Ventricular chamber-specific Pitx2 insufficiency leads to cardiac hypertrophy and arrhythmias

Abstract

Genome-wide association studies (GWAS) have identified genetic risk variant adjacent to the homeobox transcription factor PITX2 in atrial fibrillation (AF) patients. Experimental studies demonstrated that Pitx2 insufficiency leads to cellular and molecular substrates that increased atrial arrhythmias susceptibility. Pitx2 expression is present not only in the atrial but also in the ventricular myocytes. This study aims to investigate if insufficiency of Pitx2 in the developing and adult ventricular chambers increased susceptibility to ventricular arrhythmias. Conditional Pitx2 loss-offunction ventricular chamber-specific (Mlc2v-Cre) mouse mutants were generated using Cre/loxP technology. Pitx2 insufficiency in the ventricular myocardium leads interventricular septal thickening during cardiogenesis but else mice are viable until adulthood. Adult Mlc2vCre+Pitx2-/- hearts display hypertrophic and dilated ventricular chambers. ECG recordings demonstrated that Mlc2vCre+Pitx2-/- mice display increased QT and QRS intervals. Molecular analyses demonstrate that repolarization but not depolarization is severely impaired in these mutants. Microarrays analysis identified mRNAs and microRNAs altered in Pitx2 ventricular-specific mutants and provide evidences for miR-1 and miR-148 deregulation which in turn modulate Klf4 and distinct ion channel expression linked to cardiac hypertrophy and long QT-like defects. Our data demonstrate that Pitx2 insufficiency play leads to cellular and molecular ventricular remodeling which results in hypertrophic and dilated ventricular chambers and electrophysiological defects resembling long QT syndrome.