Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a^1798insD/+ mice

SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms.

We assessed electrophysiological and molecular alterations underlying AV-conduction abnormalities in mice carrying the Scn5a^1798insD/+ mutation. Langendorff-perfused Scn5a^1798insD/+ hearts showed prolonged AV-conduction compared to wild type (WT) without changes in atrial and His-ventricular (HV) conduction. The late sodium current (I_Na,L) inhibitor ranolazine (RAN) normalized AV-conduction in Scn5a^1798insD/+ mice, likely by preventing the mutation-induced increase in intracellular sodium ([Na⁺]_i) and calcium ([Ca²⁺]_i) concentrations. Indeed, further enhancement of [Na⁺]_i and [Ca²⁺]_i by the Na⁺/K⁺-ATPase inhibitor ouabain caused excessive increase in AV-conduction time in Scn5a^1798insD/+ hearts. Scn5a^1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a^1798insD/+ mice, in line with their larger mutation-induced I_Na,L. Transverse aortic constriction (TAC) caused excessive prolongation of AV-conduction in FVB/N-Scn5a^1798insD/+ mice (while HV-intervals remained unchanged), which was prevented by chronic RAN treatment. Scn5a^1798insD/+-TAC hearts showed decreased mRNA levels of conduction genes in the AV-nodal region, but no structural changes in the AV-node or His bundle. In Scn5a^1798insD/+-TAC mice deficient for the transcription factor Nfatc2 (effector of the calcium-calcineurin pathway), AV-conduction and conduction gene expression were restored to WT levels.

Our findings indicate a detrimental role for enhanced I_Na,L and consequent calcium dysregulation on AV-conduction in Scn5a^1798insD/+ mice, providing evidence for a functional mechanism underlying AV-conduction disturbances secondary to gain-of-function SCN5A mutations.