Evaluation of the role of IKACh in atrial fibrillation using a mouse knockout model

OBJECTIVES We sought to study the role of I-KACh in atrial fibrillation (AF) and the potential electrophysiologic effects of a specific I-KACh antagonist. BACKGROUND I-KACh mediates much of the cardiac responses to vagal stimulation. Vagal stimulation predisposes to AF, but the specific role of I-KACh in the generation of AF and the electrophysiologic effects of specific I-KACh blockade 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-KACh antagonist. 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-KACh predisposed to AF and lack of I-KACh prevented AF. It is likely that I-KACh plays a crucial role in the generation of AF in mice. Specific I-KACh blockers might be useful for the treatment of AF without significant adverse effects on the atrioventricular node or the ventricles. (J Am Coll Cardiol 2001;37:2136-43) (C) 2001 by the American College of Cardiology.