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

J Am Coll Cardiol. 2019 Feb 19;73(6):684-693. doi: 10.1016/j.jacc.2018.11.040.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / therapeutic use
  • Aged
  • Coronary Artery Disease / complications
  • Coronary Artery Disease / physiopathology*
  • Coronary Artery Disease / therapy
  • Coronary Circulation / physiology*
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Humans
  • Middle Aged
  • Myocardial Ischemia / etiology
  • Myocardial Ischemia / physiopathology*
  • Myocardial Ischemia / therapy
  • Prospective Studies
  • Sex Factors
  • Vasodilation / physiology*
  • Vasodilator Agents / therapeutic use


  • Vasodilator Agents
  • Acetylcholine

Associated data