Women's Ischemia Syndrome Evaluation Research Articles

Endogenous androgens, coronary atheroma and remodeling in women with suspected ischemic heart disease: A report from the Women's Ischemia Syndrome Evaluation (WISE) study

BackgroundWomen have smaller coronary size than men independent of body surface area. Female to male heart transplantation demonstrates coronary lumen enlargement. PurposeTo investigate relationships between endogenous androgens and coronary luminal size in women with suspected ischemic heart disease (IHD). MethodsWe analyzed 69 women with available androgen levels. ResultsGroup mean age was 54 ± 10 years with 64 % post-menopausal. Lumen cross-sectional area (CSA) and external elastic membrane (EEM) CSA positively correlated with free testosterone (FT) (r = 0.29, p = 0.049; r = 0.29, p = 0.01), respectively, and negatively correlated with SHBG (r = −0.26, p = 0.03; r = −0.29, p = 0.02), respectively. Atheroma CSA positively correlated with FT (r = 0.24. p = 0.05). These correlations became non-significant after adjusting for waist circumference. ConclusionsIn women with suspected ischemic heart disease, endogenous androgens, coronary atheroma and luminal size are related, and may be moderated by waist circumference.

Dietary Composition, Angiographic Coronary Disease, and Cardiovascular Outcomes in the WISE Study (Women's Ischemia Syndrome Evaluation).

Studies relating diet to angiographic coronary artery disease (CAD) and subsequent major adverse cardiac events (MACE) in women are limited. Information on diet was collected in the Women's Ischemia Syndrome Evaluation (WISE), a prospective cohort study of symptomatic women referred for coronary angiography to evaluate suspected ischemic heart disease. A consecutive subgroup (n = 201 of 936) of enrolled women completed the modified Block food frequency questionnaire (FFQ). Data on outcomes were collected and adjudicated after 8-year follow-up. A set of logistic regression models were fitted for non-obstructive versus obstructive coronary stenosis (<50% versus ≥50%). Cox proportional hazard regression models were fitted for outcomes, with each dietary composition variable adjusted for the degree of coronary stenosis. At baseline, the subgroup cohort was 58 ± 12 years old with a body mass index (BMI) of 30 ± 7 kg/m2. An increased proportion of calories consumed from protein was associated with higher levels of baseline obstructive coronary stenosis. Those individuals who ate a higher amount of protein, carotene, and servings of vegetables and meat, however, were each associated with lower subsequent adverse outcomes, respectively. Among women undergoing coronary angiography for suspected CAD, a higher percentage of protein intake was associated with higher baseline stenosis severity; however, the amount of protein intake, vegetable, meat, and carotene intake, was conversely associated with subsequent lower adverse cardiovascular outcome risk.

Association of abnormal electrocardiography response on dobutamine stress echocardiogram with longer-term major adverse cardiovascular events in women with symptoms of ischemic heart disease.

Prior work demonstrates patients with positive (+) electrocardiogram (ECG) but negative (-) echocardiogram wall motion abnormalities (WMAs) on dobutamine stress echocardiography (DSE) testing have an elevated of major adverse cardiovascular events (MACEs). In this study, we aimed to evaluate the long-term prognosis of women with suspected ischemia with no obstructive coronary artery (INOCA) disease by utilizing core lab read DSE, specifically focusing on those with + ECG findings. Among women with signs and symptoms of myocardial ischemia undergoing clinically indicated coronary angiography enrolled in the Women's Ischemia Syndrome Evaluation (WISE) [1997-2001], a prospective cohort study, 99 underwent standardized DSE by site design. Women with positive DSE (n=17), defined as an increase in score based on wall motion scoring index were excluded except for akinetic to dyskinetic (n=10), providing 82 patients in this analysis. ECG was assessed by core laboratory and (+) ECG was defined as >1 mm ST change. Non-obstructive coronary artery disease (CAD) was assessed by core laboratory quantitative coronary angiography and defined as <50% epicardial stenosis. All-cause death follow-up was an average of 8 years, while adjudicated MACE [all-cause mortality, nonfatal myocardial infarction (MI), nonfatal stroke, heart failure hospitalization] was an average of 5.5 years. Comparisons among subject groups [i.e., (+) ECG and (-) ECG] were made using chi-square or Fisher's exact tests for categorical variables and t-test or Wilcoxon rank-sum test for continuous variables. Demographic profile included a mean age 59±10 years; 55% had hypertension (HTN), 29% diabetes mellitus (DM), and 72% non-obstructive CAD. Overall, 9/82 women (11%) had (+) ECG in the absence of WMAs. There were significant differences in family history of CAD (P=0.009) and vasodilator (P=0.042) use between the (+) ECG and (-) ECG groups, but otherwise had no significant demographic or clinical differences. At longer-term follow up, patients with (+) ECG had higher risk of MACE [unadjusted hazard ratio (HR): 4.91, 95% confidence interval (CI): 1.83, 13.19, P=0.002]. Abnormal stress ECG findings on dobutamine stress testing with a negative DSE should be viewed as an indicator of longer-term risk in women with signs and symptoms of ischemia.

High levels of high-density lipoprotein cholesterol (HDL-C) and major adverse cardiovascular events and 10-year all-cause mortality:results from Women's Ischemia Syndrome Evaluation (WISE) study

Abstract Background High and low levels of high-density lipoprotein cholesterol (HDL-C) are associated with lower and higher cardiovascular risk, respectively. Emerging data in the general population and those with coronary artery disease have shown an increased risk of adverse outcomes with high (&amp;gt;1.8mmolL [70 mg/dL]) HDL-C levels. However, there are limited data on the risk of adverse of outcomes in women with suspected ischemic heart disease and high HDL-C levels. Purpose To investigate relationships between high (&amp;gt;1.8mmol/L [70 mg/dL]), average (1.3 - 1.8 mmol/L [ 50 - 70 mg/dL]), and low (&amp;lt;1.3 mmol/L [50 mg/dL]) HDL-C levels with major adverse cardiac events (MACE) (death, myocardial infarction, stroke, and heart failure hospitalization), and 10-year all-cause mortality in women referred for coronary angiography for suspected myocardial ischemia. Methods Participants (N= 935) enrolled in the Women’s Ischemia Syndrome Evaluation (WISE) study from 1997-2001 underwent baseline testing that included fasting lipids, detailed demographic, and clinical data. A total of 607 women with available HDL-C values were included in this analysis. The adjudicated MACE outcome median follow-up was 5.9 years (range, 0 - 9.3), and the all-cause mortality median follow-up was 8.4 years (range, 0 - 11.3). Associations between HDL-C level and outcomes were obtained via multivariate cox regression and adjusted for age, race, BMI, waist circumference, menopausal status, hypertension, diabetes, family history of CAD, history of stroke, smoking history, alcohol use, statin use, and CAD status. The U-shaped curve was obtained using continuous HDL-C with the cubic spline analysis before adjusting for covariates listed above. Results The mean age of the cohort was 59±12 years, 62% had 3 or more cardiac risk factors, and 66 (10.9%) had a high HDL-C. High and low HDL-C were both associated with increased MACE risk compared to average HDL-C (HR 1.80, CI 1.03 - 3.14, p = 0.038; HR 1.63, CI 1.09 - 2.42, p = 0.016, respectively. Similarly, high and low HDL-C were associated with increased risk of all-cause mortality (HR 3.64, CI 1.84 - 7.20, p &amp;lt;0.001; HR 2.81, CI 1.67 - 4.71, p &amp;lt;0.001, respectively, Figure). Conclusions High and low HDL-C levels are associated with an increased MACE and all-cause mortality in women presenting with suspected ischemia undergoing coronary angiography. Our results highlight the need for additional prospective studies to discern the mechanisms behind high HDL-C levels and elevated risk of adverse outcomes in women.

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

BackgroundAlthough 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...

Latest from the WISE: Contributions to the Understanding of Ischemia and Heart Failure among Women with No Obstructive Coronary Arteries

Since 1996, the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) has been investigating pathophysiological processes underlying ischemic heart disease in women and related outcomes. Recent findings have focused on women with signs and symptoms of ischemia and no obstructive coronary arteries (INOCA) and their elevated risk for heart failure with preserved ejection fraction (HFpEF). This review summarizes the latest WISE findings related to INOCA and pre-HFpEF characteristics, addressing our understanding of contributions from traditional vs nontraditional risk factors in women.

Pericardial fat from a single horizontal long axis cardiac magnetic resonance cine image: a validation study against three-dimensional cardiac computed tomography

Abstract Background Excess fat accumulation around the heart (i.e., pericardial fat) is positively associated with cardiovascular disease. Pericardial fat is composed of two distinct depots: (1) epicardial fat, which is a metabolically active adipose tissue located between the heart and the pericardium, and (2) paracardial fat, which is the fat deposit in the mediastinum outside of the parietal pericardium. Both depots are visible on the horizontal long axis cardiac magnetic resonance (CMR) cine (i.e., four chamber view), offering an attractive opportunity to quantify pericardial fat from standard CMR cine images. Purpose To validate pericardial fat area measured from a single horizontal long axis CMR cine against whole-heart volumetric non-contrast cardiac computed tomography (CT) measurements. Methods To accomplish our goal, we leveraged 25 cases from the Women's Ischemia Syndrome Evaluation – Coronary Vascular Dysfunction Continuation cohort who underwent both cardiac MRI and cardiac CT within a median of 35 days apart. For MRI, pericardial fat area was measured from a single high resolution steady state free precession cine image in the horizontal long axis imaging plane using commercially available software (CVI42 V5.13.5, Circle Cardiovascular Imaging, Figure 1A). For CT, pericardial fat volume was measured using a fully automated deep learning algorithm (QFAT 2.0, Figure 1A). Results Fat area measured from a single horizontal long axis cine image was closely related to fat volume measured by three-dimensional cardiac CT, with strong correlations for epicardial fat (R2=0.72, p&amp;lt;0.01, Figure 1B), paracardial fat (R2=0.80, p&amp;lt;0.01, Figure 1C), and pericardial fat (R2=0.91, p&amp;lt;0.01, Figure 1D). Conclusions Measuring pericardial fat area, and its constituent parts, from a single horizontal long axis cine image is both feasible and strongly related to reference standard pericardial fat volume by cardiac CT. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institutes of Health

Depression Symptom Patterns as Predictors of Metabolic Syndrome and Cardiac Events in Symptomatic Women with Suspected Myocardial Ischemia

Background: Ischemic heart disease (IHD) risk in women includes biomedical, behavioral, and psychosocial contributors. The purpose of this study was to build upon previous research suggesting that in women, somatic symptoms (SS) of depression may be important to the development of IHD risk factors and major adverse cardiovascular events (MACE). Based on previous findings, we hypothesized that: (1) SS would be associated with robust biomedical predictors of heart disease and functional capacity, while cognitive symptoms (CS) of depression would not, and (2) SS would independently predict adverse health outcomes while CS would not. Methods: We examined the relationships between symptoms of depression (SS/CS), metabolic syndrome (MetS), inflammatory markers (IM), coronary artery disease (CAD) severity, and functional capacity in two independent cohorts of women with suspected IHD. In the Women's Ischemia Syndrome Evaluation (WISE), we also examined these variables as predictors of all-cause mortality (ACM) + MACE over a median 9.3-year follow-up. The WISE sample included 641 women with suspected ischemia with or without obstructive CAD. The WISE-Coronary Vascular Dysfunction (WISE-CVD) sample consisted of 359 women with suspected ischemia and no obstructive CAD. All study measures were collected uniformly at baseline. Depressive symptoms were measured via the Beck Depression Inventory. MetS was assessed according to Adult Treatment Panel III (ATP-III) criteria. Results: In both studies, SS was associated with MetS (Cohen's d = 0.18, 0.26, P &lt; 0.05, respectively), while CS was not. Within WISE, using Cox Proportional Hazard Regression, SS (Hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 1.01–1.15; HR = 1.07, 95% CI = 1.00–1.13) and MetS (HR = 1.89, 95% CI = 1.16–3.08; HR = 1.74, 95% CI=1.07–2.84) were independent predictors of ACM + MACE after controlling for demographics, IM, and CAD severity, while CS was not. Conclusions: In two independent samples of women undergoing coronary angiography due to suspected ischemia, SS but not CS of depression were associated with MetS, and both SS and MetS independently predicted ACM and MACE. These results add to previous studies suggesting that SS of depression may warrant specific attention in women with elevated cardiovascular disease (CVD) risk. Future research evaluating the biobehavioral basis of the relationship between depression, MetS, and CVD is needed.

Trans-myocardial omega-3 fatty acid gradient in coronary microvascular dysfunction

BackgroundCardiac remodeling is a process mediated, in part, by 18-hydroxyeicosapentaenoic acid (HEPE), a metabolite of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA). We hypothesized that trans-myocardial levels of 18-HEPE could inform the pathophysiologic processes involved in heart failure with preserved ejection fraction (HFpEF). MethodsWe measured the concentration of 18-HEPE and EPA in trans-myocardial plasma samples from 10 subjects enrolled in The Women's Ischemia Syndrome Evaluation [WISE] Mechanisms of Coronary Microvascular Dysfunction Leading to Pre-HFpEF project. ResultsConcentrations of 18-HEPE were significantly lower in coronary venous compared to the aortic plasma (270.5 pg/mL [212.8–480.8] vs. 430.5 pg/mL [299.5–655.8], p = 0.0039). There was a significant correlation between the concentrations of coronary venous EPA and aortic 18-HEPE (r = 0.94, p = 0.0002), and aortic EPA and aortic 18-HEPE (r = 0.82, p = 0.0058). ConclusionsResults of this small pilot study support the suggestion that 18-HEPE is synthesized outside the heart and utilized within the myocardial bed.

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

AimsBody 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 ResultsWomen 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).ConclusionTo 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.

Anemia and Long-term cardiovascular outcomes in women with suspected ischemia – The Women's Ischemia Syndrome Evaluation (WISE)

BackgroundAnemia is associated with adverse cardiovascular outcomes in patients with ischemic heart disease and is more prevalent in women as compared to men. Prior studies have evaluated short-term outcomes in women with stable angina and relatively low rates of obstructive coronary artery disease (CAD). We investigated the long-term clinical significance of baseline anemia in this cohort. MethodsWe studied 885 women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) undergoing clinically indicated coronary angiography for suspected ischemia. Anemia at enrollment was defined as hemoglobin (Hgb) level < 12 g/dL. Major adverse cardiovascular events (MACE) included cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, stroke, and vascular events. Cox regression models and Kaplan-Meier methods were used. ResultsOverall, the women, mean age 58.4 ± 11.7 years, were followed for an average of seven years (range 0–11 years). Anemia was present in 21.1%. They had higher creatinine levels with more frequent history of diabetes mellitus, hypertension, and HF (p < 0.05) but similar obstructive coronary artery disease compared to non-anemic women. Anemic women had higher long-term all-cause mortality and MACE rate. In multivariable analysis, anemia was independently associated with increased MACE risk (hazard ratio (HR): 1.5, 95% confidence interval [1.117–2.017, p = 0.007]) but not all-cause mortality (HR:1.2 [0.841, 1.727, p = 0.309]). ConclusionsAmong women evaluated for symptoms of ischemia, anemia is associated with and independently predicts long-term MACE. Further research targeting anemia management in women to mitigate these adverse outcomes is warranted.

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

Study objectiveWomen 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 participantsWomen 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. ResultsDuring 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. ConclusionsThere 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.

Coronary atheroma burden predicts flow reserve in women with ischemia and nonobstructive coronary artery disease

BackgroundWomen with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD) with reduced coronary flow reserve (CFR), and compensatory coronary remodeling. Angiographic measurements of epicardial coronary anatomy (AMCA) may improve understanding of relations between CFR and atherosclerosis. We investigated AMCA and CFR in women evaluated for CMD. MethodsWomen consecutively enrolled in the Women's Ischemia Syndrome Evaluation CVD Continuation (NCT00832702) were included. All underwent clinically indicated coronary function testing measuring CFR. AMCA included coronary angiographic atheroma burden (AB), percent diameter stenosis (PDS), and tapering reference diameter Z score (RDZ), derived for the left main and left anterior descending coronary epicardial segments. ResultsThe 51 women were aged 55.8 ± 10.8 years, with 19(38%) hypertensive, 10(20.4%) hyperlipidemic, 4(7.8%) diabetic, 13(25.5%) prior smokers, and mean CFR 3.0 ± 0.8. Both average and maximal AB negatively correlated with CFR (r = −0.30 and −0.31, with p = 0.04 for both), as did average and maximal PDS (r = −0.38 and −0.41 with p = 0.009 and p = 0.005) while average RDZ was directly related (r = 0.37, p = 0.01). Multiple linear regression analyses revealed that both average PDS (Units of CFR −0.03 95% CI: −0.06, −0.002, p = 0.023) and maximal PDS (−0.04 95% CI −0.07, −0.01, p = 0.007) were negatively related to CFR. ConclusionsMeasures of epicardial coronary atheroma burden, size and tapering are related to CFR, suggesting that atherosclerotic anatomical findings may contribute to or be a consequence of CMD, with further work is needed to investigate these measures as treatment targets.

Predictors of the age at which natural menopause occurs in women with type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study.

Women with type 1 diabetes (T1D) are thought to experience menopause earlier than women without diabetes, although not all studies agree. We assessed metabolic predictors of the age at which natural menopause occurs among women with T1D participating in the Epidemiology of Diabetes Complications study. Women with childhood-onset (<17 y) of T1D who underwent natural menopause without use of hormone therapy during their menopausal transition were included in the analysis (n = 105; mean baseline age, 29.5 and diabetes duration, 20.2 y). Self-reported reproductive history and the Women's Ischemia Syndrome Evaluation hormonal algorithms were used to determine menopause status. Linear regression was used to ascertain whether time-weighted metabolic factors (eg, BMI, lipids, HbA1c, insulin dose, albumin excretion rate [AER]) were associated with age at natural menopause. Univariately, only insulin dose (β = -4.87, P = 0.04) and log (AER) (β = -0.62, P = 0.02) were associated (negatively) with age at natural menopause. Adjusting for BMI, smoking status, lipids, HbA1c, number of pregnancies, and oral contraceptive use, each 0.1 unit increase in the daily dose of insulin per kilogram body weight was associated with 0.64 years younger age at natural menopause (P = 0.01), while for every 30% increase in AER, age at natural menopause decreased by 0.18 years (P = 0.03). Higher average levels of insulin dose and AER over time were significantly associated with a younger age at which natural menopause occurred among women with T1D. The biologic mechanisms underlying the observed associations between exogenous insulin dose and AER on reproductive health should be investigated among women with T1D.

Women with Type 1 diabetes (T1D) experience a shorter reproductive period compared with nondiabetic women: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study and the Study of Women's Health Across the Nation (SWAN).

Evidence suggests that insulin deficiency and hyperglycemia may disrupt the female reproductive system's normal function, leading to delayed menarche and premature ovarian aging. We thus compared the length of the reproductive period of women with type 1 diabetes (T1D) to women without diabetes. Women with childhood-onset T1D (diagnosed in 1950-80) from the prospective Epidemiology of Diabetes Complications (EDC) study and nondiabetic women from the Pittsburgh site of the Study of Women's Health Across the Nation (SWAN) were studied. Exclusion criteria comprised not having reached natural menopause, hysterectomy/oophorectomy before menopause, and sex hormone therapy during the menopausal transition. Reproductive history was self-reported. The historical and Women's Ischemia Syndrome Evaluation hormonal algorithms were also used to assess menopause status. Women in the T1D cohort (n = 105) were younger, more likely to be White, never smokers, with lower BMI and higher high-density lipoprotein cholesterol levels (all P values < 0.05) compared with women without diabetes (n = 178). After covariate adjustment, T1D women were also older at menarche (0.5-y delay, P = 0.002) but younger at natural menopause (-2.0 y, P < 0.0001). Women with T1D thus experienced 2.5 fewer reproductive years compared to those without diabetes (P < 0.0001). These findings were restricted to the subgroup of women who were diagnosed with T1D before reaching menarche (n = 80). Women with T1D onset before menarche have a shorter reproductive period compared with nondiabetic women, exhibiting delayed menarche and earlier natural menopause. Factors that may be related to a shorter reproductive period in T1D should be investigated.

Prior Oral Contraceptive Use and Longer Term Mortality Outcomes in Women with Suspected Ischemic Heart Disease.

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 < 0.05). Prior OC use was associated with lower 10-year all-cause (p = 0.007) and CVD mortality (p = 0.019). After adjustment, this was no longer significant (p = 0.77 and p = 0.90, respectively). Atherosclerotic CAD severity score mediated one-third of the observed association. Prior OC use was associated with increased CVD mortality among women with very elevated menopausal systolic blood pressure (SBP). Conclusions: Unadjusted prior OC use was associated with lower longer-term all-cause and CVD mortality. One-third of this observed effect appears mediated by the atherosclerotic CAD severity score. Prior OC was adversely associated with CVD mortality in women with very elevated menopausal SBP. Additional investigation is needed to understand the potential benefits and harms of prior OC use. Clinical Trial Number: NCT00000554, or https://www.clinicaltrials.gov/ct2/show/NCT00000554.

Abstract 15436: Left Ventricular Ejection Fraction and MACE in Women With Signs and Symptoms of Ischemia: Data From the WISE (Women's Ischemia Syndrome Evaluation)

Background: Relatively high left ventricular ejection fraction (EF) (&gt;65%) in women was recently associated with higher all-cause mortality over 6 years follow-up in the CONFIRM study. We sought to evaluate high EF and major adverse cardiovascular events (MACE) in the Women’s Ischemia Syndrome Evaluation (WISE) study. Methods: The WISE original cohort (enrolled 1996-2000) is a multicenter prospective study of women with suspected ischemic heart disease undergoing clinically indicated invasive coronary angiography. We investigated the relationship between high (&gt;65%) and normal (55-65%) EF and MACE, defined as all-cause death, nonfatal myocardial infarction (MI), stroke and heart failure (HF) hospitalization using Kaplan Meier (KM) and regression analyses. Results: A total of 653 women were included (298 high and 355 normal EF). Mean age was 58±11 years and mean EF was 68±7%. There was no significant difference in MACE by EF group over a 10-year follow-up period (log rank p=0.54, Figure ). When patients were stratified by the presence of obstructive CAD, MACE rates remained similar between high and normal EF. High EF was not associated with stroke or HF but had a lower MI risk (log rank p=0.03, Table ). EF was not associated with MACE in a multivariable regression model. Conclusions: Among women presenting with evidence of ischemia, there was no significant difference in MACE between high and normal EF groups. High EF was associated with a lower risk of myocardial infarction as an individual component of MACE.

Abstract 14597: High Left Ventricular Ejection Fraction and All-cause Mortality in Women With Ischemia: Data From the WISE (Women's Ischemia Syndrome Evaluation)

Background: Relatively high left ventricular ejection fraction (EF) (&gt;65%) was recently associated with higher all-cause mortality in women but not men undergoing noninvasive coronary angiography in the CONFIRM study, although this did not remain significant following adjustment for risk variables and mortality was not adjudicated. We investigated high EF and adjudicated all-cause mortality in the Women’s Ischemia Syndrome Evaluation (WISE) study. Methods: The WISE original cohort (enrolled 1996-2000), is a multicenter prospective study of women with suspected ischemic heart disease undergoing clinically indicated coronary angiography. EF was calculated by invasive left ventriculography. We investigated the relationship among high (&gt;65%), normal (55-65%) and low (&lt;55%) EF and adjudicated all-cause mortality using Kaplan Meier and regression analyses. Results: Overall 734 women included 298 (41%) high, 355 (48%) normal, and 81 (11%) low EF. The mean age was 58±11 years and mean EF was 65±11% (43%, 63% and 75% in the low, normal and high groups respectively). Over 10 years of follow-up, all-cause mortality occurred in 18% of patients, ranging from 12% in the high EF group to 41% in the low EF group. EF was associated with mortality among groups ( Figure ). Low EF remained a significant predictor of mortality compared to high EF, but normal EF compared to high EF did not in a multivariable regression model. Compared to women in the CONFIRM study, our cohort had higher mean EF (65% v. 62%), higher rates of obstructive CAD and diabetes, and lower rates of hypertension and dyslipidemia. Conclusions: Higher EF was not associated with higher all-cause mortality adjudicated predominantly cardiovascular in women with evidence of ischemia. Potential explanations for the lack of concordance with the CONFIRM study may include lack of death adjudication, differences in comorbidities, or other unknown factors.

Left ventricular circumferential strain and coronary microvascular dysfunction: A report from the Women's Ischemia Syndrome Evaluation Coronary Vascular Dysfunction (WISE-CVD) Project

AimsWomen with ischemia but no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical dysfunction. Methods and resultsCardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) <1.84 during adenosine-stress perfusion cMR, was compared with CS in women without CMD. In a subset who had invasive coronary function testing (CFT), the relationship between CS and CFT metrics, LV ejection fraction (LVEF) and cardiovascular risk factors was investigated. Among 317 women with INOCA, 174 (55%) had CMD measured by MPRI. CS was greater in women with CMD compared to those without CMD (23.2 ± 2.5% vs. 22.1 ± 3.0%, respectively, P = 0.001). In the subset with CFT (n = 153), greater CS was associated with increased likelihood of reduced vasodilator capacity (OR = 1.33, 95%CI = 1.02–1.72, p = 0.03) and discriminated abnormal vs. normal coronary vascular function compared to CAD risk factors, LVEF and LV concentricity (AUC: 0.82 [0.73–0.96 95%CI] vs. 0.65 [0.60–0.71 95%CI], respectively, P = 0.007). ConclusionThe data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical dysfunction in CMD.

Phytoestrogen blood levels and adverse outcomes in women with suspected ischemic heart disease.

Prior studies linked higher blood phytoestrogen (phytoE) levels of daidzein to beneficial lipoprotein profiles, and higher genistein levels related to worse coronary microvascular dysfunction in women with suspected ischemic heart disease (IHD). However, relationships to adverse outcomes remain unclear. We investigated the associations between eight serum phytoE and major adverse cardiac events (MACE) including myocardial infarction, stroke, hospitalization for heart failure and angina, cardiovascular and all-cause mortality, in women undergoing functional coronary angiography (FCA) for suspected ischemia. We evaluated 143 women enrolled in the Women's Ischemia Syndrome Evaluation (1996-2001) for serum phytoE levels and 10-year outcomes. Median follow-up duration was 6.08 years (range 0.01-8.16) for time to MACE and 9.11 years (range 0.01-11.08 years) for time to death. Kaplan-Meier plots were analyzed and Cox regression models adjusted for age, body mass index, hypertension, diabetes, dyslipidemia and tobacco use. The median age was 54.7 (range 20.6-76.1) years and BMI was 29.3 (range 18.4-57.2). Of the cohort, 80.4% had nonobstructive coronary artery disease, 56% had hypertension, 22.4% had diabetes, 58.1% had dyslipidemia and 59.4% of the women used tobacco. Each unit decrease in log glycitin was associated with increased MACE hazard (HR 1.97, 95% [CI 1.23, 3.14], p = 0.005). Glycitin absence was associated with earlier angina hospitalization (log rank p = 0.05). After 6 years, MACE increased with each unit decrease in log genistein (HR 6.17, 95% [CI 1.81, 20.8], p = 0.0036). Other phytoE did not show statistically significant associations with outcomes. Among women with suspected IHD undergoing clinically indicated invasive FCA, low serum glycitin was associated with increased MACE and earlier angina hospitalization, while low genistein was associated with increased MACE after 6 years. Future studies are needed regarding phytoE, nutrition, outcomes and possibly supplementation.