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Title: Improved outcome prediction in tetralogy of Fallot
Author: Heng, Ee Ling
ISNI:       0000 0004 6423 6717
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Successful advances in cardiac surgery have led to a paradigm shift in the management of an expanding population of repaired tetralogy of Fallot (rTOF) patients. However, late morbidity and mortality have not been abolished, with patients vulnerable to arrhythmia and sudden death. Outcome prediction remains challenging, mandating the identification of novel sensitive and specific non-invasive biomarkers. Cardiac fibrosis in rTOF has been shown to correlate to adverse clinical features, and therefore merits further study, particularly with regards to interstitial fibrosis. Cardiac remodelling following surgical pulmonary valve replacement in patients with rTOF was investigated. Structural reverse remodelling was observed to occur immediately after surgery, followed by gradual biological remodelling. A proactive surgical approach before right ventricular (RV) end-systolic indexed volumes exceed 82ml/m2 confers optimal postoperative RV normalisation. Novel cardiovascular magnetic resonance T1 mapping techniques were developed and tested to improve identification of RV interstitial cardiac fibrosis in rTOF. Multi-echo imaging to separate fat from myocardium, combined with blood signal suppression is promising as a feasible method in saturation-recovery T1 mapping, but requires further technical study prior to clinical application and validation. The genomic signatures of the pathological RV in rTOF were investigated by next generation RNA sequencing. Differential gene expression was evident, and potential molecular determinants of fibrotic and restrictive phenotypes were ascertained. Ubiquitin C may have important functional implications as a ‘network hub’ gene in rTOF. Finally, the longitudinal predictive role of neurohormone expression in patients with rTOF was examined. Neurohormonal activation was confirmed in rTOF, with serum brain natriuretic peptide being prognostic for mortality and sustained arrhythmias during extended follow-up. In conclusion, this work reflects the complex interplay of candidate biomarkers in influencing clinical outcomes. Myocardial fibrosis in rTOF remains a key diagnostic and therapeutic target for improving risk stratification and ameliorating morbidity in the lifelong care of these individuals.
Supervisor: Gatzoulis, Michael A. ; Babu-Narayan, Sonya V. Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral