title: Imaging of hypoxia in mouse atherosclerotic plaques with (64)Cu-ATSM.
abstract: Cardiovascular disease is the leading cause of death in the United States. The identification of vulnerable plaque at risk of rupture has been a major focus of research. Hypoxia has been identified as a potential factor in the formation of vulnerable plaque, and it is clear that decreased oxygen plays a role in the development of plaque angiogenesis leading to plaque destabilization. The purpose of this study is to demonstrate the feasibility of copper-64 labeled diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM), a positron-emitting radiopharmaceutical taken up in low-oxygen-tension cells, for the identification of hypoxic and potentially unstable atherosclerotic plaque in a mouse model.
  
  
  
  (64)Cu-ATSM PET was performed in 21 atherosclerotic apolipoprotein E knockout (ApoE(-/-)) mice, 6 of which were fed high-fat diet (HFD) while the others received standard-chow diet (SCD), and 13 control wild type mice fed SCD. 4 SCD ApoE(-/-) mice and 4 SCD wild type mice also underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging one day prior to (64)Cu-ATSM PET.
  
  
  
  (64)Cu-ATSM uptake was increased in the aortic arch in SCD ApoE(-/-) mice (average aortic arch/muscle (A/M) standardized uptake value ratio 7.5-30min post injection: (5.66±0.23) compared to control mice (A/M SUV ratio 7.5-30min post injection (3.87±0.22), p<0.0001). HFD ApoE(-/-) mice also showed similarly increased aortic arch uptake on PET imaging in comparison to control mice. Immunohistochemistry in both HFD and SCD ApoE(-/-) mice revealed noticeable hypoxia by pimonidazole stain in atherosclerosis which was co-localized to macrophage by CD68 staining. Autoradiography assessment demonstrated the presence of hypoxia by (64)Cu-ATSM uptake correlated with pimonidazole uptake within the ex vivo atherosclerotic aortic arch specimens. A significant increase in (18)F-FDG uptake in the SCD ApoE(-/-) mice in comparison to controls was also observed at delayed time points.
  
  
  
  This pre-clinical study suggests that (64)Cu-ATSM is a potential PET tracer for hypoxia imaging in atherosclerosis.
  
  
  
  While studies in humans are necessary for conclusive data, in the long term, a (64)Cu-ATSM PET imaging strategy could help facilitate the study of plaque biology in human patients.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University in St. Louis.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Nie
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University in St. Louis.
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University in St. Louis.
authors.forename: Andrew
authors.initials: A
authors.lastname: Elvington
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Nilantha
authors.initials: N
authors.lastname: Bandara
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zheleznyak
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gropler
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University in St. Louis; Diabetic Cardiovascular Disease Center, Washington University in St. Louis.
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Woodard
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Division of Biology and Biomedical Sciences, Washington University in St. Louis; Department of Biomedical Engineering, Washington University in St. Louis. Electronic address: lapis@mir.wustl.edu.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Lapi
mesh_terms: D000818:Animals; D001692:Biological Transport; D015687:Cell Hypoxia; D056831:Coordination Complexes; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography; D013882:Thiosemicarbazones / Q000378:metabolism
chemical_list: D056831:Coordination Complexes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)
keywords: Apo E; Atherosclerosis; Copper-64; Cu-ATSM; Hypoxia