PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers

Abstract

BackgroundAntiarrhythmic drugs are widely used to treat patients with atrial fibrillation (AF), but the mechanisms conveying their variable effectiveness are not known. Recent data suggested that paired like homeodomain-2 transcription factor (PITX2) might play an important role in regulating gene expression and electrical function of the adult left atrium (LA).ObjectivesAfter determining LA PITX2 expression in AF patients requiring rhythm control therapy, the authors assessed the effects of Pitx2c on LA electrophysiology and the effect of antiarrhythmic drugs.MethodsLA PITX2 messenger ribonucleic acid (mRNA) levels were measured in 95 patients undergoing thoracoscopic AF ablation. The effects of flecainide, a sodium (Na+)-channel blocker, and d,l-sotalol, a potassium channel blocker, were studied in littermate mice with normal and reduced Pitx2c mRNA by electrophysiological study, optical mapping, and patch clamp studies. PITX2-dependent mechanisms of antiarrhythmic drug action were studied in human embryonic kidney (HEK) cells expressing human Na channels and by modeling human action potentials.ResultsFlecainide 1 μmol/l was more effective in suppressing atrial arrhythmias in atria with reduced Pitx2c mRNA levels (Pitx2c+/–). Resting membrane potential was more depolarized in Pitx2c+/– atria, and TWIK-related acid-sensitive K+ channel 2 (TASK-2) gene and protein expression were decreased. This resulted in enhanced post-repolarization refractoriness and more effective Na-channel inhibition. Defined holding potentials eliminated differences in flecainide’s effects between wild-type and Pitx2c+/– atrial cardiomyocytes. More positive holding potentials replicated the increased effectiveness of flecainide in blocking human Nav1.5 channels in HEK293 cells. Computer modeling reproduced an enhanced effectiveness of Na-channel block when resting membrane potential was slightly depolarized.ConclusionsPITX2 mRNA modulates atrial resting membrane potential and thereby alters the effectiveness of Na-channel blockers. PITX2 and ion channels regulating the resting membrane potential may provide novel targets for antiarrhythmic drug development and companion therapeutics in AF.

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.…”

Multi-ethnic genome-wide association study for atrial fibrillation

“…Further, reduced function of the transcription factor encoded by PITX2 has been associated with AF, shortening of the left atrial action potential, and with modulation of sodium channel blocker therapy in the adult left atrium. 22–24 A transcriptional co-regulatory network governed by transcription factors encoded by TBX5 and PITX2 has been shown to be critical for atrial development. 25 …”

Variant rs2200733 and rs10033464 on chromosome 4q25 are associated with increased risk of atrial fibrillation after catheter ablation: Evidence from a meta-analysis

“…These noncoding Jiake He et al, Variants on chromosome 4q25 are associated with increased risk of AF after catheter ablation variants existed in close proximity (~150 kb) to the cis-regulatory region of paired-like homeodomain transcription factor 2 (PITX2), and modulated PITX2 activity through transcription level as postulated [25,26]. PITX2 efficiently regulated atrial resting membrane potential and involved in the formation, differentiation and proliferation of pulmonary myocardium [27,28]. Three isoforms of PITX2 (PITX2a, PITX2b, and PITX2c) have been identified, among which PITX2c was the only isoform expressed in the left atrium [29].…”