Key points• A previous study has identified a gene mutation (KCNQ1 S140G) in some patients with a familial form of atrial fibrillation, one of the most common cardiac rhythm disturbances causing morbidity and mortality. A causal link between the mutation and genesis of atrial fibrillation has not yet been directly demonstrated.• Increased I Ks arising from the KCNQ1 S140G mutation abbreviated atrial action potential duration (APD) and effective refractory period (ERP) and flattened APD and ERP restitution curves. It reduced atrial conduction velocity at low excitation rates, but increased it at high excitation rates that facilitated the conduction of high rate atrial excitation waves.• The mutation increased tissue susceptibility for initiation and maintenance of atrial arrhythmias.• The mutation stabilizes and accelerates re-entrant excitation waves, leading to rapid and sustained re-entry.• This study provides novel insights towards understanding the mechanisms underlying the pro-arrhythmic effects of the KCNQ1 S140G mutation.Abstract Functional analysis has shown that the missense gain-in-function KCNQ1 S140G mutation associated with familial atrial fibrillation produces an increase of the slow delayed rectifier potassium current (I Ks ). Through computer modelling, this study investigated mechanisms by which the KCNQ1 S140G mutation promotes and perpetuates atrial fibrillation. In simulations, Courtemanche et al.'s model of human atrial cell action potentials (APs) was modified to incorporate experimental data on changes of I Ks induced by the KCNQ1 S140G mutation. The cell models for wild type (WT) and mutant type (MT) I Ks were incorporated into homogeneous multicellular 2D and 3D tissue models. Effects of the mutation were quantified on AP profile, AP duration (APD) restitution, effective refractory period (ERP) restitution, and conduction velocity (CV) restitution. Temporal and spatial vulnerabilities of atrial tissue to genesis of re-entry were computed. Dynamic behaviours of re-entrant excitation waves (lifespan (LS), tip meandering patterns and dominant frequency) in 2D and 3D models were characterised. It was shown that the KCNQ1 S140G mutation abbreviated atrial APD and ERP and flattened APD and ERP restitution curves. It reduced atrial CV at low excitation rates, but increased it at high excitation rates that facilitated the conduction of high rate atrial excitation waves. Although it increased slightly tissue temporal vulnerability for initiating re-entry, it reduced markedly the minimal substrate size necessary for sustaining re-entry (increasing the tissue spatial vulnerability). In the 2D and 3D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. In the 3D model, scroll waves under the mutation condition MT conditions also degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, increased I Ks due to the KCNQ1 S140G mutation increases atrial susceptibility to arrhythmia due to increased tissu...
Atrial fibrillation (AF) accounts for a large proportion of healthcare expenditure world wide. Mechanisms underlying the genesis and maintenance of AF are still poorly understood. Though AF is largely thought to be caused and perpetuated by dysfunctions of cellular ion channels, disrupted intercellular gap junctional electrical coupling, and/or structural changes in the atria, it is also associated with abnormal secretion of hormones, such as a high level of Homocysteine (Hcy). It was found that a high concentration Hcy induces electrical remodeling of ion channels in human atrial cells that include the ultra rapid potassium, inward rectifier potassium and transient outward potassium currents. Such Hcy-induced ion channel remodeling in repolarising potassium currents has been hypothesized to be pro-arrhythmic. In this study, we carried out multi-scale simulations to evaluate the effects of Hcy-induced changes in potassium currents on the electrical activity of human atrium at single cell, 1D strand of tissue, and 3D anatomical models. We found that high Hcy concentration produced marked changes in atrial action potentials, including a more hyperpolarized resting potential, elevated plateau potential during early stages of repolarization and abbreviated action potential duration (APD). Losses in rate dependent accommodation of APD and effective refractory period were observed. In the tissue models, high Hcy concentration slowed down atrial excitation conduction at low rates, but facilitated it at high rates. Simulated re-entrant scroll waves in the 3D model self-terminated under Control condition, but sustained under high Hcy condition. These results collectively demonstrate the pro-arrhythmic effects of a high level Hcy in promoting and sustaining AF.
We postulated that atrial fibrillation (AF) induced electrical remodelling in electrically heterogeneous human atria facilitates chronic AF.A modern biophysically detailed mathematical model of human atrial action potential was modified to incorporate electrophysiological properties of different cell types present within the atria. The heterogeneous cell models were then further modified to incorporate data on AF induced electrical remodelling (AFER) of ion channel kinetics and current densities. These modified models were used to simulate electrical activity in cells, 1D strands and 2D heterogeneous sheets.AFER heterogeneously reduced action potential duration in all cell types. The theme of inhomogeneous response to AFER was observed through all cell and 1D simulations. Sheet simulations showed that whilst re-entry self terminated in the control case, it persisted under AFER conditions.
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