Effects of Kinetics and State-Dependent Binding Properties of IKur Targeting Drugs on Atrial Electrophysiology

Abstract

Background: The Kv1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous Kv1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or EC50 values, which can overlook adverse cardiotoxic events.Aim: We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico, and reveal the ideal therapeutic properties of IKur-blocking drugs that maximize efficacy and minimize pro-arrhythmic risk.Methods and results: A Markov model of IKur, based on experimental voltage-clamp data in atrial myocytes from patient samples in normal sinus rhythm (nSR) and chronic AF (cAF), was developed to describe Kv1.5 gating and state-specific Kv1.5-drug interactions and was incorporated into our human atrial cell models. We simulated 1Hz and 4Hz pacing protocols in drug-free conditions, and with [drug] equal to EC50. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (Kon) and reverse (Koff) rates to the closed, open, and inactivated state of the Kv1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes in cAF (effective refractory period prolongation) at fast pacing rate, while having little effect in nSR (limited action potential prolongation and no early afterdepolarization formation) at normal heart rate.Conclusions: Our results highlight that accurately accounting for channel interaction with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti-AF options.