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Background: Coronary lesions with low fractional flow reserve (FFR) that are treated medically are associated with higher revascularization rates. High wall shear stress (WSS) has been linked with increased plaque vulnerability., Objectives: This study investigated the prognostic value of WSS measured in the proximal segments of lesions (WSS prox ) to predict myocardial infarction (MI) in patients with stable coronary artery disease (CAD) and hemodynamically significant lesions. The authors hypothesized that in patients with low FFR and stable CAD, higher WSS prox would predict MI., Methods: Among 441 patients in the FAME II (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation II) trial with FFR ≤0.80 who were randomized to medical therapy alone, 34 (8%) had subsequent MI within 3 years. Patients with vessel-related MI and adequate angiograms for 3-dimensional reconstruction (n = 29) were propensity matched to a control group with no MI (n = 29) by using demographic and clinical variables. Coronary lesions were divided into proximal, middle, and distal, along with 5-mm upstream and downstream segments. WSS was calculated for each segment., Results: Median age was 62 years, and 46 (79%) were male. In the marginal Cox model, whereas lower FFR showed a trend (hazard ratio: 0.084; p = 0.064), higher WSS prox (hazard ratio: 1.234; p = 0.002, C-index = 0.65) predicted MI. Adding WSS prox to FFR resulted in a significant increase in global chi-square for predicting MI (p = 0.045), a net reclassification improvement of 0.69 (p = 0.005), and an integrated discrimination index of 0.11 (p = 0.010)., Conclusions: In patients with stable CAD and hemodynamically significant lesions, higher WSS in the proximal segments of atherosclerotic lesions is predictive of MI and has incremental prognostic value over FFR., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)