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Title: Genetic screening and transcriptomics analysis of aortas in patients with bicuspid aortic valve
Author: Abdulkareem , Nada Riadh
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2012
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Congenital bicuspid aortic valve (BAV) is the commonest cardiac defect occurring in 2% of the general population causing aortic valve disease and is associated with ascending aortic aneurysms. Different genetic, metabolic and haemodynamic studies have tried to explain the aetiology of BA V and the development of aortic aneurysm. However, to date, the aetiology of BA V is not fully understood. 1.1.2 Aims To determine whether BAV is due to a genetic mutation in GATA5, fibrillin-l (FBN]) or transforming growth factor beta receptor-2 (TGFBR2), genes recognised as essential for valvulogenesis and aortogenesis. In addition, to perform a comprehensive transcriptomics analysis of the extracellular matrix (ECM) of BA V aortas with or without aneurysm. A third aim was to determine the dilatation of the aorta following aortic valve and/or root replacement. Our aims can aid us in understanding the different pathologies involved in aortic aneurysm development and its outcome. 1.1.3 Methods A consecutive series of 65 patients were included in the study. Thirty-five patients with BAV and 30 with tricuspid aortic valve (TA V) with and without aortic aneurysm were studied prospectively. Twenty millilitres of venous blood was collected from patients and a small aortic sample was taken from the aortotomy site during surgery. Different methods were used to analyse the samples; blood was used for genomic DNA analysis to determine the presence of genetic mutations. Gene microarray was performed on 24 aortic tissue samples to determine the differentially expressed genes amongst the different groups and real time polymerase chain reaction (qPCR) analysis was performed to validate the results. 9 • In addition 395 BAV and TAV patients with and without aortic aneurysms were studied retrospectively by collecting 2D echo cardiograms and CT scan data to determine dilatation of the remaining aorta following aortic valve and/or root replacement at 5 years follow-up. 1.1.4 Results In the cohort of 35 patients with confirmed BA V at surgery, one patient exhibited a missense mutation in GATA5 in the coding position 698 T>C; therefore, demonstrating for the first time in human cardiac disease that mutation in GATA5 might be causative of BAV. Gene expression data revealed impaired expression of VEGFA and COL3AI genes in TAV with aneurysm; a finding not present in the BA V group. Our clinical data showed no significant dilatation of the ascending aorta following A VR when aortic diameter <4.5cm at the time of surgery. Similarly, dilatation of the arch was not seen in patients with ascending aorta diameter 24.5cm following ARR comparing BA V with TAV patients at 5 years following surgery. This supports intervention with ascending aorta 24.5cm in BA V patients with concomitant valvular disease. 1.1.5 Conclusion -. Our findings can help a better understanding of the aetiology, pathology and progression of aortic aneurysms and a better identification of this phenotype and risk prediction. 10 •
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available