High resolution FDG-microPET of carotid atherosclerosis: plaque components underlying enhanced FDG uptake
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This study sought to discover which atherosclerotic plaque components co-localize with enhanced [18F]-fluorodeoxyglucose (FDG) uptake in carotid positron emission tomography (PET) images. Although in vivo PET currently lacks the resolution, high-resolution ex vivo FDG-microPET with histology validation of excised carotid plaque might accomplish this goal. Thirteen patients were injected with FDG before carotid endarterectomy. After excision, the plaque specimens were scanned by microPET and magnetic resonance imaging, and then serially sectioned for histological analysis. Two analyses were performed using generalized linear mixed models: (1) a PET-driven analysis which sampled high and low FDG uptake areas from PET images to identify their components in matched histology specimens; and (2) a histology-driven analysis where specific plaque components were selected and matched to corresponding PET images. In the PET-driven analysis, regions of high FDG uptake were more likely to contain inflammatory cells (p < 0.001) and neovasculature (p = 0.008) than regions of low FDG uptake. In the histology-driven analysis, regions with inflammatory cells (p = 0.001) and regions with loose extracellular matrix (p = 0.001) were associated with enhanced FDG uptake. Furthermore, areas of complex inflammatory cell infiltrate (co-localized macrophages, lymphocytes and foam cells) had the highest FDG uptake among inflammatory subgroups (p < 0.001). In conclusion, in carotid plaque, regions of inflammatory cell infiltrate, particularly complex one, co-localized with enhanced FDG uptake in high-resolution FDG-microPET images. Loose extracellular matrix and areas containing neovasculature also produced FDG signal. This study points to the potential ability of FDG-PET to detect the cellular components of the vulnerable plaque.
KeywordsAtherosclerosis FDG MicroPET Vulnerable plaque Carotid plaque Inflammation
The authors thank Dr. Jie Sun for his valuable discussions of pathology, and Zach Miller for his help on the manuscript. This study was funded by National Heart, Lung, and Blood Institute (Grant Number R21HL106061). This material is the result of work supported by resources from the VA Puget Sound Health Care System, Seattle, Washington.
Compliance with ethical standards
Conflict of interest
Dr. Kerwin is an employee of Presage Biosciences. Mr. Hippe has received grants from GE Healthcare. Dr. Alessio has received research support from GE Healthcare. Dr. Hatsukami has received grants from Philips Healthcare. Dr. Yuan holds grants from the NIH and Philips Healthcare. He also serves as a Member of Radiology Advisory Network, Philips. All other authors have reported that they have no relationships to disclose.
All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
All persons gave their informed consent prior to their inclusion in the study.
- 1.Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER III, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics C, Stroke Statistics S (2014) Heart disease and stroke statistics—2014 update: a report from the american heart association. Circulation 129(3):e28–e292. doi: 10.1161/01.cir.0000441139.02102.80 PubMedCrossRefGoogle Scholar
- 2.Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT (2003) From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation 108(14):1664–1672. doi: 10.1161/01.CIR.0000087480.94275.97 PubMedCrossRefGoogle Scholar
- 3.McCarthy MJ, Loftus IM, Thompson MM, Jones L, London NJM, Bell PRF, Naylor AR, Brindle NPJ (1999) Angiogenesis and the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology. J Vasc Surg 30(2):261–268. doi: 10.1016/S0741-5214(99)70136-9 PubMedCrossRefGoogle Scholar
- 4.Figueroa AL, Subramanian SS, Cury RC, Truong QA, Gardecki JA, Tearney GJ, Hoffmann U, Brady TJ, Tawakol A (2012) Distribution of inflammation within carotid atherosclerotic plaques with high-risk morphological features a comparison between positron emission tomography activity, plaque morphology, and histopathology. Circ-Cardiovasc Imaging 5(1):69–77. doi: 10.1161/Circimaging.110.959478 PubMedCrossRefGoogle Scholar
- 6.Tawakol A, Migrino R, Hoffmann U, Abbara S, Houser S, Gewirtz H, Muller J, Brady T, Fischman A (2005) Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography. J Nucl Cardiol 12(3):294–301. doi: 10.1016/j.nuclcard.2005.03.002 PubMedCrossRefGoogle Scholar
- 8.Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, Yates D, LaMuraglia GM, Furie K, Houser S, Gewirtz H, Muller JE, Brady TJ, Fischman AJ (2006) In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol 48(9):1818–1824. doi: 10.1016/j.jacc.2006.05.076 PubMedCrossRefGoogle Scholar
- 9.Laitinen I, Marjamaki P, Haaparanta M, Savisto N, Laine VJ, Soini SL, Wilson I, Leppanen P, Yla-Herttuala S, Roivainen A, Knuuti J (2006) Non-specific binding of [18F]FDG to calcifications in atherosclerotic plaques: experimental study of mouse and human arteries. Eur J Nucl Med Mol Imaging 33(12):1461–1467. doi: 10.1007/s00259-006-0159-6 PubMedCrossRefGoogle Scholar
- 11.Masteling MG, Zeebregts CJ, Tio RA, Breek JC, Tietge UJ, de Boer JF, Glaudemans AW, Dierckx RA, Boersma HH, Slart RH (2011) High-resolution imaging of human atherosclerotic carotid plaques with micro 18F-FDG PET scanning exploring plaque vulnerability. J Nucl Cardiol 18(6):1066–1075. doi: 10.1007/s12350-011-9460-2 PubMedPubMedCentralCrossRefGoogle Scholar
- 12.Kerwin W, Alessio A, Ferguson M, Hatsukami T, Caldwell J, Miyaoka R, Kohler T, Yuan C (2012) High-resolution fluorodeoxyglucose-positron emission tomography and coregistered magnetic resonance imaging of atherosclerotic plaque from a patient undergoing carotid endarterectomy. Circ-Cardiovasc Imaging 5(5):683–684. doi: 10.1161/Circimaging.112.975144 PubMedPubMedCentralCrossRefGoogle Scholar
- 20.Menezes LJ, Kotze CW, Agu O, Richards T, Brookes J, Goh VJ, Rodriguez-Justo M, Endozo R, Harvey R, Yusuf SW, Ell PJ, Groves AM (2011) Investigating vulnerable atheroma using combined (18)F-FDG PET/CT angiography of carotid plaque with immunohistochemical validation. J Nucl Med 52(11):1698–1703. doi: 10.2967/jnumed.111.093724 PubMedCrossRefGoogle Scholar
- 21.Folco EJ, Sheikine Y, Rocha VZ, Christen T, Shvartz E, Sukhova GK, Di Carli MF, Libby P (2011) Hypoxia but not inflammation augments glucose uptake in human macrophages: Implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-d-glucose positron emission tomography. J Am Coll Cardiol 58(6):603–614. doi: 10.1016/j.jacc.2011.03.044 PubMedCrossRefGoogle Scholar
- 24.Gholami S, Salavati A, Houshmand S, Werner TJ, Alavi A (2015) Assessment of atherosclerosis in large vessel walls: A comprehensive review of FDG-PET/CT image acquisition protocols and methods for uptake quantification. J Nucl Cardiol 22(3):468–479. doi: 10.1007/s12350-015-0069-8 PubMedCrossRefGoogle Scholar