Abstract 3706: Atorvastatin Attenuates Notch1/Lrp5 Induced Osteoblast Expression in Bicuspid Stenotic Aortic Valves
Calcification in the aortic valve is the number one indication for surgical valve replacement in adults in the United States. The incidence increases with age, and is often associated with a bicuspid aortic valve present in 1–2% of the population. Recent evidence has identified mutations in Notch1 in patients with calcific aortic stenosis and regulation of bone formation in bicuspid valves via the Lrp5 pathway. We designed an experimental hypercholesterolemic mouse model of bicuspid (eNOS−/ −) mouse model (Lee, Circulation, 2000, 101,(20):2345– 8) for Notch1, Cbfa1 and evidence for stenosis. eNOS−/ − mice (n=60) were treated with Group I (n=20) normal diet, Group II (n=20) 0.2% chol diet (w/w), and Group III (n=20) 0.2% (w/w) chol diet+atorvastatin for 8 weeks total. Group IV (n=20) 0.2% (w.w)chol diet for 4 weeks and the atorvastatin for 4 weeks for a total of 8 weeks, to determine the development of calcification and stenosis in the bicuspid aortic valves. The aortic valve (AV) was examined for cbfa1, osteopontin, Notch1 and Lrp5 by semiquantitative RTPCR. Hemodynamic analysis of the aortic valves and left ventricular function was tested with the 30MHz Visual Sonics mouse echo machine. Results: Cholesterol treatment in the bicuspid aortic valves demonstrate an increase in Notch1, Cbfa1, osteopontin, Lrp5 and Wnt3a and inhibition with atorvastatin. Echocardiog-raphy demonstrated a hemodynamic stenosis in the cholesterol treated valves as compared to the controls and statin treated valves. ( See Table 1⇓ for echo results, (p<0.05 (* cholesterol vs control; ** cholesterol vs atorvastatin). In conclusion, eNOS)( − /−) bicuspid mice develop stenosis and increase in bone matrix markers, Notch1 and Lrp5 signaling pathway. Atorvastatin inhibits the development of stenosis and matrix synthesis via inhibition of Notch1 and Lrp5. This provides the first in vivo experimental model to demonstrate the signaling pathway by which bicuspid aortic valve calcify.