Work

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

Year: 2026

Type: article

Abstract: Purpose 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 I Kur and transient I to 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. Methods 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. Results At the basal rate, the voltage-mediated increase in I Kr induced by 4-AP shortens the action potential duration (APD) under sinus rhythm (SR), whereas a surge in I CaL 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 Ca 2+ overload. The slowing of repolarization induced by 4-AP can suppress the reopening of Na + channels during phase 3 EADs. Conclusion In both types of EAD, a shorter, Ca 2+ -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.

Source: Frontiers in Physiology

DOI: 10.3389/fphys.2025.1704051

Authors: Fazeelat Mazhar, Stefano Severi, Chiara Bartolucci

Institution: University of Bologna

Language: English

Topic: Cardiac electrophysiology and arrhythmias

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801