Flecainide sensitizes conduction to hyponatremia through an ephaptic mechanism

Studies suggest that voltage-gated sodium channel (SC) loss-of-function (LoF), often through the use of SC blockers, such as tricyclic anti-depressants, some recreational drugs, and importantly, class 1c anti-arrhythmics, sensitizes cardiac conduction to hyponatremia. However, the mechanism driving conduction velocity (CV) sensitivity to sodium ion (Na⁺) concentration ([Na⁺]) is unknown. We recently demonstrated CV-[Na⁺] sensitivity in haploinsufficient Scn5a+/- mouse and reduced CV-[Na⁺] sensitivity when ephaptic coupling (extracellular conduction by electric fields) is also reduced.

We aimed to determine which mechanisms influence CV sensitivity to [Na⁺] during voltage-gated SC LoF induced by the class 1c anti-arrhythmic, flecainide.

CV was measured by optical mapping of Langendorff-perfused guinea pig hearts with either 145 or 120 mM [Na⁺] under control conditions, with flecainide alone, and the combination of flecainide with ephaptic coupling uncouplers mannitol or peptide sequence Leu-Gln-Leu-Glu-Glu-Asp, Na⁺-calcium ion exchanger inhibitor SEA0400, Na⁺-potassium ion (K⁺) adenosine triphosphatase inhibitor ouabain, I_Kr blocker E4031, or I_K1 inhibitor barium chloride. CV-[Na⁺] sensitivity was quantified as percent CV slowing in response to lowering Na⁺.

Reducing [Na⁺] under control conditions did not slow CV. Reducing [Na⁺] in the presence of flecainide significantly slowed conduction (ie, [Na⁺] sensitivity). Both ephaptic coupling uncouplers significantly attenuated CV-[Na⁺] sensitivity. Inhibiting the Na⁺-calcium ion exchanger did not significantly change CV-[Na⁺] sensitivity. However, inhibiting outward K⁺ currents attenuated CV-[Na⁺] sensitivity.

SC LoF sensitizes conduction to changes in Na⁺ through ephaptic coupling and outward K⁺ current-mediated mechanisms. This study has implications for the management of plasma Na⁺ levels in patients on SC-blocking drugs.