title: PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Fahima
authors.initials: F
authors.lastname: Syeda
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Holmes
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; Physical Sciences of Imaging in the Biomedical Sciences, School of Chemistry, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ting Y
authors.initials: TY
authors.lastname: Yu
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Samantha
authors.initials: S
authors.lastname: Tull
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Stefan Michael
authors.initials: SM
authors.lastname: Kuhlmann
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Davor
authors.initials: D
authors.lastname: Pavlovic
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Betney
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Genna
authors.initials: G
authors.lastname: Riley
authors.affiliation: Department of Physiology, University of Bern, Bern, Switzerland.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kucera
authors.affiliation: Department of Physiology, University of Bern, Bern, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Jousset
authors.affiliation: Heart Center, Department of Cardiology, Academisch Medisch Centrum, Amsterdam, the Netherlands.
authors.forename: Joris R
authors.initials: JR
authors.lastname: de Groot
authors.affiliation: Department of Physiology, University of Bern, Bern, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Rohr
authors.affiliation: St. George's Hospital Medical School, University of London, London, United Kingdom.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Brown
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; Department of Cardiovascular Medicine, University Hospital Muenster, Muenster, Germany; Atrial Fibrillation NETwork, Muenster, Germany; University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; Department of Cardiovascular Medicine, University Hospital Muenster, Muenster, Germany; Atrial Fibrillation NETwork, Muenster, Germany; University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom. Electronic address: p.kirchhof@bham.ac.uk.
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology*; D055724:Electrophysiological Phenomena; D005260:Female; D005424:Flecainide / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D061567:Voltage-Gated Sodium Channel Blockers / Q000627:therapeutic use*; D000097577:Homeobox Protein PITX2
chemical_list: D000889:Anti-Arrhythmia Agents; D005424:Flecainide; D018398:Homeodomain Proteins; D014157:Transcription Factors; D061567:Voltage-Gated Sodium Channel Blockers; D000097577:Homeobox Protein PITX2
keywords: antiarrhythmic drugs; atrial fibrillation; drug targets; electrophysiology; personalized medicine; rhythm control