ArticleCardiovascular research2024
PITX2 deficiency leads to atrial mitochondrial dysfunction.
Article in Cardiovascular research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Biomarker-based prediction of sinus rhythm in atrial fibrillation patients: the EAST-AFNET 4 biomolecule study.European heart journal · 2024Trial
- PITX2C deficiency promotes arrhythmogenic remodelling via oxidative stress in atrial myocytes.Journal of molecular and cellular cardiology plus · 2026Article
- Review
- Divergent mitochondrial and fibrotic signatures in atrial fibrillation: insights from organoids and GEO data.Cardiovascular diabetology · 2026Article
- Mass spectrometric proteome profiling using a deep spectral library reveals homogenization of right and left atrial proteomes in persistent atrial fibrillation patients.Cardiovascular research · 2026Article
- An epigenomic investigation of atrial fibrillation in a matched left and right atrial human cohort.Clinical epigenetics · 2026Article
- Arrhythmia-induced cardiomyopathy: focus on atrial fibrillation.Nature reviews. Cardiology · 2026Review
- Targeting Nrf3-Pitx2-ROS axis represents a promising therapeutic strategy for myocardial infarction.MedScience · 2026Article
- PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias.Nature communications · 2025Article
- Transforming atrial fibrillation management by targeting comorbidities and reducing atrial fibrillation burden: the 10th AFNET/EHRA consensus conference.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Article
- Metabolic Remodeling and Mitochondrial Stress in Atrial Fibrillation: Mechanisms and Translational Targets.Reviews in cardiovascular medicine · 2025Review
- High Rate Triggers Increased Atrial Release of BMP10, A Biomarker for Atrial Fibrillation and Stroke, and BMP10 Affects Ventricular Cardiomyocytes.Circulation. Arrhythmia and electrophysiology · 2025Article
- Genetic and epigenetic architectures of stroke: Insights from GWAS to precision medicine.Neurochemistry international · 2025Review
- Arrhythmia-Induced Cardiomyopathy in Atrial Fibrillation: Pathogenesis, Diagnosis, and Treatment.Life (Basel, Switzerland) · 2025Review
- Single-Nucleotide Polymorphisms,International journal of molecular sciences · 2025Review
- Atrial Myopathy and Heart Failure: Immunomolecular Mechanisms and Clinical Implications.International journal of molecular sciences · 2025Review
- Early Atrial Remodeling Drives Arrhythmia in Fabry Disease.Circulation. Arrhythmia and electrophysiology · 2025Article
- Involvement of Oxidative Stress in Mitochondrial Abnormalities During the Development of Heart Disease.Biomedicines · 2025Review
- SNAP25-dependent membrane trafficking of the Kv1.5 channel regulates the onset of atrial fibrillation.Nature communications · 2025Article
- Injection of ROS-Responsive Hydrogel Loaded with IL-1β-targeted nanobody for ameliorating myocardial infarction.Bioactive materials · 2025Article
Corrections and comments
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Authors and funding
34 authors.
Funding
Abstract
aimsReduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation (AF). PITX2 is restricted to left atrial cardiomyocytes (aCMs) in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy, and AF are not fully understood. METHODS AND
resultsTo identify mechanisms linking PITX2 deficiency to AF, we generated and characterized PITX2-deficient human aCMs derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganized sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared with isogenic controls. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with AF compared with 43 patients with sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria.
conclusionPITX2 deficiency causes atrial mitochondrial dysfunction and a metabolic shift to glycolysis in human aCMs. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.
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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 Socratic graph.