Published online before print August 3, 2009, doi: 10.1161/CIRCULATIONAHA.108.813998
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(Circulation. 2009;120:592-599.)
© 2009 American Heart Association, Inc.
Imaging |
Enzyme-Sensitive Magnetic Resonance Imaging Targeting Myeloperoxidase Identifies Active Inflammation in Experimental Rabbit Atherosclerotic Plaques
From Robarts Research Institute (J.A.R., Y.C., R.A.H., B.K.R.), London, Ontario, Canada; Department of Medical Biophysics (J.A.R., B.K.R.), Department of Anatomy and Cell Biology (A.M.H., K.A.R.), and Department of Diagnostic Radiology and Nuclear Medicine (B.K.R.), University of Western Ontario, London, Ontario, Canada; Center for Systems Biology (J.W.C., R.W.) and Center for Molecular Imaging Research (J.W.C., E.R., F.R., R.W.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass; Laboratory of Molecular Imaging Probes (M.Q., A.B.), Department of Radiology, University of Massachusetts Medical School, Worcester, Mass; and Department of Radiology (B.K.R.), Stanford University, Palo Alto, Calif.
Correspondence to John A. Ronald, Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, E150 James Clark Center, 318 Campus Drive, Palo Alto, CA 94306 (e-mail jronald1{at}stanfor.edu) or John W. Chen, Center for Systems Biology, Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Room 5406 CNY-149, 13th St, Charlestown, MA 02129 (e-mail chenjo@helix.mgh.harvard.edu)
Received September 25, 2008; accepted June 8, 2009.
Background— Inflammation undermines the stability of atherosclerotic plaques, rendering them susceptible to acute rupture, the cataclysmic event that underlies clinical expression of this disease. Myeloperoxidase is a central inflammatory enzyme secreted by activated macrophages and is involved in multiple stages of plaque destabilization and patient outcome. We report here that a unique functional in vivo magnetic resonance agent can visualize myeloperoxidase activity in atherosclerotic plaques in a rabbit model.
Methods and Results— We performed magnetic resonance imaging of the thoracic aorta of New Zealand White rabbits fed a cholesterol (n=14) or normal (n=4) diet up to 2 hours after injection of the myeloperoxidase sensor bis-5HT-DTPA(Gd) [MPO(Gd)], the conventional agent DTPA(Gd), or an MPO(Gd) analog, bis-tyr-DTPA(Gd), as controls. Delayed MPO(Gd) images (2 hours after injection) showed focal areas of increased contrast (>2-fold) in diseased wall but not in normal wall (P=0.84) compared with both DTPA(Gd) (n=11; P<0.001) and bis-tyr-DTPA(Gd) (n=3; P<0.05). Biochemical assays confirmed that diseased wall possessed 3-fold elevated myeloperoxidase activity compared with normal wall (P<0.01). Areas detected by MPO(Gd) imaging colocalized and correlated with myeloperoxidase-rich areas infiltrated by macrophages on histopathological evaluations (r=0.91, P<0.0001). Although macrophages were the main source of myeloperoxidase, not all macrophages secreted myeloperoxidase, which suggests that distinct subpopulations contribute differently to atherogenesis and supports our functional approach.
Conclusions— The present study represents a unique approach in the detection of inflammation in atherosclerotic plaques by examining macrophage function and the activity of an effector enzyme to noninvasively provide both anatomic and functional information in vivo.
CLINICAL PERSPECTIVE
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Clinical Summaries
Circulation 2009 120: 543-545.[Extract] [Full Text]