title: An approach towards molecular imaging of activated platelets allows imaging of symptomatic human carotid plaques in a new model of a tissue flow chamber.
abstract: The development of magnetic resonance imaging (MRI) contrast agents targeting epitopes in atherosclerosis is of general interest. In particular, early detection of activated platelets as key players in plaque rupture could provide improved triage of patients. However, so far the efficiency of contrast agents targeting human pathologies can only be examined in animal experiments, which do not necessarily reflect human in vivo conditions. We therefore describe application of a contrast agent targeting activated human platelets in an MRI tissue flow chamber, allowing detection and characterization of contrast agent binding. Microparticles of iron oxide (MPIO) were conjugated to an antibody targeting ligand-induced binding sites (LIBS) on the activated platelet glycoprotein IIb/IIIa-receptor or to control antibody, resulting in LIBS-MPIO or control-MPIO contrast agent. Human endarterectomy specimens from patients with acute stroke or transient ischemic attack were imaged ex vivo before and after contrast agent perfusion using a 9.4 T MRI system. Specimens were measured under static (n = 18) or flow conditions (n = 18) in a specially designed flow chamber setup, simulating physiological conditions in a stenosed vessel. A significant MPIO-induced negative contrast was achieved in MRI by LIBS-MPIO in specimens under static and flow conditions (LIBS-MPIO vs control-MPIO: p < 0.01), and the location of LIBS-MPIO binding corresponded well between histology and MRI (p < 0.05). The number of MPIOs per platelet area on endarterectomy specimens in histology was significantly higher with LIBS-MPIO (p < 0.001). Furthermore, the intensity of contrast agent binding and signal change showed the potential to reflect the severity of clinical symptoms. LIBS-MPIO allows the detection of activated platelets on the surface of symptomatic atherosclerotic human plaques using molecular MRI. Furthermore, the MRI tissue flow chamber setup described could help to evaluate binding properties of contrast agents, and might therefore be an interesting tool for contrast agent development from animal experiments towards clinical application.
authors.affiliation: Department of Radiology-Medical Physics, University Medical Center Freiburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: von Elverfeldt
authors.forename: Mirko
authors.initials: M
authors.lastname: Meissner
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
authors.forename: Dominik
authors.initials: D
authors.lastname: Paul
authors.forename: Fabian
authors.initials: F
authors.lastname: Meixner
authors.forename: Irene
authors.initials: I
authors.lastname: Neudorfer
authors.forename: Annette
authors.initials: A
authors.lastname: Merkle
authors.forename: Andreas
authors.initials: A
authors.lastname: Harloff
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
authors.forename: Joachim
authors.initials: J
authors.lastname: Schöllhorn
authors.forename: Michael
authors.initials: M
authors.lastname: Markl
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hennig
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Constantin
authors.initials: C
authors.lastname: von zur Muhlen
mesh_terms: D000368:Aged; D001665:Binding Sites; D016893:Carotid Stenosis / Q000503:physiopathology* / Q000601:surgery; D003287:Contrast Media; D016894:Endarterectomy, Carotid; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008297:Male; D008954:Models, Biological; D057054:Molecular Imaging / Q000379:methods*; D015539:Platelet Activation / Q000502:physiology*; D012212:Rheology / Q000295:instrumentation* / Q000379:methods*
chemical_list: D003287:Contrast Media; D005290:Ferric Compounds; D008024:Ligands; C000499:ferric oxide