Key result
Gain-of-function Kv4.3 and Kv4.2 mutations shortened action potential duration and effective refractory period, facilitating atrial excitation conduction and increasing re-entry lifespan in models.
Why the study?
Mutations in KCND3-encoded Kv4.3 and KCND2-encoded Kv4.2 causing dysfunctional Ito had been linked to AF, but the underlying pro-arrhythmic mechanisms were unclear.
Gain-of-function mutations in Kv4.3 and Kv4.2 facilitate atrial fibrillation by shortening action potential duration and increasing spatial dispersion of repolarization in human atrial computational models.
Computational models link Kv4 gain-of-function mutations to pro-arrhythmic Ito changes in AF; leaves open experimental and clinical validation.
Previous studies have linked dysfunctional I to arising from mutations to KCND3 -encoded Kv4.3 and KCND2 -encoded Kv4.2 to atrial fibrillation. Using computational models, this study aimed to investigate the mechanisms underlying pro-arrhythmic effects of the gain-of-function Kv4.3 (T361S, A545P) and Kv4.2 (S447R) mutations. Wild-type and mutant I to formulations were developed from and validated against experimental data and incorporated into the Colman et al . model of human atrial cells. Single-cell models were incorporated into one- (1D) and two-dimensional (2D) models of atrial tissue, and a three-dimensional (3D) realistic model of the human atria. The three gain-of-function mutations had similar, albeit quantitatively different, effects: shortening of the action potential duration; lowering the plateau membrane potential, abbreviating the effective refractory period (ERP) and the wavelength (WL) of atrial excitation at the tissue level. Restitution curves for the WL, the ERP and the conduction velocity were leftward shifted, facilitating the conduction of atrial excitation waves at high excitation rates. The mutations also increased lifespan and stationarity of re-entry in both 2D and 3D simulations, which further highlighted a mutation-induced increase in spatial dispersion of repolarization. Collectively, these changes account for pro-arrhythmic effects of these Kv4.3 and Kv4.2 mutations in facilitating AF. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
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Alrabghi et al. (2023) studied Atrial fibrillation. Gain-of-function Kv4.3 (T361S, A545P) and Kv4.2 (S447R) mutations vs. Wild-type was evaluated on Electrophysiological properties (action potential duration, effective refractory period, wavelength, conduction velocity, re-entry lifespan). Gain-of-function Kv4.3 and Kv4.2 mutations shortened action potential duration and effective refractory period, facilitating atrial excitation conduction and increasing re-entry lifespan in models.
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