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

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

抄録

<jats:p> <jats:bold> <jats:italic>Objective—</jats:italic> </jats:bold> 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. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> 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 <jats:sup>−/−</jats:sup> 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. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques. </jats:p>

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