Scn3b knockout mice exhibit abnormal ventricular electrophysiological properties

Abstract

We report for the first time abnormalities in cardiac ventricular electrophysiology in a genetically modified murine model lacking the Scn3b gene (Scn3b−/−). Scn3b−/− mice were created by homologous recombination in embryonic stem (ES) cells. RT-PCR analysis confirmed that Scn3b mRNA was expressed in the ventricles of wild-type (WT) hearts but was absent in the Scn3b−/− hearts. These hearts also showed increased expression levels of Scn1b mRNA in both ventricles and Scn5a mRNA in the right ventricles compared to findings in WT hearts. Scn1b and Scn5a mRNA was expressed at higher levels in the left than in the right ventricles of both Scn3b−/− and WT hearts. Bipolar electrogram and monophasic action potential recordings from the ventricles of Langendorff-perfused Scn3b−/− hearts demonstrated significantly shorter ventricular effective refractory periods (VERPs), larger ratios of electrogram duration obtained at the shortest and longest S1–S2 intervals, and ventricular tachycardias (VTs) induced by programmed electrical stimulation. Such arrhythmogenesis took the form of either monomorphic or polymorphic VT. Despite shorter action potential durations (APDs) in both the endocardium and epicardium, Scn3b−/− hearts showed ΔAPD90 values that remained similar to those shown in WT hearts. The whole-cell patch-clamp technique applied to ventricular myocytes isolated from Scn3b−/− hearts demonstrated reduced peak Na+ current densities and inactivation curves that were shifted in the negative direction, relative to those shown in WT myocytes. Together, these findings associate the lack of the Scn3b gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a+/− hearts.

Mouse models of SCN5A-related cardiac arrhythmias

“…They showed that the lack of Na V β3 induced a ≈30% decrease in cardiac Na + peak current amplitude associated with a shift of the steadystate inactivation curve toward negative potentials while other I Na biophysical parameters were not altered, thus confirming previous studies in mammalian heterologous expression system (Ko et al, 2005). As a consequence, Scn3b ] mice exhibited decreased ventricular conduction, shortened ventricular action potential duration, and refractory period and increased incidence of arrhythmias under programmed electrical stimulation in ex vivo Langendorffperfused hearts (Hakim et al, 2008). Arrhythmogenic incidence was reduced by flecainide and quinidine (Hakim et al, 2010b), in contrast to what had been observed previously for flecainide in Scn5a ± mice (Martin et al, 2011c,d).…”

“…In order to understand better the role of Na V β3 subunit on Na V 1.5 function, Hakim and co-workers generated a mouse model lacking the Scn3b gene (Scn3b −/− mouse; Hakim et al, 2008). They showed that the lack of Na V β3 induced a ≈30% decrease in cardiac Na + peak current amplitude associated with a shift of the steadystate inactivation curve toward negative potentials while other I Na biophysical parameters were not altered, thus confirming previous studies in mammalian heterologous expression system (Ko et al, 2005).…”

The Role of Non-pore-Forming β Subunits in Physiology and Pathophysiology of Voltage-Gated Sodium Channels

“…Acutely dissociated ventricular cardiomyocytes from Scn1b null mice have increased peak and persistent sodium current relative to wild-type cells. Ventricular tachycardia is observed following programmed electrical stimulation in Scn3b null, but not wild-type, Langendorff-perfused hearts (Hakim et al 2008). In hearts paced using atrial burst pacing, Scn3b null hearts were susceptible to atrial tachycardia (Hakim et al 2010).…”

“…Mutations in SCN2B have been linked to atrial fibrillation (AF) and Brugada syndrome, suggesting a role for β2 in cardiac excitability (Watanabe et al 2009;Riuro et al 2013). Cardiac excitability is also abnormal in Scn3b null mice, suggesting a role for β3 in the heart (Hakim et al 2008(Hakim et al , 2010. Upon programmed electrical stimulation, ventricular tachycardia occurs in Scn3b null, but not wild-type, Langendorff-perfused hearts (Hakim et al 2008).…”

“…Cardiac excitability is also abnormal in Scn3b null mice, suggesting a role for β3 in the heart (Hakim et al 2008(Hakim et al , 2010. Upon programmed electrical stimulation, ventricular tachycardia occurs in Scn3b null, but not wild-type, Langendorff-perfused hearts (Hakim et al 2008). Scn3b null hearts display atrial tachycardia during atrial burst pacing (Hakim et al 2010).…”