Atrial Pitx2c Overexpression Increased Atrial Arrhythmias with Altered Calcium Handling

Introduction: We have previously reported that the atrial cardiomyocyte-specific Pitx2c overexpression impaired sinus node function. It is well known that sinus node dysfunction is associated with atrial fibrillation (AF) and PITX2C increases in patients with chronic AF. Although Pitx2c overexpression in the atrium may be susceptible to atrial arrhythmias, the mechanism is not well understood. Hypothesis:Pitx2c overexpression in the atrium induces atrial arrhythmias with altered calcium handling. Methods: We generated the atrial cardiomyocyte-specific Pitx2c overexpression mice by crossing two types of mice. Then, we examined AF inducibilities, the expressions of genes related to left-right axis determination and AF, and monophasic action potential durations of B6-Tg (CAG-LSL-Pitx2c); SLNCre/+ (overexpression: OE) and B6 (wild type: WT) mice. Results, Conclusions:Pitx2c was up-regulated in the right atrium (RA) of OE than WT mice. AF increased significantly following burst pacing in OE (52%, n=6) than WT (7%, n=9) mice. Furthermore, episodes of atrial arrhythmias such as premature atrial conduction and AF were increased in OE mice. TBX3, Shox2 and Scn5a were down-regulated, and Kcne1 was up-regulated significantly in the atrium of OE than WT mice (n=8, each group). Especially in the RA of OE mice, Cacna1c and Serca2, which were calcium regulatory genes, were significantly down-regulated. In addition, we found that monophasic action potential duration was shorter in RA of the OE mice than WT mice. In conclusion, cardiomyocyte-specific Pitx2c overexpression in RA induces atrial arrhythmias with altered calcium handling. The transcription factor Pitx2c promotes electrical remodeling similar to clinical data.