Investigators Ahmed Al Badri and C. Noel Bairey Merz from the Cedars Sinai Smidt Heart Institute, in Los Angeles, California recently reported that on longer-term follow-up in women, impaired microvascular function predicted adverse cardiovascular outcomes in patients with signs and symptoms of ischemia. In their publication in JACC, they concluded that evaluation of coronary reactivity (CR) abnormality could identify those at higher risk of adverse outcomes in the absence of significant coronary artery disease (CAD).
Past literature that included predominantly men with obstructive coronary artery disease (CAD), abnormal coronary reactivity (CR) testing in a nonobstructed epicardial coronary artery predicted adverse outcomes. In present times, as many as one-half of women with suspected myocardial ischemia have no obstructive coronary artery disease (CAD), and abnormal coronary reactivity (CR) is commonly found. In this study, the authors aimed to prospectively investigate the association of coronary reactivity (CR) and longer-term adverse cardiovascular outcomes in women with and without obstructive coronary artery disease (CAD) in the National Heart, Lung, and Blood Institute-sponsored WISE (Women’s Ischemia Syndrome Evaluation) study. The investigators studied women with signs and symptoms of ischemia who were enrolled in the WISE (Women’s Ischemia Syndrome Evaluation) study from 1996 to 2000. Women (n = 224) with signs and symptoms of ischemia underwent CR testing. Coronary flow reserve and coronary blood flow were obtained in order to test microvascular function, whereas epicardial CR was tested by coronary dilation response to intracoronary (IC) acetylcholine and IC nitroglycerin. All-cause mortality, major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke, and heart failure), and angina hospitalizations served as clinical outcomes over a median follow-up of 9.7 years. Approximately 129 events were identified by Badri et al. during the follow-up period. The study noted low coronary flow reserve as a predictor of increased MACE rate (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.12; p = 0.021), whereas low coronary blood flow was found to be associated with an increased risk of mortality (HR, 1.12; 95% CI, 1.01-1.24; p = 0.038) and MACE (HR, 1.11; 95% CI, 1.03-1.20; p = 0.006) after adjusting for cardiovascular risk factors. Additionally, a decrease in cross-sectional area in response to IC acetylcholine was associated with a higher hazard of angina hospitalization (HR, 1.05; 95% CI, 1.02-1.07; p < 0.0001). However, there was no association between epicardial IC nitroglycerin dilation and outcomes. Therefore, the authors concluded that on longer-term follow-up, impaired microvascular function predicted adverse cardiovascular outcomes in women with signs and symptoms of ischemia.
“The study has substantially contributed to the care of women in their identification of participants in the WISE cohort who had impaired microvascular function. With a median follow-up of 9.7 years, these data provide substantial evidence that impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of myocardial ischemia in the absence of significant obstructive epicardial coronary disease. An estimated 10 million U.S. women have angina. This means that our traditional diagnostic strategies, although adequate to detect obstructive CAD, are likely inadequate for the etiologic assessment of myocardial ischemia in women. Sex-specific diagnostic paradigms must be developed and implemented with emphasis on noninvasive approaches and limitation of radiation; symptomatic women must be intensively treated to control their angina and secondary prevention provided to lessen adverse outcomes until the mechanisms underlying these adverse outcomes are elucidated.”- Dr. Nanette K. Wenger, M.D.
Commenting on their study findings, investigator Ahmed Al Badri stated, “On longer-term follow-up among women with signs and symptoms of ischemia, we found that impaired endothelium and non–endothelium-dependent coronary microvascular reactivity predicts adverse cardiovascular events. Abnormal response to endothelium-dependent pathways in the microvasculature also predicts increased mortality on a long-term follow-up when adjusted for various cardiovascular risk factors. In addition, impaired epicardial endothelium-dependent CR was associated with increased angina hospitalizations. Lastly, we noted no relationship between response to IC-NTG and outcomes.” Indeed, while evaluating longer-term outcomes, impaired coronary microvascular reactivity predicted adverse cardiovascular outcomes. Abnormal endothelium-dependent epicardial CR was associated with an increased rate of angina hospitalizations in women with signs and symptoms of ischemia, including those with no angiographic evidence of obstructive coronary artery disease. These findings highlighted the need for identifying patients with an objective cause for symptoms of angina such as abnormal CR and to appropriately follow and treat these patients to improve survival and avoid recurrent hospitalizations. Although they had proved that the evaluation of CR could identify those at higher risk of adverse outcomes in the absence of significant CAD, they strongly believed that only future research could evaluate feasible, preferably noninvasive, and cost-effective strategies to assess CR in clinical practice. Further studies were also needed to better understand the therapeutic implications of abnormal coronary reactivity in women with myocardial ischemia.
Summarizing these important findings in an accompanying editorial, author Dr. Nanette K. Wenger stated, “The study by Al Badri et al. in this issue of the Journal has substantially contributed to the care of women in their identification of participants in the WISE cohort who had impaired microvascular function. Among the 424 women who underwent coronary reactivity testing, low coronary flow reserve (CFR) predicted an increased major adverse cardiovascular event rate, whereas low coronary blood flow (CBF) was associated with an increased risk of mortality and major adverse cardiovascular events, after adjusting for cardiovascular risk factors. With a median follow-up of 9.7 years, these data provide substantial evidence that impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of myocardial ischemia in the absence of significant obstructive epicardial coronary disease.” Stressing on the large scale of this problem and the impending need for further scientific exploration, she remarked, “An estimated 10 million U.S. women have angina. This means that our traditional diagnostic strategies, although adequate to detect obstructive CAD, are likely inadequate for the etiologic assessment of myocardial ischemia in women. Sex-specific diagnostic paradigms must be developed and implemented with emphasis on noninvasive approaches and limitation of radiation; symptomatic women must be intensively treated to control their angina and secondary prevention provided to lessen adverse outcomes until the mechanisms underlying these adverse outcomes are elucidated.” Since CR testing is an invasive procedure that requires experienced operators, additional research is indicated to develop noninvasive and cost-effective strategies to assess CR in clinical practice.
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