PITX2c Is Expressed in the Adult Left Atrium, and Reducing Pitx2c Expression Promotes Atrial Fibrillation Inducibility and Complex Changes in Gene Expression

Paulus Kirchhof, Peter C. Kahr, Sven Kaese, Ilaria Piccini, Ismail Vokshi, Hans-Heinrich Scheld, Heinrich Rotering, Lisa Fortmueller, Sandra Laakmann, Sander Verheule, Ulrich Schotten, Larissa Fabritz, Nigel A. Brown*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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. Methods and 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 beta-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. (Circ Cardiovasc Genet. 2011;4:123-133.)
Original languageEnglish
Pages (from-to)123-U84
JournalCirculation : Cardiovascular Genetics
Issue number2
Publication statusPublished - Apr 2011


  • action potentials
  • atrium
  • fibrillation
  • genes
  • transgenic mice
  • genetic predisposition

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