Background: Aortic 3D blood flow was analyzed to investigate altered ascending aorta (AAo) hemodynamics in bicuspid aortic valve (BAV) patients and its association with differences in cusp fusion patterns (right-left, RL versus right-noncoronary, RN) and expression of aortopathy. Methods and Results: 4D flow MRI measured in vivo 3D blood flow in the aorta of 75 subjects: BAV patients with aortic dilatation stratified by leaflet fusion pattern (n=15 RL-BAV, mid AAo diameter=39.9±4.4mm; n=15 RN-BAV, 39.6±7.2mm); aorta size controls with tricuspid aortic valves (n=30, 41.1±4.4mm); healthy volunteers (n=15, 24.9±3.0mm). Aortopathy type (0-3), systolic flow angle, flow displacement, and regional wall shear stress (WSS) were determined for all subjects. Eccentric outflow jet patterns in BAV patients resulted in elevated regional WSS (p<0.0125) at the right-anterior walls for RL-BAV and right-posterior walls for RN-BAV compared to aorta size controls. Dilatation of the aortic root only (type 1) or involving the entire AAo and arch (type 3) was found in the majority of RN-BAV patients (87%) but was mostly absent for RL-BAV (87% type 2). Differences in aortopathy type between RL-BAV and RN-BAV were associated with altered flow displacement in the proximal and mid AAo for type 1 (42-81% decrease versus type 2) and distal AAo for type 3 (33-39% increase versus type 2). Conclusions: The presence and type of BAV fusion was associated with changes in regional WSS distribution, systolic flow eccentricity, and expression of BAV aortopathy. Hemodynamic markers suggest a physiologic mechanism by which valve morphology phenotype can influence phenotypes of BAV aortopathy.

Clinical reports indicate that patients with allergy/asthma commonly have associated symptoms of anxiety/depression. Anxiety/depression can be reduced by 5-hydroxytryptophan (5-HTP) supplementation. However, it is not known whether 5-HTP reduces allergic inflammation. Therefore, we determined whether 5-HTP supplementation reduces allergic inflammation. We also determined whether 5-HTP decreases passage of leukocytes through the endothelial barrier by regulating endothelial cell function. For these studies, C57BL/6 mice were supplemented with 5-HTP, treated with ovalbumin fraction V (OVA), house dust mite (HDM) extract, or IL-4, and examined for allergic lung inflammation and OVA-induced airway responsiveness. To determine whether 5-HTP reduces leukocyte or eosinophil transendothelial migration, endothelial cells were pretreated with 5-HTP, washed and then used in an in vitro transendothelial migration assay under laminar flow. Interestingly, 5-HTP reduced allergic lung inflammation by 70-90% and reduced antigen-induced airway responsiveness without affecting body weight, blood eosinophils, cytokines, or chemokines. 5-HTP reduced allergen-induced transglutaminase 2 (TG2) expression and serotonylation (serotonin conjugation to proteins) in lung endothelial cells. Consistent with the regulation of endothelial serotonylation in vivo, in vitro pretreatment of endothelial cells with 5-HTP reduced TNF-α-induced endothelial cell serotonylation and reduced leukocyte transendothelial migration. Furthermore, eosinophil and leukocyte transendothelial migration was reduced by inhibitors of transglutaminase and by inhibition of endothelial cell serotonin synthesis, suggesting that endothelial cell serotonylation is key for leukocyte transendothelial migration. In summary, 5-HTP supplementation inhibits endothelial serotonylation, leukocyte recruitment, and allergic inflammation. These data identify novel potential targets for intervention in allergy/asthma.

Aims The objective of this study was to evaluate the potential of 4D flow MRI to assess valve effective orifice area (EOA) in patients with aortic stenosis as determined by the jet shear layer detection (JSLD) method. Methods and Results An in-vitro stenosis phantom was used for validation and in-vivo imaging was performed in 10 healthy controls and 40 patients with aortic stenosis. EOA was calculated by the JSLD method using standard 2D phase contrast MRI (PC-MRI) and 4D flow MRI measurements (EOAJSLD-2D and EOAJSLD-4D, respectively). As a reference standard, the continuity equation was used to calculate EOA (EOACE) with the 2D PC-MRI velocity field and compared to the EOAJSLD measurements. The in-vitro results exhibited excellent agreement between flow theory (EOA=0.78 cm2) and experimental measurement (EOAJSLD-4D=0.78±0.01 cm2) for peak velocities ranging from 0.9 to 3.7 m/s. In-vivo results showed good correlation and agreement between EOAJSLD-2D and EOACE (r=0.91, p<0.001; bias: −0.01±0.38cm2; agreement limits: 0.75 to −0.77cm2), and between EOAJSLD-4D and EOACE (r=0.95, p<0.001; bias: −0.09±0.26cm2; limits: 0.43 to −0.62cm2). Conclusion This study demonstrates the feasibility of measuring EOAJSLD using 4D flow MRI. The technique allows for optimization of the EOA measurement position by visualizing the 3D vena contracta, and avoids potential sources of EOACE measurement variability.

Background Matrix metalloproteinases (MMPs) have been implicated in HIV associated neurological injury; however, this relationship has not been studied early in infection. Methods Plasma levels of MMP-1, -2, -7, -9, and -10 measured using Luminex technology were compared in 52 HIV and 21 seronegative participants of the Chicago Early HIV Infection study. MMP levels were also examined in HIV subgroups defined by antibody reactivity, viremia, and antiretroviral status, as well as in available CSF samples (n=9). MMPs were evaluated for patterns of relationship to cognitive function and to quantitative magnetic resonance measurements of the brain derived in vivo. Results Plasma MMP-2 levels were significantly reduced in early HIV infection and correlated with altered white matter integrity and atrophic brain changes. MMP-9 levels were higher in the treated than naïve HIV subgroup. Only MMP-2 and -9 were detected in CSF; CSF MMP-2 correlated with white matter integrity and with volumetric changes in basal ganglia. Relationships with cognitive function were also identified. Conclusions MMP-2 levels in plasma and in CSF correspond to early changes in brain structure and function. These findings establish a link between MMPs and neurological status previously unidentified in early HIV infection.