Multimodality Imaging of Aortic Valve Calcification and Function in a Murine Model of Calcific Aortic Valve Disease and Bicuspid Aortic Valve

Abstract

Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. Dcbld2^-/- mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). ¹⁸F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate ¹⁸F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in Dcbld2^-/- mice. Methods: Dcbld2^-/- mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, ¹⁸F-NaF PET/CT (n = 34, or autoradiography (n = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography (n = 12). The aortic valve signal was quantified as SUV_max on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. Results: The aortic valve ¹⁸F-NaF signal on PET/CT was significantly higher at 18-24 mo (P < 0.0001) and 10-16 mo (P < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher ¹⁸F-NaF signal than tricuspid aortic valves (P < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher ¹⁸F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson r = 0.79, P < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV (P < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT (r = 0.55, P < 0.001) and autoradiography (r = 0.45, P < 0.01). Conclusion: ¹⁸F-NaF PET/CT links valvular calcification to BAV and aging in Dcbld2^-/- mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, ¹⁸F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD.

Keywords: PET; aortic valve; calcification; molecular imaging; sodium fluoride.