In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: A double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE)

Abstract

Background: We investigated the role of the renin-angiotensin system in women with signs and symptoms of ischemia without obstructive coronary artery disease (CAD). Although microvascular dysfunction has been suggested to explain this syndrome and recently was found to predict adverse outcomes, the mechanisms and treatments remain unclear.

Methods: In a substudy within the WISE, 78 women with microvascular dysfunction (coronary flow reserve [CFR] <3.0 following adenosine) and no obstructive CAD were randomly assigned to either an angiotensin-converting enzyme inhibition (ACE-I) with quinapril or a placebo treatment group. The primary efficacy parameter was CFR at 16 weeks adjusted for baseline characteristics and clinical site. The secondary response variable was freedom from angina symptoms assessed using the Seattle Angina Questionnaire.

Results: A total of 61 women completed the 16-week treatment period with repeat CFR measurements, and treatment was well tolerated. For the primary outcome, at 16 weeks, CFR improved more with ACE-I than placebo (P < .02). For the secondary outcome of symptom improvement, ACE-I treatment (P = .037) and CFR increase (P = .008) both contributed.

Conclusions: Microvascular function improves with ACE-I therapy in women with signs and symptoms of ischemia without obstructive CAD. This improvement is associated with reduction in angina. The beneficial response of the coronary microvasculature was limited to women with lower baseline CFR values, suggesting that the renin-angiotensin system may be more involved among women with more severe microvascular defects.

Trial registration: ClinicalTrials.gov NCT00150826.

Figure 1

Relationship between (log2) coronary flow reserve (CFR) at 16 weeks and (log2) CFR at baseline stratified by treatment group: ACE-I group (shown as triangle and solid line); placebo group (shown as circle and dashed line). The regression lines were derived from the model summarized in Table I: the placebo group regression line is not different from the line of identity, whereas the ACE-I group regression line is significantly different (p=0.019). A point on this log2 scale of 1 represents an actual CFR of 2.0 and a point of 2 represents a CFR of 4.0. ACE-I, angiotensin-converting enzyme inhibition.

Figure 2

Mean angina frequency score (Seattle Angina Questionnaire [SAQ]) over time by treatment group. At baseline, mean SAQ angina scores were similar comparing treatment groups. At 4 weeks, scores improved more in the ACE-I group, and this finding persisted to 16 weeks. Beta coefficients (standard errors): ACE-I group (triangle and solid line) β=0.11(0.03), p=0.0003; placebo group (circle and dashed line) β=0.07(0.03), p=0.02. Note that higher SAQ angina score indicates decreased angina frequency (or greater freedom from angina). ACE-I, angiotensin-converting enzyme inhibition.