{"doi":"10.1113/jp283817","title":"Determinants and therapeutic potential of calcium handling abnormalities in atrial fibrillation: what can we learn from computer models?","abstract":"Atrial fibrillation (AF) remains a major clinical problem (Nattel et al., 2021). Conceptually, AF requires a trigger, often in the form of ectopic (triggered) activity, and a vulnerable substrate for the initiation and maintenance of self-sustaining tachyarrhythmias. This vulnerable substrate is characterized by cardiac dilatation, slow heterogeneous conduction, typically due to fibrosis, connexin or ion-channel dysfunction, and areas of short repolarization. In addition, there is evidence for a central role for Ca2+-handling abnormalities in the promotion, maintenance and progression of AF (Dobrev & Wehrens, 2017). However, the complexity of cardiomyocyte Ca2+ signalling, controlled at the sub-micrometre level by myriad regulatory feedback mechanisms operating over a wide range of time scales, makes the detailed experimental dissection of proarrhythmic phenotypes and their translation to therapeutic applications challenging (Dobrev & Wehrens, 2017). Computer models provide perfect control over parameters and complete observability of all components of the system of interest. Computational modelling of cardiac electrophysiology has a long history with iterative improvement of models based on a ‘ping-pong’ interplay with experimental studies (Heijman et al., 2021). Modern models can reproduce a wide range of experimental data and increasingly have real-world impact. For example, randomized clinical trials comparing simulation-guided ablation to routine pulmonary vein isolation for rhythm control of AF are currently ongoing (ClinicalTrials.gov NCT04101539), and cardiomyocyte models are extensively used for cardiac safety screening in the ‘Comprehensive In Vitro Proarrhythmia Assay’ initiative developed by the Food and Drug Administration and pharmaceutical industry (Heijman et al., 2021). However, the models available to date usually do not incorporate precise Ca2+-handling abnormalities. In this issue of The Journal of Physiology, two back-to-back papers (Zhang, Ni et al., 2022; Zhang, Smith et al., 2022) provide a novel state-of-the-art three-dimensional human atrial cardiomyocyte model that can reproduce a wide range of Ca2+-handling features at the (sub)cellular scale. The model underscores the importance of subcellular structural remodelling of atrial cardiomyocytes for the development of proarrhythmic Ca2+-handling abnormalities, something that is challenging to study experimentally. The authors show that a reduction in the transverse-axial tubule system (TATS), a complex network of cell-membrane invaginations that facilitates the interaction between transmembrane proteins and intracellular Ca2+ sources, promotes both Ca2+ and membrane-voltage instabilities (Zhang, Ni et al., 2022). Moreover, the authors identify a key role for reduced Ca2+ extrusion via the Na+/Ca2+ exchanger when TATS density is reduced. These findings have potentially important translational implications, since pharmacological inhibition of the Na+/Ca2+ exchanger has been proposed as a potential antiarrhythmic therapy, albeit with conceptual concerns and varying degrees of success. The follow-up manuscript (Zhang, Smith et al., 2022) shows that modulating the distribution of Na+/Ca2+ exchanger, ryanodine receptors, and the sarcoplasmic reticulum Ca2+-buffer calsequestrin has varying pro- and antiarrhythmic effects, which are strongly dependent on TATS density (with intermediate levels being most sensitive to variations in the distribution of Ca2+-handling proteins). These data have practical implications for the interpretation of experimental studies on mechanisms underlying AF-associated Ca2+-handling abnormalities. In particular, the results by Zhang, Smith et al. (2022) indicate that even in the absence of changes in total expression level or phosphorylation status assessed by western blot, an altered distribution of Ca2+-handling proteins may have proarrhythmic consequences. This key finding might also explain some of the controversies related to th","journal":"The Journal of Physiology","year":2022,"id":284103,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":58218,"name":"Dobromir Dobrev","orcid":"0000-0002-4612-117X","position":1,"is_corresponding":false},{"id":270328,"name":"Jordi Heijman","orcid":"0000-0002-1418-108X","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-19T00:29:32.702533Z","pmid":"36208177","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}