Abstract 18204: Activation of the Pro-Hypertrophic Calcineurin/Nfat-Pathway Mediates Atrio-Ventricular Conduction Disturbances in Cardiac Sodium Channelopathy
Introduction: SCN5A mutations have been associated with progressive atrio-ventricular conduction disturbances and development of cardiac structural abnormalities. In transgenic Scn5a-1798insD+/- mice, intracellular sodium and calcium concentrations are increased, setting the stage for potential activation of calcium-dependent signaling pathways. Here we investigated the impact of the pro-hypertrophic calcineurin/Nfat signaling pathway on atrio-ventricular (AV) conduction in Scn5a-1798insD+/- mice.
Methods and Results: Aged (12-18 months old) Scn5a-1798insD+/- (MUT) mice developed cardiac hypertrophy (increased heart weight and Anf mRNA levels) and progressive AV-conduction abnormalities on surface ECG. Isolated Langendorff-perfused aged MUT hearts showed profound AV-delay and AV-block at high right atrial stimulation frequencies (basic cycle length 90-120 ms). To study the contribution of the calcineurin/Nfat signaling pathway to the AV-conduction phenotype, adult (age 3-5 months) wild-type (WT) and MUT mice were subjected to 2 weeks of transverse aortic constriction (TAC). WT and MUT mice showed similar hypertrophic responses to TAC. However, MUT-TAC mice displayed increased PR-interval on surface ECG and a higher incidence of sudden death. Furthermore, isolated MUT-TAC hearts showed AV-block and significantly prolonged AV-delay as compared to WT-TAC or sham hearts. Atrial and His-ventricular conduction was unaffected in MUT-TAC hearts, indicating that conduction delay occurred within the AV-nodal region. Since Nfatc2 is a well-described downstream effector of the calcineurin pathway, adult MUT mice were crossed with mice lacking Nfatc2 (Nfatc2-KO). In MUT/Nfatc2-KO hearts, AV-delay after TAC was attenuated as compared to MUT-TAC, indicating rescue of the AV-conduction disturbances by Nfatc2 deficiency.
Conclusions: Scn5a-1798insD+/- mice develop profound atrio-ventricular conduction disturbances with increased age and after activation of the calcium-dependent pro-hypertrophic calcineurin/Nfat-pathway. These findings indicate that cardiac hypertrophy may modulate disease severity in cardiac sodium channelopathy.
- © 2013 by American Heart Association, Inc.