Cardiovascular disease is the leading cause of mortality among women. Among symptomatic women presenting to coronary angiography, 40-65% have no obstructive coronary artery disease (CAD). Considered low risk, they often receive no specific therapy. Yet, evidence now documents that such women have higher than expected risk for major adverse cardiac events. The WARRIOR trial is a multicenter, prospective, randomized, blinded outcome evaluation evaluating intensive medical therapy (IMT) with aspirin, statin, angiotensin converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) vs. usual care (UC) in 4,422 women with ischemic symptoms and non- obstructive CAD. The hypothesis of WARRIOR is that IMT will reduce major adverse cardiac events including angina and hospitalization. We hypothesize that the beneficial effects of IMT may be due to changes in plaque composition and flow reserve related to endothelial and microvascular dysfunction rather than from reduction in stenosis severity. Coronary computed tomographic (CT) angiography (CTA) can identify high-risk plaque features associated with endothelial dysfunction and myocardial ischemia. Recent studies have shown that plaque inflammation inhibits adipocyte maturation in pericoronary artery adipose tissue (PCAT) and in turn increases the density of PCAT. Thus, quantitative CTA can potentially allow a comprehensive noninvasive evaluation of changes in plaque burden, coronary flow and plaque inflammation. We have developed validated software for quantitative characterization of plaque and PCAT density using CTA. In this ancillary substudy, we will recruit 400 patients from the WARRIOR trial with 200 patients from each of the treatment groups (IMT vs UC). From this cohort, 150 patients per treatment group, most compliant with WARRIOR protocol will undergo a CTA at the end of 3 years; with changes in plaque and PCAT characteristics quantified. We propose 3 aims: (1) To compare changes in coronary plaque characteristics and their hemodynamic significance using CTA in WARRIOR women treated with IMT vs UC; (2) To compare changes in plaque inflammation-related characteristics in PCAT in WARRIOR women treated with IMT with statin in combination with angiotensin converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) medications vs UC; (3) To relate plaque burden and plaque composition, CT flow reserve, and PCAT density changes to angina score (Seattle Angina Questionnaire [SAQ]) changes in IMT and UC-randomized WARRIOR women. Our study will be the first to quantify the impact of IMT on plaque composition and inflammation and its relation to clinical improvement in women with ischemic symptoms and nonobstructive CAD.
Heart disease in women can present as cholesterol plaque without significant narrowing of the coronary arteries (nonobstructive plaque) and the WARRIOR trial is investigating if women with chest pain symptoms and nonobstructive plaque diagnosed by CT scans who are treated with intensive medical therapy with a combination of statin and angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) derive greater clinical benefit compared to those who are treated with usual care. We propose to use coronary CT scanning of these women at the end of the WARRIOR trial to determine if women who were treated with intensive medical therapy had a greater reduction in the amount and type of cholesterol plaque compared to women receiving usual care and if this resulted in beneficial changes in clinical symptoms. Our results will provide an understanding of how intensive medical therapy works in providing clinical benefit in women with nonobstructive plaque.
