Dose dependent antiarrhythmic effects of the potassium channel blocker 4-Aminopyridine in a virtual model of chronic atrial fibrillation

  • The block of potassium channels involving IKur is a promising approach in the pharmacotherapy of atrial fibrillation (AF). Advantage of an IKur-inhibition is that this channel is only expressed in the atrium. Among the substances blocking potassium channels is 4-Aminopyridine (4-AP) having a high affinity to block IKur potassium channels. It is reported, that 4-AP also inhibits Ito and IKr. The inhibition of these three potassium channels by 4-AP have different half maximal inhibitory concentration (IC50) and Hill-coefficient (n) in the Dose-response relationship (Hill equation).
    The question that should be answered in this work is, if there is a dose dependent antiarrhythmic or even proarrhythmic effect of 4-AP for normal atrial activity and chronic atrial fibrillation (cAF). In order to answer this question, a simulation-based study is performed. This is the first numerical model to hypothesize the effects of this multi-channel inhibitor.
    The membrane model of Courtemanche et al. is used to describe human atrial electrophysiology in combination with a monodomain model. The maximum channel conductivities for IKur, Ito and IKr have to be adjusted based on the Hill equation parameters found in literature for different dose of 4-AP. In order to describe the effects of 4-AP on healthy tissue and cAF, the action potential duration (APD), effective refractory period (ERP), conduction velocity (CV) and wave length (WL) and their respective restitution properties should be evaluated. Furthermore, the vulnerability to unidirectional block (vulnerable window) for different dose should be examined. Finally, the potential antiarrhythmic properties of 4-AP are evaluated in a 2D model. Therefore, an atrial fibrillation (AF) with 5 reentries is initiated and it is evaluated how different dose of 4-AP influence the perpetuation of this AF. Furthermore, a validation against measurement data documenting the effect of 4-AP in human atrial tissue should be performed.