Transgenic mice overexpressing Pitx2 in the atria develop tachycardia-bradycardia syndrome

Sinoatrial node (SAN) dysfunction often accompanies supraventricular tachyarrhythmias such as atrial fibrillation (AF), which is referred to as tachycardia-bradycardia syndrome (TBS). Although there have been many studies on electrical remodeling in TBS, the regulatory mechanisms that cause electrical remodeling in the SAN and atrial muscles by chronic bradycardia or tachycardia have not yet been fully investigated. Here we hypothesized that Pitx2c, a transcription factor that plays a central role in the late aspects of left-right asymmetric morphogenesis, regulates an interrelationship between the SAN and the atrial muscles and is involved in TBS-like pathology. To test this hypothesis, we generated transgenic mice overexpressing Pitx2c specifically in the atria (OE mice). Although Pitx2c is normally expressed only in left atria, the expression levels of Pitx2c protein in the right atria were significantly increased to similar levels of those in the left atria of non-transgenic control mice (WT). We found that the heart rate of OE mice was significantly variable although the average heart rate was similar between WT and OE mice. Electrophysiological examination showed that OE mice exhibited prolonged SAN recovery time and higher AF inducibility. In addition, recording of the atrial monophasic action potential duration using a Langendorff perfusion system demonstrated shorter action potential duration in OE atria. Histological analysis revealed that SAN-specific ion channel HCN4-positive cells were hardly detected in the SAN of OE mice, along with ectopic expression in the right atria. Furthermore, transcription factors associated with sinus node formation were down-regulated in the right atria of OE mice. Therefore, SAN dysfunction by Pitx2 dysregulation predisposed OE mice to a TBS-like phenotype. We conclude that Pitx2c is a key regulator that defines SAN function in the atria. ### Competing Interest Statement The authors have declared no competing interest. * LA : left atrium; RA : right atrium; LV : left ventricular; RV : right ventricular; BW : body weight HR : heart rate; FS : fraction shortening; PAT-PET : ratio of pulmonary acceleration time to pulmonary ejection time as an estimate of pulmonary hypertension maxHR/minHR/aveHR : maximum/minimum/average heart rate in 24 h. VHR : variability of heart rate PAC : premature atrial conduction, SP : sinus pause SNRT : sinus node recovery; CSNRT : rate-corrected sinus node recovery time BHR, bpm : basic heart rate in beats per minute