Exposure to fused bicuspid aortic valve wall shear stress promoted fibrosa endothelial activation, paracrine signaling (3.7-fold increase in TGF-b1), catabolic enzyme secretion, and bone matrix synthesis compared to fresh controls.
Ex vivo exposure of porcine aortic valve leaflets to bicuspid aortic valve hemodynamics demonstrates that abnormal wall shear stress directly promotes early pathogenic markers of calcific aortic valve disease.
Effect estimate: 3.7-fold increase
Absolute Event Rate: 3.7% vs 1%
p-value: p=<0.05
The bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly and is frequently associated with calcific aortic valve disease (CAVD). The most prevalent type-I morphology, which results from left-/right-coronary cusp fusion, generates different hemodynamics than a tricuspid aortic valve (TAV). While valvular calcification has been linked to genetic and atherogenic predispositions, hemodynamic abnormalities are increasingly pointed as potential pathogenic contributors. In particular, the wall shear stress (WSS) produced by blood flow on the leaflets regulates homeostasis in the TAV. In contrast, WSS alterations cause valve dysfunction and disease. While such observations support the existence of synergies between valvular hemodynamics and biology, the role played by BAV WSS in valvular calcification remains unknown. The objective of this study was to isolate the acute effects of native BAV WSS abnormalities on CAVD pathogenesis. Porcine aortic valve leaflets were subjected ex vivo to the native WSS experienced by TAV and type-I BAV leaflets for 48 hours. Immunostaining, immunoblotting and zymography were performed to characterize endothelial activation, pro-inflammatory paracrine signaling, extracellular matrix remodeling and markers involved in valvular interstitial cell activation and osteogenesis. While TAV and non-coronary BAV leaflet WSS essentially maintained valvular homeostasis, fused BAV leaflet WSS promoted fibrosa endothelial activation, paracrine signaling (2.4-fold and 3.7-fold increase in BMP-4 and TGF-β1, respectively, relative to fresh controls), catabolic enzyme secretion (6.3-fold, 16.8-fold, 11.7-fold, 16.7-fold and 5.5-fold increase in MMP-2, MMP-9, cathepsin L, cathepsin S and TIMP-2, respectively) and activity (1.7-fold and 2.4-fold increase in MMP-2 and MMP-9 activity, respectively), and bone matrix synthesis (5-fold increase in osteocalcin). In contrast, BAV WSS did not significantly affect α-SMA and Runx2 expressions and TIMP/MMP ratio. This study demonstrates the key role played by BAV hemodynamic abnormalities in CAVD pathogenesis and suggests the dependence of BAV vulnerability to calcification on the local degree of WSS abnormality.
Sun et al. (Wed,) conducted a other in Calcific Bicuspid Aortic Valve Disease (n=12). Fused bicuspid aortic valve (F-BAV) wall shear stress vs. Tricuspid aortic valve (TAV) wall shear stress and fresh controls was evaluated on TGF-b1 expression (paracrine signaling) (3.7-fold increase, p=<0.05). Exposure to fused bicuspid aortic valve wall shear stress promoted fibrosa endothelial activation, paracrine signaling (3.7-fold increase in TGF-b1), catabolic enzyme secretion, and bone matrix synthesis compared to fresh controls.