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dc.contributor.authorTarkin, Jasonen
dc.contributor.authorJoshi, FRen
dc.contributor.authorEvans, Nicholasen
dc.contributor.authorChowdhury, Mohammeden
dc.contributor.authorFigg, NLen
dc.contributor.authorShah, Aartien
dc.contributor.authorStarks, LTen
dc.contributor.authorMartin-Garrido, Aen
dc.contributor.authorManavaki, Roidoen
dc.contributor.authorYu, Een
dc.contributor.authorKuc, REen
dc.contributor.authorGrassi, Luigien
dc.contributor.authorKreuzhuber, Ren
dc.contributor.authorKostadima, MAen
dc.contributor.authorFrontini, Mattiaen
dc.contributor.authorKirkpatrick, PJen
dc.contributor.authorCoughlin, PAen
dc.contributor.authorGopalan, Deepaen
dc.contributor.authorFryer, Timothyen
dc.contributor.authorBuscombe, JRen
dc.contributor.authorGroves, AMen
dc.contributor.authorOuwehand, Willemen
dc.contributor.authorBennett, Martinen
dc.contributor.authorWarburton, Lizen
dc.contributor.authorDavenport, Anthonyen
dc.contributor.authorRudd, Jamesen
dc.date.accessioned2017-04-06T10:50:29Z
dc.date.available2017-04-06T10:50:29Z
dc.date.issued2017-04-11en
dc.identifier.issn0735-1097
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/263480
dc.description.abstract$\textbf{Background}$ Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([$^{18}$F]FDG PET), [$^{18}$F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover. $\textbf{Objectives}$ Objectives This study tested the efficacy of gallium-68-labeled DOTATATE ($^{68}$Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation. $\textbf{Methods}$ We confirmed $^{68}$Ga-DOTATATE binding in macrophages and excised carotid plaques. $^{68}$Ga-DOTATATE PET imaging was compared to [$^{18}$F]FDG PET imaging in 42 patients with atherosclerosis. $\textbf{Results}$ Target $\textit{SSTR2}$ gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific $^{68}$Ga-DOTATATE ligand binding to SST$_{2}$ receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid $\textit{SSTR2}$ mRNA was highly correlated with in vivo $^{68}$Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). $^{68}$Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBR$_{max}$) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). $^{68}$Ga-DOTATATE mTBR$_{max}$ predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [$^{18}$F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [$^{18}$F]FDG mTBR$_{max}$ differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [$^{18}$F]FDG spillover rendered coronary [$^{18}$F]FDG scans uninterpretable in 27 patients (64%). Coronary $^{68}$Ga-DOTATATE PET scans were readable in all patients. $\textbf{Conclusions}$ We validated $^{68}$Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that $^{68}$Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [$^{18}$F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)
dc.description.sponsorshipThis study was funded by the Wellcome Trust and supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit. Dr. Tarkin is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). Dr. Evans is supported by a Dunhill Medical Trust fellowship (RTF44/0114). Dr. Chowdhury is supported by Royal College of Surgeons of England and British Heart Foundation (BHF) fellowships (FS/16/29/31957). Drs. Manavaki and Warburton are supported by the NIHR Biomedical Research Centres. Drs. Yu and Frontini are supported by the BHF (RE/13/6/30180). Dr. Fryer is supported by Higher Education Funding Council for England (HEFCE). Dr. Groves is supported by the University College London Hospital NIHR Biomedical Research Centre; and has received grant support from GlaxoSmithKline. Dr. Ouwehand’s laboratory is funded by EU-FP7 project Blueprint (Health-F5-2011-282510), BHF (PG-0310-1002 and RG/09/12/28096), and National Health Service Blood and Transplant. Dr. Bennett is supported by NIHR and BHF. Dr. Davenport is supported by research grants from Wellcome Trust (107715/Z/15/Z), Medical Research Council (MC_PC_14116), and BHF (RE-13-6-3180). Dr. Rudd is supported by the NIHR, BHF, Wellcome Trust, and HEFCE.
dc.languageengen
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectatherosclerosisen
dc.subjectinflammationen
dc.subjectmacrophagesen
dc.subjectmolecular imagingen
dc.subjectpositron emission tomographyen
dc.subjectsomatostatin receptoren
dc.titleDetection of Atherosclerotic Inflammation by $^{68}$Ga-DOTATATE PET Compared to [$^{18}$F]FDG PET Imagingen
dc.typeArticle
prism.endingPage1791
prism.issueIdentifier14en
prism.publicationDate2017en
prism.publicationNameJournal of the American College of Cardiologyen
prism.startingPage1774
prism.volume69en
dc.identifier.doi10.17863/CAM.8824
dcterms.dateAccepted2017-01-20en
rioxxterms.versionofrecord10.1016/j.jacc.2017.01.060en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-04-11en
dc.contributor.orcidTarkin, Jason [0000-0002-9132-120X]
dc.contributor.orcidEvans, Nicholas [0000-0002-7640-4701]
dc.contributor.orcidManavaki, Roido [0000-0002-4384-6626]
dc.contributor.orcidGrassi, Luigi [0000-0002-6308-7540]
dc.contributor.orcidFrontini, Mattia [0000-0001-8074-6299]
dc.contributor.orcidOuwehand, Willem [0000-0002-7744-1790]
dc.contributor.orcidBennett, Martin [0000-0002-2565-1825]
dc.contributor.orcidDavenport, Anthony [0000-0002-2096-3117]
dc.contributor.orcidRudd, James [0000-0003-2243-3117]
dc.identifier.eissn1558-3597
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idRoyal College of Surgeons of England (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idEPSRC (EP/N014588/1)
pubs.funder-project-idWELLCOME TRUST (107715/Z/15/Z)
pubs.funder-project-idWELLCOME TRUST (104492/Z/14/Z)
pubs.funder-project-idMRC (MC_PC_14116 v2)
pubs.funder-project-idBritish Heart Foundation (FS/16/29/31957)
pubs.funder-project-idBritish Heart Foundation (PG/09/083/27667)
pubs.funder-project-idBritish Heart Foundation (FS/12/29/29463)
pubs.funder-project-idBritish Heart Foundation (RE/13/6/30180)
pubs.funder-project-idBritish Heart Foundation (RG/13/14/30314)
pubs.funder-project-idDunhill Medical Trust (RTF44/0114)
cam.issuedOnline2017-04-03en
cam.orpheus.successThu Jan 30 12:56:34 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
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