Identification of TNFα-mediated Inflammation As Potential Pathological Marker and Therapeutic Target for Calcification Progress of Congenital Bicuspid Aortic Valve

Backgroud: Congenital bicuspid aortic valve (cBAV) develops calcification and stenotic obstruction early compared with degenerative tricuspid aortic valve (dTAV), which requires surgical intervention. Here we report a comparative study of patients with cBAV or dTAV to identify risk factors associated with the rapid development of calcified bicuspid valves. Methods: A total of 69 aortic valves (24 dTAV and 45 cBAV) were collected at the time of surgical aortic valve replacement for comparative clinical characteristics. Ten samples were randomly selected from each group for histology, pathology, and inflammatory factors expression and comparison analyses. OM-induced calcification in porcine aortic valve interstitial cell cultures were prepared for illustrating the underlying molecular mechanisms about calcification progress of cBAV and dTAV. Results: We found that cBAV patients have increased cases of aortic valve stenosis compared with dTAV patients. Histopathological examinations revealed increased collagens deposition, neovascularization and infiltrations by inflammatory cells, especially T-lymphocytes and macrophages. We identified that tumor necrosis factor alpha (TNF alpha) and its regulated inflammatory cytokines are upregulated in cBAV. Further in vitro study indicated that TNF alpha-NF kappa B and TNF alpha-GSK3 beta pathway accelerate aortic valve interstitial cells calcification, while inhibition of TNF alpha significantly delays this process. Conclusion: The finding of intensified TNF alpha-mediated inflammation in the pathological cBAV advocates the inhibition of TNF alpha as a potential treatment for patients with cBAV by alleviating the progress of inflammation-induced valve damage and calcification.