Author + information
- Received June 22, 2000
- Revision received February 27, 2001
- Accepted March 22, 2001
- Published online June 15, 2001.
- Pramesh Kovoor, MD, PhD∗,
- Kevin Wickman, PhD†,
- Colin T Maguire‡,
- William Pu, MD‡,
- Josef Gehrmann, MD‡,
- Charles I Berul, MD‡ and
- David E Clapham, MD, PhD‡,* ()
- ↵*Reprint requests and correspondence:
Dr. David E. Clapham, Howard Hughes Medical Institute, Director of Cardiovascular Research, Children’s Hospital and Harvard Medical School, Enders 1309, 320 Longwood Avenue, Boston, Massachusetts 02115
We sought to study the role of IKAChin atrial fibrillation (AF) and the potential electrophysiologic effects of a specific IKAChantagonist.
IKAChmediates much of the cardiac responses to vagal stimulation. Vagal stimulation predisposes to AF, but the specific role of IKAChin the generation of AF and the electrophysiologic effects of specific IKAChblockade have not been studied.
Adult wild-type (WT) and IKACh-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 IKAChantagonist.
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.
Activation of IKAChpredisposed to AF and lack of IKAChprevented AF. It is likely that IKAChplays a crucial role in the generation of AF in mice. Specific IKAChblockers might be useful for the treatment of AF without significant adverse effects on the atrioventricular node or the ventricles.
☆ Dr. Kovoor was supported by a grant from the Australian Heart Foundation. Dr. Clapham was supported by the Howard Hughes Medical Institute and a grant from the National Institutes of Health, NHLBI 54873 Bethesda, Maryland. Dr. Berul was supported by a grant from the National Institutes of Health K08-03607; Dr. Gauvreau is supported in part by the Kobren Fund.
- Received June 22, 2000.
- Revision received February 27, 2001.
- Accepted March 22, 2001.
- American College of Cardiology