{"doi":"10.1242/dmm.049962","title":"Multiplatform modeling of atrial fibrillation identifies phospholamban as a central regulator of cardiac rhythm","abstract":"Atrial fibrillation (AF) is a common and genetically inheritable form of cardiac arrhythmia; however, it is currently not known how these genetic predispositions contribute to the initiation and/or maintenance of AF-associated phenotypes. One major barrier to progress is the lack of experimental systems to investigate the effects of gene function on rhythm parameters in models with human atrial and whole-organ relevance. Here, we assembled a multi-model platform enabling high-throughput characterization of the effects of gene function on action potential duration and rhythm parameters using human induced pluripotent stem cell-derived atrial-like cardiomyocytes and a Drosophila heart model, and validation of the findings using computational models of human adult atrial myocytes and tissue. As proof of concept, we screened 20 AF-associated genes and identified phospholamban loss of function as a top conserved hit that shortens action potential duration and increases the incidence of arrhythmia phenotypes upon stress. Mechanistically, our study reveals that phospholamban regulates rhythm homeostasis by functionally interacting with L-type Ca2+ channels and NCX. In summary, our study illustrates how a multi-model system approach paves the way for the discovery and molecular delineation of gene regulatory networks controlling atrial rhythm with application to AF.","journal":"Disease Models & Mechanisms","year":2023,"id":371245,"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":0.9603,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":331351,"name":"James Kezos","orcid":"0000-0002-3581-7657","position":1,"is_corresponding":false},{"id":471954,"name":"Haibo Ni","orcid":"0000-0003-0083-4286","position":2,"is_corresponding":false},{"id":564384,"name":"Michael S. Yu","orcid":"0000-0002-0202-778X","position":3,"is_corresponding":false},{"id":990703,"name":"James Marchant","orcid":"0000-0002-9551-835X","position":4,"is_corresponding":false},{"id":229960,"name":"Sean Spiering","orcid":null,"position":5,"is_corresponding":false},{"id":557742,"name":"Suraj Kannan","orcid":"0000-0002-7820-7381","position":6,"is_corresponding":false},{"id":560952,"name":"Chulan Kwon","orcid":"0000-0002-4924-2778","position":7,"is_corresponding":false},{"id":480656,"name":"Peter Andersen","orcid":"0000-0003-3971-0467","position":8,"is_corresponding":false},{"id":55687,"name":"Rolf Bodmer","orcid":"0000-0001-9087-1210","position":9,"is_corresponding":false},{"id":471958,"name":"Eleonora Grandi","orcid":"0000-0002-4401-8857","position":10,"is_corresponding":false},{"id":331354,"name":"Karen Ocorr","orcid":"0000-0003-2593-0119","position":11,"is_corresponding":false},{"id":331356,"name":"Alexandre R. Colas","orcid":"0000-0001-8489-0570","position":12,"is_corresponding":false},{"id":331350,"name":"Anaïs Kervadec","orcid":"0000-0001-8105-6871","position":0,"is_corresponding":true}],"reference_count":108,"raw_metadata":null,"created_at":"2026-07-19T01:15:45.330525Z","pmid":"37293707","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":[]}