Marfan syndrome (MFS) is a connective tissue disease with high risk of aortic rupture and aortic dissection. Two-thirds of dissections occur in the ascending aorta (AAo) with one-third occurring in the descending aorta (DAo). Diameter plays an important role in risk stratification and preventive aortic root replacement based on aortic diameter has successfully reduced adverse events in the ascending aorta. However, recent literature has shown diameter only accounts for 50% of the dissections in the DAo region¹. It is not well known how aortic hemodynamics interact with the altered vascular structure of these aortas. One such hemodynamic parameter, wall shear stress (WSS), has been associated with vascular wall remodelling² and may impact aortic dilatation. Therefore, WSS might be an important parameter to better understand disease progression in MFS patients. The aim of this study was to apply aortic 4D flow MRI³ for the analysis of aortic hemodynamics in a cohort of children and adolescents with MFS compared to an age appropriate control cohort.25 pediatric MFS patients (age 15.6±4.0 yrs, female=11) and 21 healthy subjects (age 16.0±2.6 yrs, female=12) with a tricuspid aortic valve were included in this IRB-approved study. Marfan syndrome was identified according to the 2010 Revised Ghent Criteria⁴; FBN1 mutation was proven in 21 patients. 4D flow MRI was performed at 1.5T with full 3D coverage of the thoracic aorta (spatial resolution=2.2-4.1x1.6-2.5x1.9-4.0 mm³; temporal resolution=37.6-40.8 ms) using prospective ECG gating and respiratory navigator gating. All 4D flow MRI data were corrected for velocity aliasing, Maxwell terms and eddy currents⁵. 3D PC-MR angiograms were used to segment the thoracic aorta in 3D (Mimics, Materialise, Leuven, Belgium) (Figure 1B). Systolic 3D WSS along the entire aorta lumen surface was calculated from the 4D flow dataset using a previously described algorithm⁶ (Figure 1C). Mean systolic wall shear stress (meanWSS_syst) was determined in 10 aortic segments based on anatomic landmarks (Figure 1D). Clinically performed ECG gated and navigator triggered contrast enhanced MRA data was used to measure aortic diameters at the levels illustrated in Figure 1B, according to the international guidelines⁷. To account for the range of patient age and body size, aortic Z-scores were calculated for each patient from MRI aortic measurements and body surface area (BSA) using EchoIMS (Merge Healthcare, Chicago, IL). An aortic Z-score ≥2.0 indicates aortic dilatation. The subgroup of the Marfan patients with DAo Z-scores ≥2.0 were analyzed separately.Age, gender and BSA were comparable between the MFS subgroup with dilated proximal DAo and the other groups (Table 1). As summarized in Figure 2A, Marfan patients had reduced meanWSS_syst in the proximal AAo outer segment (0.65±0.12 Pa, p=0.045) and proximal DAo inner segment (0.74±0.17 Pa, p=0.031) and higher meanWSS_syst in the inner segment of the distal AAo (0.94±0.14 Pa, p=0.031) compared to healthy subjects. Subgroup analysis of those Marfan patients with proximal DAo Z-score ≥2.0 (n=7) showed significantly lower meanWSS_syst in many of the aortic segments compared to the Marfan patients with proximal DAo Z-score <2.0 (n=18; 8/10 segments) and compared to the group of healthy subjects (n=21; 4/10 segments) (p=0.002–0.046) (Figure 2B-C). The MFS subgroup (proximal DAo Z-score ≥2.0) had significantly greater Z-scores at nearly all levels of thoracic aorta compared to both other groups (Table 1). For the entire cohort (MFS and healthy subjects) meanWSS_syst showed a strong relationship with aortic dimensions (Z-scores as well as % diameter difference within segments). The most prominent association was found between the meanWSS_syst and the proximal DAo inner segment and the diameter difference isthmus-proximal DAo (Figure 3). 3D streamline visualisation showed marked vortex flow patterns in the proximal DAo in the Marfan patients with dilated proximal DAo (Figure 4).MFS patients demonstrated significantly lower meanWSS_syst at segments in the proximal AAo and proximal DAo. These regions in the aorta correspond to the locations where aortic dissection and/or aortic rupture often originate. The subgroup of Marfan patients with already dilated proximal DAo showed prominently lower meanWSS_syst values in many of the aortic segments compared to other groups, and were associated with regional aortic size. These data suggest that Marfan syndrome consists of a heterogeneous group of patients in terms of cardiovascular hemodynamics and aortic diameters, and one in which distinct abnormalities are already present in childhood. Based on these data, one might speculate that Marfan patients with proximal DAo Z-score ≥2.0 are at higher risk of adverse (cardio)vascular events compared to Marfan patients with normal DAo dimensions. Additional longitudinal studies are warranted to further investigate the diagnostic value of inter-individual differences in MFS hemodynamics.