Abstract
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.
Highlights
The bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly and is present in 2–3% of the general population [1]
Ex vivo studies conducted in our laboratory have evidenced the existence of shear stress-sensitive pro-inflammatory pathways and potential synergies between cytokines and cell adhesion molecules in the early valvular response to wall shear stress (WSS) alterations [46,47]. Those studies have demonstrated the sensitivity of leaflet tissue to WSS magnitude and pulsatility, the elucidation of the role played by native BAV WSS abnormalities in calcific aortic valve disease (CAVD) pathogenesis has been hampered by the complexity of the native BAV hemodynamic environment and the challenge to replicate it in the laboratory setting
Specimens exposed to tricuspid aortic valve (TAV), F-BAV and NC-BAV WSS exhibited percentages of apoptotic cells (1.060.4%, 1.160.6% and 0.860.2%, respectively) statistically similar (p.0.90) to that measured in fresh tissue (0.760.2%) (Figure 4D)
Summary
The bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly and is present in 2–3% of the general population [1]. The BAV malformation has emerged as the first indication for surgical valve replacement and as a major risk factor for calcific aortic valve disease (CAVD) [4,5,6]. This condition covers a spectrum of disease from initial changes in the cell biology of the valve leaflets, through early calcification, tissue remodeling and aortic sclerosis, to outflow obstruction and aortic stenosis [7,8,9]. The later stages are characterized by fibrotic thickening of the leaflets and sidespecific formation of calcium nodules near the fibrosa [10]
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