Syeda, F;
Holmes, AP;
Yu, TY;
Tull, S;
Kuhlmann, SM;
Pavlovic, D;
Betney, D;
Riley, G;
Kucera, JP;
Jousset, F;
et al.
Syeda, F; Holmes, AP; Yu, TY; Tull, S; Kuhlmann, SM; Pavlovic, D; Betney, D; Riley, G; Kucera, JP; Jousset, F; de Groot, JR; Rohr, S; Brown, NA; Fabritz, L; Kirchhof, P
(2016)
PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers.
J Am Coll Cardiol, 68 (17).
pp. 1881-1894.
ISSN 1558-3597
https://doi.org/10.1016/j.jacc.2016.07.766
SGUL Authors: Brown, Nigel Andrew
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Abstract
BACKGROUND: Antiarrhythmic 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). OBJECTIVES: After 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. METHODS: LA 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. RESULTS: Flecainide 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. CONCLUSIONS: PITX2 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.
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