title: Identification of High-Risk Plaques by MRI and Fluorescence Imaging in a Rabbit Model of Atherothrombosis.
abstract: BACKGROUND
  The detection of atherosclerotic plaques at risk for disruption will be greatly enhanced by molecular probes that target vessel wall biomarkers. Here, we test if fluorescently-labeled Activatable Cell Penetrating Peptides (ACPPs) could differentiate stable plaques from vulnerable plaques that disrupt, forming a luminal thrombus. Additionally, we test the efficacy of a combined ACPP and MRI technique for identifying plaques at high risk of rupture.
  
  
  RESULTS
  In an atherothrombotic rabbit model, disrupted plaques were identified with in vivo MRI and co-registered in the same rabbit aorta with the in vivo uptake of ACPPs, cleaved by matrix metalloproteinases (MMPs) or thrombin. ACPP uptake, mapped ex vivo in whole aortas, was higher in disrupted compared to non-disrupted plaques. Specifically, disrupted plaques demonstrated a 4.5~5.0 fold increase in fluorescence enhancement, while non-disrupted plaques showed only a 2.2~2.5 fold signal increase. Receiver operating characteristic (ROC) analysis indicates that both ACPPs (MMP and thrombin) show high specificity (84.2% and 83.2%) and sensitivity (80.0% and 85.7%) in detecting disrupted plaques. The detection power of ACPPs was improved when combined with the MRI derived measure, outward remodeling ratio.
  
  
  CONCLUSIONS
  Our targeted fluorescence ACPP probes distinguished disrupted plaques from stable plaques with high sensitivity and specificity. The combination of anatomic, MRI-derived predictors for disruption and ACPP uptake can further improve the power for identification of high-risk plaques and suggests future development of ACPPs with molecular MRI as a readout.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Hua
authors.affiliation: Division of Head and Neck Surgery, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Fred
authors.initials: F
authors.lastname: Baik
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Tuan
authors.initials: T
authors.lastname: Pham
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom.
authors.forename: Alkystis
authors.initials: A
authors.lastname: Phinikaridou
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Nick
authors.initials: N
authors.lastname: Giordano
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Beth
authors.initials: B
authors.lastname: Friedman
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Whitney
authors.affiliation: Division of Head and Neck Surgery, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Quyen T
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, United States of America; Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA, United States of America.
authors.forename: Roger Y
authors.initials: RY
authors.lastname: Tsien
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000473:pathology*; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005456:Fluorescent Dyes / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D061848:Optical Imaging; D058226:Plaque, Atherosclerotic; D012372:ROC Curve; D011817:Rabbits; D011859:Radiography; D013917:Thrombin / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D005456:Fluorescent Dyes; D013917:Thrombin; D020782:Matrix Metalloproteinases