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

J Am Coll Cardiol. 2016 Oct 25;68(17):1881-1894. doi: 10.1016/j.jacc.2016.07.766.

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.

Keywords: antiarrhythmic drugs; atrial fibrillation; drug targets; electrophysiology; personalized medicine; rhythm control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / physiopathology*
  • Electrophysiological Phenomena
  • Female
  • Flecainide / therapeutic use*
  • Gene Expression Regulation
  • Heart Atria / physiopathology
  • Homeobox Protein PITX2
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology*
  • Humans
  • Male
  • Membrane Potentials / physiology*
  • Mice
  • Middle Aged
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Voltage-Gated Sodium Channel Blockers / therapeutic use*

Substances

  • Anti-Arrhythmia Agents
  • Homeodomain Proteins
  • Transcription Factors
  • Voltage-Gated Sodium Channel Blockers
  • Flecainide