PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis

Ana Chinchilla, Houria Daimi, Estefanía Lozano-Velasco, Jorge N. Dominguez, Ricardo Caballero, Eván Delpo, Juan Tamargo, Juan Cinca, Leif Madsen Hove, Amelia E. Aranega, Diego Franco

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142 Citations (Scopus)

Abstract

Background-Pitx2 is a homeobox transcription factor that plays a pivotal role in early left/right determination during embryonic development. Pitx2 loss-of-function mouse mutants display early embryonic lethality with severe cardiac malformations, demonstrating the importance of Pitx2 during cardiogenesis. Recently, independent genome-wide association studies have provided new evidence for a putative role of PITX2 in the adult heart. These studies have independently reported several risk variants close to the PITX2 locus on chromosome 4q25 that are strongly associated with atrial fibrillation in humans. Methods and Results-We show for the first time that PITX2C expression is significantly decreased in human patients with sustained atrial fibrillation, thus providing a molecular link between PITX2 loss of function and atrial fibrillation. In addition, morphological, molecular, and electrophysiological characterization of chamber-specific Pitx2 conditional mouse mutants reveals that atrial but not ventricular chamber-specific deletion of Pitx2 results in differences in the action potential amplitude and resting membrane potential in the adult heart as well as ECG characteristics of atrioventricular block. Lack of Pitx2 in atrial myocardium impairs sodium channel and potassium channel expression, mediated in part by miRNA misexpression. Conclusions-This study thus identifies Pitx2 as an upstream transcriptional regulator of atrial electric function, the insufficiency of which results in cellular and molecular changes leading to atrial electric and structural remodeling linked to arrhythmogenesis. © 2011 American Heart Association, Inc.
Original languageEnglish
Pages (from-to)269-279
JournalCirculation: Cardiovascular Genetics
Volume4
DOIs
Publication statusPublished - 1 Jun 2011

Keywords

  • Arrhythmia
  • Atrial fibrillation
  • Gene regulation
  • Pitx2
  • Polymorphism
  • Transcription factors

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    Chinchilla, A., Daimi, H., Lozano-Velasco, E., Dominguez, J. N., Caballero, R., Delpo, E., Tamargo, J., Cinca, J., Hove, L. M., Aranega, A. E., & Franco, D. (2011). PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circulation: Cardiovascular Genetics, 4, 269-279. https://doi.org/10.1161/CIRCGENETICS.110.958116