{"doi":"10.1016/j.jacep.2025.03.004","title":"Calcium Homeostatic Feedback Control Predicts Atrial Fibrillation Initiation, Remodeling, and Progression","abstract":"BACKGROUND: Atrial fibrillation (AF) is a progressive disorder, with arrhythmia episodes becoming increasingly longer and ultimately permanent. The chaotic electrical activity by itself is well known to drive progression, a process classically summarized as \"AF begets AF.\" However, the mechanisms underlying this progression are not yet well defined. OBJECTIVES: We hypothesize that calcium homeostatic feedback regulating ion channel expression is a critical mechanistic component of this pathological process. METHODS: We propose a modeling framework that tracks both short-term beat-to-beat electrical and calcium activity and long-term tissue substrate remodeling as a single coupled dynamical system. Importantly, the full AF progression from healthy to pathological remodeled tissue is reproduced, in contrast with prior studies that consider \"snapshots\" of various AF stages. RESULTS: Simulations predict that single cells respond to fast pacing by maintaining intracellular calcium concentrations through dynamic ion channel expression and electrical phenotype changes. In 2-dimensional homogeneous tissue, spontaneous spiral waves stabilize into permanent re-entry. In 2-dimensional heterogeneous tissue, we observe the initiation of re-entrant activity in response to fast pacing, followed by increasingly longer intermittent, and then permanent, arrhythmic activity. Simulations predict critical properties of re-entrant wave locations, leading to a novel hypothesis: spiral wave activity itself drives underlying substrate remodeling and the emergence of remodeled tissue \"niches\" that support the stabilization of fast re-entrant activity. CONCLUSIONS: Thus, the model joins multiple lines of inquiry (ie, long-term calcium regulation, ion channel coexpression and remodeling, and tissue-scale arrhythmia spatiotemporal organization) into a single coherent framework, and for the first time, captures the dynamics of the long-term natural history of AF.","journal":"JACC. Clinical electrophysiology","year":2025,"id":550577,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9634,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":428634,"name":"Seth H. Weinberg","orcid":"0000-0003-1170-0419","position":1,"is_corresponding":false},{"id":659743,"name":"Nicolae Moise","orcid":"0000-0002-6842-7305","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T02:54:16.596730Z","pmid":"40338780","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":[]}