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dc.contributor.advisorNewby, Daviden
dc.contributor.advisorDweck, Marcen
dc.contributor.authorVesey, Alexander T.en
dc.date.accessioned2019-07-23T15:27:13Z
dc.date.available2019-07-23T15:27:13Z
dc.date.issued2019-07-06
dc.identifier.urihttp://hdl.handle.net/1842/35837
dc.description.abstractIntroduction. Calcific aortic valve disease (CAVD) and atherosclerosis are important public health problems. Our ability to allocate patients to treatment strategies optimally and monitor progression is limited. Hybrid positron emission and computed tomography (PET/CT) is able to demonstrate both anatomy (CT) and molecular processes (PET) in vivo. The 18F-sodium fluoride (18F-fluoride) isotope has shown promise in early cardiovascular studies. The purpose of this thesis was to elucidate the mechanisms of cardiovascular 18Ffluoride uptake and define how 18F-fluoride PET/CT might play a role in the assessment of CAVD and atherosclerosis. Methods. Three cohorts were recruited constituting patients with: CAVD, coronary atherosclerosis and carotid atherosclerosis. Using in vitro, ex vivo and in vivo techniques, a model of the mechanism of 18F-fluoride uptake and its pharmacology was elaborated. In observational clinical studies, 18F-fluoride and 18F-FDG uptake in aortic valvular, coronary and carotid arterial tissue was assessed. Techniques for uptake quantification were evaluated for accuracy and reliability. Tissue uptake was related to established clinical and image-based variables as well as prospectively gathered clinical outcome data. Results. In the CAVD cohort, 121 volunteers were recruited. 18F-fluoride PET/CT correlated with tissue markers of active calcification and predicted the genesis of new areas of calcification within the aortic valve. 18F-fluoride uptake was associated with disease progression and clinical events. In the coronary cohort, 80 volunteers were recruited. In patients with acute myocardial infarction the highest coronary 18F-fluoride uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40–2·25] versus highest non-culprit 1·24 [1·06–1·38], p<0·0001). In patients with stable angina, plaques with focal 18F-fluoride uptake were associated with more high-risk features on intravascular ultrasound than those without uptake. In the carotid cohort, 38 volunteers were recruited (26 +12, separate studies). 18F-fluoride plaque uptake was associated with neurovascular symptoms (log10 mean standardized uptake value 0.29±0.10 versus 0.23±0.11, P=0.001) as well as image and tissue derived features of high-risk plaque. 18F-fluoride selectively highlighted areas of pathologically high risk nascent microcalcification and was proven to have pharmacological properties highly favourable for PET imaging. Conclusions. 18F-fluoride PET/CT is a valuable tool for exploring pathobiology in CAVD and atherosclerosis may represent an attractive method for assessing response to novel therapies.en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionVesey AT, Jenkins WS, Irkle A, Moss A, Sng G, Forsythe RO, Clark T, Roberts G, Fletcher A, Lucatelli C, Rudd JH, Davenport AP, Mills NL, Al- Shahi Salman R, Dennis M, Whiteley WN, van Beek EJ, Dweck MR, Newby DE. 18F-fluoride and 18F-fluorodeoxyglucose positron emission tomography after transient ischemic attack or minor ischemic stroke: case-control study. Circulation: Cardiovascular Imaging. 2017 Mar;10(3).en
dc.relation.hasversionVesey AT, Dweck, MR, Fayad Z. Utility Of Combining PET And MRI Imaging Of Carotid Plaque. Neuroimaging Clinics of North America. 2016 Feb;26(1):55-68.en
dc.relation.hasversionVesey AT*, Jenkins WSA*, Shah ASV et al. Valvular 18F-fluoride and 18F-fluorodeoxyglucose uptake predict disease progression and clinical outcome in patients with aortic stenosis. Journal of the American College of Cardiology 66(10):1200-1201. 2015 (*joint first authorship).en
dc.relation.hasversionIrkle A, Vesey AT, Lewis DY et al. Identifying active vascular microcalcification by 18F-sodium fluoride positron emission tomography. Nature Communications 2015 Jul 7;6:7495en
dc.relation.hasversionJoshi NV, Vesey AT, Williams MC, Shah AS, Calvert PA, Craighead FH, Yeoh SE, Wallace W, Salter D, Fletcher AM, van Beek EJ, Flapan AD, Uren NG, Behan MW, Cruden NL, Mills NL, Fox KA, Rudd JH, Dweck MR, Newby DE. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet. 2014 Feb 22;383(9918):705-13.en
dc.relation.hasversionDweck MR, Jenkins WS, Vesey AT, Pringle MA, Chin CW, Malley TS, Cowie WJ, Tsampasian V, Richardson H, Fletcher A, Wallace WA, Pessotto R, van Beek EJ, Boon NA, Rudd JH, Newby DE. 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis. Circulation: Cardiovascular Imaging. 2014 Mar;7(2):371-8.en
dc.relation.hasversionForsythe RO, Dweck MR, McBride OMB, Vesey AT et al. 18F-Sodium fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA3 Study. Journal of the American College of Cardiology. 2018 Feb 6;71(5):513- 523.en
dc.relation.hasversionAnand A, Chin C, Shah ASV, Kwieciński J, Vesey A, Cowell J, Weber E, Kaier T, Newby DE, Dweck M, Marber MS, Mills NL. Cardiac myosinbinding protein C is a novel marker of myocardial injury and fibrosis in aortic stenosis. Heart. 2017en
dc.relation.hasversionStoumpos S, Hennessy M, Vesey AT, Radjenovic A, Kasthuri R, Kingsmore DB, Mark PB, Roditi G. Ferumoxytol-enhanced magnetic resonance angiography for the assessment of potential kidney transplant recipients. European Radiology. 2018 Jan;28(1):115-123en
dc.relation.hasversionThe MA3RS Study Trialists. Aortic Wall Inflammation Predicts Abdominal Aortic Aneurysm Expansion, Rupture and Need for Surgical Repair. Circulation. 2017 Aug 29;136(9):787-797en
dc.relation.hasversionMiller MR, Raftis JB, Langrish JP, McLean SG, Samutrtai P, Connell SP, Wilson S, Vesey AT, Fokkens PHB, Boere AJF, Krystek P, Campbell CJ, Hadoke PWF, Donaldson K, Cassee FR, Newby DE, Duffin R, Mills NL. Inhaled Nanoparticles Accumulate at Sites of Vascular Disease. ACS Nano. 2017 May 23;11(5):4542-4552.en
dc.relation.hasversionCui L, Rashdan NA, Zhu D, Milne EM, Ajuh P, Milne G, Helfrich MH, Lim K, Prasad S, Lerman DA, Vesey AT, Dweck MR, Jenkins WS, Newby DE, Farquharson C, Macrae VE. End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles. Journal of Cellular Physiology. 2017 Nov;232(11):2985-2995en
dc.relation.hasversionChin CW, Everett RJ, Kwiecinski J, Vesey AT et al. Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis. Journal of the American College of Cardiology: Cardiovascular Imaging. 2017 Nov;10(11):1320- 1333.en
dc.relation.hasversionJenkins WSA, Vesey AT et al. Cardiac Alpha-V Beta-3 Integrin Expression Following Acute Myocardial Infarction in Humans. Heart 2017 Apr;103(8):607-615.en
dc.relation.hasversionZhu D, Hadoke PW, Wu J, Vesey AT et al. Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification. Nature Science Reports. 2016 Apr 20;6:24807.en
dc.relation.hasversionBallantyne MD, Dakin R, Pinel K, Vesey AT et al. Smooth muscle enriched long non-coding RNA (SMILER) regulates cell proliferation. Circulation 2016 May 24;133(21):2050-65.en
dc.relation.hasversionDweck MR, Puntman V, Vesey AT, Fayad ZA, Nagel E. Coronary Artery and Plaque Imaging with Cardiovascular Magnetic Resonance. Journal of the American College of Cardiology: Cardiovascular Imaging. 2016 Mar;9(3):306-16.en
dc.relation.hasversionJoshi NV, Toor I. Shah ASV, Carruthers K, Vesey AT, Alam SR, et al. Systemic Atherosclerotic Inflammation Following Acute Myocardial Infarction: Myocardial Infarction Begets Myocardial Infarction. Journal of the American Heart Association. 2015 Aug 27;4(9):e001956en
dc.relation.hasversionAdamson P, Vesey AT, Joshi et al. Salt in the Wound: 18F-fluoride positron emission tomography for identification of vulnerable coronary plaques Journal of Cardiovascular Diagnosis and Therapeutics. Cardiovascular Diagnosis and Therapy. 2015 Apr;5(2):150-5.en
dc.relation.hasversionMcBride O, Berry C, Burns, Chalmers RTA, Doyle B, Forsythe R, Garden OJ, Goodman K, Graham C, Hoskins P, Holdsworth R, MacGillvray T, McKillop G, Murray G, Oatey K, Robson JMJ, Semple S, Stuart W, van Beek EJR, Vesey AT, Newby DE. Magnetic Resonance Imaging Using Ultrasmall Superparamagnetic Particles of Iron Oxide in Patients Under Surveillance for Abdominal Aortic Aneurysms to Predict Rupture or Surgical Repair: MRI for Abdominal Aortic Aneurysms to predict Rupture or Surgery: The MA3RS trial. Open Heart, 2(1), 2015.en
dc.relation.hasversionStirrat C, Vesey AT, McBride O, Robson J, Alam S, Wallace W, et al. Ultrasmall superparamagnetic particles of iron oxide in magnetic resonance imaging of cardiovascular disease. Journal of Vascular Diagnostics 2014 Oct; 99.en
dc.relation.hasversionJoshi NV, Vesey A, Newby DE, Dweck MR. Will 18F-Sodium fluoride PET-CT Imaging Be the Magic Bullet for Identifying Vulnerable Coronary Atherosclerotic Plaques? Current Cardiology Reports. 2014 Aug 8;16(9):521.en
dc.subjectatherosclerosisen
dc.subjectaortic stenosisen
dc.subjectHybrid positron emission tomographyen
dc.subjectPET/CTen
dc.subjectcalcificationen
dc.subjectactive calcificationen
dc.subject18F-fluorideen
dc.titleMolecular imaging of calcification and inflammation in aortic valve disease and atherosclerosisen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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