In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis

A recent experimental study investigating patients with lone atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain-and loss-of-function of the atrial specific ultra-rapid delayed rectifier K+ current, I-Kur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutations on atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on I-Kur from both wild-type and mutants. The effects of the mutations on human atrial action potential and rate dependence were investigated at the cellular level. In tissue, we assessed the effects of the mutations on the vulnerability to unidirectional conduction patterns and dynamics of re-entrant excitation waves. Gain-of-function mutations shortened the action potential duration in single cells, and stabilised and accelerated re-entrant excitation in tissue. Loss-of-function mutations had heterogeneous effects on action potential duration and promoted early-after-depolarisations following beta-adrenergic stimulation. In the tissue model, loss-of-function mutations facilitated breakdown of excitation waves at more physiological excitation rates than the wild-type, and the generation of early-after-depolarisations promoted unidirectional patterns of excitation. Gain-and loss-of-function I-Kur mutations produced multiple mechanisms of atrial arrhythmogenesis, with significant differences between the two groups of mutations. This study provides new insights into understanding the mechanisms by which mutant I-Kur contributes to atrial arrhythmias. In addition, as I-Kur is an atrial-specific channel and a number of I-Kur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results on both pro-and anti-arrhythmic effects of blocking I-Kur.