Abstract
BackgroundAntiarrhythmic drugs are widely used to treat patients with atrial fibrillation (AF), but the mechanisms conveying their variable effectiveness are not known. Recent data suggested that paired like homeodomain-2 transcription factor (PITX2) might play an important role in regulating gene expression and electrical function of the adult left atrium (LA). ObjectivesAfter determining LA PITX2 expression in AF patients requiring rhythm control therapy, the authors assessed the effects of Pitx2c on LA electrophysiology and the effect of antiarrhythmic drugs. MethodsLA PITX2 messenger ribonucleic acid (mRNA) levels were measured in 95 patients undergoing thoracoscopic AF ablation. The effects of flecainide, a sodium (Na+)-channel blocker, and d,l-sotalol, a potassium channel blocker, were studied in littermate mice with normal and reduced Pitx2c mRNA by electrophysiological study, optical mapping, and patch clamp studies. PITX2-dependent mechanisms of antiarrhythmic drug action were studied in human embryonic kidney (HEK) cells expressing human Na channels and by modeling human action potentials. ResultsFlecainide 1 μmol/l was more effective in suppressing atrial arrhythmias in atria with reduced Pitx2c mRNA levels (Pitx2c+/–). Resting membrane potential was more depolarized in Pitx2c+/– atria, and TWIK-related acid-sensitive K+ channel 2 (TASK-2) gene and protein expression were decreased. This resulted in enhanced post-repolarization refractoriness and more effective Na-channel inhibition. Defined holding potentials eliminated differences in flecainide’s effects between wild-type and Pitx2c+/– atrial cardiomyocytes. More positive holding potentials replicated the increased effectiveness of flecainide in blocking human Nav1.5 channels in HEK293 cells. Computer modeling reproduced an enhanced effectiveness of Na-channel block when resting membrane potential was slightly depolarized. ConclusionsPITX2 mRNA modulates atrial resting membrane potential and thereby alters the effectiveness of Na-channel blockers. PITX2 and ion channels regulating the resting membrane potential may provide novel targets for antiarrhythmic drug development and companion therapeutics in AF.
Highlights
Antiarrhythmic drugs are widely used to treat patients with atrial fibrillation (AF), but the mechanisms conveying their variable effectiveness are not known
Resting membrane potential was more depolarized in Pitx2cþ/– atria, and TWIK-related acid-sensitive Kþ channel 2 (TASK-2) gene and protein expression were decreased
After finding that low Pitx2c enhanced the effect of flecainide, mediated by a more positive resting membrane potential (RMP), we identified reduced TWIK-related acid-sensitive Kþ channel 2 (TASK-2) expression as a possible driver of this effect and replicated these effects in cells expressing human sodium (Na) channels and in a human atrial action potential model
Summary
Antiarrhythmic drugs are widely used to treat patients with atrial fibrillation (AF), but the mechanisms conveying their variable effectiveness are not known. Reduced Pitx2c expression did not alter atrial conduction velocities or activation patterns (Online Figures 1A to 1C, Table 6), consistent with published data (8). We found that 1 mmol/l flecainide decreased atrial conduction velocities without differences between wild-type and Pitx2cþ/– mice (Online Figures 1B and 1C). Flecainide 1 mmol/l shortened 50% Ca2þ relaxation times by approximately 10% and decreased Ca2þ transient amplitude by approximately 50% in murine atria with normal and reduced Pitx2c expression (Online Figures 1E and 1F).
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