Abstract 12140: SCN1B Expression Modulates Sodium Influx in Cardiomyocytes and Diastolic Function in the Adult Heart

Abstract

Voltage-gated sodium channels (VGSCs) are macromolecular complexes composed of a number of proteins regulating channel biophysical properties. VGSCs generate Na + current (I Na ) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of I Na . Variants in the gene SCN1B , encoding the VGSC β1 and β1B subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of β1/β1B subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knock-out, cKO) were studied. Myocytes from cKO mice had decreased levels of Scn1b transcripts (-85%) and increased densities of fast- (+20%) and slow-inactivating (+140%) components of I Na , with respect to cells from corresponding control (Ctrl) animals. By echocardiography, left ventricular (LV) mass, chamber volume, and systolic function were preserved in both male and female cKO mice, with respect to sex- and age-matched Ctrl animals. However, by transmitral flow Doppler echocardiography, cKO mice presented reduced velocity of the passive filling wave (-~20%), attenuated ratio of the passive-to-active filling velocity waves (-~20%), and prolonged isovolumic relaxation time (+~16%). Moreover, by pressure-volume (PV) loop assessment, cKO mice had steeper slope of the LV end diastolic PV relation and prolonged LV relaxation tau, suggesting impairment of diastolic function. Importantly, inhibition of late I Na with GS967 (0.5 mg/kg body weight) normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice, but had no consequences in Ctrl animals. At the cellular level, cKO myocytes presented delayed kinetics of Ca 2+ transients decay and cell shortening with respect to Ctrl myocytes. These defects were partly corrected by inhibition of the late I Na . Collectively, these results document that VGSC β1/β1B subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na + influx in cardiomyocytes.