Development of a Biophysically Detailed Computer Model of the Human Atria for the Study of Familial Cardiac Arrhythmias

Abstract

Familial cardiac arrhythmias, or inherited heart conditions, can affect people at any age and can be death-dealing if not treated. Atrial fibrillation (AF), the most common and sustained arrhythmia, can also be inherited. A fundamental approach to understanding the mechanisms underlying AF and improving its treatment involves investigating genetic variations that can alter cardiac electrical activities. Three gain-of-function mutations in the transient outward K+ channel (Ito) have been reported in vitro studies to be the possible cause of AF. Another in vitro study identified two gain-of-function mutations in the K+ channel subunit KCNE2 associated with lone AF. However, the underlying mechanisms by which these mutations initiate and promote atrial arrhythmias have not been elucidated. Computational modelling, with experimental/clinical data inputs, provides an excellent framework utilised in cardiac electrophysiology to study complex arrhythmias, such as AF. This project aimed to use this powerful method to study the functional impacts of the reported mutations on atrial arrhythmogenesis. Firstly, mathematical formulations of the repolarising potassium currents were developed based on existing electrophysiological data and then implemented into single-cell, idealised 1D and 2D tissue, and 3D realistic models of the human atria in order to elucidate the mechanisms underlying the proarrhythmic effects of these mutations in the pathogenesis of AF. The first part of the thesis, which consists of Chapters 4 and 5, provides novel mechanistic insights into understanding how impaired action potential (AP) repolarisation arising from three gain-of- function mutations in Ito current increases the risks of atrial arrhythmias. At the cellular level, the three mutations accelerated the repolarisation phase and significantly lowered the plateau membrane potential due to a significantly reduced L-type calcium current (ICaL). At the tissue level, they abbreviated both the effective refractory period (ERP) and excitation wavelength (WL) and increased the tissue’s vulnerability to initiate re-entry. Furthermore, the mutations maintained and promoted re-entrant excitation waves in 2D and 3D simulations, revealing the causal link between these mutations and AF. Additionally, a multi-scale computational model incorporated the IKACh current to quantify the functional effects of the parasympathetic system through the release of acetylcholine (ACh) with and without Ito mutations. The ACh dose-dependent effects were reflected on both atrial cells and tissue. In other words, with increased concentrations of ACh, the action potential duration (APD) and ERP were remarkably shortened, leading to sustained re-entry, which was more dominant and stationary with Ito mutation conditions. The simulation results add new insights into the individual roles of Ito, the current responsible for the early notch of the AP, and IKACh, an atrial-selective target, in atrial arrhythmias perpetuation. The second part, which consists of Chapter 6, elucidated the underlying mechanisms of two gain- of-function mutations in the potassium channel subunit KCNE2 associated with AF. The mutations led to abbreviated APD, ERP, and WL and flattened their restitutions curves. Although they reduced the vulnerability of tissue to unidirectional conduction block, KCNE2 mutations increased the lifespan and stabilization of the re-entrant excitation waves at the 2D level, which was corroborated by 3D simulations. Further simulations were conducted to study possible channel blockers in managing AF induced by KCNE2 mutations. The work in this thesis represents an advance in understanding the mechanisms of familial cardiac arrhythmias and suggests possible therapeutical targets.