title: Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque.
abstract: BACKGROUND
  Apoptosis is common in advanced human atheroma and contributes to plaque instability. Because annexin V has a high affinity for exposed phosphatidylserine on apoptotic cells, radiolabeled annexin V may be used for noninvasive detection of apoptosis in atherosclerotic lesions.
  
  
  RESULTS
  Atherosclerotic plaques were produced in 5 rabbits by deendothelialization of the infradiaphragmatic aorta followed by 12 weeks of cholesterol diet; 5 controls were studied without manipulation. Animals were injected with human recombinant annexin V labeled with technetium-99m before imaging. Aortas were explanted for ex vivo imaging, macroautoradiography, and histological characterization of plaque. Radiolabeled annexin V cleared rapidly from the circulation (T1/2, alpha 9 and beta 46 minutes). There was intense uptake of radiolabel within lesions by 2 hours; no uptake was seen in controls. The results were confirmed in the ex vivo imaging of the explanted aorta. Quantitative annexin uptake was 9.3-fold higher in lesion versus nonlesion areas; the lesion-to-blood ratio was 3.0+/-0.37. Annexin uptake paralleled lesion severity and macrophage burden; no correlation was observed with smooth muscle cells. DNA fragmentation staining of apoptotic nuclei was increased in advanced lesions with evolving necrotic cores, predominantly in macrophages; the uptake of radiolabel correlated with the apoptotic index.
  
  
  CONCLUSIONS
  Because annexin V clears rapidly from blood and targets apoptotic macrophage population, it should constitute an attractive imaging agent for the noninvasive detection of unstable atherosclerotic plaques.
authors.affiliation: Armed Forces Institute of Pathology, Washington, DC, USA.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Kolodgie
authors.forename: Artiom
authors.initials: A
authors.lastname: Petrov
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.forename: Navneet
authors.initials: N
authors.lastname: Narula
authors.forename: Johan W
authors.initials: JW
authors.lastname: Verjans
authors.forename: Deena K
authors.initials: DK
authors.lastname: Weber
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hartung
authors.forename: Neil
authors.initials: N
authors.lastname: Steinmetz
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Vanderheyden
authors.forename: Mani A
authors.initials: MA
authors.lastname: Vannan
authors.forename: Herman K
authors.initials: HK
authors.lastname: Gold
authors.forename: Chris P M
authors.initials: CP
authors.lastname: Reutelingsperger
authors.forename: Leo
authors.initials: L
authors.lastname: Hofstra
authors.forename: Jagat
authors.initials: J
authors.lastname: Narula
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000032:analysis* / Q000378:metabolism; D017209:Apoptosis; D001161:Arteriosclerosis / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D001692:Biological Transport; D053938:DNA Fragmentation; D008264:Macrophages / Q000000981:diagnostic imaging / Q000473:pathology*; D008297:Male; D011817:Rabbits; D011877:Radionuclide Imaging; D013667:Technetium
chemical_list: D017304:Annexin A5; D013667:Technetium