title: Rotor termination is critically dependent on kinetic properties of I kur inhibitors in an in silico model of chronic atrial fibrillation.
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.
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
authors.affiliation: Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands.
authors.forename: Paola
authors.initials: P
authors.lastname: Carrillo-Bustamante
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Fathima
authors.initials: F
authors.lastname: Fischer
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Wilhelms
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany ; German Centre for Cardiovascular Research (DZHK) partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Dössel
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany ; German Centre for Cardiovascular Research (DZHK) partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Seemann
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003198:Computer Simulation; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004562:Electrocardiography; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers