Women's Ischemia Research Articles

Contributors to high left ventricular ejection fraction in women with ischemia and no obstructive coronary artery disease: Results from the Women's Ischemia Syndrome Evaluation—Coronary Vascular Dysfunction (WISE-CVD) Study

There are sex differences in left ventricular ejection fraction (LVEF) relevant to prognosis where women experience greater mortality at relatively higher LVEF compared to men, yet mechanistic understanding of this adverse prognosis is limited. Women with suspected ischemia with no obstructive coronary disease (INOCA) develop heart failure with preserved ejection fraction (HFpEF), yet contributors to LVEF remain largely unknown. In 370 women with suspected ischemia with no obstructive coronary disease (INOCA) who prospectively underwent cardiac magnetic resonance imaging (CMRI), we investigated the contributions of LV morphology, function, and myocardial perfusion reserve on LVEF using univariate and multiple linear regression. A majority 71% of participants had high LVEF (>65%), followed by 24% having normal LVEF (55%-65%), and only 5% having low EF (<55%). Baseline characteristics were comparable among the 3 groups, with the exception of age which was 6 years higher in the high LVEF group (P < .01). Women in the high LVEF group also had the lowest LV cavity volume, greatest LV mass-volume ratio, and highest LV end-systolic elastance (all P < .05, adjusted for age, BMI, diabetes, and blood pressure). Myocardial perfusion reserve index was low in all groups (mean MPRI < 2.1) but was not significantly different across the spectrum of LVEF (P = .458). Taken together, these data demonstrate that the majority of women with suspected INOCA have elevated LVEF related to smaller, thicker ventricles with greater contractility. Future work is needed to better understand the specific mechanisms driving morphologic and functional changes in women with INOCA, and relations to longer-term HFpEF and mortality. NCT02582021.

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.

Comparison of risk profiles of participants in the Women's IschemiA TRial to Reduce events In non-ObstRuctive CAD (WARRIOR) trial, using Coronary Computed Tomography Angiography vs Invasive Coronary Angiography

ObjectiveTo compare baseline characteristics of participants in the Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR) trial by qualification by Coronary Computed Tomography Angiography (CCTA) or Invasive Coronary Angiography (ICA). MethodsThe WARRIOR trial (NCT03417388) is an ongoing multicenter, prospective, randomized, blinded outcome evaluation of intensive medical therapy vs. usual care in women with suspected Ischemia and No Obstructive Coronary Artery Disease (INOCA) identified by either CCTA or ICA on the outcome of major adverse cardiovascular events (MACE). No obstructive coronary artery disease is defined as <50% luminal stenosis and normal coronary arteries is defined as no evidence of atherosclerosis including calcified and non-calcified plaque. Data presented was extracted on May 27, 2020. No clinical outcomes were assessed. ResultsAn initial sample cohort of 797 women was included. The majority were younger than 65 years, White participants (73.3%), 159 had diabetes (19.9%), and 676 had angina (84.8%) with the remainder having symptoms of suspected ischemic heart disease. Over 50% of randomized participants had normal coronaries without luminal irregularities by ICA or CCTA. Participants randomized to ICA were more likely to have worse baseline clinical risk profiles with older age, higher burden of cardiac risk factors and poor quality of life with disabling angina. ConclusionsAmong this initial sample of women with suspected INOCA randomized in the WARRIOR trial, there is a differential baseline cardiac risk of participants enrolled after CCTA or ICA. However, the majority had no evidence of atherosclerotic plaque or obstructive stenosis, after evaluation by ICA or CCTA. These results suggest that non-invasive evaluation with CCTA is likely to be associated with lower risk of MACE.

Pericardial fat volume is related to endothelial-mediated coronary blood flow in women with suspected coronary microvascular dysfunction. A report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study

BackgroundCoronary microvascular dysfunction is prevalent in women with signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) and is associated with an adverse prognosis. Elevated pericardial fat volume predicts adverse cardiac events, but mechanistic pathways of the association are not well understood. Methods118 women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study with suspected coronary microvascular dysfunction but no obstructive CAD underwent adenosine stress 1.5 T cardiovascular magnetic resonance imaging (CMR) imaging and invasive coronary reactivity testing. Semi-quantitative myocardial perfusion reserve index (MPR) index was derived from perfusion images. Pericardial fat volume was measured by manually contouring the cardiac margins and adjacent adipose tissue on a single trans-axial HASTE slice at the level of the left main coronary artery origin and indexed to body surface-area. Simple standard deviation analysis obtained for continuous variables and frequency (percent) for categorical variables. The relationships between pericardial fat volume and coronary reactivity testing parameters were examined by correlation and multivariable regression analyses. ResultsWomen with suspected coronary microvascular dysfunction had a mean age of 55 ± 10 years, body mass index (BMI) of 28 ± 7 kg/m2, 44 % had a history of smoking, 63 % hypertension, 8 % diabetes, and 20 % dyslipidemia. CMR imaging-derived pericardial fat volume and coronary blood flow response to intracoronary acetylcholine (Δ CBF) were negatively correlated (r = −0.32, p = 0.0013). After adjustment for age, number of risk factors, high-density lipoprotein (HDL), and cold pressor diameter response, pericardial fat volume remained a significant predictor of Δ coronary blood flow (p = 0.04). There was no association with other coronary reactivity testing measures or CMRI derived MPR index. ConclusionsAmong women with suspected coronary microvascular dysfunction but no obstructive CAD, pericardial fat volume appears to be related in a hypothesized adverse direction to coronary microvascular endothelial function. These results support further work confirming and extending these results to investigate pericardial fat volume as mechanistic pathway and potential treatment target for coronary microvascular dysfunction-related adverse events.Trial registration: clinicaltrials.govNCT00832702.

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.

Autoimmune rheumatic diseases in women with coronary microvascular dysfunction: a report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project.

While autoimmune rheumatic diseases (ARDs) have been linked with coronary microvascular dysfunction (CMD), the relationship between ARD and CMD in women with signs and symptoms of ischemia and no obstructive arteries (INOCA) are not well described. We hypothesized that among women with CMD, those with ARD history have greater angina, functional limitations, and myocardial perfusion compromise compared to those without ARD history. Women with INOCA and confirmed CMD by invasive coronary function testing were included from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project (NCT00832702). Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI), and cardiac magnetic resonance myocardial perfusion reserve index (MPRI) were collected at baseline. Chart review was performed to confirm self-reported ARD diagnosis. Of the 207 women with CMD, 19 (9%) had a confirmed history of ARD. Compared to those without ARD, women with ARD were younger (p = 0.04). In addition, they had lower DASI-estimated metabolic equivalents (p = 0.03) and lower MPRI (p = 0.008) but similar SAQ scores. There was a trend towards increased nocturnal angina and stress-induced angina in those with ARD (p = 0.05 for both). Invasive coronary function variables were not significantly different between groups. Among women with CMD, women with a history of ARD had lower functional status and worse myocardial perfusion reserve compared to women without ARD. Angina-related health status and invasive coronary function were not significantly different between groups. Further studies are warranted to understand mechanisms contributing to CMD among women with ARDs with INOCA.

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: The Women's Ischemia Syndrome Evaluation (WISE and WISE-CVD) Projects

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.

Non-obstructive Plaque and Treatment of INOCA: More to Be Learned.

A significant proportion of patients evaluated for chest pain have ischemia with non-obstructive coronary artery disease (INOCA). Studies have shown INOCA is associated with increased risk of major adverse cardiac events and significant burden on the health care system. While there is scarce scientific evidence on management of INOCA, the CorMicA trial showed that stratified medical therapy based on the type of INOCA improved patients' symptoms and quality of life. There are multiple ongoing trials, including Women's IschemiA Trial to Reduce Events in Non-ObstRuctIve CORonary Artery Disease (WARRIOR trial), assessing the benefit of intensive medical therapy versus usual care for this increasingly recognized clinical entity. In this review, we discuss the definition of INOCA, epidemiology and risk factors, pathophysiology, and management as well as the current knowledge gaps and ongoing clinical trials in this arena.

Coronary Microvascular Dysfunction in Patients with Non-Obstructive Coronary Arteries: Current Gaps and Future Directions.

There has been increasing interest in open artery syndrome, also known as ischemia with non-obstructive coronary arteries (INOCA). INOCA has been increasingly recognized as a heterogeneous clinical entity. Diagnostic evaluation of this heterogeneous entity, including invasive assessment, remains key to diagnose this clinical condition and provide the appropriate treatment. Importantly, medical stratification based on the type of INOCA has shown benefit in improving the symptoms in these patients, as illustrated in the CorMicA trial. The Women's IschemiA Trial to Reduce Events in Non-ObstRuctIve CORonary Artery Disease (WARRIOR) is another promising landmark trial that is currently enrolling patients and will address some of the unanswered questions for management of women with INOCA. In this review, we discuss the pathophysiology, management options, knowledge gaps, and future directions while highlighting the rationale and design of the ongoing WARRIOR trial.

Ultra-high sensitivity cardiac troponin-I concentration and left ventricular structure and function in women with ischemia and no obstructive coronary artery disease

AimsWomen are disproportionally impacted by ischemia and no obstructive coronary artery disease (INOCA), and such women are at increased risk of developing heart failure with preserved ejection fraction (HFpEF), however the mechanisms linking these conditions remain poorly understood. The aim of this study was to determine whether ultra-high sensitivity cardiac troponin I (u-hscTnI), an indicator of cardiomyocyte injury, is associated with abnormalities in myocardial perfusion and left ventricular (LV) structure and function in women with INOCA. Methods327 women with INOCA enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study underwent vasodilator stress cardiac magnetic resonance imaging (CMRI) and u-hscTnI measurements (Simoa HD-1 Analyzer, Quanterix Corporation). Multivariable linear regression was used to evaluate associations between u-hscTnI concentrations and myocardial perfusion (MPRI), LV mass index and feature-tracking derived strain measures of LV function. Resultsu-hscTnI concentrations were quantifiable in 100% of the cohort and ranged from 0.004 to 79.6 pg/mL. In adjusted models, u-hscTnI was associated with LV mass index (+2.03; 95% CI 1.17, 2.89; p < 0.01) and early diastolic radial strain rate (SR) (+0.13; 95% CI 0.01, 0.25; p = 0.03), early diastolic circumferential SR (−0.04; 95% CI −0.08, 0.002; p = 0.06) and early diastolic longitudinal SR (−0.03; 95% CI −0.07, 0.002; p = 0.06). u-hscTnI was not associated with MPRI (p = 0.39) in adjusted models. ConclusionTogether, these findings support cardiomyocyte injury as a putative pathway towards adverse LV remodeling and dysfunction; however, further research is needed to define the specific mechanism(s) driving myocellular injury in INOCA.

Cold pressor testing and sympathetic nervous system contribution to ischemia with no obstructive coronary artery disease: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project

Study objectiveCold pressor testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects. DesignProspective cohort. SettingAcademic hospital. Participants107 women with suspected INOCA and 21-age-matched reference women. InterventionsCPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRIRPP). Invasive coronary function testing in a subset of INOCA women (n = 42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%. Main outcome measureMPRIRPP. ResultsCompared to reference women, the INOCA group demonstrated higher resting RPP (p = 0.005) and CPT MPRIRPP (1.09 ± 0.36 vs 0.83 ± 0.18, p = 0.002). Furthermore, INOCA women with impaired ΔCBF (n = 23) had higher CPT MPRIRPP (p = 0.044) compared to reference women despite lower left ventricular ejection fraction (64 ± 7% vs 69 ± 2%, p = 0.005) and higher mass-to-volume ratio (0.79 ± 0.15 vs 0.62 ± 0.09, p < 0.0001). These differences in CPT MPRIRPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRIRPP among INOCA women did not differ based on defined acetylcholine responses. ConclusionsMyocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. This CPT response was also noted in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Therapies to modulate sympathetic activity should be studied in this population.

Specialized Proresolving Mediators in Symptomatic Women With Coronary Microvascular Dysfunction (from the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD [WARRIOR] Trial)

Resolvins and maresins, members of the specialized proresolving mediator (SPM) family, are omega-3 fatty acid-derived lipid mediators that attenuate inflammation. We hypothesized that they play a role in the pathophysiology of coronary microvascular dysfunction (CMD) in women with ischemia and no obstructive coronary disease. In a pilot study, we measured the D-series resolvins (D1, D2, D3, and D5), resolvin E1, maresin 1, docosahexaenoic acid, eicosapentaenoic acid (precursor of resolvin E1), and 18-hydroxyeicosapentaenoic acid by mass spectrometry in the peripheral blood of 31 women enrolled in the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial who had confirmed CMD assessed by coronary flow reserve. We compared SPM levels with 12 gender and age-matched reference subjects. Compared with the reference subject group, those with CMD had significantly lower plasma concentrations of resolvin D1 and maresin 1 and significantly higher levels of docosahexaenoic acid and 18-hydroxyeicosapentaenoic acid. In conclusion, insufficient or ineffective SPM production may play a role in the pathophysiology of CMD. If our results are validated in a larger cohort, omega-3 fatty acid supplementation could be tested as a novel treatment for these patients.

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.

Somatic Versus Cognitive Depressive Symptoms as Predictors of Coronary Artery Disease among Women with Suspected Ischemia: The Women's Ischemia Syndrome Evaluation.

Background:Depression is an established predictor of coronary artery disease (CAD) progression and mortality. “Somatic” symptoms of depression such as fatigue and sleep impairment overlap with symptoms of CAD and independently predict CAD events. Differentiating between “somatic” and “cognitive” depressive symptoms in at-risk patients may improve our understanding of the relationship between depression and CAD.Methods:The study utilized data from the Women’s Ischemia Syndrome Evaluation. Participants (N = 641; mean age = 58.0 [11.4] years) were enrolled to evaluate chest pain or suspected myocardial ischemia. They completed a battery of symptom and psychological questionnaires (including the Beck Depression Inventory [BDI]) at baseline, along with quantitative coronary angiography and other CAD diagnostic procedures. The BDI provided scores for total depression and for cognitive and somatic depressive symptom subscales.Results:Two hundred and fourteen (33.4%) women met criteria for obstructive CAD. Logistic regression models were used to examine relationships between depression symptoms and obstructive CAD. Neither BDI total scores (odds ratio [OR] =1.02, 95% confidence interval [CI], 0.99–1.05, P = 0.053) nor BDI cognitive scores (OR = 1.02, 95% CI, 1.00–1.04, P = 0.15) predicted CAD status. BDI somatic symptom scores, however, significantly predicted CAD status and remained statistically significant after controlling for age, race, and education (OR = 1.06, 95% CI, 1.01–1.12, P = 0.02).Conclusion:Among women with suspected myocardial ischemia, somatic but not cognitive depressive symptoms predicted an increased risk of obstructive CAD determined by coronary angiography. Consistent with prior reports, these results suggest a focus on somatic rather than cognitive depressive symptoms could offer additional diagnostic information.

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.