Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels. (May 2022)

• Record Type: Journal Article
• Authors: 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; Pavlovic, Davor
• Is Part Of: Journal of molecular and cellular cardiology. Volume 166(2022)
• Page Start: 23
• Page End: 35
• Publication Date: 2022-05
• Subjects: Atria -- Ventricles -- Sodium channels -- Flecainide -- Conduction; RMP resting membrane potential -- AF Atrial Fibrillation -- LA Left atrium -- LV Left ventricle -- CV Conduction velocity; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2022.01.009
• Languages: English
• ISSNs: 0022-2828

Abstract

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 (INa ), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial INa is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by NaV 1.5 protein expression. Flecainide displayed greater inhibition of atrial INa, 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. Graphical abstract: Unlabelled Image Highlights: Different sodium channel biophysical properties in atria and ventricles. Left atrial tissue has slower conduction then left ventricle. Flecainide is more effective at inhibiting atrial sodium channels. Flecainide displays greater inhibition of atrial conduction compared to ventricles.