Ten-Year Mortality in the WISE Study (Women's Ischemia Syndrome Evaluation).

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 (<50% stenosis). Independent predictors of mortality were obstructive CAD, age, baseline systolic blood pressure, history of diabetes mellitus, history of smoking, elevated triglycerides, and estimated glomerular filtration rate. 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.

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study.

BACKGROUND: Sudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study. METHODS AND RESULTS: Overall, 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 as SCD or non-SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person-hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P<0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively (P value 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 independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD (P=0.033). CONCLUSIONS: SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. 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.

Sex differences in presentation and outcome among patients with type 2 diabetes and coronary artery disease treated with contemporary medical therapy with or without prompt revascularization: a report from the BARI 2D Trial (Bypass Angioplasty Revascularization Investigation 2 Diabetes).

OBJECTIVES: This study evaluated differences in outcome among women and men enrolled in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. BACKGROUND: Women and men with coronary artery disease have different clinical presentations and outcomes that might be due to differences in management. METHODS: We compared baseline variables, study interventions, and outcomes between women and men enrolled in the BARI 2D trial and randomized to aggressive medical therapy alone or aggressive medical therapy with prompt revascularization. RESULTS: At enrollment, women were more likely than men to have angina (67% vs. 58%, p < 0.01) despite less disease on angiography (Myocardial Jeopardy Index 41 ± 24 vs. 46 ± 24, p < 0.01; number of significant lesions 2.3 ± 1.7 vs. 2.8 ± 1.8, p < 0.01). Over 5 years, no sex differences were observed in BARI 2D study outcomes after adjustment for difference in baseline variables (death/myocardial infarction/cerebrovascular accident: hazard ratio: 1.11, 99% confidence interval [CI]: 0.85 to 1.44). However, women reported more angina than men (adjusted odds ratio: 1.51, 99% CI: 1.21 to 1.89, p < 0.0001) and had lower scores for the Duke Activity Status Index (adjusted beta coefficient: -1.58, 99% CI: -2.84 to -0.32, p < 0.01). CONCLUSIONS: There were no sex differences in death, myocardial infarction, or cerebrovascular accident among patients enrolled in the BARI 2D trial. However, compared with men, women had more symptoms and less anatomic disease at baseline, with persistence of higher angina rates and lower DASI scores after 5 years of medical therapy with or without prompt revascularization. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305).

Clinical and angiographic risk stratification and differential impact on treatment outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial assigned patients with type 2 diabetes mellitus to prompt coronary revascularization plus intensive medical therapy versus intensive medical therapy alone and reported no significant difference in mortality. Among patients selected for coronary artery bypass graft surgery, prompt coronary revascularization was associated with a significant reduction in death/myocardial infarction/stroke compared with intensive medical therapy. We hypothesized that clinical and angiographic risk stratification would affect the effectiveness of the treatments overall and within revascularization strata. METHODS AND RESULTS: An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham Risk Score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups. Overall, no outcome differences between the intensive medical therapy and prompt coronary revascularization groups were seen in any risk stratum. The 5-year risk of death/myocardial infarction/stroke was 36.8% for intensive medical therapy compared with 24.8% for prompt coronary revascularization among the 381 coronary artery bypass graft surgery-selected patients in the highest angiographic risk tertile (P=0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% intensive medical therapy versus 27.1% prompt coronary revascularization; P=0.010; hazard ratio=2.10; P=0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the coronary artery bypass graft surgery stratum, or in any subgroups within the percutaneous coronary intervention stratum. CONCLUSION: Among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery significantly reduces the rate of death/myocardial infarction MI/stroke in those with extensive coronary artery disease or impaired left ventricular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Atherosclerotic risk factors and their association with hospital mortality among patients with first myocardial infarction (from the National Registry of Myocardial Infarction).

Few studies have examined associations between atherosclerotic risk factors and short-term mortality after first myocardial infarction (MI). Histories of 5 traditional atherosclerotic risk factors at presentation (diabetes, hypertension, smoking, dyslipidemia, and family history of premature heart disease) and hospital mortality were examined among 542,008 patients with first MIs in the National Registry of Myocardial Infarction (1994 to 2006). On initial MI presentation, history of hypertension (52.3%) was most common, followed by smoking (31.3%). The least common risk factor was diabetes (22.4%). Crude mortality was highest in patients with MI with diabetes (11.9%) and hypertension (9.8%) and lowest in those with smoking histories (5.4%) and dyslipidemia (4.6%). The inclusion of 5 atherosclerotic risk factors in a stepwise multivariate model contributed little toward predicting hospital mortality over age alone (C-statistic = 0.73 and 0.71, respectively). After extensive multivariate adjustments for clinical and sociodemographic factors, patients with MI with diabetes had higher odds of dying (odds ratio [OR] 1.23, 95% confidence interval [CI] 1.20 to 1.26) than those without diabetes and similarly for hypertension (OR 1.08, 95% CI 1.06 to 1.11). Conversely, family history (OR 0.71, 95% CI 0.69 to 0.73), dyslipidemia (OR 0.62, 95% CI 0.60 to 0.64), and smoking (OR 0.85, 95% CI 0.83 to 0.88) were associated with decreased mortality (C-statistic = 0.82 for the full model). In conclusion, in the setting of acute MI, histories of diabetes and hypertension are associated with higher hospital mortality, but the inclusion of atherosclerotic risk factors in models of hospital mortality does not improve predictive ability beyond other major clinical and sociodemographic characteristics.

Number of coronary heart disease risk factors and mortality in patients with first myocardial infarction.

CONTEXT: Few studies have examined the association between the number of coronary heart disease risk factors and outcomes of acute myocardial infarction in community practice. OBJECTIVE: To determine the association between the number of coronary heart disease risk factors in patients with first myocardial infarction and hospital mortality. DESIGN: Observational study from the National Registry of Myocardial Infarction, 1994-2006. PATIENTS: We examined the presence and absence of 5 major traditional coronary heart disease risk factors (hypertension, smoking, dyslipidemia, diabetes, and family history of coronary heart disease) and hospital mortality among 542,008 patients with first myocardial infarction and without prior cardiovascular disease. MAIN OUTCOME MEASURE: All-cause in-hospital mortality. RESULTS: A majority (85.6%) of patients who presented with initial myocardial infarction had at least 1 of the 5 coronary heart disease risk factors, and 14.4% had none of the 5 risk factors. Age varied inversely with the number of coronary heart disease risk factors, from a mean age of 71.5 years with 0 risk factors to 56.7 years with 5 risk factors (P for trend < .001). The total number of in-hospital deaths for all causes was 50,788. Unadjusted in-hospital mortality rates were 14.9%, 10.9%, 7.9%, 5.3%, 4.2%, and 3.6% for patients with 0, 1, 2, 3, 4, and 5 risk factors, respectively. After adjusting for age and other clinical factors, there was an inverse association between the number of coronary heart disease risk factors and hospital mortality adjusted odds ratio (1.54; 95% CI, 1.23-1.94) among individuals with 0 vs 5 risk factors. This association was consistent among several age strata and important patient subgroups. CONCLUSION: Among patients with incident acute myocardial infarction without prior cardiovascular disease, in-hospital mortality was inversely related to the number of coronary heart disease risk factors.

Body mass index and health status in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial (BARI 2D).

BACKGROUND: The longitudinal association between obesity, weight variability, and health status outcomes is important for patients with coronary disease and diabetes. METHODS: The BARI 2D was a multicenter randomized clinical trial designed to evaluate treatment strategies for patients with both documented stable ischemic heart disease and type 2 diabetes. We examined BARI 2D participants for 4 years to study how body mass index (BMI) was associated with health status outcomes. Health status was evaluated by the Duke Activity Status Index (DASI), RAND Energy/fatigue, Health Distress, and Self-rated Health. Body mass index was measured quarterly throughout follow-up years, and health status was assessed at each annual follow-up visit. Variation in BMI measures was separated into between-person and within-person change in longitudinal analysis. RESULTS: Higher mean BMI during follow-up years (the between-person BMI) was associated with poorer health status outcomes. Decreasing BMI (the within-person BMI change) was associated with better Self-rated health. The relationships between BMI variability and DASI or Energy appeared to be curvilinear and differed by baseline obesity status. Decreasing BMI was associated with better outcomes if patients were obese at baseline but was associated with poorer DASI and Energy outcomes if patients were nonobese at baseline. CONCLUSIONS: For patients with stable ischemic heart disease and diabetes, weight gain was associated with poorer health status outcomes, independent of obesity-related comorbidities. Weight reduction is associated with better functional capacity and perceived energy for obese patients but not for nonobese patients at baseline.

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.

Relationships of obesity and fat distribution with atherothrombotic risk factors: baseline results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

The impact of obesity on cardiovascular disease (CVD) outcomes in patients with type 2 diabetes mellitus (T2DM) and established coronary artery disease (CAD) is controversial; whether BMI and/or waist circumference correlate with atherothrombotic risk factors in such patients is uncertain. We sought to evaluate whether higher BMI or waist circumference are associated with specific risk factors among 2,273 Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study participants with T2DM and documented CAD (baseline data, mean age 62 years, 66% non-Hispanic white, 71% men). Multiple linear regression models were constructed after adjusting for sex, age, race/ethnicity, US vs. non-US site, diabetes duration, exercise, smoking, alcohol, and relevant medication use. First-order partial correlations of BMI with risk factors after controlling for waist circumference and of waist circumference with risk factors after controlling for BMI were also evaluated. Ninety percent of the patients were overweight (BMI > or =25 kg/m(2)); 68% of men and 89% of women had high-risk waist circumference measures (> or =102 and > or =88 cm, respectively). BMI and waist circumference, in separate models, explained significant variation in metabolic (insulin, lipids, blood pressure (BP)) and inflammatory/procoagulation (C-reactive protein, PAI-1 activity and antigen, and fibrinogen) risk factors. In partial correlation analyses BMI was independently associated with BP and inflammatory/procoagulation factors, waist circumference with lipids, and both BMI and waist circumference with insulin. We conclude that, in cross-sectional analyses, both BMI and waist circumference, independently, are associated with increased atherothrombotic risk in centrally obese cohorts such as the BARI 2D patients with T2DM and CAD.

Economic outcomes of treatment strategies for type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.

BACKGROUND: The economic outcomes of clinical management strategies are important in assessing their value to patients. METHODS AND RESULTS: Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized patients with type 2 diabetes mellitus and angiographically documented, stable coronary disease to strategies of (1) prompt revascularization versus medical therapy with delayed revascularization as needed to relieve symptoms and (2) insulin sensitization versus insulin provision. Before randomization, the physician declared whether coronary artery bypass grafting or percutaneous coronary intervention would be used if the patient were assigned to revascularization. We followed 2005 patients for medical utilization and costs and assessed the cost-effectiveness of these management strategies. Medical costs were higher for revascularization than medical therapy, with a significant interaction with the intended method of revascularization (P<0.0001). In the coronary artery bypass grafting stratum, 4-year costs were $80 900 for revascularization versus $60 600 for medical therapy (P<0.0001). In the percutaneous coronary intervention stratum, costs were $73 400 for revascularization versus $67 800 for medical therapy (P<0.02). Costs also were higher for insulin sensitization ($71 300) versus insulin provision ($70 200). Other factors that significantly (P<0.05) and independently increased cost included insulin use and dose at baseline, female sex, white race, body mass index > or =30, and albuminuria. Cost-effectiveness based on 4-year data favored the strategy of medical therapy over prompt revascularization and the strategy of insulin provision over insulin sensitization. Lifetime projections of cost-effectiveness showed that medical therapy was cost-effective compared with revascularization in the percutaneous coronary intervention stratum ($600 per life-year added) with high confidence. Lifetime projections suggest that revascularization may be cost-effective in the coronary artery bypass grafting stratum ($47 000 per life-year added) but with lower confidence. CONCLUSIONS: Prompt coronary revascularization significantly increases costs among patients with type 2 diabetes mellitus and stable coronary disease. The strategy of medical therapy (with delayed revascularization as needed) appears to be cost-effective compared with the strategy of prompt coronary revascularization among patients identified a priori as suitable for percutaneous coronary intervention.

The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE).

UNLABELLED: 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 <1.4, fourth quartile 3.66-18.4). Deaths (n = 33) and cardiovascular events (n = 83) increased across TG/HDL-C quartiles (both P < .05 for trend). Triglyceride/HDL-C was a strong independent predictor of mortality in models adjusted for age, race, smoking, hypertension, diabetes, and angiographic coronary disease severity (hazard ratio 1.95, 95% CI 1.05-3.64, 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.

Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006.

BACKGROUND: Although ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction (AMI) have been the focus of intense clinical investigation, limited information exists on characteristics and hospital mortality of patients not enrolled in clinical trials. Previous large databases have reported declining mortality of patients with STEMI but have not noted substantial mortality change among those with NSTEMI. METHODS: The National Registry of Myocardial Infarction enrolled 2,515,106 patients at 2,157 US hospitals from 1990 to 2006. Of these, we evaluated 1,950,561 with diagnoses reflecting acute myocardial ischemia on admission. RESULTS: From 1990 to 2006, the proportion of NSTEMI increased from 14.2% to 59.1% (P < .0001), whereas the proportion of STEMI decreased. Mean age increased (from 64.1 to 66.4 years, P < .0001) as did the proportion of females (from 32.4% to 37.0%, P < .0001). Patients were less likely to report prior angina, prior AMI, or family history of coronary artery disease but more likely to report history of diabetes, hypertension, current smoking, heart failure, prior revascularization, stroke, and hyperlipidemia. From 1994 to 2006, hospital mortality fell among all patients (10.4% to 6.3%), STEMI (11.5% to 8.0%), and NSTEMI (7.1% to 5.2%), (all P < .0001). After adjustment for baseline covariates, hospital mortality fell among all patients by 23.6% (odds ratio [OR] 0.764, 95% CI 0.744-0.785), STEMI by 24.2% (OR 0.758, 0.732-0.784), and NSTEMI by 22.6% (OR 0.774, 0.741-0.809), all P < .001. CONCLUSIONS: This large, observational database from 1990 to 2006 shows increasing prevalence of NSTEMI and, despite higher risk profile on presentation, falling risk-adjusted hospital mortality in patients with either STEMI or NSTEMI.

Trends in quality of care for patients with acute myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006.

BACKGROUND: Trends in the use of guideline-based treatment for acute myocardial infarction (AMI) as well as its association with patient outcomes have not been summarized in a large, longitudinal study. Furthermore, it is unknown whether gender-, race-, and age-based care disparities have narrowed over time. METHODS AND RESULTS: Using the National Registry of Myocardial Infarction database, we analyzed 2,515,106 patients with AMI admitted to 2,157 US hospitals between July 1990 and December 2006 to examine trends overall and in select subgroups of guideline-based admission, procedural, and discharge therapy use. The contribution of temporal improvements in acute care therapies to declines in in-hospital mortality was examined using logistic regression analysis. From 1990 to 2006, the use of all acute guideline-recommended therapies administered rose significantly for patients with ST-segment elevation myocardial infarction and patients with non-ST-segment myocardial infarction but remained below 90% for most therapies. Cardiac catheterization and percutaneous coronary intervention use increased in patients with ST-segment elevation myocardial infarction and patients with non-ST-segment myocardial infarction, whereas coronary bypass surgery use declined in both groups. Despite overall care improvements, women, blacks, and patients > or =75 years old were significantly less likely to receive revascularization or discharge lipid-lowering therapy relative to their counterparts. Temporal improvements in acute therapies may account for up to 37% of the annual decline in risk for in-hospital AMI mortality. CONCLUSION: Adherence to American Heart Association/American College of Cardiology practice guidelines has improved care of patients with AMI and is associated with significant reductions in in-hospital mortality rates. However, persistent gaps in overall care as well as care disparities remain and suggest the need for ongoing quality improvement efforts.

Phytoestrogens and coronary microvascular function in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE) Study.

AIMS: Soy phytoestrogens are popular, but information on their coronary effects in patients with suspected ischemic heart disease is limited. Accordingly, we investigated the relationship between blood phytoestrogen levels and coronary reactivity in women with suspected myocardial ischemia referred for coronary angiography. METHODS: Coronary flow velocity reserve (CFVR) and volumetric flow reserve (VFR) to adenosine (ADO) and nitroglycerin (NTG) (nonendothelial-dependent responses) and acetylcholine (ACH) (endothelial-dependent response) were assessed in 106 women from the Women's Ischemia Syndrome Evaluation (WISE). Blood phytoestrogen (daidzein and genistein) and estrogen (estradiol) levels were correlated with coronary reactivity measures. RESULTS: Participants were mostly postmenopausal (79%), mean age 56 years, and 24% had obstructive coronary artery disease (CAD) at angiography. Genistein blood levels were negatively correlated with nonendothelial-dependent coronary flow responses. The highest genistein tertile (>6.1 ng/mL) had a CFVR of 2.1 +/- 0.5 (mean +/- SD) and VFRADO of 1.0 +/- 0.6, and both were significantly (p= 0.0001) lower compared with the other genistein tertiles combined. Similar associations were noted for CFVR(NTG) and VFR(NTG) (p = 0.03 and p = 0.01, respectively). The highest genistein tertile was associated with lower CFVR(ACH) compared with the other tertiles (p = 0.03). In multivariable modeling, blood genistein levels were significant independent predictors of coronary flow responses to ADO. There were no significant correlations between coronary reactivity variables and daidzein or endogenous estrogen. CONCLUSIONS: In women with suspected myocardial ischemia, higher genistein blood levels are associated with impaired nonendothelial-dependent and endothelial-dependent coronary microvascular function.

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 economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health--National Heart, Lung, and Blood Institute--sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND: Coronary angiography is one of the most frequently performed procedures in women; however, nonobstructive (ie, < 50% stenosis) coronary artery disease (CAD) is frequently reported. Few data exist regarding the type and intensity of resource consumption in women with chest pain after coronary angiography. METHODS AND RESULTS: A total of 883 women referred for coronary angiography were prospectively enrolled in the National Institutes of Health--National Heart, Lung, and Blood Institute--sponsored Women's Ischemia Syndrome Evaluation (WISE). Cardiovascular prognosis and cost data were collected. Direct (hospitalizations, office visits, procedures, and drug utilization) and indirect (out-of-pocket, lost productivity, and travel) costs were estimated through 5 years of follow-up. Among 883 women, 62%, 17%, 11%, and 10% had nonobstructive and 1-vessel, 2-vessel, and 3-vessel CAD, respectively. Five-year cardiovascular death or myocardial infarction rates ranged from 4% to 38% for women with nonobstructive to 3-vessel CAD (P < 0.0001). Five-year rates of hospitalization for chest pain occurred in 20% of women with nonobstructive CAD, increasing to 38% to 55% for women with 1-vessel to 3-vessel CAD (P < 0.0001). The volume of repeat catheterizations or angina hospitalizations was 1.8-fold higher in women with nonobstructive versus 1-vessel CAD after 1 year of follow-up (P < 0.0001). Drug treatment was highest for those with nonobstructive or 1-vessel CAD (P < 0.0001). The proportion of costs for anti-ischemic therapy was higher for women with nonobstructive CAD (15% versus 12% for 1-vessel to 3-vessel CAD; P = 0.001). For women with nonobstructive CAD, average lifetime cost estimates were $767,288 (95% CI, $708,480 to $826,097) and ranged from $1,001,493 to $1,051,302 for women with 1-vessel to 3-vessel CAD (P = 0.0003). CONCLUSIONS: Symptom-driven care is costly even for women with nonobstructive CAD. Our lifetime estimates for costs of cardiovascular care identify a significant subset of women who are unaccounted for within current estimates of the economic burden of coronary heart disease.

Inflammation, endothelial cell activation, and coronary microvascular dysfunction in women with chest pain and no obstructive coronary artery disease.

BACKGROUND: Coronary artery microvascular dysfunction is prevalent in women with chest pain in the absence of obstructive coronary artery disease (CAD) and is manifested by attenuated coronary flow reserve (CFR). Markers of inflammation and endothelial cell activation have been found to be elevated in patients with chest pain but without CAD. The relationship between inflammation, endothelial activation, and CFR is not known. METHODS: Ninety-four women with chest pain in the absence of obstructive angiographic CAD underwent catheterization-based assessment of CFR and measurement of levels of inflammatory markers (n = 78) and endothelial cell activation in the NHLBI WISE study. RESULTS: Coronary flow reserve did not correlate with levels of C-reactive protein (high-sensitivity C-reactive protein) (rs = -0.07, P = .53), interleukin (IL)-6 (rs = -0.12, P = .31), IL-18 (rs = 0.14, P = .23), tumor necrosis factor alpha (rs = -0.09, P = .43), transforming growth factor beta1 (rs = 0.02, P = .84), and soluble intracellular adhesion molecule-1 (rs = 0.04, P = .68). Median levels of markers of inflammation and endothelial cell activation did not differ between the 57 women with abnormal CFR (< 2.5) and the 37 women with normal coronary microvascular function (high-sensitivity C-reactive protein 0.32 vs 0.25 mg/dL, P = .80; IL-6 2.89 vs 2.39 pg/mL, P = .63; IL-18 218 vs 227 pg/mL, P = .59; tumor necrosis factor alpha 2.7 vs 2.4 pg/mL, P = .43; transforming growth factor beta1 9928 vs 12436 pg/mL, P = .76; soluble intracellular adhesion molecule-1 286 vs 287 pg/mL, P = .95). Multivariable models demonstrated no evidence of associations between markers of inflammation and of endothelial cell activation and CFR. CONCLUSIONS: Coronary microvascular dysfunction is not associated with markers of inflammation and endothelial cell activation in women with chest pain in the absence of obstructive CAD. These results suggest that inflammation and endothelial cell activation may not play a pathophysiological role in coronary microvascular dysfunction.

Quality of care by classification of myocardial infarction: treatment patterns for ST-segment elevation vs non-ST-segment elevation myocardial infarction.

BACKGROUND: Practice guidelines for acute ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) recommend similar therapies and interventions, but differences in patterns of care between MI categories have not been well described in contemporary practice. METHODS: In-hospital treatments with similar recommendations from practice guidelines were compared with outcomes in 185 968 eligible patients (without listed contraindications) with STEMI (n = 53 417; 29%) vs NSTEMI (n = 132 551; 71%) from 1247 US hospitals participating in the National Registry of Myocardial Infarction 4 between July 1, 2000, and June 30, 2002. Hierarchical logistic regression modeling was used to determine adjusted differences in treatment patterns in MI categories. RESULTS: Unadjusted in-hospital mortality rates were high for NSTEMI (12.5%) and STEMI (14.3%), and the use of guideline-recommended medications and interventions was suboptimal in both categories of patients with MI. The adjusted likelihood of receiving early (within 24 hours of presentation) aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors was higher in patients with STEMI. Similar patterns of care were noted at hospital discharge: the adjusted likelihood of receiving aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, lipid-lowering agents, smoking cessation counseling, and cardiac rehabilitation referral was higher in patients with STEMI. CONCLUSIONS: Evidence-based medications and lifestyle modification interventions were used less frequently in patients with NSTEMI. Quality improvement interventions designed to narrow the gaps in care between NSTEMI and STEMI and to improve adherence to guidelines for both categories of patients with MI may reduce the high mortality rates associated with acute MI in contemporary practice.

Azithromycin for the secondary prevention of coronary events.

BACKGROUND: Epidemiologic, laboratory, animal, and clinical studies suggest that there is an association between Chlamydia pneumoniae infection and atherogenesis. We evaluated the efficacy of one year of azithromycin treatment for the secondary prevention of coronary events. METHODS: In this randomized, prospective trial, we assigned 4012 patients with documented stable coronary artery disease to receive either 600 mg of azithromycin or placebo weekly for one year. The participants were followed for a mean of 3.9 years at 28 clinical centers throughout the United States. RESULTS: The primary end point, a composite of death due to coronary heart disease, nonfatal myocardial infarction, coronary revascularization, or hospitalization for unstable angina, occurred in 446 of the participants who had been randomly assigned to receive azithromycin and 449 of those who had been randomly assigned to receive placebo. There was no significant risk reduction in the azithromycin group as compared with the placebo group with regard to the primary end point (risk reduction, 1 percent [95 percent confidence interval, -13 to 13 percent]). There were also no significant risk reductions with regard to any of the components of the primary end point, death from any cause, or stroke. The results did not differ when the participants were stratified according to sex, age, smoking status, presence or absence of diabetes mellitus, or C. pneumoniae serologic status at baseline. CONCLUSIONS: A one-year course of weekly azithromycin did not alter the risk of cardiac events among patients with stable coronary artery disease.

Social networks are associated with lower mortality rates among women with suspected coronary disease: the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation study.

OBJECTIVE: To examine the association between social relationships measured by the Social Network Scale and coronary artery disease (CAD) risk and mortality among a sample of women with suspected CAD. METHODS: Five hundred three women (mean age, 59 years) with suspected CAD warranting clinical investigation completed a diagnostic protocol including psychosocial testing, CAD risk factor assessment, and quantitative coronary angiography. Patients were subsequently followed for a mean of 2.3 years to track all-cause mortality. RESULTS: Women reporting higher social network scores showed a consistent pattern of reduced coronary artery disease risk, including lower blood glucose levels (r = -0.11; p = .03), lower smoking rates (odds ratio [OR] = 0.81; 95% confidence interval [CI] = 0.71-0.93; p = .002), lower waist-hip ratios (r = -0.18; p < .01), and lower rates of hypertension (OR = 0.90; 95% CI = 0.81-0.99; p = .04) and diabetes (OR = 0.83; 95% CI = 0.73-0.94; p = .004). Based on quantitative angiogram findings, high social network scorers also had less severe CAD (mean angiogram stenosis value, 40.8 vs. 27.2 for low and high scoring social network groups, respectively; p < .001). Finally, mortality rates over follow-up showed a dose-response pattern in relation to quartile scorers on the Social Network Index, with low scorers showing more than twice the death rate of high scorers (relative risk = 2.4; p = .03). CONCLUSIONS: Among a cohort of women with suspected CAD, smaller social circles were associated with increased CAD risk factors and mortality, an effect that appeared to be explained largely by income level. The findings extend previous studies of social network effects on health by highlighting risk among women with suspected CAD, and suggest mechanisms for further study.