Noel Bairey Merz

Women’s Ischemic Syndrome Evaluation Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2–4, 2002 : Executive Summary

The WISE workshop was convened to review results from the Women’s Ischemic Syndrome Evaluation (WISE) study and other studies of ischemic heart disease to examine the nature and scope of gender differences in both chronic and acute cardiac ischemia, in terms of clinical manifestations, detection, and treatment. The purpose of the workshop was to provide recommendations to National Heart, Lung and Blood Institute that (1) address the need for improved diagnosis of ischemia and coronary artery disease (CAD) in women; (2) explore strategies for improved translation of promising research results into clinical practice; and (3) assess opportunities for effective educational strategies, including further refinement of the key messages for women with regard to risk factors and heart attack symptoms. CAD in women continues to be a major public health problem that represents a leading cause of death and disability.1–3 Among US women, more than a quarter of a million deaths per year are attributed to CAD, and this figure is expected to increase in the first decades of the 21st century as our population ages. The increased prevalence of obesity and diabetes in women is also expected to contribute to this increase in CAD. Women have a higher frequency of angina/chest pain than men; however, women have a lower prevalence of obstructive CAD compared with men with similar symptoms.4–6 Nevertheless, young women with obstructive CAD experience a significantly worse outcome compared with men with regard to prognosis after myocardial infarction,7 and older women with obstructive CAD often have …

Opportunity for Intervention to Achieve American Heart Association Guidelines for Optimal Lipid Levels in High-Risk Women in a Managed Care Setting

Background—The American Heart Association (AHA) recently established evidence-based recommendations for cardiovascular disease (CVD) prevention in women, including lipid management. This study evaluated optimal lipid-level attainment and treatment patterns on the basis of these guidelines in high-risk women in a managed care setting. Methods and Results—We conducted a historical prospective cohort analysis of a 1.1-million-member, integrated, managed-care database. Eligible high-risk women were those with evidence of previous CVD or risk equivalent who had a full lipid panel available between October 1, 1999, and September 30, 2000; were naive to lipid therapy; and had a minimum of 12 months health plan eligibility preindex and postindex lipid panel. Optimal lipid levels were defined as LDL cholesterol (LDL-C) <100 mg/dL, HDL cholesterol (HDL-C) >50 mg/dL, non–HDL-C <130 mg/dL, and triglycerides <150 mg/dL. Laboratory values and lipid pharmacotherapy were assessed longitudinally over the postindex follow-up (up to 36 months). A total of 8353 high-risk women (mean age, 66±14 years) with a mean follow-up of 27±8 months were included. Only 7% attained optimal combined lipid levels initially, and this increased to 12% after 36 months. Lipid-modifying therapy was initiated in 32% of patients, including 35% of women with LDL-C ≥100 mg/dL and 15% with LDL-C <100 mg/dL. Conclusions—Among high-risk women, few attained the AHA’s standards for all lipid fractions, and only one third received recommended drug therapy, highlighting significant opportunities to apply evidence-based recommendations to manage lipid abnormalities in high-risk women.

Role of Noninvasive Testing in the Clinical Evaluation of Women With Suspected Ischemic Heart Disease A Consensus Statement From the American Heart Association

In recent decades, there has been an appropriate focus on ensuring gender equity in the quantity and quality of evidence to guide female-specific, optimal management strategies for suspected and known ischemic heart disease (IHD). The evolving evidence supports a multifactorial pathophysiology of coronary atherosclerosis that includes obstructive coronary artery disease (CAD) and dysfunction of the coronary microvasculature and endothelium, and therefore, the term IHD best encompasses this varied pathophysiology in women. An overwhelming body of evidence has documented undertreatment and undertesting of women, leading to higher case fatality rates and increased morbid complications among women.1–3 Accordingly, to increase our knowledge base, women were given the status of a priority population, which resulted in federal policy to include proportional representation of females in clinical trials and registries.4 The past decade provided abundant evidence to guide clinical decision making regarding diagnostic testing for suspected IHD. In 2005, the American Heart Association (AHA) published an evidence synthesis on the use of CAD imaging for the evaluation of symptomatic women with suspected myocardial ischemia.5 Numerous reports have since provided additional high-quality evidence, including data on coronary computed tomographic angiography (CCTA) and cardiac magnetic resonance imaging (CMR), which in 2005 were considered research techniques.5 The present statement provides an update to the 2005 document and synthesizes contemporary evidence on appropriate symptomatic female candidates for diagnostic testing, as well as sex-specific data on the diagnostic and prognostic accuracy for exercise treadmill testing (ETT) with electrocardiography, stress echocardiography, stress myocardial perfusion imaging (MPI) with single-photon emission computed tomography (SPECT) or positron emission tomography (PET), stress CMR, and CCTA.5 Within this document, quality evidence is synthesized, and important gaps in knowledge about the assessment of IHD risk in women are identified. The 2005 document included sections on the evaluation of asymptomatic …

Cardiac syndrome X and microvascular coronary dysfunction.

Women with cardiac chest pain indicated by signs and symptoms of myocardial ischemia in the absence of obstructive CAD are often labelled as cardiac syndrome X (CSX). A subset of patients with CSX may have symptoms of ischemia due to microvascular dysfunction. Angina due to microvascular coronary dysfunction (MCD) is an etiologic mechanism in women with vascular dysfunction. New data provide improve understanding of coronary vascular dysfunction and resultant myocardial ischemia that characterize MCD among patients with cardiac syndrome X. MCD has an adverse prognosis and health care cost expenditure comparable to obstructive CAD. The high prevalence of this condition, particularly in women, adverse prognosis and substantial health care costs, coupled with a lack of evidence regarding treatment strategies, places MCD as a research priority area.

Review articleCardiac Syndrome X and Microvascular Coronary Dysfunction

Women with cardiac chest pain indicated by signs and symptoms of myocardial ischemia in the absence of obstructive CAD are often labelled as cardiac syndrome X (CSX). A subset of patients with CSX may have symptoms of ischemia due to microvascular dysfunction. Angina due to microvascular coronary dysfunction (MCD) is an etiologic mechanism in women with vascular dysfunction. New data provide improve understanding of coronary vascular dysfunction and resultant myocardial ischemia that characterize MCD among patients with cardiac syndrome X. MCD has an adverse prognosis and health care cost expenditure comparable to obstructive CAD. The high prevalence of this condition, particularly in women, adverse prognosis and substantial health care costs, coupled with a lack of evidence regarding treatment strategies, places MCD as a research priority area.

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

BackgroundIn 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.MethodsThe 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.ResultsTo 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.ConclusionsThe 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.

Diastolic Dysfunction in Women with Signs and Symptoms of Ischemia in the Absence of Obstructive Coronary Artery Disease: A Hypothesis-Generating Study

Background—Angina, in the absence of obstructive coronary artery disease, is more common in women, is associated with adverse cardiovascular morbidity and mortality, and is a major burden to the healthcare system. Although advancements have been made to understand the mechanistic underpinning of this disease, the functional consequence remains unclear. Methods and Results—Cardiac magnetic resonance imaging was performed to assess left ventricular function in 20 women with signs and symptoms of ischemia, but no obstructive coronary artery disease (cases), and 15 age- and body mass index–matched reference controls. Functional imaging included standard cinematic imaging to assess left ventricular morphology and global function, along with tissue tagging to assess left ventricular tissue deformation. Systolic function was preserved in both cases and controls, with no differences in ejection fraction (mean±SE: 63.1±8% versus 65±2%), circumferential strain (−20.7±0.6% versus −21.9±0.5%), or systolic circumferential strain rate (−105.9±6.1% versus −109.0±3.8% per second). In contrast, we observed significant differences between cases and controls in diastolic function, as demonstrated by reductions in both diastolic circumferential strain rate (153.8±8.9% versus 191.4±8.9% per second; P<0.05) and peak rate of left ventricular untwisting (−99.4±8.0° versus −129.4±12.8° per second; P<0.05). Conclusions—Diastolic function is impaired in women with signs and symptoms of ischemia in the absence of coronary artery disease, as assessed by cardiac magnetic resonance tissue tagging. These results are hypothesis-generating. Larger studies are needed to define the exact mechanism(s) responsible and to establish viable treatment strategies.

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.

Women’s Ischemic Syndrome Evaluation Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2–4, 2002: Section 2: Stable Ischemia: Pathophysiology and Gender Differences

The WISE workshop was convened to review results from the Women’s Ischemic Syndrome Evaluation (WISE) study and other studies of ischemic heart disease to examine the nature and scope of gender differences in both chronic and acute cardiac ischemia, in terms of clinical manifestations, detection, and treatment. This section addresses research needs in understanding the pathophysiology of chronic myocardial ischemic syndromes in women and mechanisms for gender differences. Flow-limiting stenoses within epicardial coronary arteries (obstructive coronary artery disease [CAD]) may cause myocardial ischemia, which is sensed as angina pectoris or dyspnea and is associated with characteristic electrocardiographic, perfusion, or left ventricular functional abnormalities, on conventional testing in women with CAD, as in men. The issue of contention for several decades has been whether women who do not have obstructive CAD experience myocardial ischemia by a pathophysiology different from that of the majority of men with CAD. In this regard, several large cohort studies, including the Coronary Artery Surgery Study sponsored by the National Heart, Lung and Blood Institute,1 documented that women (mean age of 54 years) presenting with chest pain are less likely to have obstructive CAD at diagnostic coronary angiography than are men. In the WISE cohort, the majority of women (mean age of 59±12 years) were not found to have obstructive CAD at catheterization.2 Some of this disparity may be explained by the Bayes theorem, where the prevalence of age-predicted obstructive CAD in women is lower than in men. Possible explanations for chest pain in this setting include (1) underestimation of the extent and severity of …

Reproducibility of myocardial perfusion reserve - variations in measurements from post processing using commercially available software

PURPOSE Adenosine stress first pass cardiac magnetic resonance imaging (CMRI) is a rapidly evolving tool in the diagnosis of ischemic heart disease (IHD). The rest and stress first pass myocardial perfusion data may be interpreted using commercially available software for calculation of time intensity curves in order to generate a numeric value of the segmental or whole heart myocardial perfusion reserve index (MPRI). The objective of this study was to determine the inter- and intra-observer reliability of the data generated by standard commercially available software. METHODS Data from 20 adenosine stress CMRI (1.5 T) studies were analyzed using commercially available CAAS MRV 3.3 software (Pie Medical Imaging B.V., Netherlands) for calculation of the MPRI. The stress CMRI was performed using a standardized protocol in 20 women including 10 women with angina and the absence of obstructive CAD and 10 healthy volunteers. MPRI calculation was made in a standardized manner on separate occasions by two independent observers. A single observer repeated the calculation of MPRI three months later, without reference to the prior data. Basal, mid, and apical segments, for the whole myocardium, sub-endocardium, and sub-epicardium were analyzed. Intra-class correlation coefficients (ICC), repeatability coefficients (RC), and coefficients of variation (CoV) were determined. RESULTS The MPRI results by repeated software measurements were highly correlated, with potentially important variations in measurement observed. The myocardial inter-observer ICC was 0.80 (95% CI, 0.57, 0.92) with a CoV of 7.5%, and intra-observer ICC was 0.89 (95% CI, 0.77, 0.95) with a CoV of 3.6%. The mid-ventricular level MPRI was most reproducible, with intra-observer ICC at 0.91 (95% CI, 0.77, 0.97); intra-observer measurement was more reproducible than inter-observer measurement. CONCLUSIONS There is variation in measurement of MPRI observed in post processing of perfusion data when using a standardized approach and commercially available software. This has implications in the interpretation of data obtained for clinical and research purposes.