{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T04:59:44Z","timestamp":1780549184422,"version":"3.54.1"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20bm0104001 JP21bm0804022 JP23bm1423011 JP23bm1323001 JP24bm1123054 JP22mk0101241 JP24mk0121280"],"award-info":[{"award-number":["JP20bm0104001 JP21bm0804022 JP23bm1423011 JP23bm1323001 JP24bm1123054 JP22mk0101241 JP24mk0121280"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJSF2323"],"award-info":[{"award-number":["JPMJSF2323"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["18CVD05"],"award-info":[{"award-number":["18CVD05"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Numerous reports investigating channelopathies, including Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), have successfully reproduced using cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (hiPSCs). However, the relationship between action potentials (AP) and calcium transient waveforms\u2014especially after drug treatment\u2014remains unclear. In this study, we simultaneously loaded a membrane potential dye FluoVolt and the new calcium indicator Calbryte<jats:sup>TM<\/jats:sup> 590 AM and optimized stimulation and detection of both dyes to successfully obtain a higher signal-to-noise (S\/N) ratio than the conventional membrane potential dye-red fluorescence Ca<jats:sup>2+<\/jats:sup> dye combination, thus enabling the simultaneous recording of both AP and calcium transient waveforms in single hiPSC-CMs, which continued even after gradual increases in drug concentration. In drug-loading experiments on CPVT1 (RyR2-I4587V) hiPSC-derived ventricular-like CMs, carvedilol and flecainide demonstrated some effectiveness, while JTV519 at 3 \u00b5M exhibited both efficacy and alterations in AP waveforms. The Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent serine-threonine protein kinase II (CaMKII) inhibitor KN-93 at 1 \u00b5M was highly effective (93%) at reducing Ca<jats:sup>2+<\/jats:sup> transient abnormalities without altering AP waveforms.<\/jats:p>","DOI":"10.3389\/fphys.2025.1579815","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T15:23:56Z","timestamp":1749050636000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Simultaneous optical recording of action potentials and calcium transients in cardiac single cells differentiated from type 1 CPVT-iPS cells"],"prefix":"10.3389","volume":"16","author":[{"given":"Tadashi","family":"Takaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihisa","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Imahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Nishimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1056\/nejm198108273050901","article-title":"Oral flecainide acetate for the treatment of ventricular arrhythmias","volume":"305","author":"Anderson","year":"1981","journal-title":"N. Engl. J. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1161\/CIRCRESAHA.116.305347","article-title":"The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2","volume":"116","author":"Bannister","year":"2015","journal-title":"Circ. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1146\/annurev-physiol-020911-153308","article-title":"Cardiac sarcoplasmic reticulum calcium leak: basis and roles in cardiac dysfunction","volume":"76","author":"Bers","year":"2014","journal-title":"Annu. Rev. Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.3389\/fphar.2019.01566","article-title":"The hyperpolarization-activated cyclic-nucleotide-gated channel blocker ivabradine does not prevent arrhythmias in catecholaminergic polymorphic ventricular tachycardia","volume":"10","author":"Bueno-Levy","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s11154-023-09855-9","article-title":"Role of CaMKII in diabetes induced vascular injury and its interaction with anti-diabetes therapy","volume":"25","author":"Chacar","year":"2024","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"B6","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1124\/mol.115.102277","article-title":"K201 (JTV519) is a Ca2+-dependent blocker of SERCA and a partial agonist of ryanodine receptors in striated muscle","volume":"90","author":"Darcy","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e843","DOI":"10.1038\/cddis.2013.369","article-title":"CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia","volume":"4","author":"Di Pasquale","year":"2013","journal-title":"Cell Death Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"246","DOI":"10.5105\/jse.27.246","article-title":"A novel missense mutation in the human cardiac ryanodine receptor gene (I4587V) in a patient with catecholaminergic polymorphic ventricular tachycardia","volume":"27","author":"Dochi","year":"2007","journal-title":"Jpn. J. Electrocardiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1159\/000335753","article-title":"In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells","volume":"28","author":"Fatima","year":"2011","journal-title":"Cell Physiol. Biochem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"19111","DOI":"10.1038\/srep19111","article-title":"Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes","volume":"6","author":"Funakoshi","year":"2016","journal-title":"Sci. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e011387","DOI":"10.1161\/circep.122.011387","article-title":"Novel calmodulin variant p.E46K associated with severe catecholaminergic polymorphic ventricular tachycardia produces robust arrhythmogenicity in human induced pluripotent stem cell-derived cardiomyocytes","volume":"16","author":"Gao","year":"2023","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"B12","volume-title":"GeneReviews is a registered trademark of the University of Washington, Seattle","year":"2024"},{"key":"B13","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1016\/j.jacc.2012.02.066","article-title":"Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells","volume":"60","author":"Itzhaki","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/emmm.201100194","article-title":"Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia","volume":"4","author":"Jung","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1002\/ddr.430330406","article-title":"New 1,4-benzothiazepine derivative, K201, demonstrates cardioprotective effects against sudden cardiac cell death and intracellular calcium blocking action","volume":"33","author":"Kaneko","year":"1994","journal-title":"Drug Dev. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1254\/jjp.79.275","article-title":"Effects of a novel cardioprotective drug, JTV-519, on membrane currents of Guinea pig ventricular myocytes","volume":"79","author":"Kimura","year":"1999","journal-title":"Jpn. J. Pharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1007\/s002100000230","article-title":"Effects of JTV-519, a novel anti-ischaemic drug, on the delayed rectifier K+ current in Guinea-pig ventricular myocytes","volume":"361","author":"Kiriyama","year":"2000","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1253\/circj.CJ-11-0210","article-title":"Safety and tolerability of once-daily controlled-release carvedilol 10-80mg in Japanese patients with chronic heart failure","volume":"76","author":"Kitakaze","year":"2012","journal-title":"Circ. J."},{"key":"B19","doi-asserted-by":"publisher","first-page":"H1035","DOI":"10.1152\/ajpheart.00722.2002","article-title":"A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure","volume":"284","author":"Kohno","year":"2003","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1161\/circresaha.120.316819","article-title":"RYR2 channel inhibition is the principal mechanism of flecainide action in CPVT","volume":"128","author":"Kryshtal","year":"2021","journal-title":"Circ. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"23a","DOI":"10.1016\/j.bpj.2023.11.247","article-title":"Effects of a high-affinity and selective RyR2 inhibitor on Ca2+ signals in cardiomyocytes and arrhythmias in CPVT model mice","volume":"123","author":"Kurebayashi","year":"2024","journal-title":"Biophys. J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3275","DOI":"10.3791\/3275","article-title":"Optical mapping of action potentials and calcium transients in the mouse heart","volume":"55","author":"Lang","year":"2011","journal-title":"J. Vis. Exp."},{"key":"B23","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1007\/s00424-012-1135-6","article-title":"Simultaneous measurement and modulation of multiple physiological parameters in the isolated heart using optical techniques","volume":"464","author":"Lee","year":"2012","journal-title":"Pflugers Arch."},{"key":"B24","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1161\/01.RES.0000235869.50747.e1","article-title":"Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model","volume":"99","author":"Liu","year":"2006","journal-title":"Circ. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1161\/circresaha.111.247338","article-title":"Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity","volume":"109","author":"Liu","year":"","journal-title":"Circ. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.yjmcc.2010.10.001","article-title":"Calmodulin kinase II inhibition prevents arrhythmias in RyR2(R4496C+\/-) mice with catecholaminergic polymorphic ventricular tachycardia","volume":"50","author":"Liu","year":"","journal-title":"J. Mol. Cell Cardiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.cardiores.2007.06.014","article-title":"K201 modulates excitation-contraction coupling and spontaneous Ca2+ release in normal adult rabbit ventricular cardiomyocytes","volume":"76","author":"Loughrey","year":"2007","journal-title":"Cardiovasc Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e004725","DOI":"10.1161\/circep.116.004725","article-title":"Patient-Specific drug screening using a human induced pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia type 2","volume":"10","author":"Maizels","year":"2017","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1080\/19336950.2022.2055521","article-title":"Mechanism of carvedilol induced action potential and calcium alternans","volume":"16","author":"Martinez-Hernandez","year":"2022","journal-title":"Channels"},{"key":"B30","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1001\/jamacardio.2022.0219","article-title":"Outcomes of patients with catecholaminergic polymorphic ventricular tachycardia treated with \u03b2-blockers","volume":"7","author":"Mazzanti","year":"2022","journal-title":"JAMA Cardiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/j.stem.2015.04.005","article-title":"Efficient detection and purification of cell populations using synthetic MicroRNA switches","volume":"16","author":"Miki","year":"2015","journal-title":"Cell Stem Cell"},{"key":"B32","article-title":"Catecholaminergic Polymorphic Ventricular Tachycardia","volume-title":"GeneReviews(\u00ae)","author":"Napolitano","year":"2022"},{"key":"B33","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1161\/CIRCULATIONAHA.121.056018","article-title":"An international multicenter cohort study on \u03b2-blockers for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia","volume":"145","author":"Peltenburg","year":"2022","journal-title":"Circulation"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e0135806","DOI":"10.1371\/journal.pone.0135806","article-title":"Novel analysis software for detecting and classifying Ca2+ transient abnormalities in stem cell-derived cardiomyocytes","volume":"10","author":"Penttinen","year":"","journal-title":"PLoS One"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0125366","DOI":"10.1371\/journal.pone.0125366","article-title":"Antiarrhythmic effects of dantrolene in patients with catecholaminergic polymorphic ventricular tachycardia and replication of the responses using iPSC models","volume":"10","author":"Penttinen","year":"","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"9109503","DOI":"10.1155\/2018\/9109503","article-title":"Antiarrhythmic effects of carvedilol and flecainide in cardiomyocytes derived from catecholaminergic polymorphic ventricular tachycardia patients","volume":"2018","author":"P\u00f6l\u00f6nen","year":"2018","journal-title":"Stem Cells Int."},{"key":"B37","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1242\/dmm.026823","article-title":"A human pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia recapitulates patient-specific drug responses","volume":"9","author":"Preininger","year":"2016","journal-title":"Dis. Model Mech."},{"key":"B38","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1113\/jphysiol.2004.065003","article-title":"State-dependent trapping of flecainide in the cardiac sodium channel","volume":"560","author":"Ramos","year":"2004","journal-title":"J. Physiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1146\/annurev-pharmtox-051421-111814","article-title":"CaMKII as a therapeutic target in cardiovascular disease","volume":"63","author":"Reyes Gaido","year":"2023","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1111\/j.1476-5381.2012.01995.x","article-title":"JTV519 (K201) reduces sarcoplasmic reticulum Ca2+ leak and improves diastolic function in vitro in murine and human non-failing myocardium","volume":"167","author":"Sacherer","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"4307","DOI":"10.3390\/ijms22094307","article-title":"The calcium\/calmodulin-dependent kinases II and IV as therapeutic targets in neurodegenerative and neuropsychiatric disorders","volume":"22","author":"Sa\u0142aciak","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e0164795","DOI":"10.1371\/journal.pone.0164795","article-title":"Patient-Specific human induced pluripotent stem cell model assessed with electrical pacing validates S107 as a potential therapeutic agent for catecholaminergic polymorphic ventricular tachycardia","volume":"11","author":"Sasaki","year":"2016","journal-title":"PLoS One"},{"key":"B43","doi-asserted-by":"publisher","first-page":"468","DOI":"10.5966\/sctm.2014-0245","article-title":"Dual optical recordings for action potentials and calcium handling in induced pluripotent stem cell models of cardiac arrhythmias using genetically encoded fluorescent indicators","volume":"4","author":"Song","year":"2015","journal-title":"Stem Cells Transl. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s13578-024-01236-2","article-title":"Unveiling the role of CaMKII in retinal degeneration: from biological mechanism to therapeutic strategies","volume":"14","author":"Sun","year":"2024","journal-title":"Cell Biosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1161\/CIRCRESAHA.111.243956","article-title":"Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias","volume":"110","author":"Swaminathan","year":"2012","journal-title":"Circ. Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"7532657","DOI":"10.1155\/2019\/7532657","article-title":"Optical recording of action potentials in human induced pluripotent stem cell-derived cardiac single cells and monolayers generated from long QT syndrome type 1 patients","volume":"2019","author":"Takaki","year":"2019","journal-title":"Stem Cells Int."},{"key":"B48","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1124\/molpharm.123.000720","article-title":"Screening for novel type 2 ryanodine receptor inhibitors by endoplasmic reticulum Ca(2+) monitoring","volume":"104","author":"Takenaka","year":"2023","journal-title":"Mol. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s00395-009-0057-8","article-title":"K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum","volume":"105","author":"Toischer","year":"2010","journal-title":"Basic Res. Cardiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1016\/j.jacc.2011.01.026","article-title":"Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia","volume":"57","author":"van der Werf","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"e202302278","DOI":"10.26508\/lsa.202302278","article-title":"A dual-targeted drug inhibits cardiac ryanodine receptor Ca(2+) leak but activates SERCA2a Ca(2+) uptake","volume":"7","author":"Wegener","year":"2024","journal-title":"Life Sci. Alliance"},{"key":"B52","doi-asserted-by":"publisher","first-page":"e61","DOI":"10.1161\/01.res.0000125626.33738.e2","article-title":"Ca2+\/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor","volume":"94","author":"Wehrens","year":"2004","journal-title":"Circ. Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"e1101","DOI":"10.1002\/cpz1.1101","article-title":"Simultaneous optical imaging of action potentials and calcium transients in human induced pluripotent stem cell-derived cardiomyocytes","volume":"4","author":"Yang","year":"2024","journal-title":"Curr. Protoc."},{"key":"B54","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.yjmcc.2021.05.007","article-title":"Mechanisms of flecainide induced negative inotropy: an in silico study","volume":"158","author":"Yang","year":"2021","journal-title":"J. Mol. Cell Cardiol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1093\/chromsci\/bmv157","article-title":"HPLC\/Fluorometric detection of carvedilol in real human plasma samples using liquid\u2013liquid extraction","volume":"54","author":"Yilmaz","year":"2016","journal-title":"J. Chromatogr. Sci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.hrthm.2020.09.007","article-title":"Calcium signaling consequences of RyR2 mutations associated with CPVT1 introduced via CRISPR\/Cas9 gene editing in human-induced pluripotent stem cell-derived cardiomyocytes: comparison of RyR2-R420Q, F2483I, and Q4201R","volume":"18","author":"Zhang","year":"2021","journal-title":"Heart Rhythm"},{"key":"B57","doi-asserted-by":"publisher","first-page":"240a","DOI":"10.1016\/j.bpj.2018.11.1315","article-title":"New red fluorescent calcium indicators for functional analysis of GPCRs and Ca2+ channel targets","volume":"116","author":"Zhao","year":"2019","journal-title":"Biophys. J."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1038\/nm.2406","article-title":"Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release","volume":"17","author":"Zhou","year":"2011","journal-title":"Nat. Med."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2025.1579815\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T15:23:58Z","timestamp":1749050638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2025.1579815\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":58,"alternative-id":["10.3389\/fphys.2025.1579815"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2025.1579815","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,4]]},"article-number":"1579815"}}