Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Ca v 1.3 (Ca v 1.3 −/−), t-type ca v 3.1 (Ca v 3.1 −/−), or both (Ca v 1.3 −/− /ca v 3.1 −/−). We also studied mice haplo-insufficient for the na + channel na v 1.5 (Na v 1.5 +/) and mice in which the cAMP-dependent regulation of hyperpolarizationactivated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K + current (I KACh) by the peptide tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Ca v 1.3 −/− (19%), Ca v 1.3 −/− /ca v 3.1 −/− (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Na v 1.5 +/− mice by 24%. Our data suggest that the development of pharmacological I KACh inhibitors for the management of SND and conduction disease is a viable approach.

Na.LS Gap junction GW788388Cardiac fibroblasts Down-regulation of Connexin43 (Cx43) has often been associated with the development of cardiac fibrosis. We showed previously that ScnSa heterozygous knockout mice (ScnS a+ 1 -¡, which mimic familial progressive cardiac conduction defect, exhibit an age-dependent decrease of Cx43 expression and phosphorylation concomitantly with activation of TGF-¡3 pathway and fibrosis development in the myocardium between 45 and 60 weeks of age. The aim of this study was to investigate whether Gap-134 prevents Cx43 down-regulation with age and fibrosis development in ScnSa + t-mice.We observed in 60-week-old ScnSa+I-mouse heart a Cx43 expression and localization remodeling correlated with fibrosis. Chronic administration of a potent and selective gap junction modifier, , between 45 and 60 weeks, increased Cx43 expression and phosphorylation on serine 368 and prevented Cx43 delocalization. Furthermore, we found that Gap-134 prevented fibrosis despite the persistence of the conduction defects and the TGF-¡3 canonical pathway activation.ln conclusion, the present study demonstrates that the age-dependent decrease of Cx43 expression is involved in the ventricular fibrotic process occurring in ScnSa+I-mice. Finally, our study suggests that gap junction modifier, such as Gap-134, could be an effective anti-fibrotic agent in the context of age-dependent fibrosis in progressive cardiac conduction disease.

The Scn5a mouse model recapitulates the clinical phenotype of mutation carriers and provides new and unexpected insights into the pathological development of the disease in patients carrying the QKP1507-1509 deletion.