Improved Robustness for Deep Learning-based Segmentation of Multi-Center Myocardial Perfusion MRI Datasets Using Data Adaptive Uncertainty-guided Space-time Analysis.

BACKGROUND: Fully automatic analysis of myocardial perfusion MRI datasets enables rapid and objective reporting of stress/rest studies in patients with suspected ischemic heart disease. Developing deep learning techniques that can analyze multi-center datasets despite limited training data and variations in software (pulse sequence) and hardware (scanner vendor) is an ongoing challenge. METHODS: Datasets from 3 medical centers acquired at 3T (n = 150 subjects; 21,150 first-pass images) were included: an internal dataset (inD; n = 95) and two external datasets (exDs; n = 55) used for evaluating the robustness of the trained deep neural network (DNN) models against differences in pulse sequence (exD-1) and scanner vendor (exD-2). A subset of inD (n = 85) was used for training/validation of a pool of DNNs for segmentation, all using the same spatiotemporal U-Net architecture and hyperparameters but with different parameter initializations. We employed a space-time sliding-patch analysis approach that automatically yields a pixel-wise "uncertainty map" as a byproduct of the segmentation process. In our approach, dubbed Data Adaptive Uncertainty-Guided Space-time (DAUGS) analysis, a given test case is segmented by all members of the DNN pool and the resulting uncertainty maps are leveraged to automatically select the "best" one among the pool of solutions. For comparison, we also trained a DNN using the established approach with the same settings (hyperparameters, data augmentation, etc.). RESULTS: The proposed DAUGS analysis approach performed similarly to the established approach on the internal dataset (Dice score for the testing subset of inD: 0.896 ± 0.050 vs. 0.890 ± 0.049; p = n.s.) whereas it significantly outperformed on the external datasets (Dice for exD-1: 0.885 ± 0.040 vs. 0.849 ± 0.065, p < 0.005; Dice for exD-2: 0.811 ± 0.070 vs. 0.728 ± 0.149, p < 0.005). Moreover, the number of image series with "failed" segmentation (defined as having myocardial contours that include bloodpool or are noncontiguous in ≥1 segment) was significantly lower for the proposed vs. the established approach (4.3% vs. 17.1%, p < 0.0005). CONCLUSIONS: The proposed DAUGS analysis approach has the potential to improve the robustness of deep learning methods for segmentation of multi-center stress perfusion datasets with variations in the choice of pulse sequence, site location or scanner vendor.

Improved Robustness for Deep Learning-based Segmentation of Multi-Center Myocardial Perfusion MRI Datasets Using Data Adaptive Uncertainty-guided Space-time Analysis.

Background: Fully automatic analysis of myocardial perfusion MRI datasets enables rapid and objective reporting of stress/rest studies in patients with suspected ischemic heart disease. Developing deep learning techniques that can analyze multi-center datasets despite limited training data and variations in software (pulse sequence) and hardware (scanner vendor) is an ongoing challenge. Methods: Datasets from 3 medical centers acquired at 3T (n = 150 subjects; 21,150 first-pass images) were included: an internal dataset (inD; n = 95) and two external datasets (exDs; n = 55) used for evaluating the robustness of the trained deep neural network (DNN) models against differences in pulse sequence (exD-1) and scanner vendor (exD-2). A subset of inD (n = 85) was used for training/validation of a pool of DNNs for segmentation, all using the same spatiotemporal U-Net architecture and hyperparameters but with different parameter initializations. We employed a space-time sliding-patch analysis approach that automatically yields a pixel-wise "uncertainty map" as a byproduct of the segmentation process. In our approach, dubbed Data Adaptive Uncertainty-Guided Space-time (DAUGS) analysis, a given test case is segmented by all members of the DNN pool and the resulting uncertainty maps are leveraged to automatically select the "best" one among the pool of solutions. For comparison, we also trained a DNN using the established approach with the same settings (hyperparameters, data augmentation, etc.). Results: The proposed DAUGS analysis approach performed similarly to the established approach on the internal dataset (Dice score for the testing subset of inD: 0.896 ± 0.050 vs. 0.890 ± 0.049; p = n.s.) whereas it significantly outperformed on the external datasets (Dice for exD-1: 0.885 ± 0.040 vs. 0.849 ± 0.065, p < 0.005; Dice for exD-2: 0.811 ± 0.070 vs. 0.728 ± 0.149, p < 0.005). Moreover, the number of image series with "failed" segmentation (defined as having myocardial contours that include bloodpool or are noncontiguous in ≥1 segment) was significantly lower for the proposed vs. the established approach (4.3% vs. 17.1%, p < 0.0005). Conclusions: The proposed DAUGS analysis approach has the potential to improve the robustness of deep learning methods for segmentation of multi-center stress perfusion datasets with variations in the choice of pulse sequence, site location or scanner vendor.

Myocardial ischaemic syndromes: a new nomenclature to harmonize evolving international clinical practice guidelines.

Since the 1960s, cardiologists have adopted several binary classification systems for acute myocardial infarction (MI) that facilitated improved patient management. Conversely, for chronic stable manifestations of myocardial ischaemia, various classifications have emerged over time, often with conflicting terminology-e.g. 'stable coronary artery disease' (CAD), 'stable ischaemic heart disease', and 'chronic coronary syndromes' (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with 'acute coronary syndromes' (ACS), the 2023 American guidelines endorsed the alternative term 'chronic coronary disease'. An unintended consequence of these competing classifications is perpetuation of the restrictive terms 'coronary' and 'disease', often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischaemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. We, therefore, propose a new binary classification of 'acute myocardial ischaemic syndromes' and 'non-acute myocardial ischaemic syndromes', which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. We herein retain accepted categories of ACS, ST-segment elevation MI, and non-ST-segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischaemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischaemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischaemia and infarction.

Clinical aspects of ischemia with no obstructive coronary artery disease (INOCA).

Ischemia with no obstructive coronary arteries (INOCA) is defined as patients with evidence of myocardial ischemia without obstructive coronary artery disease. About 3-4 million people in the United States have INOCA, more commonly affecting women, and carries adverse morbidity, mortality, and relatively high healthcare costs. The pathophysiology of INOCA appears to be multi-factorial with a variety of contributing mechanisms. Diagnosis of INOCA is suggested by non-invasive or invasive testing consistent with myocardial ischemia. Due to the high prevalence of coronary risk factors and atherosclerosis in the INOCA population, current treatment strategies target angina, coronary atherosclerosis, and atherosclerotic risk factors, as well as burgeoning treatment of coronary microvascular dysfunction (CMD). Ongoing clinical trials are assessing different options.

Contemporary Diagnosis and Management of Patients with MINOCA.

PURPOSE OF REVIEW: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is defined as acute myocardial infarction (MI) with angiographically no obstructive coronary artery disease or stenosis ≤ 50%. MINOCA is diagnostically challenging and complex, making it difficult to manage effectively. This condition accounts for 6-8% of all MI and poses an increased risk of morbidity and mortality after diagnosis. Prompt recognition and targeted management are essential to improve outcomes and our understanding of this condition, but this process is not yet standardized. This article offers a comprehensive review of MINOCA, delving deep into its unique clinical profile, invasive and noninvasive diagnostic strategies for evaluating MINOCA in light of the lack of widespread availability for comprehensive testing, and current evidence surrounding targeted therapies for patients with MINOCA. RECENT FINDINGS: MINOCA is not uncommon and requires comprehensive assessment using various imaging modalities to evaluate it further. MINOCA is a heterogenous working diagnosis that requires thoughtful approach to diagnose the underlying disease responsible for MINOCA further.

Factors associated with duration of breastfeeding in women giving birth for the first time.

OBJECTIVE: To examine maternal, psychosocial, and pregnancy factors associated with breastfeeding for at least 6 months in those giving birth for the first time. METHODS: We performed a planned secondary analysis of an observational cohort study of 5249 women giving birth for the first time. Women were contacted at least 6 months after delivery and provided information regarding breastfeeding initiation, duration, and exclusivity. Maternal demographics, psychosocial measures, and delivery methods were compared by breastfeeding groups. RESULTS: 4712 (89.8%) of the women breastfed at some point, with 2739 (58.2%) breastfeeding for at least 6 months. Of those who breastfed, 1161 (24.7% of the entire cohort), breastfed exclusively for at least 6 months. In the multivariable model among those who ever breastfed, not smoking in the month prior to delivery (adjusted odds ratio [aOR] 2.04, 95%CI 1.19-3.45), having a Master's degree of higher (aOR 1.89, 95%CI 1.51-2.36), having a planned pregnancy (aOR 1.48, 95%CI 1.27-1.73), older age (aOR 1.02, 95% CI, 1.01-1.04), lower BMI (aOR 0.96 95% CI 0.95-0.97), and having less anxiety measured during pregnancy (aOR 0.990, 95%CI 0.983-0.998) were associated with breastfeeding for at least 6 months. Compared to non-Hispanic White women, Hispanic women, while being more likely to breastfeed initially (aOR 1.40, 95%CI 1.02-1.92), were less likely to breastfeed for 6 months (aOR 0.72, 95%CI 0.59-0.88). While non-Hispanic Black women were less likely than non-Hispanic White women to initiate breastfeeding (aOR 0.68, 95%CI 0.51-0.90), the odds of non-Hispanic Black women of continuing to breastfeed for at least 6 months was similar to non-Hispanic White women (aOR 0.92, 95%CI 0.71-1.19). CONCLUSIONS: In this cohort of women giving birth for the first time, duration of breastfeeding was associated with several characteristics which highlight groups at greater risk of not breastfeeding as long as currently recommended. TRIAL REGISTRATION: NCT01322529 (nuMoM2b) and NCT02231398 (nuMoM2b-Heart Health).

Subclinical cardiovascular disease and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) impacts approximately 6%-10% of women worldwide, with hallmark features of hyperandrogenism, irregular menses, infertility, and polycystic appearing ovaries on ultrasound. In addition, PCOS is associated with several endocrine and metabolic disorders, including obesity, insulin resistance and diabetes mellitus, hypertension, dyslipidemia and metabolic syndrome, which all increase the risk for subclinical cardiovascular disease (CVD), the presence of altered vascular endothelium without overt CVD. In this review, we summarize the most recent literature regarding subclinical CVD in women with PCOS, including markers such as flow-mediated dilation, arterial stiffness, coronary artery calcium scores, carotid intima-media thickness and visceral and epicardial fat.

Childbearing Among Women Cardiologists: The Interface of Experience, Impact, and the Law.

BACKGROUND: Maternity leave is highly variable in the United States given the lack of a federal workforce mandate. OBJECTIVES: The purpose of this study was to describe the experiences and impact of childbearing on women cardiologists and their careers, within a legal framework. METHODS: A survey was sent to women cardiologists, asking about their experiences while pregnant and on maternity leave. The incidence of complications and career impacts on the cardiologists was assessed. RESULTS: Of 323 respondents who had been pregnant as a practicing cardiologist, extra service or call before maternity leave was required in 37.2%. Of those who performed extra service or call, 17.5% were placed on bedrest before delivery, compared with 7.4% who did not perform extra service or call (P = 0.005). During the year of pregnancy, 41.2% experienced a salary decrease; only 7.4% had their relative value units prorated for time on maternity leave; 23.2% had no paid maternity leave. Self-reported pregnancy complications occurred in 36.5%, those with complications had a 60% greater chance of reporting that pregnancy adversely affected their career, compared with those without complications. Nearly three-fourths (237 respondents) reported experiencing at least one of several troubling practices that are illegal in many circumstances. CONCLUSIONS: Women cardiologists report wide variances in maternity leave in the United States, with many experiencing likely violations of the Family and Medical Leave Act or other statues. Childbearing issues in cardiologists should be addressed to improve the professional and personal lives of women cardiologists and the attractiveness of cardiology to potential trainees.

Coronary Optical Coherence Tomography and Cardiac Magnetic Resonance Imaging to Determine Underlying Causes of Myocardial Infarction With Nonobstructive Coronary Arteries in Women.

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 6% to 15% of myocardial infarctions (MIs) and disproportionately affects women. Scientific statements recommend multimodality imaging in MINOCA to define the underlying cause. We performed coronary optical coherence tomography (OCT) and cardiac magnetic resonance (CMR) imaging to assess mechanisms of MINOCA. METHODS: In this prospective, multicenter, international, observational study, we enrolled women with a clinical diagnosis of myocardial infarction. If invasive coronary angiography revealed <50% stenosis in all major arteries, multivessel OCT was performed, followed by CMR (cine imaging, late gadolinium enhancement, and T2-weighted imaging and T1 mapping). Angiography, OCT, and CMR were evaluated at blinded, independent core laboratories. Culprit lesions identified by OCT were classified as definite or possible. The CMR core laboratory identified ischemia-related and nonischemic myocardial injury. Imaging results were combined to determine the mechanism of MINOCA, when possible. RESULTS: Among 301 women enrolled at 16 sites, 170 were diagnosed with MINOCA, of whom 145 had adequate OCT image quality for analysis; 116 of these underwent CMR. A definite or possible culprit lesion was identified by OCT in 46.2% (67/145) of participants, most commonly plaque rupture, intraplaque cavity, or layered plaque. CMR was abnormal in 74.1% (86/116) of participants. An ischemic pattern of CMR abnormalities (infarction or myocardial edema in a coronary territory) was present in 53.4% (62/116) of participants undergoing CMR. A nonischemic pattern of CMR abnormalities (myocarditis, takotsubo syndrome, or nonischemic cardiomyopathy) was present in 20.7% (24/116). A cause of MINOCA was identified in 84.5% (98/116) of the women with multimodality imaging, higher than with OCT alone (P<0.001) or CMR alone (P=0.001). An ischemic cause was identified in 63.8% of women with MINOCA (74/116), a nonischemic cause was identified in 20.7% (24/116) of the women, and no mechanism was identified in 15.5% (18/116). CONCLUSIONS: Multimodality imaging with coronary OCT and CMR identified potential mechanisms in 84.5% of women with a diagnosis of MINOCA, 75.5% of which were ischemic and 24.5% of which were nonischemic, alternate diagnoses to myocardial infarction. Identification of the cause of MINOCA is feasible and has the potential to guide medical therapy for secondary prevention. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02905357.

Psychological stress, cardiac symptoms, and cardiovascular risk in women with suspected ischaemia but no obstructive coronary disease.

This paper evaluated cross-sectional relationships between psychological stress and coronary artery disease (CAD) risk among women with suspected ischaemia and no obstructive coronary artery disease (INOCA). Between 1996 and 2000, 551 women with INOCA were enrolled in the Women's Ischemia Syndrome Evaluation (WISE) cohort from four U.S. institutions. Between 2009 and 2012, 376 women with INOCA were recruited from two U.S. institutions for an independent cohort study titled WISE-Coronary Vascular Dysfunction (WISE-CVD). Participants underwent coronary angiography and testing for CAD symptoms and risk factors at baseline. Psychological stress was assessed in the form of home/work stress in WISE and home/work stress and financial stress in WISE-CVD. Results showed that home/work stress predicted greater depression, functional impairment, CAD symptoms, and lower self-rated health in WISE but was inconsistent as a predictor in WISE-CVD. In contrast, >60% of WISE-CVD women reported moderate or severe financial stress. Financial stress levels predicted more CAD risk factors and cardiac symptoms, poorer self-rated health, and greater depression and functional impairment. Among women with INOCA, psychological stress was associated with CAD symptoms and CAD risk factors. The prevalence and predictive value of psychological stress in this population supports the inclusion of stress measures in future CAD research.

Adverse Pregnancy Outcomes Are Associated with Reduced Coronary Flow Reserve in Women With Signs and Symptoms of Ischemia Without Obstructive Coronary Artery Disease: A Report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Study.

Background: We assessed history of adverse pregnancy outcomes (APOs) and coronary microvascular dysfunction (CMD) in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) cohort of women with signs and symptoms of ischemia without obstructive coronary artery disease (CAD). We hypothesized that women with CMD with symptoms and signs of ischemia, without obstructive CAD, are more likely to have a history of APO. Materials and Methods: WISE-CVD recruited women with suspected ischemia found to have no obstructive CAD (n = 324). A subset of these women underwent coronary reactivity testing, including coronary flow reserve (CFR) (n = 185). Relationship between history of any APO and CMD was assessed by multivariable linear regression analyses. APOs included any of the following: hypertension during pregnancy, preeclampsia, eclampsia, gestational diabetes, or intrauterine growth restriction (low-birth-weight child). Results: Overall, 79/324 (24%) women reported at least one APO. Women with APOs were younger (52 vs. 56 years, p = 0.001), were more likely obese (body mass index 32 vs. 29 kg/m2, p = 0.004), and had a history of hypertension (56% vs 36%, p = 0.002), but otherwise had no additional differences in cardiac risk variables versus women without APOs. Among the subgroup who underwent invasive CFR testing (n = 185), those with an APO had lower CFR (2.53 vs. 2.76, p = 0.016) versus those without APO. Conclusions: History of APOs in women with signs and symptoms of ischemia without obstructive CAD is associated with lower CFR indicative of CMD. Whether common pathways involving diffuse microvascular dysfunction may account for this suggested association remains unclear. Further investigation is needed to expand on these exploratory findings.

Premature atherosclerosis in premenopausal women: Does cytokine balance play a role?

Contributory risk factors to premature coronary artery disease (CAD) in premenopausal women are poorly understood and data on this subset of women is lacking. There is growing evidence that the process of inflammation is a part of the atherosclerotic process. Mechanistic insights from animal work suggest that the profile of circulating cytokines reflects both endothelial integrity and the presence of immune and progenitor cells. Significant differences in pro- and anti-inflammatory cytokine concentrations between patients with and without CAD exist. Young women with obstructive CAD may experience differences in pro-inflammatory cytokines and the recruitment of reparative cells that secrete T-Helper (Th2 cytokines compared to women without CAD. Thus, cytokine balance may play a role in obstructive CAD in young women. In this pilot study we set out to identify an array of circulating inflammatory marker profiles which could be useful for the development of risk assessment and preventive strategies. We tested the hypothesis that an increase in serologic Th1 cytokines relative to Th2)/hematopoietic regulatory (HR) cytokines is related to premature coronary atherosclerosis in premenopausal women.

Role of Stress Cardiac Magnetic Resonance Imaging in Women with Suspected Ischemia but No Obstructive Coronary Artery Disease.

OBJECTIVE: Signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) is often a diagnostic dilemma in women. The use of stress cardiac magnetic resonance imaging (CMRI) for advanced diagnostic assessment in these patients is a non-ionizing radiation option, but the diagnostic utility in this population is unknown. We examined the diagnostic role of stress CMRI in our patient population of these women. METHODS: We analyzed 113 consecutive female patients from 2/2006-11/2007 who had prior cardiac evaluations for signs and symptoms of ischemia but no obstructive CAD who underwent stress CMRI, which included anatomic, functional, adenosine stress perfusion and delayed enhancement imaging. RESULTS: The population demographics of 113 women included a mean age of 55±12.2 years with an average body mass index (BMI) of 25 ± 4.5. Overall, 43% had hypertension, 4% had diabetes and 3% were smokers. Overall, 80/113 (70%) demonstrated abnormal stress CMRI results. The majority of patients demonstrated findings consistent with subendocardial perfusion abnormalities suggestive of coronary microvascular dysfunction (CMD). Of note, 3 patients (4%) were diagnosed with congenital coronary anomalies or cardiomyopathy not detected in prior cardiac evaluations. CONCLUSION: Among women with signs and symptoms of ischemia but no obstructive CAD, stress CMRI is frequently abnormal and is valuable in diagnosis of CMD. Stress CMRI appears useful for advanced diagnostic assessment in these diagnostically challenged patients.

Strategies and methods to study female-specific cardiovascular health and disease: a guide for clinical scientists.

BACKGROUND: In 2001, the Institute of Medicine's (IOM) report, "Exploring the Biological Contributions to Human Health: Does Sex Matter?" advocated for better understanding of the differences in human diseases between the sexes, with translation of these differences into clinical practice. Sex differences are well documented in the prevalence of cardiovascular (CV) risk factors, the clinical manifestation and incidence of cardiovascular disease (CVD), and the impact of risk factors on outcomes. There are also physiologic and psychosocial factors unique to women that may affect CVD risk, such as issues related to reproduction. METHODS: The Society for Women's Health Research (SWHR) CV Network compiled an inventory of sex-specific strategies and methods for the study of women and CV health and disease across the lifespan. References for methods and strategy details are provided to gather and evaluate this information. Some items comprise robust measures; others are in development. RESULTS: To address female-specific CV health and disease in population, physiology, and clinical trial research, data should be collected on reproductive history, psychosocial variables, and other factors that disproportionately affect CVD in women. Variables related to reproductive health include the following: age of menarche, menstrual cycle regularity, hormone levels, oral contraceptive use, pregnancy history/complications, polycystic ovary syndrome (PCOS) components, menopause age, and use and type of menopausal hormone therapy. Other factors that differentially affect women's CV risk include diabetes mellitus, autoimmune inflammatory disease, and autonomic vasomotor control. Sex differences in aging as well as psychosocial variables such as depression and stress should also be considered. Women are frequently not included/enrolled in mixed-sex CVD studies; when they are included, information on these variables is generally not collected. These omissions limit the ability to determine the role of sex-specific contributors to CV health and disease. Lack of sex-specific knowledge contributes to the CVD health disparities that women face. CONCLUSIONS: The purpose of this review is to encourage investigators to consider ways to increase the usefulness of physiological and psychosocial data obtained from clinical populations, in an effort to improve the understanding of sex differences in clinical CVD research and health-care delivery for women and men.

The association of statin use after cancer diagnosis with survival in pancreatic cancer patients: a SEER-medicare analysis.

BACKGROUND: Pancreatic cancer has poor prognosis and existing interventions provide a modest benefit. Statin has anti-cancer properties that might enhance survival in pancreatic cancer patients. We sought to determine whether statin treatment after cancer diagnosis is associated with longer survival in those with pancreatic ductal adenocarcinoma (PDAC). METHODS: We analyzed data on 7813 elderly patients with PDAC using the linked Surveillance, Epidemiology, and End Results (SEER) - Medicare claims files. Information on the type, intensity and duration of statin use after cancer diagnosis was extracted from Medicare Part D. We treated statin as a time-dependent variable in a Cox regression model to determine the association with overall survival adjusting for follow-up, age, sex, race, neighborhood income, stage, grade, tumor size, pancreatectomy, chemotherapy, radiation, obesity, dyslipidemia, diabetes, chronic pancreatitis and chronic obstructive pulmonary disease (COPD). RESULTS: Overall, statin use after cancer diagnosis was not significantly associated with survival when all PDAC patients were considered (HR = 0.94, 95%CI 0.89, 1.01). However, statin use after cancer diagnosis was associated with a 21% reduced hazard of death (Hazard ratio = 0.79, 95% confidence interval (CI) 0.67, 0.93) in those with grade I or II PDAC and to a similar extent in those who had undergone a pancreatectomy, in those with chronic pancreatitis and in those who had not been treated with statin prior to cancer diagnosis. CONCLUSIONS: We found that statin treatment after cancer diagnosis is associated with enhanced survival in patients with low-grade, resectable PDAC.

Improving diagnosis and treatment of women with angina pectoris and microvascular disease: the iPOWER study design and rationale.

BACKGROUND: The iPOWER study aims at determining whether routine assessment of coronary microvascular dysfunction (CMD) in women with angina and no obstructive coronary artery disease is feasible and identifies women at risk. METHODS: All women with angina referred to invasive angiographic assessment in Eastern Denmark are invited to join the study according to in- and exclusion criteria. Assessment includes demographic, clinical and psychosocial data, symptoms, electrocardiogram, blood- and urine samples and transthoracic echocardiography during rest and dipyridamol stress with measurement of coronary flow reserve (CFR) by Doppler of the left anterior descending artery. In substudies CMD will be assessed by positron emission tomography, peripheral endothelial function, magnetic resonance imaging-and computed tomography derived myocardial perfusion scans, angiographic corrected TIMI frame counts, advanced echocardiographic modalities at rest and during stress, and invasive measures of CFR and coronary vascular reactivity. The study will include 2000 women who will be followed for 5 years for cardiovascular outcomes. RESULTS: By May 2013, 1685 women have been screened, 759 eligible patients identified, 530 contacted, and 299 (56%) agreed to participate. Among the first 50 patients, Doppler CFR was successfully measured in 49 (98%). CONCLUSIONS: Among women with suspected ischemic heart disease and no obstructive coronary artery disease, non-invasive Doppler CFR is feasible as a routine assessment. The study will provide information on methods to diagnose CMD and determine the prognostic value of routine non-invasive assessment of microvascular function. Future study will provide women identified with CMD participation in interventional substudies designed to test treatment strategies.