{"doi":"10.1113/jp283363","title":"Mechanisms of spontaneous Ca <sup>2+</sup> release‐mediated arrhythmia in a novel 3D human atrial myocyte model: I. Transverse‐axial tubule variation","abstract":"Abstract Intracellular calcium (Ca 2+ ) cycling is tightly regulated in the healthy heart ensuring effective contraction. This is achieved by transverse (t)‐tubule membrane invaginations that facilitate close coupling of key Ca 2+ ‐handling proteins such as the L‐type Ca 2+ channel and Na + ‐Ca 2+ exchanger (NCX) on the cell surface with ryanodine receptors (RyRs) on the intracellular Ca 2+ store. Although less abundant and regular than in the ventricle, t‐tubules also exist in atrial myocytes as a network of transverse invaginations with axial extensions known as the transverse‐axial tubule system (TATS). In heart failure and atrial fibrillation, there is TATS remodelling that is associated with aberrant Ca 2+ ‐handling and Ca 2+ ‐induced arrhythmic activity; however, the mechanism underlying this is not fully understood. To address this, we developed a novel 3D human atrial myocyte model that couples electrophysiology and Ca 2+ ‐handling with variable TATS organization and density. We extensively parameterized and validated our model against experimental data to build a robust tool examining TATS regulation of subcellular Ca 2+ release. We found that varying TATS density and thus the localization of key Ca 2+ ‐handling proteins has profound effects on Ca 2+ handling. Following TATS loss, there is reduced NCX that results in increased cleft Ca 2+ concentration through decreased Ca 2+ extrusion. This elevated Ca 2+ increases RyR open probability causing spontaneous Ca 2+ releases and the promotion of arrhythmogenic waves (especially in the cell interior) leading to voltage instabilities through delayed afterdepolarizations. In summary, the present study demonstrates a mechanistic link between TATS remodelling and Ca 2+ ‐driven proarrhythmic behaviour that probably reflects the arrhythmogenic state observed in disease. image Key points Transverse‐axial tubule systems (TATS) modulate Ca 2+ handling and excitation–contraction coupling in atrial myocytes, with TATS remodelling in heart failure and atrial fibrillation being associated with altered Ca 2+ cycling and subsequent arrhythmogenesis. To investigate the poorly understood mechanisms linking TATS variation and spontaneous Ca 2+ release, we built, parameterized and validated a 3D human atrial myocyte model coupling electrophysiology and spatially‐detailed subcellular Ca 2+ handling governed by the TATS. Simulated TATS loss causes diastolic Ca 2+ and voltage instabilities through reduced Na + ‐Ca 2+ exchanger‐mediated Ca 2+ removal, cleft Ca 2+ accumulation and increased ryanodine receptor open probability, resulting in spontaneous Ca 2+ release and promotion of arrhythmogenic waves and delayed afterdepolarizations. At fast electrical rates typical of atrial tachycardia/fibrillation, spontaneous Ca 2+ releases are larger and more frequent in the cell interior than at the periphery. Our work provides mechanistic insight into how atrial TATS remodelling can lead to Ca 2+ ‐driven instabilities that may ultimately contribute to the arrhythmogenic state in disease.","journal":"The Journal of Physiology","year":2022,"id":250742,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9632,"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":471954,"name":"Haibo Ni","orcid":"0000-0003-0083-4286","position":1,"is_corresponding":false},{"id":322548,"name":"Stefano Morotti","orcid":"0000-0001-8679-665X","position":2,"is_corresponding":false},{"id":892997,"name":"Charlotte Smith","orcid":"0000-0002-1165-1752","position":3,"is_corresponding":false},{"id":692580,"name":"Daisuke Sato","orcid":"0000-0001-9341-0970","position":4,"is_corresponding":false},{"id":380698,"name":"William E. Louch","orcid":"0000-0002-0511-6112","position":5,"is_corresponding":false},{"id":471957,"name":"Andrew G. Edwards","orcid":"0000-0001-7421-5977","position":6,"is_corresponding":false},{"id":471958,"name":"Eleonora Grandi","orcid":"0000-0002-4401-8857","position":7,"is_corresponding":false},{"id":561900,"name":"Xianwei Zhang","orcid":"0000-0003-4665-9145","position":0,"is_corresponding":true}],"reference_count":124,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"36094888","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":[]}