Altered biophysical properties of atrial sodium channels increase flecainide effectiveness

Johnson, D. M; O'Brien, S.; Holmes, A.; O'Shea, C.; Kabir, S. N; O'Reilly, M.; Avezzu, A.; Reyat, J.; Hall, A.; Apicella, C.; Ellinor, P.; Niederer, S.; Tucker, N.; Fabritz, L.; Kirchhof, P. and Pavlovic, D. (2022). Altered biophysical properties of atrial sodium channels increase flecainide effectiveness. Acta Physiologica, 236(S725)

DOI: https://doi.org/10.1111/apha.13877

Abstract

Introduction
Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. Sodium channel blockade is a common treatment for AF. A feared side effect of inhibitors of the cardiac voltage-gated sodium current (INa), such a flecainide, however, is ventricular arrhythmia. We investigated the biophysical reasons for the relative safety of sodium channel blockers.

Methods
Whole cell patch clamping was performed to measure INa and action potentials (APs). Optical mapping of the LA and LV was performed in the intact mouse heart using voltage dye Di-4- ANEPPS and analysed using ElectroMap (1). LA and LV INa data were used to model changes in AP morphology using a modified mathematical model of the ventricular cardiomyocyte (2). Expression of NaV1.5, NaVβ2 and NaVβ4 was measured by Western blotting and SCN5A, SCN4B and SCN2B by RNAseq analysis in matched mouse and non-failing human LA and LV.

Results
At physiological holding potentials (-75mV), LA peak INa current density was significantly reduced compared to LV. Western blotting data demonstrate that this is not due to reduced atrial NaV1.5/SCN5A expression in either mouse or human. AP recordings revealed LA cells exhibit reduced upstroke velocity (238.6±27.7vs304.2±27.9mV/ms, p=0.0018) compared to the LV (n=23-40/5 cells/mice). Modelling studies confirmed these findings. At all holding potentials, 1µM flecainide inhibited INa to a larger extent in the LA compared to LV cells (Figure 1). Furthermore, flecainide decreased AP upstroke velocity to a higher degree in LA (47.9±18.8%) when compared to LV cells (18.6±9.8%, p=0.04, n=4 mice). Optical mapping demonstrated reduced conduction velocity in the LA (24.4±2.7cm/s) compared to LV (36.1±6.2cm/s, p=0.03, n=5). Flecainide significantly decreased conduction velocity in the LA (-40.4±7.2%, p<0.05 vs time control), but not LV.

Conclusion
Significant differences exist in the biophysical properties of sodium channels in the LA and LV, and their response to flecainide. The reduced effectiveness of flecainide in the LV can explain the relative safety of sodium channel blocker therapy.