ArticleCardiovascular research2023
Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis.
Article in Cardiovascular research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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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
11 citing papers in PubMed, 18 citations in OpenAlex.
- Structural and Functional Regulation of RyR2 in Cardiac Calcium Handling and Arrhythmogenesis.Biomedicines · 2026Review
- Predicting Sex-Specific Antiarrhythmic Strategies for Atrial Fibrillation through a Regression-Guided Computational Modeling Pipeline.bioRxiv : the preprint server for biology · 2026Article
- The mechanism of electrical remodeling in atrial fibrillation and current research status of natural drugs and active ingredients inhibiting atrial electrical remodeling.Frontiers in cardiovascular medicine · 2026Review
- The slow delayed rectifier KScientific reports · 2025Article
- Mechanistic insights into sex differences in atrial electrophysiology and arrhythmia vulnerability through sex-specific computational models.The Journal of physiology · 2025Article
- Calcium Homeostatic Feedback Control Predicts Atrial Fibrillation Initiation, Remodeling, and Progression.JACC. Clinical electrophysiology · 2025Article
- Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation.The Journal of clinical investigation · 2025Article
- Sex Differences in Electrophysiology and Calcium Handling in Atrial Health and Fibrillation.Annual review of physiology · 2025Review
- Enhanced CaJACC. Clinical electrophysiology · 2024Article
- Beta-Adrenergic Activation of the Inward Rectifier KInternational journal of molecular sciences · 2024Article
- Dual effects of the small-conductance CaAmerican journal of physiology. Heart and circulatory physiology · 2023Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 3 countries.
Funding
Abstract
aimsAtrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodelling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca2+-handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex pathophysiological network, which renders AF resistant to existing pharmacotherapies that predominantly target transmembrane ion channels. Developing innovative therapeutic strategies requires a systems approach to disentangle quantitatively the pro-arrhythmic contributions of individual AF-induced alterations. METHODS AND
resultsHere, we built a novel computational framework for simulating electrophysiology and Ca2+-handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signalling pathways [i.e. protein kinase A (PKA), and Ca2+/calmodulin-dependent protein kinase II (CaMKII)] involved in AF-pathogenesis. Populations of atrial cardiomyocyte models were constructed to determine the influence of subcellular ionic processes, signalling components, and regulatory networks on atrial arrhythmogenesis. Our results reveal a novel synergistic crosstalk between PKA and CaMKII that promotes atrial cardiomyocyte electrical instability and arrhythmogenic triggered activity. Simulations of heterogeneous tissue demonstrate that this cellular triggered activity is further amplified by CaMKII- and PKA-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis.
conclusionsOur analysis reveals potential mechanisms by which the stress-associated adaptive changes turn into maladaptive pro-arrhythmic triggers at the cellular and tissue levels and identifies potential anti-AF targets. Collectively, our integrative approach is powerful and instrumental to assemble and reconcile existing knowledge into a systems network for identifying novel anti-AF targets and innovative approaches moving beyond the traditional ion channel-based strategy.
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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.