No abstract

Background-C-reactive protein (CRP) has been suggested to actively participate in the development of atherosclerosis.In the present study, we examined the role of the potent endothelium-derived vasoactive factor endothelin-1 (ET-1) and the inflammatory cytokine interleukin-6 (IL-6) as mediators of CRP-induced proatherogenic processes. Methods and Results-Saphenous vein endothelial cells (HSVECs) were incubated with human recombinant CRP (25 g/mL, 24 hours) and the expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and monocyte chemoattractant chemokine-1 was determined. The effects of CRP on LDL uptake were assessed in macrophages using immunofluorescent labeling of CD32 and CD14. In each study, the effect of endothelin antagonism (bosentan) and IL-6 inhibition (monoclonal anti-IL-6 antibodies) was examined. The effects of CRP on the secretion of ET-1 and IL-6 from HSVECs were also evaluated. Incubation of HSVECs with recombinant human CRP resulted in a marked increase in ICAM-1 and VCAM-1 expression (PϽ0.001). Likewise, CRP caused a significant increase in monocyte chemoattractant chemokine-1 production, a key mediator of leukocyte transmigration (PϽ0.001). CRP caused a marked and sustained increase in native LDL uptake by macrophages (PϽ0.05). These proatherosclerotic effects of CRP were mediated, in part, via increased secretion of ET-1 and IL-6 (PϽ0.01) and were attenuated by both bosentan and IL-6 antagonism (PϽ0.01). Conclusions-CRP actively promotes a proatherosclerotic and proinflammatory phenotype. These effects are mediated, in part, via the production of ET-1 and IL-6 and are attenuated by mixed ET A/B receptor antagonism and IL-6 inhibition. Bosentan may be useful in decreasing CRP-mediated vascular disease.

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.