PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers

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• 作者：Fahima Syeda ; PhD^a ; Andrew P. Holmes ; PhD^a ; Ting Y. Yu ; PhD^a ; ^b ; Samantha Tull ; PhD^a ; Stefan Michael Kuhlmann ; BSc^a ; Davor Pavlovic ; DPhil^a ; Daniel Betney ; BMedSc ; MBBS^a ; Genna Riley ; DPhil^a ; Jan P. Kucera ; MD^c ; Florian Jousset ; PhD^c ; Joris R. de Groot ; MD^d ; Stephan Rohr ; MD^c ; Nigel A. Brown ; PhD^e ; Larissa Fabritz ; MD^a ; ^f ; ^g ; ^h ; Paulus Kirchhof ; MD^a ; ^f ; ^g ; ^h ; ⁱ ; ^{p.kirchhof@bham.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：antiarrhythmic drugs ; atrial fibrillation ; drug targets ; electrophysiology ; personalized medicine ; rhythm control
• 刊名：Journal of the American College of Cardiology
• 出版年：2016
• 出版时间：25 October 2016
• 年：2016
• 卷：68
• 期：17
• 页码：1881-1894
• 全文大小：1731 K

文摘

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 Na_v1.5 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.