Objective

Many patients with bicuspid aortic valves develop life-threatening aortic complications. Notch1 mutations are implicated and increased smooth muscle cell apoptosis is observed histologically. The Notch1 signalling pathway influences cell fate including apoptosis. In recent cancer studies Notch1 activation enhanced XIAP, a protein known to inhibit apoptosis. The objective is to elucidate the role of XIAP as a potential therapeutic target in preventing progression of biscuspid valve aortopathy.

Methods

With ethical approval 30 aortic wall samples were taken intraoperatively from patients with both bicuspid and tricuspid aortic valves. Blood samples were also collected. Samples were either snap frozen or fixed in formalin. Immunohistochemical labelling with antibodies to Notch1, XIAP and apoptosis related proteins was performed. In addition RNA was extracted from snap frozen tissue and PCR performed to quantify the differing expression of these genes. Serum biomarkers are under investigation.

Results

Preliminary results show for the first time that x-linked inhibitor of apoptosis protein (XIAP) is present alongside Notch1 in the ascending aortic wall. Ongoing investigation aims to quantify this expression and correlate with valve morphology and aortic diameter. It is hoped that vascular smooth muscle cell culture and modulation of notch1 pathway may provide a means for reducing apoptosis and subsequent aneurysm formation. Additionally biomarker analysis could provide a surveillance method.

Conclusion

The Notch1 pathway through its interaction with the x-linked inhibitor of apoptosis protein and downstream apoptotic proteins is a novel mechanism by which the development of aneurysms in patients with bicuspid aortic valves could be monitored and potentially treated.