K+ channel blockade limits AF and suppresses phase 3 EADs by slowing repolarization in an electromechanical cell computational model

TL;DR

Blocking K+ channels can reduce atrial fibrillation and phase 3 early afterdepolarizations by slowing repolarization in a computational model.

Contribution

The study reveals novel anti-arrhythmic mechanisms of K+ channel blockade in suppressing phase 3 EADs through computational modeling.

Findings

K+ channel blockade slows repolarization and suppresses phase 3 EADs in arrhythmic conditions.

4-AP reduces susceptibility to DADs by eliminating cytosolic Ca2+ overload.

Slowed repolarization from K+ channel blockade reduces AF propensity in the model.

Abstract

Selective inhibition of atrial proarrhythmicity can be therapeutic for reducing the atrial fibrillation (AF) burden. Atrial-selective K+-channel blockade (mainly Kv1.5 and Kv4.3 channels conducting the sustained IKur and transient Ito outward currents) promises to suppress AF with a favorable benefit-to-harm ratio. The mechanisms underlying the efficacy of K+ channel blockade under arrhythmic conditions and its association with electrophysiological and contractile remodeling in AF remain to be investigated.

Using our electromechanically coupled model MBS2023, we have simulated the effects of 4-aminopyridine (4-AP) and AVE0118 at different basic cycle lengths (2–0.25s). We have dissociated the primary and secondary responses to determine the drug’s underlying mechanisms of action. We have analyzed the effects of K+-channel blockers under arrhythmogenic conditions induced by either forward excitation-contraction coupling (ECC) or mechano-calcium feedback.

At the basal rate, the voltage-mediated increase in IKr induced by 4-AP shortens the action potential duration (APD) under sinus rhythm (SR), whereas a surge in ICaL prolongs APD under AF. 4-AP can exacerbate the vulnerability to phase 2 early afterdepolarizations (EADs) by slowing repolarization and prolonging myofilament activation. K+-channel blockade can decimate the susceptibility of delayed afterdepolarizations (DADs) by eliminating the cytosolic Ca2+ overload. The slowing of repolarization induced by 4-AP can suppress the reopening of Na+ channels during phase 3 EADs.

In both types of EAD, a shorter, Ca2+-desensitized sarcomere can reduce the propensity for AF in the model. In general, K+ channel blockade has anti-arrhythmic potential to suppress phase 3 EADs by slowing repolarization.

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