PITX2Insufficiency Leads to Atrial Electrical and Structural Remodeling Linked to Arrhythmogenesis

Abstract

Background—Pitx2is a homeobox transcription factor that plays a pivotal role in early left/right determination during embryonic development.Pitx2loss-of-function mouse mutants display early embryonic lethality with severe cardiac malformations, demonstrating the importance ofPitx2during cardiogenesis. Recently, independent genome-wide association studies have provided new evidence for a putative role ofPITX2in the adult heart. These studies have independently reported several risk variants close to thePITX2locus on chromosome 4q25 that are strongly associated with atrial fibrillation in humans.Methods and Results—We show for the first time thatPITX2Cexpression is significantly decreased in human patients with sustained atrial fibrillation, thus providing a molecular link betweenPITX2loss of function and atrial fibrillation. In addition, morphological, molecular, and electrophysiological characterization of chamber-specificPitx2conditional mouse mutants reveals that atrial but not ventricular chamber-specific deletion ofPitx2results in differences in the action potential amplitude and resting membrane potential in the adult heart as well as ECG characteristics of atrioventricular block. Lack ofPitx2in atrial myocardium impairs sodium channel and potassium channel expression, mediated in part by miRNA misexpression.Conclusions—This study thus identifiesPitx2as 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.