title: Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model.
abstract: The mechanisms by which Na+-channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical "leading-circle" theory suggests that Na+-channel blockade should, if anything, promote re-entry. We used an ionically-based mathematical model of vagotonic AF to evaluate the effects of applying pure Na+-current (I(Na)) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory propagation at critical levels of action potential duration (APD) dispersion. I(Na) inhibition terminated AF increasingly with increasing block, terminating all AF at 65% block. During 1:1 conduction, I(Na) inhibition reduced APD (by 13% at 4 Hz and 60% block), conduction velocity (by 37%), and re-entry wavelength (by 24%). During AF, I(Na) inhibition increased the size of primary rotors and reduced re-entry rate (eg, dominant frequency decreased by 33% at 60% I(Na) inhibition) while decreasing generation of secondary wavelets by wavebreak. Three mechanisms contributed to I(Na) block-induced AF termination in the model: (1) enlargement of the center of rotation beyond the capacity of the computational substrate; (2) decreased anchoring to functional obstacles, increasing meander and extinction at boundaries; and (3) reduction in the number of secondary wavelets that could provide new primary rotors. Optical mapping in isolated sheep hearts confirmed that tetrodotoxin dose-dependently terminates AF while producing effects qualitatively like those of I(Na) inhibition in the mathematical model. We conclude that pure INa inhibition terminates AF, producing activation changes consistent with previous clinical and experimental observations. These results provide insights into previously enigmatic mechanisms of class I antiarrhythmic drug-induced AF termination. The full text of this article is available online at http://circres.ahajournals.org
authors.affiliation: Research Center and Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Kneller
authors.forename: Jérôme
authors.initials: J
authors.lastname: Kalifa
authors.forename: Renqiang
authors.initials: R
authors.lastname: Zou
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Zaitsev
authors.forename: Mark
authors.initials: M
authors.lastname: Warren
authors.forename: Omer
authors.initials: O
authors.lastname: Berenfeld
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Vigmond
authors.forename: L Joshua
authors.initials: LJ
authors.lastname: Leon
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000465:Algorithms; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy*; D003198:Computer Simulation; D004569:Electroencephalography; D005583:Fourier Analysis; D008955:Models, Cardiovascular; D012756:Sheep; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D015222:Sodium Channels / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology / Q000627:therapeutic use; D014741:Video Recording
chemical_list: D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium