PROJECT SUMMARY/ABSTRACT Internal carotid artery (ICA) stenosis is a leading cause of stroke, long-term disability, and death. Current assessment of ICA stenosis is based on estimation of % stenosis via duplex ultrasound (DUS) or cross-sectional angiography. Landmark studies suggested that asymptomatic patients with stenotic lesions >60% should be considered for carotid endarterectomy (CEA), however intervention is often reserved to those with stenotic lesions >80% and/or vulnerable plaques. The % stenosis alone is a poor surrogate for plaque vulnerability and does not identify patients at high risk for stroke. Moreover, stenosis severity does not account for indices such as plaque burden, wall shear stress (WSS), pressure gradients, and cerebral flow compensation which are key to understand stroke risk. Optimal patient selection for carotid artery revascularization, particularly in asymptomatic patients, remains a significant clinical need. We have developed a workflow based on patient-specific CFD modeling informed by MRI data, and demonstrated that patients with similar degrees of stenosis (> 70% stenosis diagnosed using DUS and/or cross sectional angiography) have differences in pressure gradients and cerebral blood flow. These results suggest again that anatomic and flow data alone fail to identify markers for stroke risk and patients who would benefit from carotid revascularization. In this proposal, we will leverage MRI to characterize plaque composition and CFD modeling to assess hemodynamic loads on the plaque to thus provide a better assessment of vulnerability. We hypothesize that patients with similar degrees of asymptomatic high-grade (> 70% stenosis on DUS velocity criteria) extracranial ICA stenosis will have differences in plaque morphology, hemodynamics stresses on the plaque, and cerebral perfusion that are independent of their DUS velocity profiles and stenosis severity. To test this hypothesis, we will pursue the following Aims: 1) To determine plaque composition using T1/T2 MRI, hemodynamic loads on the plaque and cerebral flow using MRI-calibrated CFD workflows in a cohort of patients with asymptomatic high grade ICA stenosis who have similar velocity profiles on DUS. 2) To characterize the degree of variability in the above metrics, and therefore test the validity of our hypothesis. 3) In a subset of the patients who are chosen for CEA, we will investigate the differences in pre-operative and post-operative hemodynamic to assess the efficacy of the surgical repair.