Cardiac conduction is dependent on NaV1.5 function and intercalated disc adhesion, both of which have been shown to be affected by the β1-subunit of NaV1.5. Importantly, the effect of reducing β1 functional expression on cardiac conduction remains poorly understood. We hypothesize that reducing β1 will slow conduction and increase sensitivity to modulating intercalated disc adhesion. Mice haplo-insufficient for the β1 gene (Scn1b+/-) and age-matched, wild-type littermates were studied. mRNA and protein expression were quantified using qT-PCR and Western blot. Ventricular cardiomyocytes were whole-cell patch-clamped to record sodium current. Transmission electron microscopy was used to measure perinexal width within intercalated discs of left ventricular tissue. Hearts were optically mapped with baseline solution followed by either time control, intercalated disc expander mannitol (26.1g/L), or dehydrator dextran 2MDa (10g/L) to assess conduction. Scn1b mRNA was reduced by 50% in Scn1b+/- hearts, as expected. Neither of the canonical conduction proteins, NaV1.5 or Cx43, was reduced in Scn1b+/- hearts. Peak sodium current density was not changed in Scn1b+/- hearts. Interestingly, Scn1b+/- hearts had significantly wider perinexi at baseline. Mannitol caused perinexal widening in wild-type mice, and dextran caused perinexal narrowing in Scn1b+/- mice. There was no difference in baseline conduction between wild-type and Scn1b+/- mice. However, in Scn1b+/- mice, mannitol slowed conduction to a greater extent, and dextran increased conduction. Mice with sodium channel β1 loss of function do not demonstrate a cardiac conduction phenotype at baseline, but they are more sensitive to osmotic agents that affect intercalated disc adhesion. Taken together with previous studies evaluating both genetic and pharmacological sodium channel loss of function, cardiac edema may be a generalizable mechanism that unmasks conduction deficits, which may increase arrhythmogenicity.
Maisonneuve et al. (2026) studied this question.