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Investigating the micro-RNA and metabolic signature of human postoperative atrial fibrillation

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Title: Investigating the micro-RNA and metabolic signature of human postoperative atrial fibrillation
Authors: Harling, Leanne
Item Type: Thesis or dissertation
Abstract: Atrial fibrillation (AF) is the commonest disorder of cardiac rhythm. Following coronary artery surgery approximately 1 in 3 patients will develop de novo post-operative AF (POAF) leading not only to prolonged hospital stay but also to increased morbidity and mortality. The pathophysiology of this arrhythmia is highly complex, and combines factors such as ion channel dysfunction, inflammation, oxidative stress, fibrosis and autonomic dysfunction that through electrical and structural remodelling promote both triggering and maintenance of this arrhythmia. For many years POAF has been regarded as a reactive phenomenon, occurring in response to post surgical inflammatory stressors and electrolyte imbalance. However, it is also possible that in a proportion of patients, prior cardiomyocyte remodelling predisposes to atrial arrhythmogenesis when exposed to surgical stress. Understanding the genomic and metabolic mechanisms that underlie this substrate may not only provide novel diagnostic biomarkers to identify at risk patients, but also isolate previously unrecognised therapeutic targets for prevention and treatment. In this work, a clinical observational study was utilised to obtain microRNA, gene expression and metabolic profiles of patients developing POAF after coronary artery bypass graft (CABG) surgery. Based on these results, a network of genomic and subsequent downstream pathway interactions was established to characterise the atrial substrate of post-operative AF. Furthermore, analysis of pre-operative blood was performed in order to identify novel microRNA that may provide a platform for biomarker development. Finally, the metabolic signature of the atrial myocardium and its relationship with the surrounding epicardial adipose were investigated to complete a comprehensive overview of the central mechanisms thought to underlie POAF pathogenesis. This work demonstrates that prior to surgery and the onset of arrhythmia, several distinct genomic and post-translational characteristics are evident in the both the myocardium and circulating blood of patients going on to develop POAF. Analysis of right atrial biopsies highlights a characteristic microRNA profile associated with POAF, and identifies target genes regulating intracellular signalling pathways, leukocyte recruitment, and ion channel remodelling. Furthermore, selected gene expression analysis demonstrates a de-differentiated phenotype similar to that seen in chronic AF, whilst at the same time establishing that disordered cardiomyocyte calcium handling is apparent at the time of surgery. Finally, analysis of the pre-operative circulating blood serum highlights microRNA selectively upregulated in POAF and establishes the potential for future biomarker development. In summary, the results presented here support the presence of a pre-existing atrial substrate in POAF, suggesting the potential exists for high-risk patients to be identified prior to surgery and the onset of arrhythmia. Furthermore, for the first time a number of similarities have been made apparent between post-operative and chronic AF, implying a common mechanistic spectrum of structural and electrical remodelling. As a consequence, the results presented in this thesis have not only improved our understanding of the complex interplay of factors leading to the pathogenesis of AF, but also provide a platform for both the development of a unique clinical biomarker and the identification of novel therapeutic targets.
Content Version: Open Access
Issue Date: Sep-2014
Date Awarded: Feb-2015
URI: http://hdl.handle.net/10044/1/29130
DOI: https://doi.org/10.25560/29130
Supervisor: Athanasiou, Thanos
Gooderham, Nigel
Holmes, Elaine
Sponsor/Funder: Wellcome Trust (London, England)
Imperial College Healthcare Charity
National Institute for Health Research (Great Britain)
Funder's Grant Number: 100023/Z/12/Z; WT100023MA Wellcome Trust
5117/R20R Imperial Charity
P31532 Biomedical Research Centre
Department: Department of Surgery & Cancer
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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