Abstract Introduction Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital condition believed to carry an increased risk for myocardial ischemia. However, correlation between anatomical characteristics and ischemia remains unclear. Therefore, this study aimed to assess: 1. The difference of invasive fractional flow reserve (FFR) and intravascular ultrasound (IVUS)-based minimal lumen area (MLA) between baseline and stress. 2. The association of coronary computed tomography angiography (CCTA)-based anatomical characteristics to invasively measured hemodynamics and IVUS in AAOCA. Methods Consecutive patients with AAOCA and presence of ≥1 anatomical high-risk features (i.e. intramural course (IM), slit-like ostium, acute take-off angle or proximal narrowing), were systematically evaluated as part of the NARCO trial using CCTA, FFR using adenosine (140 µg/kg/min), dobutamine-volume stress (20-40mcg/kg/min, 0.5-1mg atropine and 3L of saline solution) and IVUS- MLA of IM. Anatomic high-risk features were quantified by CCTA including ostial lumen area and IM-MLA, IM-width, IM-height, IM-elliptic ratio, take-off angle, proximal narrowing and IM length of the anomalous coronary segment. Results A total of 94 patients with AAOCA were screened, whereas 48 showed high-risk anatomic features and underwent the complete stress protocol. Mean age was 54±12 years and 36 (75%) were male and 39 (81%) presented with symptoms. FFRstress was significantly lower than FFRadenosine (0.88 [0.81-0.91] vs. 0.91 [0.87-0.94], p<0.001) (Figure 1). FFRadenosine was ≤0.8 in 5 patients (10%), and FFRdobutamine was ≤0.8 in 12 patients (25%), resulting in 7 (15%) with FFRadenosine >0.8 while FFRdobutamine was ≤0.8. IVUS-MLA was decreased from 6.3 (5.4-8.2) mm2 to 5.4 (4.2-7.1) mm2 during stress (p<0.001) (Figure 2), while elliptic ratio increased from 2.6 (2.1-3.4) to 3.3 (2.5-4.4) (p<0.001). Logistic regression analysis for body surface area adjusted CCTA derived high-risk features showed, that only ostial lumen area, IM-MLA, -elliptic ratio and -width could predict FFRstress ≤0.8. Receiver operating curve analysis showed that ostial width had the greatest AUC with 0.86 (accuracy 83%, sensitivity 83%, and specificity 83%). Eight out of 12 (67%) patients with hemodynamic relevance underwent surgery, 2 (17%) underwent stenting and 2 (17%) were treated with medication. Conclusion In patients with AAOCA and anatomic high-risk features, only one quarter are hemodynamic relevant. FFR during dobutamine-volume stress showed to be the more sensitive stress modality as compared to FFRadenosine. CCTA derived ostial and IM anatomical severity is associated with ischemia under stress. Comprehensive functional and anatomical assessment of AAOCA helps to optimize patient management and avoid unnecessary revascularization.Figure 1:FFRadenosine vs FFRstressFigure 2:IVUS-MLArest vs IVUS-MLAstress