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Cardiac electrical alternans (CEA), manifested as T-wave alternans in ECG, is a clinical biomarker for predicting cardiac arrhythmias and sudden death. However, the mechanism underlying the spontaneous transition from CEA to arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular models were used to study the transition and a potential role of INa in perpetuating such a transition. It was shown CEA evolved into either concordant or discordant action potential (AP) conduction alternans in a homogeneous one-dimensional tissue model, depending on tissue AP duration and conduction velocity (CV) restitution properties. Discordant alternans was able to cause conduction failure in the model, which was promoted by impaired sodium channel with either a reduced or increased channel current. In a two-dimensional homogeneous tissue model, a combined effect of rate- and curvature-dependent CV broke-up alternating wavefronts at localised points, facilitating a spontaneous transition from CEA to re-entry. Tissue inhomogeneity or anisotropy further promoted break-up of re-entry, leading to multiple wavelets. Similar observations have also been seen in human atrial cellular and tissue models. In conclusion, our results identify a mechanism by which CEA spontaneously evolves into re-entry without a requirement for premature ventricular complexes or pre-existing tissue heterogeneities, and demonstrated the important pro-arrhythmic role of impaired sodium channel activity. These findings are model-independent and have potential human relevance., Competing Interests: The authors have declared that no competing interests exist.

Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche-Ramirez-Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca(2+) handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate initiation and maintenance of re-entrant excitation waves.

Objectives: Although previous studies in dogs have indicated a minimal role for changes in I(K1) in the shortening of action potential duration (APD) associated with atrial fibrillation (AF), in humans, there is evidence for significant AF-induced up-regulation of this current. In this computer model study, we investigated the relative contributions of the remodeling of I(K1), L-type calcium current, and other remodeled ionic channel currents to AF-induced APD reduction in human atrium., Methods: Two computer models of electrical activity of human atrial cell were modified by incorporating experimental data of AF-induced changes in human atrial ionic channel conductance and kinetics reported by Bosch et al. (I(CaL), I(to), I(K1), and I(Na)) (AF-1) and Workman et al. (I(CaL), I(to), and I(K1)) (AF-2). The roles and relative importance of individually remodeled ion channels in the APD reduction in human atrium were evaluated by the removal and exclusive methods, in which remodeling of specific currents was omitted, or considered in isolation, in the two models., Results: When tested together, previously reported AF-induced changes in sarcolemmal ion currents result in marked shortening of atrial APD(90). With the AF-1 remodeled parameters, there is a 62% reduction in APD(90) for the Nygren et al. model, and a 68% reduction for the Courtemanche et al. model, which are comparable to experimental results of 60% reduction seen in humans. When tested individually, AF-1-induced changes in I(CaL), I(K1), or I(to) alone result in APD(90) reduction of 20%, 64%, and -10%, respectively, for the Nygren et al. model, and 27%, 40%, and 11.6%, respectively, for the Courtemanche et al. model. With the AF-2 remodeled parameters, there is a 47% reduction in APD(90) for the Nygren et al. model and a 49% reduction for the Courtemanche et al. model, which are also comparable to experimental results of 45% reduction. When tested individually, AF-2-induced changes in I(CaL) or I(K1) alone result in APD(90) reduction of 20% and 40%, respectively, for the Nygren et al. model, and 14% and 21%, respectively, for the Courtemanche et al. model., Conclusion: Previously reported changes in L-type Ca(2+) current are insufficient to account for the observed reduction in atrial APD associated with persistent AF. Up-regulation of I(K1) has a greater influence on atrial APD in the human model.

Abstract: Atrial fibrillation (AF) has been linked to increased inward rectifier potassium current, I K1, either due to AF-induced electrical remodelling, or from functional changes due to the Kir2.1 V93I mutation. The aim of this simulation study was to identify at cell and tissue levels'' mechanisms by which increased I K1 facilitates and perpetuates AF. The Courtemanche et al. human atrial cell action potential (AP) model was modified to incorporate reported changes in I K1 induced by the Kir2.1 V93I mutation in both heterozygous (Het) and homozygous (Hom) mutant forms. The modified models for wild type (WT), Het and Hom conditions were incorporated into homogeneous 1D, 2D and 3D tissue models. Restitution curves of AP duration (APD), effective refractory period (ERP) and conduction velocity (CV) were computed and both the temporal and the spatial vulnerability of atrial tissue to re-entry were measured. The lifespan and tip meandering pattern of re-entry were also characterised. For comparison, parallel simulations were performed by incorporating into the Courtmanche et al. model a linear increase in maximal I K1 conductance. It was found that the gain-in-function of V93I ‘mutant’I K1 led to abbreviated atrial APs and flattened APD, ERP and CV restitution curves. It also hyperpolarised atrial resting membrane potential and slowed down intra-atrial conduction. V93I ‘mutant’I K1 reduced the tissue''s temporal vulnerability but increased spatial vulnerability to initiate and sustain re-entry, resulting in an increased overall susceptibility of atrial tissue to arrhythmogenesis. In the 2D model, spiral waves self-terminated for WT (lifespan < 3.3 s) tissue, but persisted in Het and Hom tissues for the whole simulation period (lifespan > 10 s). The tip of the spiral wave meandered more in WT tissue than in Het and Hom tissues. Increased I K1 due to augmented maximal conductance produced similar results to those of Het and Hom Kir2.1 V93I mutant conditions. In the 3D model the dynamic behaviour of scroll waves was stabilized by increased I K1. In conclusion, increased I K1 current, either by the Kir2.1 V93I mutation or by augmented maximal conductance, increases atrial susceptibility to arrhythmia by increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue, thereby facilitating initiation and maintenance of re-entrant circuits. [Copyright &y& Elsevier]

Abstract: Computational models of human atrial cells, tissues and atria have been developed. Cell models, for atrial wall, crista terminalis, appendage, Bachmann’s bundle and pectinate myocytes are characterised by action potentials, ionic currents and action potential duration (APD) restitution. The principal effect of the ion channel remodelling of persistent atrial fibrillation (AF), and a mutation producing familial AF, was APD shortening at all rates. Electrical alternans was abolished by the modelled action of Dronedarone. AF induced gap junctional remodelling slows propagation velocity at all rates. Re-entrant spiral waves in 2-D models are characterised by their frequency, wavelength, meander and stability. For homogenous models of normal tissue, spiral waves self-terminate, due to meander to inexcitable boundaries, and by dissipation of excitation. AF electrical remodelling in these homogenous models led to persistence of spiral waves, and AF fibrotic remodelling to their breakdown into fibrillatory activity. An anatomical model of the atria was partially validated by the activation times of normal sinus rhythm. The use of tissue geometry from clinical MRI, and tissue anisotropy from ex vivo diffusion tensor magnetic resonance imaging is outlined. In the homogenous model of normal atria, a single scroll breaks down onto spatio-temporal irregularity (electrical fibrillation) that is self-terminating; while in the AF remodelled atria the fibrillatory activity is persistent. The persistence of electrical AF can be dissected in the model in terms of ion channel and intercellular coupling processes, that can be modified pharmacologically; the effects of anatomy, that can be modified by ablation; and the permanent effects of fibrosis, that need to be prevented. [Copyright &y& Elsevier]