Computational simulations of the effects of the V17M missense mutation on atrial electrical activity

[EN] Atrial fibrillation is a cardiac arrhythmia responsible for disorganized electrical activity of the upper chambers of the heart. Recently genetic mutations have been associated to episodes of atrial fibrillation in asymptomatic patients, a condition called Lone AF. Indeed, genetic defects in ion channel protein structures can alter the flowing of the current through the pore. The aim of this work is to model and simulate the gain of function missense mutation V17M affecting the accessory subunit KCNE3 of the rapid delayed rectifier potassium channel, Kv11.1, found in a 46-years-old man affected by Lone AF. To accomplish this, the ventricular IKr Markov model proposed by Martin Fink and colleagues has been refitted to reproduce the behavior of the atrial IKr using an optimization procedure. Then, it was introduced into the atrial cellular model developed by Courtemanche Ramirez Nattel (CRN). Additionally, this model has been adjusted to fit experiments in literature in order to accurately reproduce the effects of the V17M mutation. The resulting wild-type IKr formulation mimics the CRN IKr time course at 0.5, 1 and 2 Hz, the activation time constants and the steady-state activation and inactivation curves. In addition, the V17M mutation formulation reproduces the experimentally reported electrophysiological alterations, which are approximately 3-fold increment of the current at high voltages and an almost 2-fold prolongation of the deactivation time constant. Simulation of the V17M mutation at the cellular level showed a 300% increase of the IKr peak, which shortened the action potential duration in 118.30 ms.Generalitat Valenciana, Prometeo programme 2016/088 and grant agreement 766082 European Union's Horizon 2020Belletti, R.; Martínez Mateu, L.; Romero Pérez, L.; Saiz Rodríguez, FJ. (2019). Computational simulations of the effects of the V17M missense mutation on atrial electrical activity. Grupo de Técnicas Ópticas Aplicadas, Universidad de Cantabria. 203-206. http://hdl.handle.net/10251/19057120320