ArticleProceedings of the National Academy of Sciences of the United States of America2010
Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 179 papers, 4 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
179 citing papers in PubMed, 4 syntheses or guidelines pooled it, 329 citations in OpenAlex.
- Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.Nature genetics · 2025Pooled it
- Multi-ethnic genome-wide association study for atrial fibrillation.Nature genetics · 2018Pooled it
- Chromosome 4q25 Variants rs2200733, rs10033464, and rs1906591 Contribute to Ischemic Stroke Risk.Molecular neurobiology · 2016Pooled it
- Expert consensus document: Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment.Nature reviews. Cardiology · 2016Guideline
- Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation.JCI insight · 2020Trial
- Genetic Variants Associated With Nonpulmonary Vein Triggers of Atrial Fibrillation: A Genome-Wide Association Study.JACC. Advances · 2026Article
- The cardiac conduction system: development, function and therapeutic targets.Nature reviews. Cardiology · 2026Review
- Cardiac conduction system malformations in heterotaxy result from dysregulated Pitx2 expression.JCI insight · 2026Article
- Hedgehog and Bmp signaling pathways play opposing roles during establishment of the cardiac inflow tract in zebrafish.Development (Cambridge, England) · 2026Article
- PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias.Nature communications · 2025Article
- MERFISH+, a large-scale, multi-omics spatial technology resolves the molecular holograms of the 3D human developing heart.bioRxiv : the preprint server for biology · 2025Article
- Single-Nucleotide Polymorphisms,International journal of molecular sciences · 2025Review
- In Silico Characterization of Pathogenic Homeodomain Missense Mutations in the PITX2 Gene.Biochemical genetics · 2025Article
- Prevalence of Genetic Variants Associated with Atrial Fibrillation Risk in the Asymptomatic Young Adult Population.Medicina (Kaunas, Lithuania) · 2025Article
- The Neglected Internodal Tract-A Cardiac Conduction System Structure Homologous to the Development and Regulation of the Sinoatrial Node.Reviews in cardiovascular medicine · 2025Review
- Atrial Fibrillation Begets Atrial Fibrillation in Small Animals: Characterization of New Rat Model of Spontaneous Atrial Fibrillation.Biomedicines · 2025Article
- Review
- Oxidative Stress Causes Mitochondrial and Electrophysiologic Dysfunction to Promote Atrial Fibrillation inCirculation. Arrhythmia and electrophysiology · 2025Article
- Association between body size and atrial myopathy: Investigation using the prevalence of left atrial low-voltage areas.Heliyon · 2025Article
- Transgenic mice overexpressing Pitx2 in the atria develop tachycardia-bradycardia syndrome.PloS one · 2025Article
119 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, often coexists with the related arrhythmia atrial flutter (AFL). Limitations in effectiveness and safety of current therapies make an understanding of the molecular mechanism underlying AF more urgent. Genome-wide association studies implicated a region of human chromosome 4q25 in familial AF and AFL, approximately 150 kb distal to the Pitx2 homeobox gene, a developmental left-right asymmetry (LRA) gene. To investigate the significance of the 4q25 variants, we used mouse models to investigate Pitx2 in atrial arrhythmogenesis directly. When challenged by programmed stimulation, Pitx2(null+/-) adult mice had atrial arrhythmias, including AFL and atrial tachycardia, indicating that Pitx2 haploinsufficiency predisposes to atrial arrhythmias. Microarray and in situ studies indicated that Pitx2 suppresses sinoatrial node (SAN)-specific gene expression, including Shox2, in the left atrium of embryos and young adults. In vivo ChIP and transfection experiments indicated that Pitx2 directly bound Shox2 in vivo, supporting the notion that Pitx2 directly inhibits the SAN-specific genetic program in left atrium. Our findings implicate Pitx2 and Pitx2-mediated LRA-signaling pathways in prevention of atrial arrhythmias.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.