ArticlePLoS computational biology2020
In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2.
Article in PLoS computational biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 2 of them syntheses that pooled it.
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Who cites it
21 citing papers in PubMed, 2 syntheses or guidelines pooled it, 33 citations in OpenAlex.
- Cross-population GWAS and proteomics improve risk prediction and reveal mechanisms in atrial fibrillation.Nature communications · 2025Pooled it
- Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis.Frontiers in cardiovascular medicine · 2021Pooled it
- Single-Nucleotide Polymorphisms,International journal of molecular sciences · 2025Review
- Digital twin for sex-specific identification of class III antiarrhythmic drugs based on in vitro measurements, computer models, and machine learning tools.PLoS computational biology · 2025Article
- The Association Between the rs2200733 SNP and Atrial Fibrillation Among Arabs: A Study from Jordan.Biologics : targets & therapy · 2024Article
- Mechanisms of pulmonary arterial hypertension-induced atrial fibrillation: insights from multi-scale models of the human atria.Interface focus · 2023Article
- Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2Herz · 2023Article
- What determines the optimal pharmacological treatment of atrial fibrillation? Insights from in silico trials in 800 virtual atria.The Journal of physiology · 2023Article
- Bone Morphogenetic Protein 10-A Novel Biomarker to Predict Adverse Outcomes in Patients With Atrial Fibrillation.Journal of the American Heart Association · 2023Article
- Editorial: Diagnosis, monitoring, and treatment of heart rhythm: new insights and novel computational methods.Frontiers in physiology · 2023Article
- Identification of atrial-enriched lncRNA Walras linked to cardiomyocyte cytoarchitecture and atrial fibrillation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Mechanisms of flecainide induced negative inotropy: An in silico study.Journal of molecular and cellular cardiology · 2021Article
- Transcriptional factors in calcium mishandling and atrial fibrillation development.Pflugers Archiv : European journal of physiology · 2021Review
- Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models.International journal of molecular sciences · 2021Review
- Characterizing the arrhythmogenic substrate in personalized models of atrial fibrillation: sensitivity to mesh resolution and pacing protocol in AF models.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 · 2021Article
- Comprehensive evaluation of electrophysiological and 3D structural features of human atrial myocardium with insights on atrial fibrillation maintenance mechanisms.Journal of molecular and cellular cardiology · 2021Review
- In Silico Assessment of Class I Antiarrhythmic Drug Effects onInternational journal of molecular sciences · 2021Article
- Mechanisms underlying pro-arrhythmic abnormalities arising from Pitx2-induced electrical remodelling: an in silico intersubject variability study.Annals of translational medicine · 2021Article
- Translational applications of computational modelling for patients with cardiac arrhythmias.Heart (British Cardiac Society) · 2020Review
- PITX2 upregulation increases the risk of chronic atrial fibrillation in a dose-dependent manner by modulatingAnnals of translational medicine · 2020Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that paired-like homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na+ channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency.
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Registered trials
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