{"doi":"10.1016/j.yjmcc.2025.07.014","title":"Compromised repolarization reserve in a murine model of catecholaminergic polymorphic ventricular tachycardia caused by RyR2-R420Q mutation","abstract":"Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca 2+ cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca 2+ leak during systole disrupts repolarization in a transgenic mouse model of CPVT. Methods Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes. Results R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca 2+ leak during the Ca 2+ transient decay, in the form of late Ca 2+ sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs. Conclusions Ca 2+ -mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.","journal":"Journal of Molecular and Cellular Cardiology","year":2025,"id":550853,"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":0.9627,"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":1446745,"name":"Pavel Kirilenko","orcid":null,"position":1,"is_corresponding":false},{"id":668294,"name":"Aitana Braza‐Boïls","orcid":"0000-0002-9888-6705","position":2,"is_corresponding":false},{"id":668298,"name":"Esther Zorio","orcid":"0000-0003-3608-4210","position":3,"is_corresponding":false},{"id":1446383,"name":"Yueyi Wang","orcid":"0000-0001-8613-2239","position":4,"is_corresponding":false},{"id":646789,"name":"Ana M. Gómez","orcid":"0000-0003-0009-2884","position":5,"is_corresponding":false},{"id":1144406,"name":"Mark B. Cannell","orcid":"0000-0002-4816-0463","position":6,"is_corresponding":false},{"id":30268,"name":"Branko Latinkic","orcid":"0000-0003-4952-123X","position":7,"is_corresponding":false},{"id":1446384,"name":"Ewan D. Fowler","orcid":"0000-0001-5580-2156","position":8,"is_corresponding":false},{"id":1446382,"name":"Spyros Zissimopoulos","orcid":"0000-0001-5196-9450","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:54:20.915388Z","pmid":"40714045","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":[]}