title: Targeted Near-Infrared Fluorescence Imaging of Atherosclerosis: Clinical and Intracoronary Evaluation of Indocyanine Green.
abstract: This study sought to determine whether indocyanine green (ICG)-enhanced near-infrared fluorescence (NIRF) imaging can illuminate high-risk histologic plaque features of human carotid atherosclerosis, and in coronary atheroma of living swine, using intravascular NIRF-optical coherence tomography (OCT) imaging.
  
  
  
  New translatable imaging approaches are needed to identify high-risk biological signatures of atheroma. ICG is a U.S. Food and Drug Administration-approved NIRF imaging agent that experimentally targets plaque macrophages and lipid in areas of enhanced endothelial permeability. However, it is unknown whether ICG can target atheroma in patients.
  
  
  
  Eight patients were enrolled in the BRIGHT-CEA (Indocyanine Green Fluorescence Uptake in Human Carotid Artery Plaque) trial. Five patients were injected intravenously with ICG 99 ± 25 min before clinically indicated carotid endarterectomy. Three saline-injected endarterectomy patients served as control subjects. Excised plaques underwent analysis by intravascular NIRF-OCT, reflectance imaging, microscopy, and histopathology. Next, following ICG intravenous injection, in vivo intracoronary NIRF-OCT and intravascular ultrasound imaged 3 atheroma-bearing coronary arteries of a diabetic, cholesterol-fed swine.
  
  
  
  ICG was well tolerated; no adverse clinical events occurred up to 30 days post-injection. Multimodal NIRF imaging including intravascular NIRF-OCT revealed that ICG accumulated in all endarterectomy specimens. Plaques from saline-injected control patients exhibited minimal NIRF signal. In the swine experiment, intracoronary NIRF-OCT identified ICG uptake in all intravascular ultrasound-identified plaques in vivo. On detailed microscopic evaluation, ICG localized to plaque areas exhibiting impaired endothelial integrity, including disrupted fibrous caps, and within areas of neovascularization. Within human plaque areas of endothelial abnormality, ICG was spatially related to localized zones of plaque macrophages and lipid, and, notably, intraplaque hemorrhage.
  
  
  
  This study demonstrates that ICG targets human plaques exhibiting endothelial abnormalities and provides new insights into its targeting mechanisms in clinical and experimental atheroma. Intracoronary NIRF-OCT of ICG may offer a novel, clinically translatable approach to image pathobiological aspects of coronary atherosclerosis. (Indocyanine Green Fluorescence Uptake in Human Carotid Artery Plaque [BRIGHT-CEA]; NCT01873716).
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Verjans
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts; Cardiology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Osborn
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Giovanni J
authors.initials: GJ
authors.lastname: Ughi
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Marcella A
authors.initials: MA
authors.lastname: Calfon Press
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Hamidi
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Antonios P
authors.initials: AP
authors.lastname: Antoniadis
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michail I
authors.initials: MI
authors.lastname: Papafaklis
authors.affiliation: Division of Vascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Conrad
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Stone
authors.affiliation: Division of Vascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Cambria
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: gtearney@mgh.harvard.edu.
authors.forename: Guillermo J
authors.initials: GJ
authors.lastname: Tearney
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts; Cardiology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: fjaffer@mgh.harvard.edu.
authors.forename: Farouc A
authors.initials: FA
authors.lastname: Jaffer
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000000981:diagnostic imaging*; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging*; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging*; D003331:Coronary Vessels / Q000000981:diagnostic imaging*; D004195:Disease Models, Animal; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007208:Indocyanine Green / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D061848:Optical Imaging / Q000379:methods*; D058226:Plaque, Atherosclerotic; D011237:Predictive Value of Tests; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D034421:Sus scrofa; D041623:Tomography, Optical Coherence / Q000379:methods*; D018084:Ultrasonography, Interventional
chemical_list: D005456:Fluorescent Dyes; D007208:Indocyanine Green
keywords: atherosclerosis; endothelium; indocyanine green; inflammation; intraplaque hemorrhage; intravascular imaging; lipid; molecular imaging; near-infrared fluorescence