title: In vivo fluorescence-mediated tomography imaging demonstrates atorvastatin-mediated reduction of lesion macrophages in ApoE-/- mice.
abstract: BACKGROUND
  Macrophage recruitment into atherosclerotic plaques drives lesion progression, destabilization, and rupture. Chronic statin treatment reduces macrophage plaque content. Information on dynamics of macrophage recruitment would help assessing plaque vulnerability and guiding therapy. Techniques to image macrophage homing to vulnerable plaques in vivo are scarcely available. The authors tested if noninvasive fluorescence-mediated tomography (FMT) can assess plaque-stabilizing effects of short-term high-dosage atorvastatin.
  
  
  METHODS
  Macrophages from green-fluorescent-protein-transgenic mice were labeled with a near-infrared fluorescent dye and were injected IV in apolipoprotein E-deficient mice (n=9) on Western diet 7 days after guidewire-injury of the carotid artery. FMT-scans, 2 and 7 days thereafter, quantified macrophage recruitment into carotid artery plaques. Atorvastatin was tested for macrophage adhesion, proliferation, and viability (n=5 to 6) in vitro. Fourteen mice received atorvastatin or vehicle for 4 days after 16 weeks on Western diet. FMT assessed macrophage recruitment into aortic and innominate artery lesions. Means (±SD)% are reported.
  
  
  RESULTS
  Double-labeled macrophages were recruited into carotid artery lesions. FMT resolved fluorescence projecting on the injured carotid artery and detected a signal increase to 300% (±191) after guidewire injury. Atorvastatin reduced macrophage adhesion to activated endothelial cells by 36% (±19). In a clinically relevant proof-of-concept intervention, FMT-imaging detected that 4 days atorvastatin treatment reduced macrophage recruitment by 57% (±8) indicating plaque stabilization. Immunohistochemistry confirmed reduced macrophage infiltration.
  
  
  CONCLUSIONS
  FMT optical imaging proved its high potential for clinical applicability for tracking recruitment of near-infrared fluorescent-labeled macrophages to vulnerable plaques in vivo. FMT-based quantification of macrophage recruitment demonstrated rapid plaque stabilization by 4-day atorvastatin treatment in apolipoprotein E-deficient mice.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Larmann
authors.forename: Tim
authors.initials: T
authors.lastname: Frenzel
authors.forename: Martina
authors.initials: M
authors.lastname: Schmitz
authors.forename: Anke
authors.initials: A
authors.lastname: Hahnenkamp
authors.forename: Philipp
authors.initials: P
authors.lastname: Demmer
authors.forename: Stephan
authors.initials: S
authors.lastname: Immenschuh
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Christoph
authors.initials: C
authors.lastname: Bremer
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001158:Arteries / Q000166:cytology / Q000187:drug effects; D000069059:Atorvastatin; D054442:Cell Migration Assays, Macrophage; D002478:Cells, Cultured; D004032:Diet; D005453:Fluorescence; D049452:Green Fluorescent Proteins; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D014054:Tomography
chemical_list: D001057:Apolipoproteins E; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D011758:Pyrroles; D049452:Green Fluorescent Proteins; D000069059:Atorvastatin