Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies "sick sinus" syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Cav1.3 Ca2+ channels (Cav1.3-/-) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K+ channel (IKACh) could rescue SSS and heart block in Cav1.3-/- mice. We found that genetic inactivation of IKACh abolished SSS symptoms in Cav1.3-/- mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of IKACh either in Cav1.3-/- mice or following selective inhibition of Cav1.3-mediated L-type Ca2+ (ICa,L) current in vivo. Ablation of IKACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from IKACh suppression achieved by gene therapy or selective pharmacological inhibition.
|Original language||English (US)|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Feb 16 2016|
Bibliographical noteFunding Information:
We thank former Prof. Denis Escande (Institut du Thorax) for input and support. We also thank Prof. Philippe Chevalier (Centre Hospitalier Universitaire) for critical reading of the manuscript. We are indebted to the staff of the RAM (R?seau des Animaleries de Montpellier) animal facility of the University of Montpellier for managing mouse lines. The project was supported Agence Nationale pour la Recherche (ANR) Grants ANR-06-PHISIO-004-01, ANR-09-GENO-034, and ANR-2010-BLAN-1128-01 (to M.E.M.); by the Fondation de France, Paris (Cardiovasc 2008002730 to J.N.); by the Austrian Science Fund (FWF F44020 to J.S.); and by NIH Grants R01 HL087120-A2 (to M.E.M.) and R01 HL105550 (to K.W.). P.M. and A.G.T. were supported by the CavNet, a Research Training Network funded through the European Union Research Programme (6FP) MRTN-CT-2006-035367. L.M. received a postdoctoral fellowship from the Fondation Lefoulon-Delalande (Paris). The Institut de Genomique Fonctionnelle group is a member of the Laboratory of Excellence "Ion Channel Science and Therapeutics" supported by a grant from the ANR (ANR-11-LABX-0015).
- Heart block
- Heart rate regulation
- Sick sinus syndrome