Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Left ventricular ejection fraction and long-term outcomes in women presenting with signs and symptoms of ischaemia.

BACKGROUND: Although women are known to have a relatively higher left ventricular ejection fraction (LVEF) compared with men, a sex-neutral LVEF threshold continues to be used for clinical management. We sought to investigate the relationship among high (>65%), normal (55%-65%) and low (<55%) LVEF and long-term all-cause mortality and major adverse cardiovascular events (MACEs) in women presenting with suspected myocardial ischaemia. METHODS: A total of 734 women from the Women's Ischemia Syndrome Evaluation (WISE) were analysed. LVEF was calculated by invasive left ventriculography. The relationship between baseline characteristics, LVEF and outcomes was evaluated. A multivariable Cox regression model was used to assess the association of LVEF with outcomes, after adjusting for known risk factors. RESULTS: Low LVEF was associated with higher rates of mortality and MACE compared with normal and high LVEF (p<0.0001). Normal LVEF was associated with higher mortality (p=0.047) and rate of myocardial infarctions (MIs) compared with high LVEF (p=0.03). Low LVEF remained a significant predictor of mortality compared with high LVEF (p=0.013) in a multivariable regression model and normal compared with high LVEF trended towards higher mortality (p=0.16). CONCLUSION: Among women with suspected ischaemia, women with LVEF above the defined normal threshold (>65%) had lower rates of all-cause mortality and non-fatal MI. Further investigation is needed to determine the optimal LVEF in women. TRIAL REGISTRATION NUMBER: NCT00000554.

Body weight and physical fitness in women with ischaemic heart disease: does physical fitness contribute to our understanding of the obesity paradox in women?

AIMS: Body mass index (BMI) defined obesity is paradoxically associated with lower all-cause mortality in patients with known cardiovascular disease. This study aims to determine the role of physical fitness in the obesity paradox in women with ischaemic heart disease (IHD). METHODS AND RESULTS: Women undergoing invasive coronary angiography with signs/symptoms of IHD in the Women's Ischemia Syndrome Evaluation (WISE) prospective cohort (enrolled 1997-2001) were analysed. This study investigated the longer-term risk of major adverse cardiovascular events (MACE) and all-cause mortality associated with BMI and physical fitness measured by Duke Activity Status Index (DASI). Overweight was defined as BMl ≥25 to 30 kg/m2, obese as BMI ≥30 kg/m2, unfit as DASI scores <25, equivalent to ≤7 metabolic equivalents. Among 899 women, 18.6% were normal BMI-fit, 11.4% overweight-fit, 10.4% obese-fit, 15.3% normal BMI-unfit, 23.8% overweight-unfit, and 30.4% obese-unfit. In adjusted models compared to normal BMI-fit, normal BMI-unfit women had higher MACE risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.17-2.32; P = 0.004]; whereas obese-fit and overweight-fit women had lower risk of mortality (HR 0.60, 95% CI 0.40-0.89; P = 0.012 and HR 0.62, 95% CI 0.41-0.92; P = 0.018, respectively). CONCLUSION: To address the paradox of body weight and outcomes in women, we report for the first time that among women with signs/symptoms of IHD overweight-fit and obese-fit were at lower risk of long-term all-cause mortality; whereas normal BMI-unfit were at higher risk of MACE. Physical fitness may contribute to the obesity paradox in women, warranting future studies to better understand associations between body weight, body composition, and physical fitness to improve cardiovascular outcomes in women.

Risk factors for heart failure in women with ischemia and no obstructive coronary artery disease.

Study objective: Women with ischemia and no obstructive coronary artery disease (INOCA) are at increased risk for heart failure (HF) hospitalizations, which is predominantly HF with preserved ejection fraction (HFpEF). We aimed to identify predictors for the development of heart failure HF in a deeply phenotyped cohort of women with INOCA and long-term prospective follow-up. Design setting and participants: Women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) were evaluated for baseline characteristics including clinical history, medications, physical exam, laboratory data and angiographic data. Using a multivariate Cox analysis, we assessed the association between baseline characteristics and the occurrence of HF hospitalizations in 493 women with evidence of ischemia but no obstructive coronary disease, no prior history of HF, and available follow-up data. Results: During a median follow-up of 6-years, 18 (3.7%) women were hospitalized for HF. Diabetes mellitus and tobacco use were associated with HF hospitalization. In a multivariate analysis adjusting for known HFpEF predictors including age, diabetes, hypertension, tobacco use, and statin use, novel predictive variables included higher resting heart rate, parity and IL-6 levels and lower coronary flow reserve (CFR) and poor functional status. Conclusions: There is a considerable incidence of HF hospitalization at longer term follow-up in women with INOCA. In addition to traditional risk factors, novel risk variables that independently predict HF hospitalization include multi-parity, high IL-6, low CFR, and poor functional status. These novel risk factors may be useful to understand mechanistic pathways and future treatment targets for prevention of HFpEF.

Not typical angina and mortality in women with obstructive coronary artery disease: Results from the Women's Ischemic Syndrome Evaluation study (WISE).

BACKGROUND: Women frequently present with symptoms not typical of angina (NTA) making ischemic heart disease recognition, diagnosis and treatment challenging. We compared mortality in women with obstructive coronary artery disease (CAD) with NTA vs typical angina (TA). METHODS: We studied 326 Women's Ischemia Syndrome Evaluation (WISE) participants undergoing coronary angiography for suspected myocardial ischemia with core-lab measured obstructive CAD. TA was defined as sub-sternal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin; NTA did not meet criteria for TA. The women were followed for non-fatal events and death for a median of 5.9 and 9.6 years respectively. Multivariate cox proportional hazards regression determined relations to events. RESULTS: Overall, 115 (35%) of the women had TA. Baseline demographics, risk factors or additional symptom characteristics were similar between the two angina groups. Non-fatal events did not differ between groups. Women with NTA had a higher mortality compared to TA women (36% vs 26%, respectively, p = 0.047). Despite adjustment for additional major risk variables, NTA was an independent predictor of mortality compared to TA with a hazard ratio of 1.73 (95% Confidence interval: 1.04, 2.89). CONCLUSIONS: Among women with suspected ischemia undergoing coronary angiography with obstructive CAD, NTA was more common than TA, and predicted a higher longer-term mortality. Further investigation is needed to confirm these results, and investigate potential explanations for the higher mortality observed in women with NTA women, including lower recognition or action in the setting of obstructive CAD.

Angina Hospitalization Rates in Women With Signs and Symptoms of Ischemia But no Obstructive Coronary Artery Disease: A Report from the WISE (Women's Ischemia Syndrome Evaluation) Study.

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%

Prevalence of Coronary Endothelial and Microvascular Dysfunction in Women with Symptoms of Ischemia and No Obstructive Coronary Artery Disease Is Confirmed by a New Cohort: The NHLBI-Sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD).

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 <20% epicardial coronary dilation to nitroglycerin (NTG). 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<0.0001), and smoking (46% vs 56%, p=0.036). Similar rates were observed in WISE-CVD and WISE cohorts for CMD (mean CFR 2.7±0.6 vs 2.6±0.8, p=0.35), mean change in diameter with intracoronary ACH (0.2±10.0 vs 1.6±12.8 mm, p=0.34), and mean change in diameter with intracoronary NTG (9.7±13.0 vs 9.8±13.5 mm, p=0.94), respectively. 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.

BARI 2D: A Reanalysis Focusing on Cardiovascular Events.

OBJECTIVE: To reanalyze the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial using a new composite cardiovascular disease (CVD) outcome to determine how best to treat patients with type 2 diabetes mellitus and stable coronary artery disease. PATIENTS AND METHODS: From January 1, 2001, to November 30, 2008, 2368 patients with type 2 diabetes mellitus and angiographically proven coronary artery disease were randomly assigned to insulin-sensitizing (IS) or insulin-providing (IP) therapy and simultaneously to coronary revascularization (REV) or no or delayed REV (intensive medical therapy [MED]), with all patients receiving intensive medical treatment. The outcome of this analysis was a composite of 8 CVD events. RESULTS: Four-year Kaplan-Meier rates for the composite CVD outcome were 35.8% (95% CI, 33.1%-38.5%) with IS therapy and 41.6% (95% CI, 38.7%-44.5%) with IP therapy (P=.004). Much of this difference was associated with lower in-trial levels of fibrinogen, C-reactive protein, and hemoglobin A1c with IS therapy. Four-year composite CVD rates were 32.7% (95% CI, 30.0%-35.4%) with REV and 44.7% (95% CI, 41.8%-47.6%) with MED (P<.001). A beneficial effect of IS vs IP therapy was present with REV (27.7%; 95% CI, 24.0%-31.4% vs 37.5%; 95% CI, 33.6%-41.4%; P<.001), but not with MED (43.6%; 95% CI, 39.5%-47.7% vs 45.7%; 95% CI, 41.6%-49.8%; P=.37) (homogeneity, P=.05). This interaction between IS therapy and REV was limited to participants preselected for coronary artery bypass grafting (CABG). The lowest composite CVD rates occurred in patients preselected for CABG and assigned to IS therapy and REV (17.3%; 95% CI, 11.8%-22.8%). CONCLUSION: In the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial, the IS treatment strategy and the REV treatment strategy each reduces cardiovascular events. The combination of IS drugs and CABG results in the lowest risk of subsequent CVD events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00006305.

Impact of Abnormal Coronary Reactivity on Long-Term Clinical Outcomes in Women.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).

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

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

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.

Aortic flow conditions predict ejection efficiency in the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: The Windkessel model of the cardiovascular system, both in its original wind-chamber and flow-pipe form, and in its electrical circuit analog has been used for over a century to modeled left ventricular ejection conditions. Using parameters obtained from aortic flow we formed a Flow Index that is proportional to the impedance of such a "circuit". We show that the impedance varies with ejection fraction (EF) in a manner characteristic of a resonant circuit with multiple resonance points, with each resonance point centrally located in a small range of EF values, i.e., corresponding to multiple contiguous EF bands. METHODS: Two target populations were used: (I) a development group comprising male and female subjects (n=112) undergoing cardiovascular magnetic resonance (CMR) imaging for a variety of cardiac conditions. The Flow Index was developed using aortic flow data and its relationship to left ventricular EF was shown. (II) An illustration group comprised of female subjects from the Women's Ischemia Syndrome Evaluation (WISE) (n=201) followed for 5 years for occurrence of major adverse cardiovascular events (MACE). Flow data was not available in this group but since the Flow Index was related to the EF we noted the MACE rate with respect to EF. RESULTS: The EFs of the development population covered a wide range (9%-76%) traversing six Flow Index resonance bands. Within each Flow Index resonance band the impedance varied from highly capacitive at the lower range of EF through minimal impedance at resonance, to highly inductive at the higher range of EF, which is characteristic of a resonant circuit. When transitioning from one EF band to a higher band, the Flow Index made a sudden transition from highly inductive to capacitive impedance modes. MACE occurred in 26 (13%) of the WISE (illustration) population. Distance in EF units (Deltacenter) from the central location between peaks of MACE activity was derived from EF data and was predictive of MACE rate with an area under the receiver operator curve of 0.73. Of special interest, Deltacenter was highly predictive of MACE in the sub-set of women with EF >60% (AUC 0.79) while EF was no more predictive than random chance (AUC 0.48). CONCLUSIONS: A Flow Index that describes impedance conditions of left ventricular ejection can be calculated using data obtained completely from the ascending aorta. The Flow Index exhibits a periodic variation with EF, and in a separate illustration population the occurrence of MACE was observed to exhibit a similar periodic variation with EF, even in cases of normal EF.

Inflammatory biomarkers as predictors of heart failure in women without obstructive coronary artery disease: A report from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Women with signs and symptoms of ischemia, no obstructive coronary artery disease (CAD) and preserved left ventricular ejection fraction (EF) often have diastolic dysfunction and experience elevated rates of major adverse cardiac events (MACE), including heart failure (HF) hospitalization with preserved ejection fraction (HFpEF). We evaluated the predictive value of inflammatory biomarkers for long-term HF hospitalization and all-cause mortality in these women. METHODS: We performed a cross-sectional analysis to investigate the relationships between inflammatory biomarkers [serum interleukin-6 (IL-6), C-reactive protein (hs-CRP) and serum amyloid A (SAA)] and median of 6 years follow-up for all-cause mortality and HF hospitalization among women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF. Multivariable Cox regression analysis tested associations between biomarker levels and adverse outcomes. RESULTS: Among 390 women, mean age 56 ± 11 years, median follow up of 6 years, we observed that there is continuous association between IL-6 level and HF hospitalization (adjusted hazard ratio [AHR] 2.5 [1.2-5.0], p = 0.02). In addition, we found significant association between IL-6, SAA levels and all-cause mortality AHR (1.8 [1.1-3.0], p = 0.01) (1.5 [1.0-2.1], p = 0.04), respectively. CONCLUSION: In women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF, elevated IL-6 predicted HF hospitalization and all-cause mortality, while SAA level was only associated with all-cause mortality. These results suggest that inflammation plays a role in the pathogenesis of development of HFpEF, as well all-cause mortality.

SYNTAX Score and Long-Term Outcomes: The BARI-2D Trial.

BACKGROUND: The extent of coronary disease affects clinical outcomes and may predict the effectiveness of coronary revascularization with either coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score quantifies the extent of coronary disease. OBJECTIVES: This study sought to determine whether SYNTAX scores predicted outcomes and the effectiveness of coronary revascularization compared with medical therapy in the BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. METHODS: Baseline SYNTAX scores were retrospectively calculated for BARI-2D patients without prior revascularization (N = 1,550) by angiographic laboratory investigators masked to patient characteristics and outcomes. The primary outcome was major cardiovascular events (a composite of death, myocardial infarction, and stroke) over 5 years. RESULTS: A mid/high SYNTAX score (≥23) was associated with a higher risk of major cardiovascular events (hazard ratio: 1.36, confidence interval: 1.07 to 1.75, p = 0.01). Patients in the CABG stratum had significantly higher SYNTAX scores: 36% had mid/high SYNTAX scores compared with 13% in the PCI stratum (p < 0.001). Among patients with low SYNTAX scores (≤22), major cardiovascular events did not differ significantly between revascularization and medical therapy, either in the CABG stratum (26.1% vs. 29.9%, p = 0.41) or in the PCI stratum (17.8% vs. 19.2%, p = 0.84). Among patients with mid/high SYNTAX scores, however, major cardiovascular events were lower after revascularization than with medical therapy in the CABG stratum (15.3% vs. 30.3%, p = 0.02), but not in the PCI stratum (35.6% vs. 26.5%, p = 0.12). CONCLUSIONS: Among patients with diabetes and stable ischemic heart disease, higher SYNTAX scores predict higher rates of major cardiovascular events and were associated with more favorable outcomes of revascularization compared with medical therapy among patients suitable for CABG. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes; NCT00006305).

Menopausal symptoms and cardiovascular disease mortality in the Women's Ischemia Syndrome Evaluation (WISE).

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Use of bio-informatics assessment schema (BIAS) to improve diagnosis and prognosis of myocardial perfusion data: results from the NHLBI-sponsored women's ischemia syndrome evaluation (WISE).

BACKGROUND: We introduce an algorithmic approach to optimize diagnostic and prognostic value of gated cardiac single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) modalities in women with suspected myocardial ischemia. The novel approach: bio-informatics assessment schema (BIAS) forms a mathematical model utilizing MPI data and cardiac metrics generated by one modality to predict the MPI status of another modality. The model identifies cardiac features that either enhance or mask the image-based evidence of ischemia. For each patient, the BIAS model value is used to set an appropriate threshold for the detection of ischemia. METHODS: Women (n=130), with symptoms and signs of suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two different modalities: gated SPECT and MR. To determine perfusion status, MR data were evaluated qualitatively (MRIQL) and semi-quantitatively (MRISQ) while SPECT data were evaluated using conventional clinical criteria. Evaluators were masked to results of the alternate modality. These MPI status readings were designated "original". Two regression models designated "BIAS" models were generated to model MPI status obtained with one modality (e.g., MRI) compared with a second modality (e.g., SPECT), but importantly, the BIAS models did not include the primary Original MPI reading of the predicting modality. Instead, the BIAS models included auxiliary measurements like left ventricular chamber volumes and myocardial wall thickness. For each modality, the BIAS model was used to set a progressive threshold for interpretation of MPI status. Women were then followed for 38±14 months for the development of a first major adverse cardiovascular event [MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for heart failure]. Original and BIAS-augmented perfusion status were compared in their ability to detect coronary artery disease (CAD) and for prediction of MACE. RESULTS: Adverse events occurred in 14 (11%) women and CAD was present in 13 (10%). There was a positive correlation of maximum coronary artery stenosis and BIAS score for MRI and SPECT (P<0.001). Receiver operator characteristic (ROC) analysis was conducted and showed an increase in the area under the curve of the BIAS-augmented MPI interpretation of MACE vs. the original for MRISQ (0.78 vs. 0.54), MRIQL (0.78 vs. 0.64), SPECT (0.82 vs. 0.63) and the average of the three readings (0.80±0.02 vs. 0.60±0.05, P<0.05). CONCLUSIONS: Increasing values of the BIAS score generated by both MRI and SPECT corresponded to the increasing prevalence of CAD and MACE. The BIAS-augmented detection of ischemia better predicted MACE compared with the Original reading for the MPI data for both MRI and SPECT.

Cardiovascular Disease and 10-Year Mortality in Postmenopausal Women with Clinical Features of Polycystic Ovary Syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have greater cardiac risk factor clustering but the link with mortality is incompletely described. OBJECTIVE: 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. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.