI may be able to detect CMD in this population. Methods and Results— Vasodilator stress cardiac MRI was performed in 118 women with suspected CMD who had undergone CRT and 21 asymptomatic reference subjects. Semi-quantitative evaluation of the first-pass perfusion images was completed to determine myocardial perfusion reserve index (MPRI). The relationship between CRT findings and MPRI was examined by Pearson correlations, logistic regression, and sensitivity/specificity. Symptomatic women had lower mean pharmacological stress MPRI compared with reference subjects (1.71±0.43 versus 2.23±0.37; P P Conclusions— Noninvasive cardiac MRI MPRI can detect CMD defined by invasive CRT. Further work is aimed to optimize the noninvasive identification and management of CMD patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00832702.

Classification of menopausal status is important for epidemiological and clinical studies as well as for clinicians treating midlife women. Most epidemiological studies, including the Study of Women's Health Across the Nation (SWAN), classify women based on self-reported bleeding history.The Women's Ischemia Syndrome Evaluation (WISE) study developed an algorithm using menstrual and reproductive history and serum hormone levels to reproduce the menopausal status classifications assigned by the WISE hormone committee. We applied that algorithm to women participating in SWAN and examined characteristics of women with concordant and discordant SWAN and WISE classifications.Of the 3215 SWAN women with complete information at baseline (1995-1997), 2466 (76.7%) received concordant classifications (kappa = 0.52); at the fifth annual follow-up visit, of the 1623 women with complete information, 1154 (72.7%) received concordant classifications (kappa = 0.57). At each time point, we identified subgroups of women with discordant SWAN and WISE classifications. These subgroups, ordered by chronological age, showed increasing trends for menopausal symptoms and follicle-stimulating hormone (FSH) and a decreasing trend for estrogen (p0.001).The WISE algorithm is a useful tool for studies that have access to blood samples for hormone data unrelated to menstrual cycle phase, with or without an intact uterus, and no resources for adjudication. Future studies may want to combine aspects of the SWAN and WISE algorithms by adding hormonal measures to the series of bleeding questions in order to determine more precisely where women are in the perimenopausal continuum.

Purpose There are conflicting data regarding the association between migraines and cardiovascular events. We evaluated the relationship between migraine headaches, angiographic coronary artery disease, and cardiovascular events in women. Subjects and Methods The Women's Ischemia Syndrome Evaluation (WISE) study is a National Heart, Lung and Blood Institute (NHLBI)-sponsored prospective, multicenter study aiming to improve ischemia evaluation in women. A total of 944 women presenting with chest pain or symptoms suggestive of myocardial ischemia were enrolled and underwent complete demographic, medical, and psychosocial history, physical examination, and coronary angiography testing. A smaller subset of 905 women, representing a mean age of 58 years, answered questions regarding a history of migraines. We prospectively followed 873 women for 4.4 years for cardiovascular events and all-cause mortality. Results Women reporting a history of migraines (n=220) had lower angiographic coronary severity scores, and less severe (≥ 70% luminal stenosis) angiographic coronary artery disease compared to women without a history of migraines (n=685). These differences remained statistically significant after adjustment for age and other important cardiac risk factors. On prospective follow-up of a median of 4.4 years, women with a history of migraines were not more likely to have a cardiovascular event (hazard ratio [HR] 1.2; 95% confidence interal [CI], 0.93–1.58) and migraines did not predict all-cause mortality (HR 0.96; 95% CI, 0.49–1.99). Conclusion Among women undergoing coronary angiography for suspected ischemia, those reporting migraines had less severe angiographic coronary artery disease. We could not support an association between migraines and cardiovascular events or death. Further research studying the common pathophysiology underlying migraines and cardiovascular disease is warranted.

Objective To evaluate past oral contraceptive use and angiographic coronary artery disease in women. Setting Academic medical centers. Patient(s) Six hundred seventy-two postmenopausal women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia. Intervention(s) Past oral contraceptive use, assessed by reproductive questionnaire. Main Outcome Measure(s) Quantitative coronary artery disease, assessed by a core angiography laboratory. Result(s) Past oral contraceptive use was associated with a lower mean coronary artery disease severity index score (mean ± SD: 11.8 ± 10.3 vs. 18.7 ± 17.3) compared with non–prior users, despite age adjustment. Past oral contraceptive use remained a significant independent negative predictor of coronary artery disease severity when adjusting for coronary risk factors, including age, diabetes mellitus, triglycerides, low-density lipoprotein cholesterol, smoking, aspirin use, and lipid-lowering medication (model R 2 = 0.19). The modeling indicated that past oral contraceptive use was associated with a 2.44 lower coronary artery disease severity score index. There was no apparent relationship between duration of past oral contraceptive use and the coronary artery disease severity index score. Conclusion(s) Past oral contraceptive use is associated with less coronary artery disease, measured by quantitative coronary angiography, among postmenopausal women with suspected myocardial ischemia. These findings suggest that a prospective study should address the hypothesis that past oral contraceptive use during the premenopausal years might offer women protection from atherosclerotic coronary disease later in life.