Effects of sex on coronary microvascular dysfunction and cardiac outcomes

Abstract

Background: Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown.

Methods and results: We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve <2.0 was used to define the presence of CMD. Major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, late revascularization, and hospitalization for heart failure, were assessed in a blinded fashion over a median follow-up of 1.3 years (interquartile range, 0.5-2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; Fisher exact test =0.39; equivalence P=0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 [95% confidence interval, 0.75-086] per 10% increase in coronary flow reserve; P<0.0001) and resulted in favorable net reclassification improvement (0.280 [95% confidence interval, 0.049-0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (n=404; 307 women/97 men) without evidence of coronary artery calcification on gated computed tomography imaging, CMD was common in both sexes, despite normal stress perfusion imaging and no coronary artery calcification (44% of men versus 48% of women; Fisher exact test P=0.56; equivalence P=0.041).

Conclusions: CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions.

Keywords: atherosclerosis; blood flow velocity; microcirculation; sex; women.

Conflict of interest statement

Conflict of Interest Disclosures: Dr. Murthy owns equity in General Electric and has received research support from INVIA Medical Imaging Solutions. Dr. Dorbala received research grant support from Astellas Global Pharma Development and Bracco Diagnostics. Dr. Blankstein received research grant support from Astellas Global Pharma Development. Dr. Camici is a consultant for Servier International.

© 2014 American Heart Association, Inc.

Figures

Figure 1

Distribution of Coronary Flow Reserve by Gender. Histogram (top) showing the distribution of coronary flow reserve for men (blue) and women (red). Areas of overlap are shown in purple. Fitted log-normal distribution for men (dashed blue line) and women (dashed red line) are also displayed. Similar data are also shown in box plots (bottom). No statistically significant difference was seen between genders using t-test with log-normal distribution (P=0.73). CFR was equivalent between the genders (P=0.0005 for

Figure 2

Cumulative Incidence of MACE by Gender and Coronary Flow Reserve. Unadjusted (panel A) and adjusted (panel B) cumulative rate of major adverse cardiac events (MACE) by gender and coronary flow reserve (CFR). Data in panel B are adjusted for the modified Duke clinical risk score and rest LVEF.

Figure 2

Cumulative Incidence of MACE by Gender and Coronary Flow Reserve. Unadjusted (panel A) and adjusted (panel B) cumulative rate of major adverse cardiac events (MACE) by gender and coronary flow reserve (CFR). Data in panel B are adjusted for the modified Duke clinical risk score and rest LVEF.

Figure 3

Annualized MACE Rates by Gender and Coronary Flow Reserve. Unadjusted (panel A) and adjusted (panel B) annualized major adverse cardiac events (MACE) rate by gender and coronary flow reserve (CFR). Data in panel B are adjusted for the modified Duke clinical risk score. Rates are computed as the number of first MACE events divided by the number of person-years of follow-up in each subgroup. Comparisons were made using Poisson regression.

Figure 3

Annualized MACE Rates by Gender and Coronary Flow Reserve. Unadjusted (panel A) and adjusted (panel B) annualized major adverse cardiac events (MACE) rate by gender and coronary flow reserve (CFR). Data in panel B are adjusted for the modified Duke clinical risk score. Rates are computed as the number of first MACE events divided by the number of person-years of follow-up in each subgroup. Comparisons were made using Poisson regression.