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Calcific Aortic Valve Disease is the number one indication for cardiac valve replacement in the US. The mechanisms of valve calcification are under intense investigation. Mutations in the low-density lipoprotein-related receptor 5 and 6 have been implicated in a number of disease processed in the field of bone, cancer, eye, neurodegenerative disease, congenital heart abnormalities and cardiovascular disease. This study proposes to test the effect of the LDL-Density-Pressure Receptor mechanism on the development of valvular heart disease. To test this hypothesis in an experimental hypercholesterolemia mouse model ApoE-/-,Lrp5-/-,ApoE-/-/Lrp5-/- mice (n=60) were tested. Group I (n=20) normal diet, Group II (n=20) 0.25% chol diet (w/w), for the development of calcification. The aortic valve (AVA) was examined for calcification, and bone matrix markers. Bone formation was assessed by micro Computed Tomography (microCT), Lrp5, Lrp6, and cbfa-1 expression. Echocardiographic measurements were performed using the Vevo mouse echo machine to determine hemodynamic progression with the diets. Echocardiographic Peak Jet Velocity (Control vs cholesterol) ApoE-/-1.6±0.1m/sec vs 1.7±0.1m/sec,Lrp5-/-1.3±0.1m/sec vs 1.56±0.1m/sec, ApoE-/-/Lrp5-/-1.84±0.3m/sec vs 2.03±0.3m/sec, (p>0.05 for all groups). Calcification analysis demonstrates increased in calcification for the ApoE-/-, and ApoE-/-/Lrp5-/- mice in the cholesterol treatments but no evidence in calcification for the Lrp5-/-,cholesterol treatments by MicroCT and Synchotron measurements. RTPCR analysis demonstrates ApoE-/- increase in Runx2 and Lrp5 in the cholesterol treatment(p<0.05)Lrp5-/-no change in Runx2 and no expression of Lrp5 in the cholesterol treatment, ApoE-/-/Lrp5-/- increase in Runx2 and Lrp6 in the cholesterol treatment(p<0.05). This data demonstrates ApoE, Lrp5 and Lrp6 are critical in the development of valve calcification and that a combination of these receptors play a unique role in the development of calcification in the heart valve for the development of valve calcification.