{"doi":"10.3390/ijms22115645","title":"Intracellular Na+ Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis","abstract":"Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca2+-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na+]i is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na+ homeostasis in SAN pacemaking and test whether [Na+]i dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na+ entry (Na+/Ca2+ exchanger, NCX) and removal (Na+/K+ ATPase, NKA). Results: We found that changes in intracellular Na+ homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca2+ and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na+ homeostasis to Ca2+ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.","journal":"International Journal of Molecular Sciences","year":2021,"id":176386,"datarank":0.4636563680037475,"base_score":3.091042453358316,"endowment":3.091042453358316,"self_citation_contribution":0.4636563680037475,"citation_network_contribution":0.0,"self_endowment_contribution":0.4636563680037475,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9413,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","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":499863,"name":"Colin H. Peters","orcid":"0000-0001-8557-9100","position":2,"is_corresponding":false},{"id":718897,"name":"Christian Rickert","orcid":"0000-0001-7396-4335","position":3,"is_corresponding":false},{"id":718898,"name":"Ameneh Asgari-Targhi","orcid":"0000-0002-1971-3962","position":4,"is_corresponding":false},{"id":692580,"name":"Daisuke Sato","orcid":"0000-0001-9341-0970","position":5,"is_corresponding":false},{"id":367303,"name":"Alexey V. Glukhov","orcid":"0000-0003-2076-9688","position":6,"is_corresponding":false},{"id":499867,"name":"Catherine Proenza","orcid":"0000-0003-4324-6206","position":7,"is_corresponding":false},{"id":471958,"name":"Eleonora Grandi","orcid":"0000-0002-4401-8857","position":8,"is_corresponding":false},{"id":322548,"name":"Stefano Morotti","orcid":"0000-0001-8679-665X","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:47:23.605867Z","pmid":"34073281","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":[]}