Imaging inflammation in experimental calcific aortic valve disease using Al18F-NOTA-folate PET

Abstract Background Inflammation, characterized by infiltration of macrophages, contributes to fibro-calcific leaflet remodeling in calcific aortic valve disease (CAVD). Folate receptor β (FR-β) is a membrane-bound protein upregulated on activated macrophages and therefore represents a potential target for in vivo imaging of inflammation (1, 2). Purpose We evaluated Al18F-NOTA-folate (18F-FOL), a positron emission tomography (PET) tracer targeting FR-β, for its ability to assess aortic valve inflammation in a mouse model of CAVD. Methods One-year-old atherosclerotic LDLR-/-ApoB100/100 mice (n=8) fed with a high-fat diet for 7-8 months were used as an experimental model of CAVD. Healthy, age matched C57BL/6N mice (n=8) fed with a regular chow diet served as controls. Echocardiography was performed to detect aortic stenosis. The mice underwent 18F-FOL PET, 18F-NaF PET (microcalcification), and contrast-enhanced computed tomography (CT) imaging. Target-to-background (TBR) ratios (valve-to-blood) were calculated from mean standardized uptake values (SUV) at 50-60 min after tracer injection. The uptake of 18F-FOL in the aortic valve was studied in more detail by ex vivo autoradiography of tissue sections, coupled with histological analyses. Results Doppler echocardiography demonstrated elevated transvalvular peak flow velocity in CAVD mice compared to healthy controls, indicating the presence of aortic stenosis (1400±250 vs. 650±210 mm/s, p