title: Increased microvascularization and vessel permeability associate with active inflammation in human atheromata.
abstract: BACKGROUND
  Studies have shown the feasibility of imaging plaques with 2-deoxy-2-[(18)F]fluoroglucose (FDG) positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging with inconsistent results. We sought to investigate the relationship between markers of inflammatory activation, plaque microvascularization, and vessel wall permeability in subjects with carotid plaques using a multimodality approach combining FDG positron emission tomography, dynamic contrast-enhanced magnetic resonance imaging, and histopathology.
  
  
  RESULTS
  Thirty-two subjects with carotid stenoses underwent noninvasive imaging with FDG positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging, 46.9% (n=15) before carotid endarterectomy. We measured FDG uptake (target:background ratio [TBR]) by positron emission tomography and K(trans) (reflecting microvascular permeability and perfusion) by magnetic resonance imaging and correlated imaging with immunohistochemical markers of macrophage content (CD68), activated inflammatory cells (major histocompatibility complex class II), and microvessels (CD31) in plaque and control regions. TBR and K(trans) correlated significantly with tertiles of CD68(+) (P=0.009 and P=0.008, respectively), major histocompatibility complex class II(+) (P=0.003 and P<0.001, respectively), and CD31(+) (P=0.004 and P=0.008, respectively). Regions of plaques were associated with increased CD68(+) (P=0.002), major histocompatibility complex class II(+) (P=0.002), CD31(+) (P=0.02), TBR (P<0.0001), and K(trans) (P<0.0001), as compared with those without plaques. Microvascularization correlated with macrophage content (rs=0.52; P=0.007) and inflammatory activity (rs=0.68; P=0.0001) and TBR correlated with K(trans) (rs=0.53; P<0.0001). In multivariable mixed linear regression modeling, TBR remained independently associated with K(trans) (β[SE], 2.68[0.47]; P<0.0001).
  
  
  CONCLUSIONS
  Plaque regions with active inflammation, as determined by macrophage content and major histocompatibility complex class II expression, showed increased FDG uptake, which correlated with increased K(trans) and microvascularization. The correlation between K(trans) and TBR was moderate, direct, highly significant, and independent of clinical symptoms and plaque luminal severity.
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Viviany R
authors.initials: VR
authors.lastname: Taqueti
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Di Carli
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Michael
authors.initials: M
authors.lastname: Jerosch-Herold
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Venkatesh L
authors.initials: VL
authors.lastname: Murthy
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Folco
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Kwong
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: C Keith
authors.initials: CK
authors.lastname: Ozaki
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Michael
authors.initials: M
authors.lastname: Belkin
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.).
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: From the Heart and Vascular Institute (V.R.T., M.F.D.C., G.K.S., E.J.F., R.Y.K., C.K.O., M.B., P.L.), Noninvasive Cardiovascular Imaging Program, Nuclear Medicine and Molecular Imaging Division, Department of Radiology (V.R.T., M.F.D.C., M.J.-H., R.Y.K.), Brigham and Women's Hospital, and Center for Systems Biology, Massachusetts General Hospital (M.N., R.W.), Harvard Medical School, Boston, MA; and Divisions of Nuclear Medicine, Cardiothoracic Imaging, and Cardiovascular Medicine, Departments of Medicine and Radiology, University of Michigan, Ann Arbor (V.L.M.). plibby@rics.bwh.harvard.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002199:Capillary Permeability; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D003287:Contrast Media; D005260:Female; D019788:Fluorodeoxyglucose F18; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D016014:Linear Models; D008264:Macrophages / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D055806:Microvessels / Q000473:pathology*; D008875:Middle Aged; D064847:Multimodal Imaging; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic; D058226:Plaque, Atherosclerotic; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D019275:Radiopharmaceuticals; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18
keywords: atherosclerotic plaque; inflammation; molecular imaging; neovascularization