ORIGINAL RESEARCH article
Front. Physiol.
Sec. Computational Physiology and Medicine
K+-Channel Blockade can Suppress Phase 3 EADs by Slowing the Repolarization in an Electromechanical Cell Computational Model
Provisionally accepted
- 1University of California Davis Department of Pharmacology, Davis, United States
- 2University of Bologna, Bologna, Italy
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Purpose: Selective inhibition of atrial proarrhythmicity can be therapeutic for reducing the AF burden. Atrial-selective K+-channel block (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 mechanism underlying the efficacy of K+ channel block in arrhythmic conditions and its link to electrophysiological and contractile remodeling in AF needs to be investigated. Methods: Using our electromechanically coupled model MBS2023, we have simulated the effects of 4-AP and AVE0118 at different basic cycle lengths (2 to 0.25sec). 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 ECC or mechano-calcium feedback. Results: Under basal rate, the voltage-mediated rise in IKr induced by 4-AP, shortens the APD under sinus rhythm (SR), and a surge in ICaL lengthens it under AF. 4-AP can exacerbate the vulnerability to phase 2 early afterdepolarizations (EADs) by slowing repolarization and prolonging myofilament activation. K+-channel block can decimate the susceptibility of delayed afterdepolarizations (DADs) by eliminating the cytosolic Ca2+ overload. The slowing of repolarization induced by 4-AP can favor stopping the reopening of Na+ channels during phase 3 EADs. Conclusion: 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 antiarrhythmic potential to suppress phase 3 EADs by slowing repolarization.
Keywords: anti-arrhythmic, Atrial Fibrillation, atrial-specific blockers, Contraction, electromechanical coupling, Human atrial cells, in-silico modeling
Received: 12 Sep 2025; Accepted: 19 Dec 2025.
Copyright: © 2025 Mazhar, Severi and Bartolucci. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Chiara Bartolucci
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