Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque.
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.
Kolodgie
Frank D
FD
Armed Forces Institute of Pathology, Washington, DC, USA.
Petrov
Artiom
A
Virmani
Renu
R
Narula
Navneet
N
Verjans
Johan W
JW
Weber
Deena K
DK
Hartung
Dagmar
D
Steinmetz
Neil
N
Vanderheyden
Jean Luc
JL
Vannan
Mani A
MA
Gold
Herman K
HK
Reutelingsperger
Chris P M
CP
Hofstra
Leo
L
Narula
Jagat
J
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
D017304:Annexin A5; D013667:Technetium