Molecular and Cellular Imaging of Atherosclerosis
Emerging Applications
Farouc A. Jaffer, MD, PhD*, , ,*,
Peter Libby, MD, FACC*, , and
Ralph Weissleder, MD, PhD*,,1
* Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Donald W. Reynolds Cardiovascular Clinical Research Center, Harvard Medical School, Boston, Massachusetts.
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Figure 1 The biology of atherosclerosis initiation, progression, and complications. This road map identifies important targets for molecular imaging (Table 1). Imaging agents are available for a range of targets and imaging modalities, and several agents have been tested in clinical studies. Modified by permission from reference 10. CCR2 = chemokine (CC motif) receptor 2; MCP = monocyte chemoattractant protein; M-CSF = monocyte colony-stimulating factor; MMP = matrix metalloproteinase; ROS = reactive oxygen species; VCAM = vascular cell adhesion molecule.
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Figure 2 Cellular magnetic resonance image of macrophage (Mac) endocytosis in clinical (53,54) and experimental (52) atherosclerosis using magnetic nanoparticles. (A) Dextranated magnetic nanoparticle injection (ferumoxtran, 2.6 mg/kg) produces focal signal loss within a carotid plaque of a neurologically symptomatic patient (top, "Pre" and [57] "Post" images, arrow). Histological examination of the carotid endarterectomy specimen demonstrates colocalization of macrophages (C, anti-CD68 macrophage antibody, original magnification x100), and iron (Fe) (D, Perls iron stain, neutral red counterstain; original magnification x400). Images provided courtesy of Dr. Jonathan Gillard, Dr. Rikin Trivedi, Dr. Simon Howarth, and Dr. Martin Graves, Addenbrooke’s Hospital, Cambridge, United Kingdom. Reproduced by permission from reference 8. (B) Multimodality magnetic resonance image and near infrared fluorescent imaging of murine atherosclerosis using a magnetofluorescent nanoparticle (MFNP) (52). (E) In vivo 9.4-T electrocardiogram- and respiratory-gated magnetic resonance image of an apolipoprotein E–/–-deficient mouse. Injection of a clinical-type near infrared fluorescent dextranated magnetic nanoparticle (15 mg/kg of iron, 24 h circulation time) produces focal signal loss (arrow) in the aortic root, a known site of atherosclerosis in the apo E–/– mouse. (F) Fluorescence reflectance imaging of the resected aorta confirms a focal near-infrared fluorescent signal within the aortic root (arrow). (G) On fluorescence microscopy, the near-infrared fluorescent MFNP accumulates in intimal macrophages (red, arrow) within aortic root plaque sections (original magnification x200). In contrast, smooth muscle cells (stained here with a spectrally distinct  -actin fluorescent antibody, green) modestly colocalize with the MFNP.
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Figure 3 Cellular imaging of macrophage metabolism using 18F-fluorodeoxyglucose (18FDG) (44). (A) Positron emission tomography (left), contrast computed tomography (middle), and offline co-registered positron emission tomography/computed tomography (right) images of a neurologically symptomatic patient who received an intravenous bolus of 18FDG (dose 370 Mbq). The positron emission tomography image demonstrates focal 18FDG uptake by a right carotid plaque (arrow), corroborated by the computed tomography angiogram and co-registered positron emission tomography/computed tomography images. (B) Relatively weaker 18FDG accumulation is seen in the carotid plaque of an asymptomatic patient. (C, D) A surgically resected carotid plaque from a symptomatic patient was incubated with tritiated deoxyglucose, an analogue of 18FDG. Autoradiography (C, original magnification x100) shows colocalization of silver grains with plaque macrophages (D, anti-CD68 antibody, x200) in areas of the fibrous cap and lipid core. Images provided courtesy of Dr. James Rudd and Dr. Peter Weissberg, Addenbrooke’s Hospital, Cambridge, United Kingdom. Reproduced by permission from reference 44.
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Figure 4 Molecular imaging of cathepsin B protease activity in atherosclerosis using an injectable protease-activatable near-infrared fluorescent (NIRF) agent (41). (A) In vivo murine magnetic resonance image of an aortic plaque (arrow) co-registers with NIRF signal enhancement on (B) in vivo fluorescence mediated tomography, a three-dimensional noninvasive and quantitative fluorescence imaging method (63). (C) Sudan IV-stained lipid-rich aortic lesions correlate well with (D) protease-generated NIRF signal within plaques. (E) Immunoreactive cathepsin B enzyme (x200 original magnification) correlates with (F) focal NIRF signal on microscopic sections, consistent with cathepsin-B–mediated activation of the imaging agent. Reproduced by permission from reference 41.
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Figure 5 Molecular imaging of apoptosis in atherosclerosis using radiolabeled annexin (94). 99mTc-radiolabeled annexin A5 accumulates in a carotid lesion (A, single-photon emission computed tomography images, arrows) of a patient with a recent transient ischemic attack (TIA). (B, D) Annexin A5 in sections of the resected plaque stains strongly (B, anti-annexin A5 polyclonal antibody, original magnification x400) in a macrophage-rich area. In contrast, minimal annexin A5 signal (C) appears in the carotid artery of a patient with a remote TIA. (D) Annexin A5 immunoreactivity is at a background level in the corresponding smooth muscle cell-rich lesion. Images provided courtesy of Dr. Bas Kietselaer and Dr. Leonard Hofstra, University Hospital of Maastricht, Maastricht, the Netherlands. Reproduced by permission from reference 94. ant = anterior; l = left.
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