Aim
The voltage-gated sodium channel NaV 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 (INa ) becomes functionally relevant in the murine embryonic heart and how Scn5a/NaV 1.5 dysfunction impacts on cardiac development.
Conclusion
We here demonstrate that NaV 1.5 is involved in cardiac electrical function from E10.5 onwards. Scn5a-1798insD-/- embryos displayed cardiac structural abnormalities at E9.5, indicating that NaV 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 NaV 1.5 dysfunction.
Methods
Involvement of NaV 1.5-generated INa 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). INa 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 INa 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 INa , in addition to reduced cardiac tissue volume compared to WT littermates.