The online version of this article (https://doi.org/10.1007/s12350-019-01946-y) contains supplementary material, which is available to authorized users.
The authors of this article have provided a PowerPoint file, available for download at SpringerLink, which summarizes the contents of the paper and is free for re-use at meetings and presentations. Search for the article DOI on SpringerLink.com.
The authors have also provided an audio summary of the article, which is available to download as ESM, or to listen to via the JNC/ASNC Podcast.
All editorial decisions for this article, including selection of reviewers and the final decision, were made by guest editor Jeroen J. Bax, MD, PhD.
Increased cellular proliferation in the AngII abdominal aortic aneurysm mouse model can be detected using [18F]FLT PET/CT.
This research was funded in part by the David Gamble Award for Secondments in PET-CT Imaging, a charitable donation from the James Ellis charitable trust, and The Academy of Medical Sciences (Clinical Lecturer Starter Grant to Dr Bailey, SGL017\1056). Dr. Bailey is personally funded by the British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/12/33270). Ms. Gandhi is funded by the EPSRC Centre for Doctoral Training in Tissue Engineering and Regenerative Medicine-Innovation in Medical and Biological Engineering (EP/L014823/1). Dr. Tsoumpas is funded by a Royal Society Industry Fellowship (IF170011) and a Horizon 2020 Marie Skłodowska-Curie Action Research & Innovation Staff Exchange (645757). Dr. He, Dr. Domarkas, and Professor Archibald are funded by the Daisy Appeal (DA-hul2011). Mr. Wright and Mrs. Koch-Paszkowski are funded by the British Heart Foundation, UK (SI/14/1/30718).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abdominal aortic aneurysm (AAA) is a focal aortic dilatation progressing towards rupture. Non-invasive AAA-associated cell proliferation biomarkers are not yet established. We investigated the feasibility of the cell proliferation radiotracer, fluorine-18-fluorothymidine ([18F]FLT) with positron emission tomography/computed tomography (PET/CT) in a progressive pre-clinical AAA model (angiotensin II, AngII infusion).
Fourteen-week-old apolipoprotein E-knockout (ApoE−/−) mice received saline or AngII via osmotic mini-pumps for 14 (n = 7 and 5, respectively) or 28 (n = 3 and 4, respectively) days and underwent 90-minute dynamic [18F]FLT PET/CT. Organs were harvested from independent cohorts for gamma counting, ultrasound scanning, and western blotting. [18F]FLT uptake was significantly greater in 14- (n = 5) and 28-day (n = 3) AAA than in saline control aortae (n = 5) (P < 0.001), which reduced between days 14 and 28. Whole-organ gamma counting confirmed greater [18F]FLT uptake in 14-day AAA (n = 9) compared to saline-infused aortae (n = 4) (P < 0.05), correlating positively with aortic volume (r = 0.71, P < 0.01). Fourteen-day AAA tissue showed increased expression of thymidine kinase-1, equilibrative nucleoside transporter (ENT)-1, ENT-2, concentrative nucleoside transporter (CNT)-1, and CNT-3 than 28-day AAA and saline control tissues (n = 3 each) (all P < 0.001).
[18F]FLT uptake is increased during the active growth phase of the AAA model compared to saline control mice and late-stage AAA.
Blanchard JF, Armenian HK, Friesen PP. Risk factors for abdominal aortic aneurysm: Results of a case-control study. Am J Epidemiol 2000;151:575-83. CrossRef
Chichester Aneurysm Screening Group, Viborg Aneurysm Screening Study, Western Australian Abdominal Aortic Aneurysm Program, Multicentre Aneurysm Screening Study. A comparative study of the prevalence of abdominal aortic aneurysms in the United Kingdom, Denmark, and Australia. J Med Screen 2001;8:46-50. CrossRef
Zucker EJ, Misono AS, Prabhakar AM. Abdominal aortic aneurysm screening practices: Impact of the 2014 U.S. Preventive Services Task Force Recommendations. J Am Coll Radiol 2017;14:868-74. CrossRef
Sweeting MJ, Thompson SG, Brown LC, Powell JT. Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms. Br J Surg 2012;99:655-65. CrossRef
Powell JT, Brown LC, Forbes JF, et al. Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial. Br J Surg 2007;94:702-8. CrossRef
Sakalihasan N, Van Damme H, Gomez P, et al. Positron emission tomography (PET) evaluation of abdominal aortic aneurysm (AAA). Eur J Vasc Endovasc Surg 2002;23:431-6. CrossRef
Nie M-X, Zhang X-H, Yan Y-F, Zhao Q-M. Relationship between inflammation and progression of an abdominal aortic aneurysm in a rabbit model based on 18F-FDG PET/CT imaging. Vascular 2018;26:571-80. CrossRef
English SJ, Piert MR, Diaz JA, et al. Increased (18)F-FDG uptake is predictive of rupture in a novel rat abdominal aortic aneurysm rupture model. Ann Surg 2015;261:395-404. CrossRef
Huang Y, Teng Z, Elkhawad M, et al. High structural stress and presence of intraluminal thrombus predict abdominal aortic aneurysm 18F-FDG uptake: Insights from biomechanics. Circ Cardiovasc Imaging 2016;9:e004656. CrossRef
Reeps C, Essler M, Pelisek J, et al. Increased 18F-fluorodeoxyglucose uptake in abdominal aortic aneurysms in positron emission/computed tomography is associated with inflammation, aortic wall instability, and acute symptoms. J Vasc Surg 2008;48:417-23. CrossRef
Courtois A, Nusgens BV, Hustinx R, et al. 18F-FDG uptake assessed by PET/CT in abdominal aortic aneurysms is associated with cellular and molecular alterations prefacing wall deterioration and rupture. J Cardiovasc Surg 2013;54:1740-7.
Nchimi A, Cheramy-Bien JP, Gasser TC, et al. Multifactorial relationship between 18F-fluoro-deoxy-glucose positron emission tomography signaling and biomechanical properties in unruptured aortic aneurysms. Circ Cardiovasc Imaging 2014;7:82-91. CrossRef
Kotze CW, Groves AM, Menezes LJ, et al. What is the relationship between (1)(8)F-FDG aortic aneurysm uptake on PET/CT and future growth rate? Eur J Nucl Med Mol Imaging 2011;38:1493-9. CrossRef
Barwick TD, Lyons OT, Mikhaeel NG, Waltham M, O’Doherty MJ. 18F-FDG PET-CT uptake is a feature of both normal diameter and aneurysmal aortic wall and is not related to aneurysm size. Eur J Nucl Med Mol Imaging 2014;41:2310-8. CrossRef
Forsythe RO, Dweck MR, McBride OMB, et al. (18)F-sodium fluoride uptake in abdominal aortic aneurysms: The SoFIA(3) study. J Am Coll Cardiol 2018;71:513-23. CrossRef
Maegdefessel L, Azuma J, Toh R, et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med 2012;4:122ra122-122ra122. CrossRef
Ailawadi G, Moehle CW, Pei H, et al. Smooth muscle phenotypic modulation is an early event in aortic aneurysms. J Thorac Cardiovasc Surg 2009;138:1392-9. CrossRef
Salmon M, Johnston WF, Woo A, et al. KLF4 regulates abdominal aortic aneurysm morphology and deletion attenuates aneurysm formation. Circulation 2013;128:S163-74. CrossRef
Bridge K, Revill C, Macrae F, et al. Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms. PLoS ONE 2017;12:e0177117. CrossRef
Rasband WS [Internet]. U. S. National Institutes of Health, Bethesda, Maryland, USA. https://ci.nii.ac.jp/naid/20000508795/en/.
Miller I, Min M, Yang C, et al. Ki67 is a graded rather than a binary marker of proliferation versus quiescence. Cell Rep 2018;24:1105-12. CrossRef
Paproski RJ, Ng AML, Yao SYM, et al. The role of human nucleoside transporters in uptake of 3′-deoxy-3′-fluorothymidine. Mol Pharmacol 2008;74:1372. CrossRef
Paproski RJ, Wuest M, Jans H-S, et al. Biodistribution and uptake of 3′-deoxy-3′-fluorothymidine in ENT1-knockout mice and in an ENT1-knockdown tumor model. J Nucl Med 2010;51:1447-55. CrossRef
Shields AF, Grierson JR, Dohmen BM, et al. Imaging proliferation in vivo with [F-18] FLT and positron emission tomography. Nat Med 1998;4:1334. CrossRef
Barthel H, Cleij MC, Collingridge DR, et al. 3’-deoxy-3’-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63:3791-8. PubMed
Viertl D, Delaloye AB, Lanz B, et al. Increase of [18 F] FLT tumor uptake in vivo mediated by FdUrd: Toward improving cell proliferation positron emission tomography. Mol Imaging Biol 2011;13:321-31. CrossRef
Salskov A, Tammisetti VS, Grierson J, Vesselle H. FLT: Measuring tumor cell proliferation in vivo with positron emission tomography and 3’-deoxy-3’-[18F]fluorothymidine. Semin Nucl Med 2007;37:429-39. CrossRef
Yue J, Chen L, Cabrera AR, et al. Measuring tumor cell proliferation with 18F-FLT PET during radiotherapy of esophageal squamous cell carcinoma: A pilot clinical study. J Nucl Med 2010;51:528-34. CrossRef
Ye YX, Calcagno C, Binderup T, et al. Imaging macrophage and hematopoietic progenitor proliferation in atherosclerosis. Circ Res 2015;117:835-45. CrossRef
Barthel H, Perumal M, Latigo J, et al. The uptake of 3’-deoxy-3’-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels. Eur J Nucl Med Mol Imaging 2005;32:257-63. CrossRef
Seitz U, Wagner M, Neumaier B, et al. Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3’-[18F]fluoro-3’-deoxythymidine ([18F]FLT) in pancreatic cancer cell lines. Eur J Nucl Med Mol Imaging 2002;29:1174-81. CrossRef
Bagegni N, Thomas S, Liu N, et al. Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. Breast Cancer Res 2017;19:123. CrossRef
Mao Y, Wu J, Skog S, et al. Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling. Oncol Rep 2005;13:837-46. PubMed
Chen G, He C, Li L, et al. Nuclear TK1 expression is an independent prognostic factor for survival in pre-malignant and malignant lesions of the cervix. BMC Cancer 2013;13:249. CrossRef
Riches K, Angelini TG, Mudhar GS, et al. Exploring smooth muscle phenotype and function in a bioreactor model of abdominal aortic aneurysm. J Transl Med 2013;11:208. CrossRef
Riches K, Clark E, Helliwell RJ, et al. Progressive development of aberrant smooth muscle cell phenotype in abdominal aortic aneurysm disease. J Vasc Res 2018;55:35-46. CrossRef
Jibawi A, Ahmed I, El-Sakka K, Yusuf SW. Management of concomitant cancer and abdominal aortic aneurysm. Cardiol Res Pract 2011;2011:516146. CrossRef
- Cell proliferation detected using [18F]FLT PET/CT as an early marker of abdominal aortic aneurysm
MSc Richa Gandhi
PhD Christopher Cawthorne
PhD Lucinda J. L. Craggs
MSc John D. Wright
PhD Juozas Domarkas
PhD Ping He
MSc Joanna Koch-Paszkowski
BMBS Andrew F. Scarsbrook
PhD Stephen J. Archibald
PhD Charalampos Tsoumpas
MB, ChB, PhD Marc A. Bailey
- Springer International Publishing
Journal of Nuclear Cardiology
Print ISSN: 1071-3581
Elektronische ISSN: 1532-6551
Neu im Fachgebiet Kardiologie
Mail Icon II