Complex plaques ≥4 mm thickness of the ascending aorta and arch are associated with a high number of embolic strokes (odds ratio=13.8) [1]. Plaques located in the descending aorta (DAo) were previously not considered an etiology for embolic stroke due to their location distal to the great vessel origins. However, recent 4D flow MRI studies showed that retrograde flow from complex DAo plaques is frequent and can be considered a mechanism for embolization to all cerebrovascular territories constituting the only probable source of cerebral infarction in a subset of patients with cryptogenic stroke [2]. Because previous studies did not take into account the vascular anatomy of aortic arch and the Circle of Wills, they are unable to establish a causal link between aortic retrograde flow into the great vessel origins and the stroke territory. The purpose of this prospective study was to further evaluate the presence of retrograde diastolic flow from the DAo into the great vessels as a potential mechanism for cryptogenic stroke. We hypothesize that retrograde aortic flow pathways assessed using 4D flow MRI in combination with the evaluation of cerebrovascular cerebrovascular anatomy (e.g. Circle of Willis architecture) based on 3D TOF brain MR angiography (MRA) will increase the number of patients with cryptogenic stoke in which retrograde embolization constitutes a potential mechanism.35 patients (17 men, 63±17 years) with cryptogenic stroke were included and underwent 4D flow MRI and 3D TOF MRA at 1.5 or 3T (Aera, Avanto, or Skyra, Siemens Medical Systems, Germany). ECG and respiration synchronized 4D flow MRI (3-directional venc=150cm/s, spatial res 2.0-2.8mm3, temp res 40-44 msec) was performed to measure in-vivo time-resolved 3D blood flow with full volumetric coverage of the thoracic aorta. To account for frequently encountered inter-individual differences in vascular architecture of the Circle of Willis, high resolution 3D TOF MRA (isotropic 0.5 mm3) was performed in each patient. The brain territory affected by embolic stroke or transient ischemic attack (TIA) was determined on diffusion weighted MRI. The extent of retrograde flow originating in the descending aorta (DAo) was evaluated using 3D blood flow visualization (EnSight, CEI, Apex, NC). To measure the maximum distance of diastolic retrograde flow in the DAo, a series of 5 emitter planes were positioned at 10 mm intervals from the left subclavian artery origin and 3D pathlines were displayed to depict blood flow direction and pattern (Fig. 1A). An experienced radiologist analyzed all TOF MRA and MRI data to classify cerebrovascular architecture by noting the patency of the anterior and posterior communicating arteries, aortic arch anatomy, posterior circulation anatomy, and vertebral artery dominance. Retrograde embolization was considered a potential mechanism if reverse flow extended from the DAo to a great vessel origin (LSA, CCA, or BCT, see Fig. 1A). As summarized in figure 2, diastolic retrograde flow was observed in 20 patients (57%), visualized from the DAo into the innominate artery (InA) in 3 subjects (8.8%), into the left common carotid artery (LCCA) in 8 (23.6%), and into the left subclavian artery (LSA) in 20 patients (57%). Retrograde flow originated from DAo locations as far as 30mm distal to the LSA. As summarized in table 1, non-conventional cerebrovascular architecture was found in a large fraction of patients (e.g. non-conventional Circle of Willis in 60% of patients). These findings led to the reclassification of retrograde embolization risk as present in 5 (14.3%) patients (i.e. matching retrograde flow brain supplying artery that supplied the vascular territory affected by stroke after accounting for variant cerebrovascular anatomy). In total, the retrograde embolization mechanism with matching embolic stoke territory was detected in 46% (16 of 35) patients with otherwise cryptogenic stroke. The findings in this study in 35 patients with cryptogenic stroke demonstrated close to 50% concordance with stroke location on imaging with retrograde diastolic flow into the feeding vessels of the affected cerebral area, identifying a potential etiology for cryptogenic stroke. Our findings further document the importance of taking into account variant anatomy of the circle of Willis, posterior circulation, and aortic arch in individual patients, which identified a vascular pathway connecting retrograde embolization to the great vessel origins with stroke location in an additional 14% of subjects. Future studies are needed to investigate the potential of medical therapy to alter aortic stiffness and retrograde flow and thus reduce the extent of retrograde embolization in stroke patients with plaques in the DAo.