Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568640
Title: Biophysically detailed modelling of the functional impact of gene mutations associated with the 'short QT syndrome'
Author: Adeniran, Ismail
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Abstract:
The recently identified genetic short QT syndrome is characterised by abbreviated QT intervals on the electrocardiogram, an increased risk of atrial and ventricular arrhythmias, and an increased risk of sudden death. Although the short QT syndrome has been suggested to provide a paradigm for increasing understanding of the role of potassium channels in ventricular fibrillation, the basis for arrhythmogenesis in the short QT syndrome is incompletely understood. There are no animal models that accurately reproduce a short QT phenotype, and whilst in vitro electrophysiology of short QT mutant channels provides a route to greater understanding of the effects of short QT mutants on action potential repolarisation, on its own, this approach is insufficient to explain how arrhythmias arise and are maintained at the tissue level. Consequently, this thesis is concerned with the use of the viable alternative; in silico (computational) modelling to elucidate how the short QT syndrome facilitates the genesis and maintenance of ventricular arrhythmias and its effects on ventricular contraction. Using extant biophysical data on changes induced by the short QT mutations and data from BHF-funded in vitro electrophysiology, three novel mathematical models of the first three variants of the short QT syndrome were developed; a Markov chain model for short QT variant 1, a Markov chain model for short QT variant 2 and a Hodgkin-Huxley model for short QT variant 3. These models were incorporated into single cell and anatomically detailed tissue and organ computer models to elucidate how these variants lead to ventricular arrhythmias. The developed short QT models were then incorporated into electromechanically coupled single cell and tissue models to investigate the effects of the short QT mutants on ventricular contraction. It was found that each short QT variant uniquely increased the transmural dispersion of action potential duration across the ventricular wall, increased the temporal window of tissue vulnerability to premature excitation stimulus, leading to increased susceptibility to re-entrant arrhythmia.
Supervisor: Zhang, Henggui Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.568640  DOI: Not available
Keywords: Short QT Syndrome ; Arrhythmia ; Ventricular fibrillation
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