Inhibition of IKACh current rescues bradycardia and atrioventricular block in models of congenital sino-atrial dysfunction ; Normalisation de la fréquence cardiaque et de la conduction auriculo-ventriculaire dans des modèles de bradycardie congénitale par l'inhibition pharmacologique du courant IkACh

Inhibition of KACh channels by the bee venom peptide tertiapin-Q rescues inherited cardiac conduction defects, sino-atrial bradycardia, and atrioventricular block in models of congenital dysfunctionSinus node dysfunction (SND) is a widespread disease of heart automaticity. SND refers to a multitude of sinus node (SAN) disorders characterized by failure to generate or conduct the cardiac impulse. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Epidemiological studies forecast an increasing need for pacemaker implantation during the next 50 years, with the ageing of the population. It is thus an important medical and societal issue, to develop innovative therapies for SND. Pharmacologic inhibition of the G-protein activated K+ current (IKACh) could be a new therapeutic option to treat bradycardia and SND associated with other cardiac pathologies.We tested whether inhibition of IKAch by the peptide Tertiapin-Q could rescue SND and conduction dysfunction in Cav1.3-/- mice carrying concurrent ablation of L-type Cav1.3 and T-type Cav3.1 channels (Cav1.3-/-/Cav3.1-/-), mice carrying loss-of-function of f-channels (HCN4-CNBD) and Nav1.5 haploinsufficient (Scn5a+/-) mice.We employed telemetric ECG recordings of heart rate (HR), SAN pacemaking and AV dysfunction in mice before and after administration of different doses of Tertiapin-Q.Tertiapin-Q significantly improves the HR of Cav1.3-/-, Cav1.3-/-/Cav3.1-/-, and HCN4-CNBD from doses of 0.1 to 5 mg/kg. HRs of Tertiapin-Q-treated mice were similar to those recorded in untreated wild-type mice. Tertiapin-Q also improved cardiac conduction of Scn5a+/- mice by 24%.Pharmacological inhibition of IKAch by Tertiapin-Q prevents SAN dysfunction and improves conduction in three models of congenital bradycardia suggesting the possibility of pharmacologic development of IKACh targeting to manage SND and conduction disease, to delay or replace the implantation of an electronic pacemaker. ; Correction de la bradycardie et des ...