Wall Shear Stress from the Fused Bicuspid Aortic Valve Leaflet Induces Acute Remodeling and Cytokine Responses in Normal Porcine Aortic Valve Tissue
Samantha K. Atkins1, Janet Liu2, Johana Barrientos2, Philippe Sucosky2.
1University of Notre Dame, South Bend, IN, USA, 2Wright State University, Dayton, OH, USA.
OBJECTIVE: The bicuspid aortic valve (BAV), which is comprised of two leaflets instead of the usual three, has a higher susceptibility for the development of calcific aortic valve disease (CAVD) than the normal tricuspid aortic valve (TAV). Wall shear stress (WSS) has been indicated to play a role in remodeling and cytokine expression in the BAV, which may lead to earlier CAVD progression that appears to initialize on the fused BAV leaflet. However, the acute role of BAV WSS is unknown in terms of valve mechanobiology. The objective of this study is to subject normal porcine TAV tissue to the WSS environments of the non-coronary and fused BAV (nBAV and fBAV, respectively) leaflets to assess potential changes in acute biological expression after ex vivo conditioning.
METHODS: WSS environments from the fibrosa and ventricularis of TAV, nBAV and fBAV leaflets obtained from computational simulations were used to condition normal porcine TAV leaflet tissue (n=6) for 24 hours in a double cone-and-plate bioreactor. Tissue biology was assessed in terms of remodeling response (MMP-2 and MMP-9) and cytokine expression (BMP-4 and TGF-β1) through immunohistochemistry, Western blotting and zymography.
RESULTS: While the remodeling and cytokine expression of the TAV conditioned valve tissue was not significantly different from fresh controls, the nBAV group showed increased remodeling through MMP-2 (3.8 fold) and MMP-9 (1.7 fold) expression; however, the fBAV group had significantly higher MMP-9 expression (4.8 fold) while maintaining increased MMP-2 expression (2.7 fold) and moderate TGF-β1 responses (2 fold vs TAV). Fig.1 shows MMP-9 immunohistochemistry in fresh valves (a), TAV (b), nBAV (c), and fBAV (d) conditioned groups (blue=DAPI, green=FITC, positively stained).
CONCLUSIONS: This study demonstrates the propensity of the abnormal WSS environment on the fused BAV leaflet, as opposed to the non-coronary leaflet or normal TAV leaflets, to play a role in CAVD progression through the acute expression of remodeling and osteogenic proteins.
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