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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:425.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Evaluation of Matrix Metalloproteinases in Atherosclerosis Using a Novel Noninvasive Imaging Approach

Eric Lancelot^*; Vardan Amirbekian^*; Irène Brigger^*; Jean-Sébastien Raynaud; Sébastien Ballet; Christelle David; Olivier Rousseaux; Soizic Le Greneur; Marc Port; Henri R. Lijnen; Patrick Bruneval; Jean-Baptiste Michel; Tanja Ouimet; Bernard Roques; Smbat Amirbekian; Fabien Hyafil; Esad Vucic; Juan Gilberto S. Aguinaldo; Claire Corot; Zahi A. Fayad

From the Imaging Science Laboratories, Department of Radiology, the Zena and Michael A. Wiener Cardiovascular Institute, the Marie-Josée and Henry R. Kravis Cardiovascular Health Center, and Department of Medicine, Mount Sinai School of Medicine (V.A., S.A., F.H., E.V., J.G.S.A., Z.A.F); Guerbet (E.L., I.B., J-S.R., S.B., C.D., O.R., S.LG., M.P., C.C.), Aulnay-sous-Bois, France; Center for Molecular and Vascular Biology (H.R.L.), University of Leuven, Belgium; INSERM U-652 (P.B.), Paris, France; INSERM U-698 (J-B.M.), Paris, France; Pharmaleads (T.O., B.R.), Paris, France; Emory University School of Medicine (S.A.), Atlanta, Ga; Brigham and Women’s Hospital (V.A.), Harvard Medical School, Boston, Mass; and the Sarnoff Cardiovascular Research Foundation (V.A.).

Correspondence to Zahi A. Fayad, PhD, FAHA, FACC, Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, Box 1234, One Gustave L. Levy Place, New York, NY 10029. E-mail Zahi.Fayad{at}mssm.edu

Objective— Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques.

Methods and Results— The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE^–/– mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques.

Conclusions— P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.

Noninvasively assessing MMPs in atherosclerosis may aid in evaluating plaque stability. In controlled experiments we tested the molecular MRI probe, P947, which specifically targets MMPs. We showed that P947 significantly improved the ability of MRI to delineate atherosclerosis and was associated with higher uptake in MMP-rich versus MMP-poor human plaques.

Key Words: atherosclerosis • matrix metalloproteinases • MRI • atherosclerotic plaque • molecular imaging

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