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Title: Modelling and simulation of phenotypic variability in cardiac tissue and application to stem cell-derived cardiomyocytes
Author: Bowler, Louise
ISNI:       0000 0004 7966 1994
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Prediction of the safety of a novel pharmaceutical compound at the earliest possible stage of development is of great importance for drug discovery. Cardiac side-effects are a particular cause for concern, with several drugs such as Terfenadine and Cisapride having being withdrawn from the market due to adverse events. Investigation of the properties of novel compounds can be facilitated by the use of in silico models, which can provide a high-throughput and low-cost method of translating the known effects of a novel compound on multiple ion channels to effects on tissue-level electrophysiology. In this thesis, we examine the case of monolayers of human stem cell-derived cardiomyocytes (hSC-CMs). In recent years, experimental systems utilising such monolayers have become more widely used, especially following their inclusion in the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. In contrast to cells found in the adult heart, hSC-CMs beat spontaneously and are not necessarily spatially segregated by their subtype, or phenotype. These properties mean that the overall electrophysiological activity of a monolayer is sensitive to the spatial arrangement of the different types of cells. The simulation framework must therefore permit different spatial distributions of phenotypes. The first part of this thesis is dedicated to the development of a simulation framework for modelling monolayers of hSC-CMs that incorporate phenotypic variability. While tissue containing regions of distinct cell types can be modelled using the bidomain equations, this approach is not computationally efficient when the cells are well-mixed. We test a novel approach, the homogenised phenotypes model, where the homogenisation process that underpins the bidomain equations is carried out over a small unit that contains two cell types. In the second part of this thesis, we utilise the homogenised phenotypes model in simulations of the micro-electrode array, a device which is used to record extracellular field potentials from a monolayer of hSC-CMs, and compare our simulation predictions with experimental recordings. We investigate how variability in cellular phenotype and the distribution of these phenotypes throughout the monolayer affects the field potential, how this variability is manifest in simulations of drug block, and discuss the implications of our findings for the safety assessment process.
Supervisor: Mirams, Gary ; Gavaghan, David Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Computational biology