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Title: Aortic valve stenosis : an understanding of the disease process from fetus to adult, and an insight into its treatment
Author: Ahmed, Saadullah Husayn
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Aortic Valve Disease (AVD) is a progressive disease process of the aortic valve that affects an average of about 3-4 % of the world population and is the most common cause of cardiac valve disease in the Western World. Recent studies have shown that AVD is, not merely a degenerative process on its own, but instead there are genetic and developmental factors that contribute to disease initiation and its progression prior to the environmental factors that add to the disease development. The current management of AVD largely relies upon aortic valve replacement (AVR), and despite treating the disease, AVR comes with a lot of risks and delayed complications. This project was aimed at: identifying the genetic pathways that are involved in aortic valve development using Gene Ontology; bridging the gap in the understanding of the development of the disease process across age groups by performing a detailed morphological analyses of stenosed aortic valves in fetal, pediatric and adult specimens; and, examining tissues from a laboratory inbred strain of pigs, the Gottingen minipig to evaluate its feasibility for use as a source of bioprosthetic valves. In order to explore the genetic pathways involved in aortic valve development, I used Gene Ontology (GO) terms to capture the role of 28 proteins to aortic valve development, 25 of which had not been previously annotated to aortic valve development in GO, by creating over 300 new annotations. In addition, 6 other proteins were annotated to other cardiac developmental processes. Secondly, in the cardiac morphology section, 56 specimens and 11 scans were studied for gross examination and high definition imaging, respectively. Standard gross morphological examination showed that there was a significant correlation between; the age of sample and site of fusion to the nature of raphe present; the nature of raphe and area of interleaflet triangle; the site of fusion and progression of severity fibrosis/endocardial fibroelastosis (EFE); and left ventricle (LV) remodeling in relation to the fibrosis/EFE. Comparison of measurements acquired using gross examination to those obtained using a high definition novel imaging technique (micro-CT) showed that new imaging techniques allowed for the visualisation of greater detail, and more precise measurements. However, there were differences between the measurements of both techniques. Efforts to optimise technique for micro-CT imaging showed that: siliconization of the sample led to less distortion and thus, significant differences when measuring the cross-sectional area of the aorta in comparison to a non-siliconized sample; and, under- or over-iodination affected the quality of the images studied. Lastly, using a set of molecular biology techniques, tissues from two strains of pigs, were tested for the presence of xenogeneic antigens that have been shown to contribute towards the degeneration of current bioprosthetic devices. The tissues tested expressed Sda antigen and therefore, were not useful as a potential source of bioprosthetic heart valve development. Since all porcine tissues tested previously, and in this project, have xenogeneic glycans present on their surfaces, it is essential to have a standard uniform assay to measure antibody reactivity to all three xenogeneic glycans. I showed that a pig kidney cell line, PK15, expressed B4GALNT2, the gene responsible for the production of the Sda antigen. Since this cell also makes other xenogeneic antigens, Gal and Neu5Gc, this cell line could act as a uniform assay to assess antibody reactivity to all glycans. This will allow for monitoring the immune response after BHV replacement could help explore the development of long-lasting bioprosthetic devices. This thesis is the first to my knowledge that looks into aortic valve stenosis in a multi-faceted approach, therefore, providing an integrative platform for future research to be carried out in the development and treatment of this disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available