Abstract
A recent study has identified six novel genetic variations (D322H, E48G, A305T, D469E, Y155C, P488S) in KCNA5 (encoding Kv1.5 which carries the atrial-specific ultra-rapid delayed rectifier current, IKur) in patients with early onset of lone atrial fibrillation. These mutations are distinctive, resulting in either gain-of-function (D322H, E48G, A305T) or loss-of-function (D469E, Y155C, P488S) of IKur channels. Though affecting potassium channels, they may modulate the cellular active force and therefore atrial mechanical functions, which remains to be elucidated. The present study aimed to assess the inotropic effects of the identified six KCNA5 mutations on the human atria. Multiscale electromechanical models of the human atria were used to investigate the impact of the six KCNA5 mutations on atrial contractile functions. It was shown that the gain-of-function mutations reduced active contractile force primarily through decreasing the calcium transient (CaT) via a reduction in the L-type calcium current (ICaL) as a secondary effect of modulated action potential, whereas the loss-of-function mutations mediated positive inotropic effects by increased CaT via enhancing the reverse mode of the Na+/Ca2+ exchanger. The 3D atrial electromechanical coupled model predicted different functional impacts of the KCN5A mutation variants on atrial mechanical contraction by either reducing or increasing atrial output, which is associated with the gain-of-function mutations or loss-of-function mutations in KCNA5, respectively. This study adds insights to the functional impact of KCNA5 mutations in modulating atrial contractile functions.
Highlights
The ultra-rapid rectifier delayed potassium channel current, IKur, is atrial specific and plays an important role in modulating atrial repolarisation as well as contractility [1,2]
The gain-offunction mutations abbreviated APD, and reduced the amplitude of calcium transient (CaT), leading to a pronounced decrease in the active force of the myocytes: the maximum active force was reduced by 22.0%, 13.2% and 23.0% for D322H, E48G and A305T vs. the WT conditions, respectively (Fig. 1Ci)
We developed a family of single cell models for human atrial electro-mechanics as well as a 3D anatomical model of atrial electromechanical coupling for WT and six KCN5A gene mutations identified in familial lone-atrial fibrillation (AF) patients [6]
Summary
The ultra-rapid rectifier delayed potassium channel current, IKur, is atrial specific and plays an important role in modulating atrial repolarisation as well as contractility [1,2]. A recent study has identified six novel genetic variations of the KCNA5 gene (D322H, E48G, A305T, D469E, Y155C, P488S) encoding Kv1.5 channels carrying IKur in patients with early-onset of lone atrial fibrillation (AF) [6]. These mutations produced different modulations on IKur channel properties, which can be classified into two different groups, the first (D322H, E48G, A305T) resulting in a gain-of-function, and the other (D469E, Y155C, P488S) resulting in loss-of-function of. By using multi-scale models of the human atria, the pro-arrhythmogenic effects of these genetic variants have been studied, revealing the causative link between the gene mutations and disturbed electrical excitation in the human atria [7]. The difference and similarity between the two groups in their arrhythmogenesis were investigated [7]
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