心拍薬のリスクをナトリウム濃度の関係で解明(Researchers identify why some heart rhythm drugs heighten risks when sodium levels drop)

2025-07-14 バージニア工科大学(Virginia Tech)

<関連情報>

• https://news.vt.edu/articles/2025/07/research-fralinbiomed-arrhythmia.html
• https://www.heartrhythmjournal.com/article/S1547-5271(25)02396-3/abstract

フレカイニドは低ナトリウム血症に対してエファプス機序を介して伝導を感作する Flecainide sensitizes conduction to hyponatremia through an ephaptic mechanism

William P. Adams, PhD ∙ Gregory S. Hoeker, PhD ∙ Steven Poelzing, PhD, FHRS
Heart Rhythm  Published:April 26, 2025
DOI:https://doi.org/10.1016/j.hrthm.2025.04.048

Graphical abstract

Abstract

Background

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.

Objective

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

Methods

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⁺.

Results

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.

Conclusion

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.