{"doi":"10.1113/jp289051","title":"Beat‐to‐beat QT interval variability as a tool to detect the underlying cellular mechanisms of arrhythmias","abstract":"Abstract Increased beat‐to‐beat QT interval variability (QTV) on the electrocardiogram (ECG) has been associated with arrhythmia risk and sudden cardiac death. However, the underlying mechanisms driving increased QTV are not fully understood. Our previous work showed that membrane voltage instability is a major contributor to QTV. In this study, we investigated how intracellular calcium (Ca 2+ ) cycling instability is also a major contributor to QTV using a mathematical model of a ventricular myocyte that incorporates stochastic ion channel gating and detailed Ca 2+ cycling. By independently modulating membrane voltage instability (via the L‐type Ca 2+ channel recovery time constant, τ f ) and intracellular Ca 2+ cycling instability (via the steepness of the sarcoplasmic reticulum Ca 2+ release‐load relationship, u ), we show that both voltage and Ca 2+ instabilities significantly increase action potential duration (APD) variability, which contributes to QTV, even in the absence of overt arrhythmic patterns. Ca 2+ transient variability increases with intracellular Ca 2+ cycling instability, contributing to APD variability via Ca 2+ ‐sensitive currents, and consequently to QTV. Notably, APD variability/QTV significantly increases just before the onset of alternans, regardless of whether instability originates from voltage or Ca 2+ dynamics. Thus, QTV may serve as a precursor to both voltage‐driven and Ca 2+ ‐driven alternans. Furthermore, pharmacological interventions that selectively stabilize voltage vs . Ca 2+ cycling may selectively reduce QTV. These findings suggest that QTV can help distinguish between arrhythmias caused by electrical dysfunction and those caused by Ca 2+ cycling dysfunction. Therefore, QTV has potential as a non‐invasive tool not only to identify individuals at risk but also to predict the specific type and underlying cause of arrhythmias. image Key points Both membrane voltage and intracellular Ca 2+ cycling instabilities contribute to increased QTV, even without overt arrhythmic patterns. Ca 2+ transient variability increases with intracellular Ca 2+ cycling instability and independently contributes to QTV, regardless of voltage instability. QTV serves as a precursor to both electrical and Ca 2+ alternans, highlighting its potential as an early non‐invasive marker for arrhythmic events. The response of QTV to specific pharmacological interventions may differentiate between voltage‐driven and Ca 2+ ‐driven instability, guiding personalized treatment strategies. The study suggests QTV as a promising tool for personalized arrhythmia risk assessment and mechanism‐specific therapeutic strategies.","journal":"The Journal of Physiology","year":2025,"id":524599,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9669,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"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":229026,"name":"Bence Hegyi","orcid":"0000-0003-3113-221X","position":1,"is_corresponding":false},{"id":338682,"name":"Crystal M. Ripplinger","orcid":"0000-0002-9908-4106","position":2,"is_corresponding":false},{"id":229037,"name":"Donald M. Bers","orcid":"0000-0002-2237-9483","position":3,"is_corresponding":false},{"id":692580,"name":"Daisuke Sato","orcid":"0000-0001-9341-0970","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:50:12.083054Z","pmid":"41051064","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":[]}