The sodium channel Na 1.5 impacts on early murine embryonic cardiac development, structure and function in a non-electrogenic manner.

Aim: The voltage-gated sodium channel Na 1.5, encoded by SCN5A, is essential for cardiac excitability and ensures proper electrical conduction. Early embryonic death has been observed in several murine models carrying homozygous Scn5amutations. We investigated when sodium current (I ) becomes functionally relevant in the murine embryonic heart and how Scn5a/Na 1.5 dysfunction impacts on cardiac development.

Methods: Involvement of Na 1.5-generated I in murine cardiac electrical function was assessed by optical mapping in wild type (WT) embryos (embryonic day (E)9.5 and E10.5) in the absence and presence of the sodium channel blocker tetrodotoxin (30 µmol/L). I was assessed by patch-clamp analysis in cardiomyocytes isolated from WT embryos (E9.5-17.5). In addition, cardiac morphology and electrical function was assessed in Scn5a-1798insD embryos (E9.5-10.5) and their WT littermates.

Results: In WT embryos, tetrodotoxin did not affect cardiac activation at E9.5, but slowed activation at E10.5. Accordingly, patch-clamp measurements revealed that I was virtually absent at E9.5 but robustly present at E10.5. Scn5a-1798insD embryos died in utero around E10.5, displaying severely affected cardiac activation and morphology. Strikingly, altered ventricular activation was observed in Scn5a-1798insD E9.5 embryos before the onset of I , in addition to reduced cardiac tissue volume compared to WT littermates.

Conclusion: We here demonstrate that Na 1.5 is involved in cardiac electrical function from E10.5 onwards. Scn5a-1798insD embryos displayed cardiac structural abnormalities at E9.5, indicating that Na 1.5 dysfunction impacts on embryonic cardiac development in a non-electrogenic manner. These findings are potentially relevant for understanding structural defects observed in relation to Na 1.5 dysfunction.