Résumé
We aimed to test if genetic inactivation of the cardiac IKACh current could improve the phenotype of mice lacking L-type Cav1.3 Ca2+ channels (Cav1.3-/-), a mouse model recapitulating the sino-atrial node dysfunction and supraventricular arrhythmias typical of the “sick sinus” syndrome (SSS) in humans.
SSS is an invalidating disease. The only currently available therapy consists in the implantation of an electronic pacemaker. Cav1.3-/- mice present several characteristics of the SSS, including bradycardia associated with atrial fibrillation or flutter, as well as type I and II atrioventricular conduction blocks. IKACh is involved in autonomic regulation of heart rate and in the triggering of atrial fibrillation by the parasympathetic nervous system, but its role in establishing the symptoms of SSS is unknown.
We crossed IKACh-deficient mice (Kir3.4-/-), with Cav1.3-/- mice to obtain double knockout (Cav1.3-/-/Kir3.4-/-) animals. Telemetric recordings of heart rate and ECG waveforms of wild-type, Cav1.3-/-, Kir3.4-/- and Cav1.3-/-/ Kir3.4-/- mice were performed. The frequency of occurrence of episodes of atrial arrhythmias was evaluated by intracardiac recordings.
Genetic inactivation of IKACh in Cav1.3-/-/Kir3.4-/- mice significantly improved the mean heart rate of Cav1.3-/- mice and completely abolished atrioventricular conduction blocks. Atrial fibrillation and flutter that were typical of Cav1.3-/- mice could not be observed or triggered in Cav1.3-/-/Kir3.4-/- mice.
Inactivation of IKACh effectively improved SSS in Cav1.3-/- mice. Our study indicates that SSS patients can benefit of IKACh suppression by gene therapy or selective pharmacologic inhibitors.