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Am J Nucl Med Mol Imaging 2013;3(5):384-392
Original Article
18F-FDG imaging of human atherosclerotic carotid plaques reflects gene
expression of the key hypoxia marker HIF-1α
Sune Folke Pedersen, Martin Græbe, Anne Mette F Hag, Liselotte Højgaard, Henrik Sillesen, Andreas Kjær
Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of
Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; Department of Vascular Surgery, Rigshospitalet, University of
Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark
Received May 26, 2013; Accepted June 20, 2013; Epub September 19, 2013; Published September 30, 2013
Abstract: To investigate the association between gene expression of key molecular markers of hypoxia and inflammation in
atherosclerotic carotid lesions with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) uptake as determined clinically by positron emission
tomography (PET). Studies using PET have demonstrated 18F-FDG-uptake in patients with confirmed plaques of the carotid artery.
Inflammatory active or “vulnerable” plaques progressively increase in bulk, develop necrotic cores, poor vessel-wall vascularization
and become prone to hypoxia. We used quantitative polymerase-chain reaction (qPCR) to determine gene expression of hypoxia-
inducible factor 1α (HIF-1α) and cluster of differentiation 68 (CD68) on plaques recovered by carotid endarterectomy (CEA) in 18
patients. Gene expression was compared with 18F-FDG-uptake quantified as the maximum standardized uptake value (SUVmax) on
co-registered PET/computed tomography (CT) scans performed the day before CEA. Immunohistochemistry was used to validate
target-gene protein expression. In univariate linear regression analysis HIF-1α was significantly correlated with 18F-FDG-uptake
(SUVmax) as was CD68. A two-tailed Pearson regression model demonstrated that HIF-1α and CD68 gene expression co-variated
and accordingly when entering the variables into multivariate linear regression models with SUV-values as dependent variables, HIF-
1α was eliminated in the final models. 18F-FDG-uptake (SUVmax) is correlated with HIF-1α gene expression indicating an
association between hypoxia and glucose metabolism in vivo. The marker of inflammation CD68 is also associated with 18F-FDG-
uptake (SUVmax). As CD68 and HIF-1α gene expression co-variate their information is overlapping. (ajnmmi1306001).
Keywords: Hypoxia, 18F-FDG PET/CT imaging, carotid atherosclerosis, gene expression, HIF-1α
Address correspondence to: Sune Folke Pedersen, MSc, Cluster for Molecular Imaging, Department of Biomedical Sciences,
Faculty of Health, Room 12.3.38, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Tel: +45 35326007;
Fax: +45 35327546; E-mail: sfolkep@sund.ku.dk; Dr. Andreas Kjær, Department of Clinical Physiology, Nuclear Medicine & PET and
Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail:
akjaer@sund.ku.dk