Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels

O' Brien, Sian; Holmes, Andrew P.; Johnson, Daniel M.; Kabir, S. Nashitha; O' Shea, Christopher; O' Reilly, Molly; Avezzu, Adelisa; Reyat, Jasmeet S.; Hall, Amelia W.; Apicella, Clara; Ellinor, Patrick T.; Niederer, Steven; Tucker, Nathan R.; Fabritz, Larissa; Kirchhof, Paulus and Pavlovic, Davor (2022). Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels. Journal of Molecular and Cellular Cardiology(166) pp. 23–35.

DOI: https://doi.org/10.1016/j.yjmcc.2022.01.009

Abstract

Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known. Our data demonstrates intrinsic differences between atrial and ventricular cardiac voltage-gated sodium currents (I_Na), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial I_Na is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by Na_V1.5 protein expression. Flecainide displayed greater inhibition of atrial I_Na, greater reduction of maximum upstroke velocity of action potential, and slowed conduction in atrial cells and tissue. Our work highlights differences in biophysical properties of sodium channels in left atria and ventricles and their response to flecainide. These differences can explain the relative safety of sodium channel blocker therapy in patients with atrial fibrillation.

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