Objective We investigated whether coronary microvascular dysfunction predicts major adverse outcomes during follow-up among women with signs and symptoms of ischemia. Background Altered coronary reactivity occurs frequently in women evaluated for suspected ischemia and the endothelium-dependent component is linked with adverse outcomes. Possible links between endothelium-independent microvascular coronary reactivity and adverse outcomes remain uncertain. Methods As part of the National Heart, Lung and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated relationships between major adverse outcomes and baseline coronary flow reserve (CFR) following intracoronary adenosine in 189 women referred to evaluate suspected ischemia. Results At 5.4 (mean) years, we observed significant associations between CFR and major adverse outcomes (death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). An exploratory ROC analysis identified CFR <2.32 as the best discriminating threshold for adverse outcomes (event rate 26.7% and ≥2.32 event rate 12.2%; p = 0.01). Lower CFR was associated with increased risk for major adverse outcomes (HR 1.16, 95% CI 1.04 to 1.30; p = 0.009). This held true among the 152 women without obstructive coronary artery disease (CAD) (HR 1.20, 95% CI 1.05 to 1.38; p = 0.008). CFR significantly improved prediction of adverse outcomes over angiographic CAD severity and other risk conditions. Conclusions Among women with suspected ischemia and atherosclerosis risk factors, coronary microvascular reactivity to adenosine significantly improves prediction of major adverse outcomes over angiographic CAD severity and CAD risk factors. These findings suggest coronary microvessels represent novel targets for diagnostic and therapeutic strategies to predict and limit adverse outcomes in women.

Among postmenopausal women evaluated for suspected ischemia, clinical features of PCOS are associated with more angiographic CAD and worsening CV event-free survival. Identification of postmenopausal women with clinical features of PCOS may provide an opportunity for risk factor intervention for the prevention of CAD and CV events.

Coronary heart disease is the leading cause of death and disability in the U.S., but recent advances have not led to declines in case fatality rates for women. The current review highlights gender-specific issues in ischemic heart disease (IHD) presentation, evaluation, and outcomes with a special focus on the results derived from the National Institutes of Health-National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. In the second part of this review, we will assess new evidence on gender-based differences in vascular wall or metabolic alterations, atherosclerotic plaque deposition, and functional expression on worsening outcomes of women. Additionally, innovative cardiovascular imaging techniques will be discussed. Finally, we identify critical areas of further inquiry needed to advance this new gender-specific IHD understanding into improved outcomes for women.

Despite a dramatic decline in mortality over the past three decades, coronary heart disease is the leading cause of death and disability in the U.S. Importantly, recent advances in the field of cardiovascular medicine have not led to significant declines in case fatality rates for women when compared to the dramatic declines realized for men. The current review highlights gender-specific issues in ischemic heart disease presentation, evaluation, and outcomes with a special focus on the results published from the National Institutes of Health-National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. We will present recent evidence on traditional and novel risk markers (e.g., high sensitivity C-reactive protein) as well as gender-specific differences in symptoms and diagnostic approaches. An overview of currently available diagnostic test evidence (including exercise electrocardiography and stress echocardiography and single-photon emission computed tomographic imaging) in symptomatic women will be presented as well as data using innovative imaging techniques such as magnetic resonance subendocardial perfusion, and spectroscopic imaging will also be discussed.

High triglycerides (TG) and low high density lipoprotein cholesterol (HDL-C) are important cardiovascular risk factors in women. The prognostic utility of the TG/HDL-C ratio, a marker for insulin resistance and small dense low density lipoprotein particles, is unknown among high risk women. Methods We studied 544 women without prior myocardial infarction or coronary revascularization, referred for clinically indicated coronary angiography and enrolled in the Women’s Ischemia Syndrome Evaluation (WISE). Fasting lipid profiles and detailed demographic and clinical data were obtained at baseline. Multi-variate Cox-proportional hazards models for all cause mortality and cardiovascular events (death, myocardial infarction, heart failure, stroke) over a median follow-up of 6 years were constructed using log TG/HDL-C ratio as a predictor variable and accounting for traditional cardiovascular risk factors. Results Mean age was 57±11 years, 84% were white, 55% hypertensive, 20% diabetic, 50% current or prior smokers. TG/HDL-C ranged from 0.3 to 18.4 (median 2.2, first quartile 0.35 to <1.4, fourth quartile 3.66–18.4). Deaths (n=33) and CV events (n=83) increased across TG/HDL-C quartiles (both p<0.05 for trend). TG/HDL-C was a strong independent predictor of mortality in models adjusted for age, race, smoking, hypertension, diabetes, and angiographic coronary disease severity (HR 1.95, 95% CI 1.05, 3.64, p=0.04). For cardiovascular events, the multivariate HR was 1.54 (95% CI 1.05, 2.22, p=0.03) when adjusted for demographic and clinical variables, but became non-significant when angiographic results were included. Conclusion Among women with suspected ischemia, the TG/HDL-C ratio is a powerful independent predictor of all cause mortality and cardiovascular events.