PITX2‐dependent gene regulation in atrial fibrillation and rhythm control

Abstract

Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF‐associated morbidity and mortality. There are several major mechanisms that cause AF in patients, including a genetic predisposition to develop AF. Genome‐wide association studies have identified genetic variants associated with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription factor PITX2. The effect of these common gene variants on cardiac PITX2 mRNA is currently under study. PITX2 protein regulates right–left differentiation of the embryonic heart, thorax and aorta. PITX2 is expressed in the adult left atrium, but much less so in other heart chambers. Pitx2 deficiency results in electrical and structural remodelling, and impaired repair of the heart in murine models, all of which may influence AF through divergent mechanisms. PITX2 levels and single nucleotide polymorphisms on chromosome 4q25 may also be a predictor of the effectiveness of anti‐arrhythmic drug therapy.

A cellular atlas of Pitx2-dependent cardiac development

“…Pitx2 encodes a paired related homeodomain transcription factor that is essential for both human and mouse development. Investigations aimed at dissecting the biological role of Pitx2 are important, especially given that Pitx2 has been implicated in several human diseases, including Rieger syndrome, ocular dysgenesis with glaucoma, acute appendicitis and atrial fibrillation (AF), the most common sustained human arrhythmia (Ellinor et al, 2010;Gudbjartsson et al, 2007;Lin et al, 1999;Lu et al, 1999;Semina et al, 1996;Syeda et al, 2017). In postnatal cardiomyocytes (CMs), Pitx2 regulates genes that are important for the cellular response to reactive oxygen species (ROS), and is itself a target of Nrf2 (also known as Nfe2l2), a master transcriptional regulator of the cellular antioxidant response (Tao et al, 2016).…”

Chromosome 4q25 variants and biomarkers of myocardial fibrosis in patients with atrial fibrillation

“…This locus is near the paired‐like homeodomain transcription factors ( PITX2 ) gene, which is critical for left‐right asymmetry of the pulmonary vein (PV) . Recent studies have shown that changes in PITX2c RNA levels can lead to a change in atrial membrane potential . Anatomically, the PV are an important source of triggers for the initiation of AF and a main target of catheter‐based treatment .…”

“…2 Recent studies have shown that changes in PITX2c RNA levels can lead to a change in atrial membrane potential. 3,4 Anatomically, the PV are an important source of triggers for the initiation of AF and a main target of catheter-based treatment. 5 However, there are no data regarding 4q25 variants and how they impact left atrial substrate.…”

Cardiac regulatory mechanisms: new concepts and challenges

“…Fabritz and coworkers tackle the controversies surrounding the PITX2 gene in atrial fibrillation (Syeda et al . ). Based on genome‐wide association studies, the PITX2 gene locus is near many single nucleotide polymorphisms linked to high atrial fibrillation risk, but its mechanistic role in atrial fibrillation remains enigmatic.…”