Trine P Ludvigsen1, Sune F Pedersen2, Andreas Vegge1, Rasmus S Ripa2, Helle H Johannesen2, Adam E Hansen2, Johan Löfgren2, Camilla Schumacher-Petersen3, Rikke K Kirk1, Henrik D Pedersen4, Berit Ø Christoffersen1, Mathilde Ørbæk2, Julie L Forman5, Thomas L Klausen2, Lisbeth H Olsen3, Andreas Kjaer6. 1. Global Drug Discovery, Novo Nordisk Park, Novo Nordisk A/S, DK-2760, Måløv, Denmark. 2. Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Dept. of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. 3. Department of Veterinary and Animal Sciences, University of Copenhagen, Ridebanevej 9, DK-1870, Frederiksberg, Denmark. 4. Department of Veterinary and Animal Sciences, University of Copenhagen, Ridebanevej 9, DK-1870, Frederiksberg, Denmark; Ellegaard Göttingen Minipigs A/S, Sorø Landevej 302, DK-4261, Dalmose, Denmark. 5. Section of Biostatistics, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, DK-1014, Copenhagen, Denmark. 6. Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Dept. of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. Electronic address: akjaer@sund.ku.dk.
Abstract
BACKGROUND AND AIMS: The advantage of combining molecular and morphological imaging, e.g. positron emission tomography and magnetic resonance imaging (PET/MRI), is reflected in the increased use of these modalities as surrogate end-points in clinical trials. This study aimed at evaluating plaque inflammation using 18F-fluorodeoxyglucose (18F-FDG)-PET/MRI, and gene expression in a minipig model of atherosclerosis. METHODS: Göttingen Minipigs were fed for 60 weeks with fat/fructose/cholesterol-rich diet (FFC), chow (Control) or FFC-diet changed to chow midway (diet normalization group; DNO). In all groups, 18F-FDG-PET/MRI of the abdominal aorta was assessed midway and at study-end. The aorta was analyzed using histology and gene expression. RESULTS: At study-end, FFC had significantly higher FDG-uptake compared to Control (target-to-background maximal uptake, TBRMax (95% confidence interval) CITBRMax: 0.092; 7.32) and DNO showed significantly decreased uptake compared to FFC (CITBRMax: -5.94;-0.07). No difference was observed between DNO and Control (CITBRMax: -2.71; 4.11). FFC displayed increased atherosclerosis and gene expression of inflammatory markers, including vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 68 (CD68), matrix metalloproteinase 9 (MMP9), cathepsin K (CTSK) and secreted phosphoprotein 1 (SPP1) compared to Control and DNO (all, p < 0.05). FDG-uptake correlated with gene expression of inflammatory markers, including CD68, ρs = 0.58; MMP9, ρs = 0.46; SPP1, ρs = 0.44 and CTSK, ρs = 0.49; (p ≤ 0.01 for all). CONCLUSIONS: In a model of atherosclerosis, 18F-FDG-PET/MRI technology allows for detection of inflammation in atherosclerotic plaques, consistent with increased inflammatory gene expression. Our findings corroborate clinical data and are important in pre-clinical drug development targeting plaque inflammation.
BACKGROUND AND AIMS: The advantage of combining molecular and morphological imaging, e.g. positron emission tomography and magnetic resonance imaging (PET/MRI), is reflected in the increased use of these modalities as surrogate end-points in clinical trials. This study aimed at evaluating plaque inflammation using 18F-fluorodeoxyglucose (18F-FDG)-PET/MRI, and gene expression in a minipig model of atherosclerosis. METHODS: Göttingen Minipigs were fed for 60 weeks with fat/fructose/cholesterol-rich diet (FFC), chow (Control) or FFC-diet changed to chow midway (diet normalization group; DNO). In all groups, 18F-FDG-PET/MRI of the abdominal aorta was assessed midway and at study-end. The aorta was analyzed using histology and gene expression. RESULTS: At study-end, FFC had significantly higher FDG-uptake compared to Control (target-to-background maximal uptake, TBRMax (95% confidence interval) CITBRMax: 0.092; 7.32) and DNO showed significantly decreased uptake compared to FFC (CITBRMax: -5.94;-0.07). No difference was observed between DNO and Control (CITBRMax: -2.71; 4.11). FFC displayed increased atherosclerosis and gene expression of inflammatory markers, including vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 68 (CD68), matrix metalloproteinase 9 (MMP9), cathepsin K (CTSK) and secreted phosphoprotein 1 (SPP1) compared to Control and DNO (all, p < 0.05). FDG-uptake correlated with gene expression of inflammatory markers, including CD68, ρs = 0.58; MMP9, ρs = 0.46; SPP1, ρs = 0.44 and CTSK, ρs = 0.49; (p ≤ 0.01 for all). CONCLUSIONS: In a model of atherosclerosis, 18F-FDG-PET/MRI technology allows for detection of inflammation in atherosclerotic plaques, consistent with increased inflammatory gene expression. Our findings corroborate clinical data and are important in pre-clinical drug development targeting plaque inflammation.
Authors: Nicholas R Evans; Jason M Tarkin; Elizabeth Pv Le; Rouchelle S Sriranjan; Andrej Corovic; Elizabeth A Warburton; James Hf Rudd Journal: Br J Radiol Date: 2020-04-03 Impact factor: 3.039