title: PET/MRI of Hypoxic Atherosclerosis Using 64Cu-ATSM in a Rabbit Model.
abstract: The macrophage-rich core of advanced human atheroma has been demonstrated to be hypoxic, which may have implications in plaque stability. The goal of this study was to determine the feasibility of the hypoxia PET imaging agent64Cu-ATSM to detect hypoxia in a rabbit model of atherosclerosis imaged on a simultaneous PET/MR scanner, using MR for both attenuation correction and depiction of lesion location.
  
  
  METHODS
  New Zealand White rabbits fed a Western diet for 4-6 wk underwent endothelial denudation of the right femoral artery by air desiccation to induce an atherosclerotic-like lesion and underwent a sham operation on the left femoral artery. Four and 8 wk after injury, a 0- to 60-min dynamic whole-body PET/MR examination was performed after injection of approximately 111 MBq of64Cu-ATSM. After 24 h, a 0- to 75-min dynamic PET/MR examination after injection of approximately 111 MBq of18F-FDG was performed. The rabbits were euthanized, and the injured femoral artery (IF) and sham-operated femoral artery (SF) were collected for immunohistochemistry assessment of hypoxic macrophages (hypoxia marker pimonidazole, macrophage marker RAM-11, and hypoxia-inducible factor-1 α subunit [HIF-1α]). Regions of interest of IF, SF, and background muscle (BM) were drawn on fused PET/MR images, and IF-to-BM and SF-to-BM SUV ratios were compared using the Student t test.
  
  
  RESULTS
  Elevated uptake of64Cu-ATSM was found in the rabbits' IF compared with the SF.64Cu-ATSM imaging demonstrated IF-to-SF SUVmeanratios (±SD) of 1.75 ± 0.21 and 2.30 ± 0.26 at 4 and 8 wk after injury, respectively.18F-FDG imaging demonstrated IF-to-SF SUVmeanratios of 1.84 ± 0.12 at 8 wk after injury. IF-to-BM SUVmeanratios were significantly higher (P < 0.001) than SF-to-BM SUVmeanratios both 4 and 8 wk after injury for64Cu-ATSM and 8 wk after injury for18F-FDG (P < 0.05). Pimonidazole immunohistochemistry at 8 wk colocalized to RAM-11 and HIF-1α.
  
  
  CONCLUSIONS
  The results show that hypoxia is present in this rabbit model of atherosclerosis and suggest that64Cu-ATSM PET/MR is a potentially promising method for the detection of hypoxic and potentially vulnerable atherosclerotic plaque in human subjects.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.|Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Nie
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Richard
authors.initials: R
authors.lastname: Laforest
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri.
authors.forename: Andrew
authors.initials: A
authors.lastname: Elvington
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri.
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Tom
authors.initials: T
authors.lastname: Voller
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri.|Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Dana R
authors.initials: DR
authors.lastname: Abendschein
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.|Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri.|Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Lapi
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri woodardp@mir.wustl.edu.|Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri.|Diabetic Cardiovascular Disease Center, Washington University in St. Louis, St. Louis, Missouri.
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Woodard
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D001692:Biological Transport; D015687:Cell Hypoxia; D056831:Coordination Complexes; D004195:Disease Models, Animal; D008264:Macrophages / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D064847:Multimodal Imaging; D009942:Organometallic Compounds / Q000378:metabolism; D049268:Positron-Emission Tomography; D011817:Rabbits; D013882:Thiosemicarbazones / Q000378:metabolism
chemical_list: D056831:Coordination Complexes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)
keywords: 64Cu-ATSM; PET/MR; hypoxic atherosclerosis; rabbit model