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Development of a multiscale model of the rabbit heart for the study of cardiac arrhythmogenesis
[Thesis]. Manchester, UK: The University of Manchester; 2019.
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Abstract
Cardiac arrhythmia including atrial fibrillation (AF) and ventricular fibrillation (VF) is a group of conditions manifested as abnormal heart rhythms, which affects millions of people. Among them, AF is associated with the increased risk of blood clots and is a major cause of stroke, and VF is the leading cause of sudden cardiac death. However, the mechanism(s) underlying cardiac arrhythmogenesis still remains unclear due to its complexity. In this thesis, multiscale computational models of a rabbit heart were developed and used to investigate possible mechanisms underlying cardiac arrhythmia. First, cell, one- (1D) and two-dimensional (2D) models of rabbit ventricular models were used to investigate how a spontaneous transition from cardiac alternans to arrhythmias can occur. It was found that cardiac alternans at cellular level evolved into either concordant or discordant alternans in one-dimensional homogeneous tissue, depending on the action potential duration and conduction velocity restitution properties. Discordant alternans can further evolve into wave breaks and re-entries in two-dimensional tissue, which was facilitated by tissue inhomogeneity or anisotropy. When INa was impaired, with it being either reduced or increased, the transition was promoted, demonstrating an important pro-arrhythmic role of an impaired sodium channel. Then, multiscale models of the rabbit sinoatrial node (SAN) and atrium were developed to investigate possible mechanism(s) responsible for the transition from bradycardia to tachycardia, i.e., the bradycardia-tachycardia syndrome (BTS). It was found that a synergistic effect of impaired funny current and high vagal tone on the pacemaking activity of the SAN and its driving ability to the surrounding atrium produced the main pacemaker shift, leading to unidirectional conduction block and consequent development of BTS. Finally, a three- dimensional rabbit whole heart model was developed using image data from micro-computed tomography. The model coupled detailed anatomical and electrophysiological details of the heart, including fibre structures and heterogeneity in cellular electrophysiology of cardiac conduction system, forming an invaluable platform for investigating cardiac diseases.