bioRxiv [Preprint]. 2025 Dec 9:2025.12.04.692461. doi: 10.64898/2025.12.04.692461.
ABSTRACT
Cardiac voltage-gated sodium channel gain-of-function (NavGOF) is characterized by action potential duration (APD) prolongation. Hypernatremia and perinexal widening synergistically prolong cardiac APD in guinea pig. However, guinea pig lack the transient outward potassium current (Ito), which could be increased by hypernatremia and thereby shorten APD.
OBJECTIVE: Determine whether hypernatremia and perinexal expansion synergistically prolong APD in an animal model functionally expressing Ito.
METHODS: Whole-cell Ito was measured in isolated genetically-modified NavGOF (ΔKPQ) mouse ventricular myocytes. Ventricular APD at 30 (APD30) and 90 (APD90) percent repolarization were measured from optically mapped, Langendorff-perfused wild-type (WT) and ΔKPQ mouse hearts at different perfusate sodium concentrations (145 or 160mM), without and with the perinexal adhesion antagonist βadp1.
RESULTS: In isolated myocytes, hypernatremia (160mM sodium) increased Ito. In whole-heart, hypernatremia significantly decreased both APD30 and APD90 in WT but only APD30 in ΔKPQ preparations. Perinexal disruption with βadp1 did not change APD30 or APD90 in WT hearts, however it decreased APD30 and increased APD90 in ΔKPQ hearts. Combination of hypernatremia and βadp1 did not synergistically change APD in ΔKPQ hearts. Computational models predict that Ito activation can prevent synergistic APD prolongation in mouse during hypernatremia and perinexal expansion that was observed previously in a guinea pig NavGOF model lacking Ito.
CONCLUSIONS: Hypernatremia during NavGOF prevents early ventricular repolarization due to Ito activation (mouse) and prolongs repolarization in the absence of Ito (guinea pig). Future studies in animal models electrophysiologically similar to humans are needed to determine if hypernatremia and perinexal expansion are proarrhythmic during NavGOF.
PMID:41427381 | PMC:PMC12713656 | DOI:10.64898/2025.12.04.692461