Rotor termination is critically dependent on kinetic properties of I kur inhibitors in an in silico model of chronic atrial fibrillation

PLoS One. 2013 Dec 20;8(12):e83179. doi: 10.1371/journal.pone.0083179. eCollection 2013.

Abstract

Inhibition of the atrial ultra-rapid delayed rectifier potassium current (I Kur) represents a promising therapeutic strategy in the therapy of atrial fibrillation. However, experimental and clinical data on the antiarrhythmic efficacy remain controversial. We tested the hypothesis that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of channel blockade. A mathematical description of I Kur blockade was introduced into Courtemanche-Ramirez-Nattel models of normal and remodeled atrial electrophysiology. Effects of five model compounds with different kinetic properties were analyzed. Although a reduction of dominant frequencies could be observed in two dimensional tissue simulations for all compounds, a reduction of spiral wave activity could be only be detected in two cases. We found that an increase of the percent area of refractory tissue due to a prolongation of the wavelength seems to be particularly important. By automatic tracking of spiral tip movement we find that increased refractoriness resulted in rotor extinction caused by an increased spiral-tip meandering. We show that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of blockade. We find that an increase of the percent area of refractory tissue is the underlying mechanism for an increased spiral-tip meandering, resulting in the extinction of re-entrant circuits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Anti-Arrhythmia Agents / pharmacology*
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / physiopathology
  • Computer Simulation
  • Delayed Rectifier Potassium Channels / antagonists & inhibitors*
  • Delayed Rectifier Potassium Channels / metabolism
  • Electrocardiography
  • Heart Atria / drug effects*
  • Heart Atria / metabolism
  • Heart Atria / physiopathology
  • Humans
  • Kinetics
  • Models, Biological*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Potassium Channel Blockers / pharmacology*

Substances

  • Anti-Arrhythmia Agents
  • Delayed Rectifier Potassium Channels
  • Potassium Channel Blockers

Grants and funding

This work was supported by grants from the German Research Foundation [Scho1350/2-1 to ES, Se1758/3-1 to GS]. FF was supported by the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS). HAK was supported by the DZHK (German Centre for Cardiovascular Research). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.