101 Differential effectors of the atrial resting membrane potential on the sodium channel blocking efficacy of propafenone and dronedarone

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Abstract

Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is prevalent in 3% of the population. AF is a major driver of stroke, heart failure, unplanned hospitalisations and death. Despite the increasing use of catheter ablation, many (10%–20%) patients with AF require rhythm control therapy using antiarrhythmic drugs. Antiarrhythmic drugs can be highly effective in some patients, but do not work in others. Therefore, there is an important clinical need to develop new drugs or new methods to enhance the effectiveness of current antiarrhythmic drugs used to treat AF. Following on from our recent discovery that PITX2 modulates the atrial resting membrane potential (RMP), we evaluated if the RMP affects the effectiveness of two major antiarrhythmic drugs used in AF, propafenone and dronedarone.

Methods

The inhibitory effect of propafenone (300 nM) and dronedarone (5 µM) on whole cell peak sodium currents was assessed at different holding potentials (VH) ranging from −100 to −70 mV, in HEK293 cells expressing the human Nav1.5 channel and its beta-1 accessory subunit and in murine left atrial cardiac myocytes.

Results

In HEK293 cells, peak sodium current inhibition by propafenone (300 nM) was enhanced at more positive VH (e.g. −100 mV: 34±2%, −80 mV: 50±3%, p<0.05, n=15). Dronedarone (5 µM) was also more effective at more positive RMPs (e.g. −100 mV: 20±3%, −80 mV: 57±4%, p<0.05, n=14). At these concentrations, drug sensitivity to VH was significantly greater for dronedarone than propafenone (propafenone: 0.9±0.1%block/mV, dronedarone 1.9±0.1%block/mV, p<0.05) (figure 1). A more positive VH also significantly delayed the sodium channel recovery times (P50 recovery, −100 mV: 20±2 ms, −70 mV: 70±4 ms, p<0.05, n=14) but this was not further altered by either of the antiarrhythmic agents. In murine left atrial cardiac myocytes, peak sodium current inhibition by propafenone and dronedarone was increased at more positive holding potentials. Again, drug sensitivity to VH was significantly greater for dronedarone than propafenone (propafenone: 1.0±0.08% block/mV, dronedarone 1.8±0.1% block/mV, p<0.05) (figure 2).

Conclusion

Propafenone and dronedarone inhibit sodium currents more effectively at a more positive VH. At the concentrations used, dronedarone is more sensitive to changes in VH than propafenone. These agents may provide more effective treatment in patients with a more positive atrial RMP caused by genetic predisposition (e.g. reduced PITX2) or different underlying disease mechanisms.

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