title: PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression.
abstract: BACKGROUND
  Intergenic variations on chromosome 4q25, close to the PITX2 transcription factor gene, are associated with atrial fibrillation (AF). We therefore tested whether adult hearts express PITX2 and whether variation in expression affects cardiac function.
  
  
  RESULTS
  mRNA for PITX2 isoform c was expressed in left atria of human and mouse, with levels in right atrium and left and right ventricles being 100-fold lower. In mice heterozygous for Pitx2c (Pitx2c(+/-)), left atrial Pitx2c expression was 60% of wild-type and cardiac morphology and function were not altered, except for slightly elevated pulmonary flow velocity. Isolated Pitx2c(+/-) hearts were susceptible to AF during programmed stimulation. At short paced cycle lengths, atrial action potential durations were shorter in Pitx2c(+/-) than in wild-type. Perfusion with the β-receptor agonist orciprenaline abolished inducibility of AF and reduced the effect on action potential duration. Spontaneous heart rates, atrial conduction velocities, and activation patterns were not affected in Pitx2c(+/-) hearts, suggesting that action potential duration shortening caused wave length reduction and inducibility of AF. Expression array analyses comparing Pitx2c(+/-) with wild-type, for left atrial and right atrial tissue separately, identified genes related to calcium ion binding, gap and tight junctions, ion channels, and melanogenesis as being affected by the reduced expression of Pitx2c.
  
  
  CONCLUSIONS
  These findings demonstrate a physiological role for PITX2 in the adult heart and support the hypothesis that dysregulation of PITX2 expression can be responsible for susceptibility to AF.
authors.affiliation: Department of Cardiology and Angiology, University Hospital Muenster, Germany.
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kahr
authors.forename: Sven
authors.initials: S
authors.lastname: Kaese
authors.forename: Ilaria
authors.initials: I
authors.lastname: Piccini
authors.forename: Ismail
authors.initials: I
authors.lastname: Vokshi
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Scheld
authors.forename: Heinrich
authors.initials: H
authors.lastname: Rotering
authors.forename: Lisa
authors.initials: L
authors.lastname: Fortmueller
authors.forename: Sandra
authors.initials: S
authors.lastname: Laakmann
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Brown
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016275:Atrial Function; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000378:metabolism*; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D009921:Metaproterenol / Q000494:pharmacology; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000097577:Homeobox Protein PITX2
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018398:Homeodomain Proteins; D009921:Metaproterenol; D020033:Protein Isoforms; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2