Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728823
Title: In silico investigations into human ventricular pro-arrhythmic mechanisms combined with in vivo and in vitro experiments
Author: Zhou, Xin
ISNI:       0000 0004 6496 6007
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Abstract:
Sudden cardiac death (SCD) is one of the largest causes of natural mortality throughout the world. SCD can be triggered through ventricular arrhythmias due to many pathological conditions, including coronary artery diseases, arrhythmogenic cardiomyopathies and genetic mutations of ionic channel proteins. Although considerable research has been conducted to study proarrhythmic mechanisms, most studies were in animal models due to ethical limitations in human cardiac research. Therefore, more research is needed to investigate the proarrhythmic ionic mechanisms in human. In this thesis, we use biophysically-detailed models of human cardiac electrophysiology to explore the ionic mechanisms underlying several proarrhythmic conditions. A first study is to use traditional modeling approach to explore the effect of ionic remodelling in human epicardial border zone (EBZ) cells post myocardial infarction by introducing the analogous remodelling observed in canine. Sensitivity analysis of the human EBZ models leads to our interest in developing new techniques to include general variability into human cardiac electrophysiology research. Therefore, a novel methodology to include the effect of in vivo cardiac variability in human electrophysiology is developed in this study by constructing a population of models calibrated using in vivo human data. The experimentally-calibrated population of human ventricular cell models is then applied to investigate the proarrhythmic ionic mechanisms underlying cardiac alternans, and to test the effects of potential anti-arrhythmic drug therapies on alternans. We then explore the interaction between cardiac variability and a mutation of slow delayed rectifier potassium channel. Our simulation results reveal the complex interactions between different ionic components in the integrated electrophysiological system, highlighting the importance of cardiac variability in the development of proarrhythmic conditions.
Supervisor: Rodriguez, Blanca ; Bueno-Orovio, Alfonso ; Burrage, Kevin Sponsor: China Scholarship Council ; Welcome Trust ; Engineering and Physical Sciences Research Council ; British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.728823  DOI: Not available
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