Impact of Abnormal Coronary Reactivity on Long-Term Clinical Outcomes in Women

Abstract

Background: Currently 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.

Objectives: The authors prospectively investigated CR and longer-term adverse cardiovascular outcomes in women with and with no obstructive CAD in the National Heart, Lung, and Blood Institute-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.

Methods: Women (n = 224) with signs and symptoms of ischemia underwent CR testing. Coronary flow reserve and coronary blood flow were obtained 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.

Results: The authors identified 129 events during the follow-up period. Low coronary flow reserve was a predictor of increased MACE rate (hazard ratio [HR]: 1.06; 95% confidence interval [CI]: 1.01 to 1.12; p = 0.021), whereas low coronary blood flow was associated with increased risk of mortality (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.038) and MACE (HR: 1.11; 95% CI: 1.03 to 1.20; p = 0.006) after adjusting for cardiovascular risk factors. In addition, a decrease in cross-sectional area in response to IC acetylcholine was associated with higher hazard of angina hospitalization (HR: 1.05; 95% CI: 1.02 to 1.07; p < 0.0001). There was no association between epicardial IC-nitroglycerin dilation and outcomes.

Conclusions: On longer-term follow-up, impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of ischemia. Evaluation of CR abnormality can identify those at higher risk of adverse outcomes in the absence of significant CAD. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00000554).

Keywords: cardiovascular outcome; coronary flow reserve; coronary reactivity; endothelial function; microvasculature.

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

Figures

Figure 1.. Distribution of selected coronary reactivity testing in 224 women with signs and symptoms of ischemia.

Most women underwent evaluation of more than one coronary reactivity pathway. Green color represents women who underwent evaluation of non-endothelium dependent microvascular reactivity using coronary flow reserve (CFR); orange color represents women who underwent evaluation of endothelium dependent microvascular reactivity using coronary blood flow (CBF); yellow color represents women who underwent evaluation of endothelium dependent epicardial coronary reactivity using change in coronary artery cross sectional area in response to intracoronary acetylcholine (IC-Ach); while blue color represents women who underwent evaluation of non-endothelium dependent epicardial coronary reactivity using change in coronary artery cross sectional area in response to intracoronary nitroglycerine (IC-NTG).

Figure 2:. Relationship between coronary microvascular function and cardiovascular events.

(1A) Kaplan-Meier analysis showing percentage of women surviving free from the 4-component major adverse cardiovascular event (MACE) including cardiovascular death, nonfatal MI, nonfatal stroke and HF during long-term follow-up stratified by coronary flow reserve (CFR). (1B) Kaplan-Meier analysis showing percentage of women with no obstructive coronary artery disease stratified by CFR surviving free from the 4-component MACE during long-term follow-up. (2A) Kaplan-Meier analysis showing percentage of women stratified by coronary blood flow (CBF) surviving free from the 4-component MACE during long-term follow-up. (2B) Kaplan-Meier analysis showing percentage of women with no obstructive coronary artery disease stratified by CBF surviving free from the 4-component MACE during long-term follow-up.

Figure 3.. Relationship between endothelium-dependent epicardial coronary function stratified by change in coronary artery cross-sectional area (CSA) in response to intra-coronary acetylcholine (IC-Ach) and cardiovascular events.

(A) Kaplan-Meier analysis showing percentage of women surviving free from angina hospitalization during long-term follow-up. (B) Kaplan-Meier analysis showing percentage of women with no obstructive coronary artery disease surviving free from angina hospitalization during long-term follow-up.

Figure 4.. Relationship between endothelium-independent epicardial coronary function stratified by change in coronary artery cross-sectional area (CSA) in response to intra-coronary nitroglycerin (IC-NTG) and cardiovascular events.

(A) Kaplan-Meier analysis showing percentage of women surviving free from the 4-component MACE during long-term follow-up. (B) Kaplan-Meier analysis showing percentage of women with no obstructive coronary artery disease surviving free from the 4-component MACE during long-term follow-up.

Central Illustration.. Women with signs and symptoms of ischemia with no obstructive coronary artery disease and the potential role of coronary reactivity testing.

women with no obstructive coronary artery disease (CAD) and potential role of coronary reactivity testing to identify those at higher risk for adverse events. CFR: coronary flow reserve, CBF: coronary blood flow.