Evaluation of the role of I_KAChin atrial fibrillation using a mouse knockout model

Abstract

OBJECTIVES

We sought to study the role of I_KAChin atrial fibrillation (AF) and the potential electrophysiologic effects of a specific I_KAChantagonist.

BACKGROUND

I_KAChmediates much of the cardiac responses to vagal stimulation. Vagal stimulation predisposes to AF, but the specific role of I_KAChin the generation of AF and the electrophysiologic effects of specific I_KAChblockade have not been studied.

METHODS

Adult wild-type (WT) and I_KACh-deficient knockout (KO) mice were studied in the absence and presence of the muscarinic receptor agonist carbachol. The electrophysiologic features of KO mice were compared with those of WT mice to assess the potential effects of a specific I_KAChantagonist.

RESULTS

Atrial fibrillation lasting for a mean of 5.7 ± 11 min was initiated in 10 of 14 WT mice in the presence of carbachol, but not in the absence of carbachol. Atrial arrhythmia could not be induced in KO mice. Ventricular tachyarrhythmia could not be induced in either type of mouse. Sinus node recovery times after carbachol and sinus cycle lengths were shorter and ventricular effective refractory periods were greater in KO mice than in WT mice. There was no significant difference between KO and WT mice in AV node function.

CONCLUSIONS

Activation of I_KAChpredisposed to AF and lack of I_KAChprevented AF. It is likely that I_KAChplays a crucial role in the generation of AF in mice. Specific I_KAChblockers might be useful for the treatment of AF without significant adverse effects on the atrioventricular node or the ventricles.