Multiple Endotypes and Angina Burden in Patients With Nonobstructive Coronary Arteries

Importance: Coronary function testing (CFT) can be used to delineate the underlying mechanisms of chest pain in angina with nonobstructive coronary arteries (ANOCA). However, the association between overlapping ANOCA endotypes and angina burden remains poorly defined. Objective: To investigate the impact of multiple ANOCA endotypes on angina burden. Design, Setting, and Participants: This cross-sectional study included patients with suspected ANOCA who underwent acetylcholine provocation testing for endothelium-dependent abnormalities, adenosine-mediated physiology testing for endothelium-independent abnormalities, and intravascular ultrasound with hemodynamic testing for a functionally significant myocardial bridge between August 2007 and February 2025 at Stanford Hospital. Data were analyzed from March 2025 through May 2025. Main Outcomes and Measures: The primary outcome was the association between the number of ANOCA endotypes and angina burden. The Seattle Angina Questionnaire (SAQ) was used to evaluate overall angina burden. Exposure: Patients undergoing comprehensive CFT for ANOCA. Results: A total of 485 patients (mean [SD] age, 52 [14] years; 352 female patients [73%]) were included. There were 36 patients (7%) with no abnormalities, 150 patients (31%) with 1 endotype, 215 patients (44%) with 2 endotypes, and 84 patients (17%) with 3 endotypes identified on CFT. Mean (SD) SAQ summary scores were comparable among patients with an endothelium-dependent abnormality (50.5 [18.3]), an endothelium-independent abnormality (49.3 [19.9]), and myocardial bridging (49.8 [19.2]), and worsened with an increasing number of endotypes identified at CFT (normal CFT finding: 55.9 [17.6]; 1 endotype: 53.8 [17.7]; 2 endotypes: 51.2 [18.3]; and 3 endotypes: 45.7 [20.0]; P = .003). After multivariable adjustment, each additional endotype identified on CFT was associated with a lower SAQ summary score (B = -3.55; 95% CI, -5.56 to -1.54; P < .001). Conclusions and Relevance: In this observational cross-sectional study, multiple endotypes frequently coexisted in patients with ANOCA, and a greater number of endotypes identified on CFT was associated with worse angina.