Mechanisms of Atrial Fibrillation Termination by Pure Sodium Channel Blockade in an Ionically-Realistic Mathematical Model
The mechanisms by which Na ϩ -channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical "leading-circle" theory suggests that Na ϩ -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 ϩ -current (I Na ) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory
... 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 I Na 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 (Circ Res. 2005;96:e35-e47.