Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684413
Title: Role of functional imaging in determining inflammation and extracellular matrix degradation in aortic aneurysms
Author: Attia, Rizwan
ISNI:       0000 0004 5921 1902
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Abstract:
Aneurysmal disease of the aorta is a degenerative condition characterised by inflammation and extracellular protein loss, in particular, loss of cross-linked elastin. 18F-FDG is currently the most widely available tracer used in assessing the metabolic activity of tissues and is known to be taken up in aneurysmal wall, but its biological correlates, other than metabolism, have yet to be evaluated. Other novel tracers for more specific functional imaging of proteins such as elastin in the aneurysm wall have also yet to be evaluated in the context of aneurysmal disease. 18F-FDG uptake in aneurysms was characterised using a combination of laser scintigraphic 3D aortic masks generated from PET-CT that allowed precise aortic biopsy of areas of high and low tracer uptake. Positive correlations were obtained between 18F-FDG uptake and total leukocyte, B-cell, T-cell and NK-cell content in human aneurysmal wall, while elastin and collagen content was reduced at sites of inflammatory cell infiltrate. B and T-cells had significant modulatory affects on vascular smooth muscle cell (VSMC) proliferation, survival and protein synthesis in-vitro. 18F-FDG uptake and its inflammatory correlates were similarly characterised in ApoE-/--ATII model. There was a temporal, heterogeneous 18F-FDG uptake in the aneurysms associated with increased immune cell content, but no correlation was found between uptake and aortic expansion or diameter. Elastin-specific MR contrast agent (ESMA) uptake was characterised in the ApoE-/--ATII model and found to correlate with elastin, tropoelastin, immune cell content and extracellular matrix organisation, as well as aortic expansion. Treatment with elastin modulating antagomirs decreased aneurysm expansion and rupture. This was through modulated down-stream gene and protein expression of proteins and enzymes involved in elastin and collagen homeostasis namely TGFβ, LOX and MMP’s. It appears therefore that 18F-FDG uptake correlates with specific immune cell infiltrates, in particular that of B- and T-cells that can modulate VSMC function. There are distinct cellular populations that are responsible for a pro-aneurysmal phenotype and B-T-regulatory cell populations that lead to aortic remodeling response. ESMA uptake was related to elastin remodelling and may provide a novel predictor of aneurysm behavior. Antagomir mediated alteration of VSMC phenotype might alter the natural history of aneurysmal disease.
Supervisor: Smith, Alberto ; Waltham, Matthew ; Modarai, Bijan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.684413  DOI: Not available
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