title: Imaging of the vulnerable carotid plaque: biological targeting of inflammation in atherosclerosis using iron oxide particles and MRI.
abstract: OBJECTIVE
  Identification of those patients with high-risk asymptomatic carotid plaques remains an elusive but essential step in stroke prevention. Inflammation is a key process in plaque destabilization and the propensity of atherosclerotic lesions to cause clinical sequelae. There is currently no clinical imaging technique available to assess the degree of inflammation associated with plaques. This study aims at visualizing and characterizing atherosclerosis using antibody-conjugated superparamagnetic iron oxide (SPIO) particles as an MRI probe to assess inflammation in human atherosclerotic plaques.
  
  
  METHODS
  Atherosclerotic plaques were collected from 20 consecutive patients (n=10 from symptomatic patients, n=10 from asymptomatic patients) undergoing carotid endarterectomy (CEA) for extracranial high-grade internal carotid artery (ICA) stenosis (>70% luminal narrowing). Inflammatory markers on human atherosclerotic plaques were detected and characterized by ex vivo magnetic resonance imaging (MRI) using anti-VCAM-1 antibody and anti-E-selectin antibody-conjugated SPIO with confirmatory immunohistochemistry.
  
  
  RESULTS
  Inflammation associated with human ex vivo atherosclerotic plaques could be imaged using dual antibody-conjugated SPIO by MRI. Symptomatic plaques could be distinguished from asymptomatic ones by the degree of inflammation, and the MR contrast effect was significantly correlated with the degree of plaque inflammation (r=.64, p<.001). The asymptomatic plaque population exhibited heterogeneity in terms of inflammation. The dual-targeted SPIO-induced MR signal not only tracked closely with endothelial activation (i.e. endothelial expression of VCAM-1 and E-selectin), but also reflected the macrophage burden within plaque lesions, offering a potential imaging tool for quantitative MRI of inflammatory activity in atherosclerosis.
  
  
  CONCLUSIONS
  These functional molecular MRI probes constitute a novel imaging tool for ex vivo characterization of atherosclerosis at a molecular level. Further development and translation into the clinical arena will facilitate more accurate risk stratification in carotid artery disease in the future.
authors.affiliation: Regional Vascular Unit, St Mary's Hospital, Imperial College Healthcare NHS Trust, Imperial College London, UK.
authors.forename: J M S
authors.initials: JM
authors.lastname: Chan
authors.affiliation: Cytokine Biology of Atherosclerosis, Kennedy Institute of Rheumatology, Imperial College London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Monaco
authors.affiliation: Biological Imaging Centre, Clinical Sciences Centre, Medical Research Council, Imperial College London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Wylezinska-Arridge
authors.affiliation: Biological Imaging Centre, Clinical Sciences Centre, Medical Research Council, Imperial College London, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Tremoleda
authors.affiliation: Regional Vascular Unit, St Mary's Hospital, Imperial College Healthcare NHS Trust, Imperial College London, UK. Electronic address: r.gibbs@imperial.ac.uk.
authors.forename: R G J
authors.initials: RG
authors.lastname: Gibbs
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016893:Carotid Stenosis / Q000175:diagnosis* / Q000209:etiology / Q000601:surgery; D003287:Contrast Media; D019040:E-Selectin / Q000378:metabolism*; D016894:Endarterectomy, Carotid; D005260:Female; D005290:Ferric Compounds; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000175:diagnosis / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D058226:Plaque, Atherosclerotic / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism; D015203:Reproducibility of Results; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D019040:E-Selectin; D005290:Ferric Compounds; D019010:Vascular Cell Adhesion Molecule-1; C000499:ferric oxide
keywords: Atherosclerosis; Inflammation; Iron oxide particles; Magnetic resonance imaging; Vulnerable plaque