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Computational Investigation of the Mechanisms Underlying the Cardiac Pacemaker and its Dysfunction
[Thesis]. Manchester, UK: The University of Manchester; 2016.
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Abstract
The sinoatrial node is the primary cardiac pacemaker, which is responsible for generating spontaneous depolarisation of cellular membranes, leading to pacemaking action potentials that control the initiation and regulation of the rhythms of the heart. Previous studies in experimental electrophysiology have gathered a large amount of experimental data about the mechanisms of cardiac pacemaking activities at the molecular, ionic and cellular levels, however, the precise mechanisms underlying the genesis of spontaneous pacemaking action potentials still remain controversial. Mathematical models of the electrophysiology provide a unique alternative tool complimentary to experimental investigations, enabling us to analyse the fundamental physiological mechanisms of cardiac pacemaking activities in an efficient way that would be more difficult to conduct in experimental approaches. In this thesis, an integrated model, incorporating the detailed cellular ion channel kinetics, multi-compartment intracellular Ca2+ handling system and cell morphology, was developed for simulating the spontaneous pacemaking action potentials as well as the stochastic nature of local Ca2+ dynamics in the murine SA node cells. By using the model, the ionic mechanisms underlying the automaticity of primary cardiac pacemaking cells were investigated, the individual role of the ‘membrane clock’ (the cell membrane events) and ‘Ca2+ clock’ (intracellular Ca2+ activities) on generating the pacemaking action potentials were examined. In addition, the model also considered the regulation of the autonomic nervous systems on cardiac pacemaking action potentials. For the first time, competitive regulation of electrical action potentials of the murine SA node cells by the circadian sympathetic and parasympathetic systems during 24-hours were investigated. Furthermore, the individual role of the neurotransmitters, ACh- and ISO-induced actions on variant ion channel and Ca2+ handling in regulating cardiac pacemaking action potentials were also analysed. At the tissue level, an anatomically detailed 2D model of the intact SA node and atrium was developed to investigate the ionic mechanisms underlying sinus node dysfunctions in variant genetic defect conditions. Effects of these genetic defects in impairing cardiac pacemaker ability in pacing and driving the surrounding atrium as seen in the sinus node dysfunction were investigated.