Computational Investigation of the Role of Ion Channels Remodelling Associated with Age Development in the Cardiac Pacemaker Cells

Abstract

The sinoatrial node (SAN) is the primary cardiac pacemaker, which generates spontaneous action potentials (APs) and regulates the rhythms of the heart. The function of the SAN declines with age development, and this results in marked differences in the morphology and characteristics of APs and affects the pacemaking activities, consequently increases the incidence of sinus node dysfunction (SND) in older adults. These changes may be attributable to different sets of ion-channel interactions at different ages. The mechanism underlying the pathogenesis for cardiac pacemaker dysfunctions associated with ageing remain uncertain. In this project, using a computer modelling approach, we investigated the role of age-related remodelling of ion channels on pacemaking activites of the SAN at single-cell and tissue level. The research explained in this thesis utilised electrophysiological data from experiments in different species at the ion-channel level to develop novel mathematical models of neonatal, aged and diabetic conditions. A mathematical model of neonatal rabbit SAN cells was developed by modifying the current densities and/or kinetics of ion channels (INa, ICa,L, If, INaCa, IKr and IKs) in a SAN adult-cell model. At single cell level, simulation results showed that the ion channels altered during maturation play a functional role in slowing down the pacemaking APs. At the tissue level, these integral effects increase the activation time across the intact SAN-atrium, leading to decreased AP conduction velocity and heart rate. Moreover, vagal nerve activity elucidated a high sensitivity of neonatal SAN cells to acetylcholine. The effect of ACh amplified in neonates, under high concentration, leading to possible sinus arrest or conduction exit. Similarly, the ionic mechanisms underlying SND associated with ageing were assessed. A mathematical model of adult rat SAN cells was modified to investigate two case studies of cardiac pacemaker dysfunction, identified experimentally, which arose from different pathways of electrical remodelling in ion channels (If, ICaL, INaCa) and Ca2+ handling proteins proteins (RyR2, and SERCA2a) in the ageing rat heart. Our results suggest that the integral action of all remodelled ion channels and Ca2+ handling can be accounted for producing bradycardic effects as manifested by heart rate reduction, the remodelled ICa,L, either via a gain or loss of function, contributes primarily to ageing-related bradycardia. Therefore, ageing-related bradycardia can be linked to different remodelling “pathways”. A one-dimensional string model of SAN-atrium was constructed, through incorporating the regional heterogeneity of SAN tissue, and coupled to atrial tissue. The new model was utilised to simulate the spontaneous activity and AP conduction across the SAN-atrium under normal conditions and SND associated with ion channel deficiency in diabetes. The model successfully produced similar 12 propagation and conduction activities to experimental observations in normal SAN.The functional alternation of ion channel; ICa,L, ICa,T, If and INaCa in diabetic rat closely resemble those observed in experimental SND. Finally, a mathematical model of mouse SAN cells was utilised to investigate the effect of changes in abundance of hyperpolarisation-activated cyclic nucleotide-gated channel (HCN) on the APs and pacemaker rate, during over-expression of gene target TBX18, which is used to enhance pacemaker function in a rat subsidiary atrial pacemaker (SAP), a model of sick sinus syndrome (SSS). Simulation results showed that the changes of the HCN abundance could explain the observed changes in beating rate. This suggests that TBX18 may have the potential to restore pacemaker function in human SSS.