Pro‐arrhythmogenic effects of atrial fibrillation‐induced electrical remodelling: insights from the three‐dimensional virtual human atria

Abstract

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 Ca2+ 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.

Synergistic Anti:arrhythmic Effects of Combined Blockade of Sodium and Ultra:rapid Delayed Rectifier Potassium Channels in Human Atria

“…The diffusion coefficient was chosen so that the model gives a conduction velocity of 0.7 m/s measured using plane wave for the tissue with normal human atrial cells. The numerical method used in our previous study [6] was adopted here. The mono-domain equation was integrated at a time step of 0.02 ms.…”

“…The formulation of IKur was updated based on recently published data [4]. cAF induced electrical remodelling were incorporated based on a previously published model (AF-4 in [6]). …”

“…A recent mathematical model for human atrial electrophysiology [6] was employed to simulate the human atrial electrical activities under both sinus rhythm (SR) and cAF conditions. The formulation of IKur was updated based on recently published data [4].…”

“…To solve the excitation wave propagation problem, the well-known mono-domain equation [6] was used, given by:…”

Reconstruction of Atrial Ectopic Focal and Re:entrant Excitations from Body Surface Potentials: Insights from 3D Virtual Human Atria and Torso

“…Especially AF has a high incidence (>2% of population with ageing over 65), and such an incidence is expected to be increased due to the ageing society in the next decade (7). In addition, the morphology of the atrial action potential (AP) varies from almost a triangular to an almost squared shapes from region to region (8), which differs to the ventricular epicardial APs. As AF is normally associated with either rapid focal pacing (spontaneous rapid firing of nonpacemaker cells) (9), fibrillatory conduction of multiple wavelets (10), re-entrant excitation scroll waves (i.e., rotors) (9,10) or combined of the three, its electrical activity is characterised by rapid and irregular electrical activation of the atria.…”