Pathophysiologic basis of angina symptoms in women with nonobstructive atherosclerosis using artificial intelligence-enabled plaque characterization from coronary computed tomography angiography

Background A significant proportion of women with ischemic symptoms have nonobstructive coronary artery disease (CAD). However, the pathophysiologic basis for their clinical presentation has not been well characterized. Noncalcified (NCP) and low attenuation plaque (LAP) burden quantified from coronary computed tomography angiography (CTA) is associated with increased risk of myocardial ischemia. We hypothesized that ischemic symptoms may be related to NCP burden in women with nonobstructive CAD. Objective To examine the association between CTA-derived quantitative plaque characteristics and ischemic symptoms in women with nonobstructive CAD using AI-enabled analysis in a prospective study. Methods Women with nonobstructive CAD on CTA (<50% stenosis) enrolled in the prospective WARRIOR ancillary study were assessed for angina severity at baseline with the Seattle Angina Questionnaire (SAQ). CTA scans from 117 women were analyzed with AI-based software (Autoplaque 3.0, Cedars Sinai) for quantitative characterization of atherosclerotic plaque to measure NCP, LAP (defined as NCP<30 Hounsfield units) and calcified plaque (CP) volumes, and burden (%, normalized to vessel volume) in the entire coronary tree. Machine-learning ischemia risk score (ML-IRS) was quantified based on CTA lumen and plaque measures. Results Among 109 women with plaque on CTA (age 61.9±10.3 years, BMI 30.2±7.4 kg/m2) median total plaque burden was 26.6% (IQR 18.6, 32.0) and median SAQ was 61.4 (IQR 54.6, 69.1). Patients with weekly angina (SAQ≤60) were younger (58.1 vs. 62.0 years, p=0.015), had higher cholesterol (195 vs. 165 mg/dL, p=0.006), but less frequently received statin (31.8 vs. 64.4%, p=0.006) compared with patients with less severe symptoms (SAQ>60). Patients with SAQ≤60 had higher median total plaque (33.3 vs. 24.3%, p=0.001), and NCP burden (33.3 vs. 23.2%, p<0.001), and lower CP burden (0.0 vs. 0.3%, p=0.005) compared with patients with SAQ>60. On multivariable linear regression adjusted for clinical risk factors, increased NCP burden (β=-0.50, P=0.001), LAP burden (β=-4.50, P=0.008) and ML-IRS (β=-3.09, P=0.04) were associated with lower SAQ thus, more frequent angina. Conclusion In women with nonobstructive CAD, high-risk atherosclerotic plaque phenotypes of increased NCP and LAP burden are related to more frequent angina.