Published Online
on December 15, 2003

A more recent version of this article appeared on December 23, 2003

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Submitted on May 16, 2003
Revised on July 31, 2003
Accepted on August 21, 2003

Targeting of Apoptotic Macrophages and Experimental Atheroma With Radiolabeled Annexin V. A Technique With Potential for Noninvasive Imaging of Vulnerable Plaque

Frank D. Kolodgie PhD, Artiom Petrov PhD, Renu Virmani MD, Navneet Narula MD, Johan W. Verjans MS, Deena K. Weber BS, Dagmar Hartung MD, Neil Steinmetz MD, Jean Luc Vanderheyden PhD, Mani A. Vannan MD, Herman K. Gold MD, Chris P.M. Reutelingsperger PhD, Leo Hofstra MD, PhD, and Jagat Narula MD, PhD^*

From the Armed Forces Institute of Pathology (F.D.K., R.V., D.K.W.), Washington, DC; Drexel University College of Medicine (A.P., J.W.V., D.H., M.A.V., J.N.) and University of Pennsylvania Medical Center (N.N.), Philadelphia, Pa; Theseus Imaging (N.S., J.L.V.) and Massachusetts General Hospital (H.K.G.), Boston, Mass; and Cardiovascular Research Institute (C.P.M.R., L.H.), Maastricht, the Netherlands.

^* To whom correspondence should be addressed. E-mail: narula{at}uci.edu.

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.

Methods and 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 (T_1/2, 9 and 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.

Key words: apoptosis • atherosclerosis • imaging • nuclear medicine

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