{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:24:43Z","timestamp":1791473083688,"version":"4.3.4"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chang Gung Memorial Hospital Medical Research Program","award":["CMRPG3M1671"],"award-info":[{"award-number":["CMRPG3M1671"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The electrophysiological mechanisms underlying melatonin\u2019s actions and the electrophysiological consequences of superimposed therapeutic hypothermia (TH) in preventing cardiac ischemia-reperfusion (IR) injury-induced arrhythmias remain largely unknown. This study aimed to unveil these issues using acute IR-injured hearts. Rabbits were divided into heart failure (HF), HF+melatonin, control, and control+melatonin groups. HF was induced by rapid right ventricular pacing. Melatonin was administered orally (10 mg\/kg\/day) for four weeks, and IR was created by 60-min coronary artery ligation and 30-min reperfusion. The hearts were then excised and Langendorff-perfused for optical mapping studies at normothermia, followed by TH. Melatonin significantly reduced ventricular fibrillation (VF) maintenance. In failing hearts, melatonin reduced the spatially discordant alternans (SDA) inducibility mainly by modulating intracellular Ca2+ dynamics via upregulation of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and calsequestrin 2 and attenuating the downregulation of phosphorylated phospholamban protein expression. In control hearts, melatonin improved conduction slowing and reduced dispersion of action potential duration (APDdispersion) by upregulating phosphorylated connexin 43, attenuating the downregulation of SERCA2a and phosphorylated phospholamban and attenuating the upregulation of phosphorylated Ca2+\/calmodulin-dependent protein kinase II. TH significantly retarded intracellular Ca2+ decay slowed conduction, and increased APDdispersion, thereby facilitating SDA induction, which counteracted the beneficial effects of melatonin in reducing VF maintenance.<\/jats:p>","DOI":"10.3390\/ijms26020615","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T07:40:08Z","timestamp":1736754008000},"page":"615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanistic Insights into Melatonin\u2019s Antiarrhythmic Effects in Acute Ischemia-Reperfusion-Injured Rabbit Hearts Undergoing Therapeutic Hypothermia"],"prefix":"10.3390","volume":"26","author":[{"given":"Hui-Ling","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Anesthesia, Chang Gung Memorial Hospital, Taipei Branch, Taipei 10507, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Cheng","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan Branch, Taoyuan 33304, Taiwan"},{"name":"School of Medicine, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Ta","family":"Wo","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan Branch, Taoyuan 33304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Chun","family":"Chou","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan Branch, Taoyuan 33304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4465-0016","authenticated-orcid":false,"given":"Chung-Chuan","family":"Chou","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan Branch, Taoyuan 33304, Taiwan"},{"name":"School of Medicine, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1161\/CIRCRESAHA.117.310083","article-title":"Calcium signaling and cardiac arrhythmias","volume":"120","author":"Landstrom","year":"2017","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1093\/cvr\/cvs116","article-title":"Calcium-mediated cell death during myocardial reperfusion","volume":"94","author":"Inserte","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_3","first-page":"I16","article-title":"Potential electrophysiologic mechanisms responsible for dysrhythmias associated with reperfusion of ischemic myocardium","volume":"68","author":"Corr","year":"1983","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.yjmcc.2015.02.017","article-title":"Perspective: A dynamics-based classification of ventricular arrhythmias","volume":"82","author":"Weiss","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5622","DOI":"10.1073\/pnas.0305778101","article-title":"Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling","volume":"101","author":"Lebeche","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1161\/CIRCRESAHA.110.220673","article-title":"Reactive oxygen species originating from mitochondria regulate the cardiac sodium channel","volume":"107","author":"Liu","year":"2010","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.cardiores.2004.01.033","article-title":"Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis","volume":"62","author":"Coronel","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/0002-9149(92)91295-F","article-title":"Holter recording of ventricular arrhythmias during intravenous thrombolysis for acute myocardial infarction","volume":"69","author":"Gressin","year":"1992","journal-title":"Am. J. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/jpi.12175","article-title":"A review of melatonin as a suitable antioxidant against myocardial ischemia\u2013reperfusion injury and clinical heart diseases","volume":"57","author":"Yang","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/j.1600-079X.1998.tb00558.x","article-title":"Ischemia\/reperfusion-induced arrhythmias in the isolated rat heart: Prevention by melatonin","volume":"25","author":"Tan","year":"1998","journal-title":"J. Pineal Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1034\/j.1600-079X.2002.01869.x","article-title":"Protective effects of melatonin on myocardial ischemia\/reperfusion injury in vivo","volume":"33","author":"Lee","year":"2002","journal-title":"J. Pineal Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1600-079X.2006.00383.x","article-title":"Melatonin reduces ventricular arrhythmias and preserves capillary perfusion during ischemia-reperfusion events in cardiomyopathic hamsters","volume":"42","author":"Bertuglia","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sedova, K.A., Bernikova, O.G., Cuprova, J.I., Ivanova, A.D., Kutaeva, G.A., Pliss, M.G., Lopatina, E.V., Vaykshnorayte, M.A., Diez, E.R., and Azarov, J.E. (2019). Association between antiarrhythmic, electrophysiological, and antioxidative effects of melatonin in ischemia\/reperfusion. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246331"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Durkina, A.V., Szeiffova Bacova, B., Bernikova, O.G., Gonotkov, M.A., Sedova, K.A., Cuprova, J., Vaykshnorayte, M.A., Diez, E.R., Prado, N.J., and Azarov, J.E. (2023). Blockade of melatonin receptors abolishes its antiarrhythmic effect and slows ventricular conduction in rat hearts. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241511931"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/sj.bjp.0707409","article-title":"Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: Opportunities and obstacles for survival signaling","volume":"152","author":"Burley","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","first-page":"141","article-title":"Melatonin pretreatment does not modify extrasystolic burden in the rat ischemia-reperfusion model","volume":"72","author":"Durkina","year":"2021","journal-title":"J Physiol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yamada, K.P., Kariya, T., Aikawa, T., and Ishikawa, K.J.F.i.C.M. (2021). Effects of Therapeutic Hypothermia on Normal and Ischemic Heart. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.642843"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1097\/PCC.0000000000002346","article-title":"Hypothermia plus melatonin in asphyctic newborns: A randomized-controlled pilot study","volume":"21","year":"2020","journal-title":"Pediatr. Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"H1035","DOI":"10.1152\/ajpheart.00786.2011","article-title":"Hypothermia-induced spatially discordant action potential duration alternans and arrhythmogenesis in nonhibernating versus hibernating mammals","volume":"303","author":"Egorov","year":"2012","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e202012568","DOI":"10.1085\/jgp.202012568","article-title":"Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans","volume":"153","author":"Millet","year":"2021","journal-title":"J. Gen. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/0022-2828(89)90804-3","article-title":"Sarcoplasmic reticulum function in the \u201cstunned\u201d myocardium","volume":"21","author":"Limbruno","year":"1989","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.ijcard.2013.12.033","article-title":"Piceatannol facilitates conduction block and ventricular fibrillation induction in ischemia-reperfused rabbit hearts with pacing-induced heart failure","volume":"171","author":"Chou","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_23","first-page":"44","article-title":"Melatonin-induced protective effects on cardiomyocytes against reperfusion injury partly through modulation of IP3R and SERCA2a via activation of ERK1","volume":"110","author":"Hu","year":"2018","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"H1250","DOI":"10.1152\/ajpheart.00779.2011","article-title":"Calsequestrin 2 and arrhythmias","volume":"302","author":"Faggioni","year":"2012","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_25","first-page":"1","article-title":"Impaired sarcoplasmic reticulum calcium uptake and release promote electromechanically and spatially discordant alternans: A computational study","volume":"10","author":"Weinberg","year":"2016","journal-title":"Clin. Med. Insights Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s00395-019-0748-8","article-title":"Connexin 43 dephosphorylation contributes to arrhythmias and cardiomyocyte apoptosis in ischemia\/reperfusion hearts","volume":"114","author":"Xue","year":"2019","journal-title":"Basic Res. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1139\/cjpp-2012-0393","article-title":"Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythmias","volume":"91","author":"Benova","year":"2013","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/biof.23","article-title":"Melatonin: Signaling mechanisms of a pleiotropic agent","volume":"35","author":"Hardeland","year":"2009","journal-title":"Biofactors"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20058","DOI":"10.1074\/jbc.M311137200","article-title":"Regulation of purified and reconstituted connexin 43 hemichannels by protein kinase C-mediated phosphorylation of Serine 368","volume":"279","author":"Bao","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1161\/01.RES.65.5.1426","article-title":"Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study","volume":"65","author":"Lesh","year":"1989","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lee, H.-L., Chang, P.-C., Wo, H.-T., Liu, H.-T., Wen, M.-S., and Chou, C.-C. (2021). Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia\u2013Reperfusion Injury. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.726389"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e12798","DOI":"10.1111\/jpi.12798","article-title":"Melatonin treatment improves ventricular conduction via upregulation of nav1. 5 channel proteins and sodium current in the normal rat heart","volume":"73","author":"Durkina","year":"2022","journal-title":"J. Pineal Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1755-5922.2010.00210.x","article-title":"Sodium channel (dys) function and cardiac arrhythmias","volume":"28","author":"Remme","year":"2010","journal-title":"Cardiovasc. Ther."},{"key":"ref_34","first-page":"483","article-title":"Melatonin does not affect oxidative\/inflammatory biomarkers in a closed-chest porcine model of acute myocardial infarction","volume":"28","author":"Halladin","year":"2014","journal-title":"In Vivo"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Bernikova, O.G., Tsvetkova, A.S., Ovechkin, A.O., Demidova, M.M., Azarov, J.E., and Platonov, P.G. (2022). Ecg markers of acute melatonin treatment in a porcine model of acute myocardial ischemia. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911800"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1177\/107424849800300208","article-title":"The effect of melatonin on hemodynamics, blood flow, and myocardial infarct size in a rabbit model of ischemia-reperfusion","volume":"3","author":"Dave","year":"1998","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1007\/s10517-020-04881-y","article-title":"Preventive administration of melatonin attenuates electrophysiological consequences of myocardial ischemia","volume":"169","author":"Bernikova","year":"2020","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"H2001","DOI":"10.1152\/ajpheart.00987.2003","article-title":"Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall","volume":"286","author":"Poelzing","year":"2004","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.ijcard.2016.07.108","article-title":"Melatonin effects on myocardial ischemia\u2013reperfusion injury: Impact on the outcome in patients undergoing coronary artery bypass grafting surgery","volume":"221","author":"Dwaich","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s40119-022-00287-1","article-title":"Effects of Melatonin on Cardiac Injury and Inflammatory Biomarkers in Patients Undergoing Coronary Artery Bypass Graft Surgery: A Meta-analysis","volume":"12","author":"Farshidianfar","year":"2023","journal-title":"Cardiol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Casper, E.A., Wakeel, L.E., Sabri, N.A., Khorshid, R., Gamal, M.A., and Fahmy, S.F. (2024). Melatonin ameliorates inflammation and improves outcomes of ischemia\/reperfusion injury in patients undergoing coronary artery bypass grafting surgery: A randomized placebo-controlled study. Apoptosis, 1\u201315.","DOI":"10.1007\/s10495-024-02040-6"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1253\/circj.CJ-17-0145","article-title":"Arrhythmogenic delayed afterdepolarizations are promoted by severe hypothermia but not therapeutic hypothermia","volume":"82","author":"Fukaya","year":"2017","journal-title":"Circ. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1152\/ajplegacy.1914.33.3.397","article-title":"The nature of fibrillary contraction of the heart.\u2014Its relation to tissue mass and form","volume":"33","author":"Garrey","year":"1914","journal-title":"Am. J. Physiol.-Leg. Content"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1253\/circj.CJ-10-1001","article-title":"Short-duration therapeutic hypothermia causes prompt connexin43 gap junction remodeling in isolated rabbit hearts","volume":"75","author":"Hsieh","year":"2011","journal-title":"Circ. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/BF00374970","article-title":"Temperature dependence of gap junction properties in neonatal rat heart cells","volume":"423","author":"Bukauskas","year":"1993","journal-title":"Pfl\u00fcgers Arch."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/jpi.12085","article-title":"Melatonin ameliorates vascular endothelial dysfunction, inflammation, and atherosclerosis by suppressing the TLR 4\/NF-\u03baB system in high-fat-fed rabbits","volume":"55","author":"Hu","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1097\/FJC.0000000000000751","article-title":"Single bolus rosuvastatin accelerates calcium uptake and attenuates conduction inhomogeneity in failing rabbit hearts with regional ischemia\u2013reperfusion injury","volume":"75","author":"Chou","year":"2020","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lee, H.-L., Chang, P.-C., Wo, H.-T., Liu, H.-T., Wen, M.-S., and Chou, C.-C. (2024). Eleclazine Suppresses Ventricular Fibrillation in Failing Rabbit Hearts with Ischemia-Reperfusion Injury Undergoing Therapeutic Hypothermia. Pharmacology, 1\u201314.","DOI":"10.1159\/000542292"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chou, C.-C., Lee, H.-L., Chang, G.-J., Wo, H.-T., Yen, T.-H., Wen, M.-S., Chu, Y., Liu, H.-T., and Chang, P.-C. (2020). Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db\/db mice with acute regional ischemia\u2013reperfusion injury. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-77014-0"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/2\/615\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:27:50Z","timestamp":1759919270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/2\/615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,13]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26020615"],"URL":"https:\/\/doi.org\/10.3390\/ijms26020615","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,13]]}}}