{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T12:58:17Z","timestamp":1778849897434,"version":"3.51.4"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T00:00:00Z","timestamp":1631491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p><jats:bold>Aims:<\/jats:bold> Whether therapeutic hypothermia (TH) is proarrhythmic in preexisting failing hearts with acute ischemia\u2013reperfusion (IR) injury is unknown. Additionally, the effectiveness of rotigaptide on improving conduction slowing in hearts with IR injury is ambiguous. We investigated the electrophysiological effects of TH and rotigaptide in failing rabbit hearts with acute IR injury and determined the underlying molecular mechanisms.<\/jats:p><jats:p><jats:bold>Methods and Results:<\/jats:bold> Heart failure was induced by right ventricular pacing (320 beats\/min, 4 weeks). Rabbits with pacing-induced heart failure were randomly divided into TH (<jats:italic>n<\/jats:italic> = 14) and non-TH (<jats:italic>n<\/jats:italic> = 7) groups. The IR rabbit model was created by ligating the coronary artery for 60 min, followed by reperfusion for 15 min <jats:italic>in vivo<\/jats:italic>. Then, the hearts were excised quickly and Langendorff-perfused for simultaneous voltage and intracellular Ca<jats:sup>2+<\/jats:sup> (Ca<jats:sub>i<\/jats:sub>) optical mapping. Electrophysiological studies were conducted, and vulnerability to ventricular fibrillation (VF) was evaluated using pacing protocols. TH (33\u00b0C) was instituted after baseline studies, and electrophysiological studies were repeated. Rotigaptide (300 nM) was infused for 20 min, and electrophysiological studies were repeated under TH. Cardiac tissues were sampled for Western blotting. TH increased the dispersion and beat-to-beat variability of action potential duration (APD), aggravated conduction slowing, and prolonged Ca<jats:sub>i<\/jats:sub> decay to facilitate spatially discordant alternans (SDA) and VF induction. Rotigaptide reduced the dispersion and beat-to-beat variability of APD and improved slowed conduction to defer the onset of arrhythmogenic SDA by dynamic pacing and elevate the pacing threshold of VF during TH. However, the effect of rotigaptide on TH-enhanced VF inducibility was statistically insignificant. TH attenuated IR-induced dysregulation of protein expression, but its functional role remained uncertain.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Therapeutic hypothermia is proarrhythmic in failing hearts with acute IR injury. Rotigaptide improves TH-induced APD dispersion and beat-to-beat variability and conduction disturbance to defer the onset of arrhythmogenic SDA and elevate the VF threshold by dynamic pacing, but these beneficial electrophysiological effects are unable to suppress TH-enhanced VF inducibility significantly.<\/jats:p>","DOI":"10.3389\/fphys.2021.726389","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T05:45:55Z","timestamp":1631511955000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia\u2013Reperfusion Injury"],"prefix":"10.3389","volume":"12","author":[{"given":"Hui-Ling","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Po-Cheng","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-Ta","family":"Wo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao-Tien","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-Shien","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Chuan","family":"Chou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1161\/01.res.0000194329.41863.89","article-title":"Ca2+\/calmodulin\u2013dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure.","volume":"97","author":"Ai","year":"2005","journal-title":"Circ. Res."},{"key":"B2","doi-asserted-by":"crossref","first-page":"H1223","DOI":"10.1152\/ajpheart.00079.2007","article-title":"Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure.","volume":"293","author":"Akar","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B3","doi-asserted-by":"crossref","first-page":"19856","DOI":"10.1074\/jbc.M111.322537","article-title":"Ca2+\/calmodulin-dependent protein kinase II (CaMKII) regulates cardiac sodium channel NaV1. 5 gating by multiple phosphorylation sites.","volume":"287","author":"Ashpole","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1161\/01.res.87.8.656","article-title":"Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia.","volume":"87","author":"Beardslee","year":"2000","journal-title":"Circ. Res."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00096","article-title":"CaMKII-dependent responses to ischemia and reperfusion challenges in the heart.","volume":"5","author":"Bell","year":"2014","journal-title":"Front. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1093\/cvr\/27.6.946","article-title":"Effects of temperature on cycle length dependent changes and restitution of action potential duration in guinea pig ventricular muscle.","volume":"27","author":"Bj\u00f8rnstad","year":"1993","journal-title":"Cardiovasc. Res."},{"key":"B7","doi-asserted-by":"publisher","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 Archiv."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1111\/pace.13424","article-title":"Inhomogeneous Down-regulation of INa underlies piceatannol pro-arrhythmic Mechanism in regional ischemia-reperfusion.","volume":"41","author":"Chang","year":"","journal-title":"Pacing Clin. Electrophysiol."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/6032631","article-title":"LCZ696 therapy reduces ventricular tachyarrhythmia inducibility in a myocardial infarction-induced heart failure rat model.","volume":"2019","author":"Chang","year":"2019","journal-title":"Cardiovasc. Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1097\/fjc.0000000000000598","article-title":"Paradoxical effects of sodium\u2013calcium exchanger inhibition on torsade de pointes and early afterdepolarization in a heart failure rabbit model.","volume":"72","author":"Chang","year":"","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B11","first-page":"1","article-title":"Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db\/db mice with acute regional ischemia\u2013reperfusion injury.","volume":"10","author":"Chou","year":"","journal-title":"Sci. Rep."},{"key":"B12","doi-asserted-by":"publisher","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":"","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1113\/jphysiol.2006.120659","article-title":"Remodelling of action potential and intracellular calcium cycling dynamics during subacute myocardial infarction promotes ventricular arrhythmias in Langendorff-perfused rabbit hearts.","volume":"580","author":"Chou","year":"2007","journal-title":"J. Physiol."},{"key":"B14","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.120.020006","article-title":"Rotigaptide infusion for the first 7 days after myocardial infarction\u2013reperfusion reduced late complexity of myocardial architecture of the healing border-zone and arrhythmia inducibility.","volume":"10","author":"Chowdhury","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"B15","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.cardiores.2004.01.033","article-title":"Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis.","volume":"62","author":"De Groot","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1006\/jmcc.2000.1308","article-title":"Altered connexin expression in human congestive heart failure.","volume":"33","author":"Dupont","year":"2001","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B17","doi-asserted-by":"crossref","first-page":"H1035","DOI":"10.1152\/ajpheart.00786.2011","article-title":"Physiology C. 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":"B18","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.1016\/j.hrthm.2008.08.030","article-title":"Electrophysiological mechanisms of antiarrhythmic protection during hypothermia in winter hibernating versus nonhibernating mammals.","volume":"5","author":"Fedorov","year":"2008","journal-title":"Heart Rhythm"},{"key":"B19","doi-asserted-by":"publisher","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":"B20","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.112.004234","article-title":"Delayed treatment with hypothermia protects against the no-reflow phenomenon despite failure to reduce infarct size.","volume":"2","author":"Hale","year":"2013","journal-title":"J. Am. Heart Assoc."},{"key":"B21","doi-asserted-by":"crossref","first-page":"H565","DOI":"10.1152\/ajpheart.00209.2010","article-title":"Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart.","volume":"300","author":"Harada","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1529\/biophysj.106.091009","article-title":"Dynamic origin of spatially discordant alternans in cardiac tissue.","volume":"92","author":"Hayashi","year":"2007","journal-title":"Biophys. J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1124\/jpet.105.096933","article-title":"Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia\/reperfusion injury in open-chest dogs.","volume":"317","author":"Hennan","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.amjcard.2010.02.033","article-title":"Usefulness of short-term variability of QT intervals as a predictor for electrical remodeling and proarrhythmia in patients with nonischemic heart failure.","volume":"106","author":"Hinterseer","year":"2010","journal-title":"Am. J. Cardiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.hrthm.2015.07.023","article-title":"Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts.","volume":"13","author":"Hsieh","year":"2016","journal-title":"Heart Rhythm"},{"key":"B26","doi-asserted-by":"publisher","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":"B27","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1056\/nejmoa012689","article-title":"Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.","volume":"346","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1085\/jgp.89.2.239","article-title":"Temperature dependence of Na currents in rabbit and frog muscle membranes.","volume":"89","author":"Kirsch","year":"1987","journal-title":"J. Gen. Physiol."},{"key":"B29","doi-asserted-by":"crossref","first-page":"H41","DOI":"10.1152\/ajpheart.01089.2006","article-title":"Maintenance of intercellular coupling by the antiarrhythmic peptide rotigaptide suppresses arrhythmogenic discordant alternans.","volume":"294","author":"Kj\u00f8lbye","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1097\/00005344-200211000-00015","article-title":"Anti-arrhythmic peptide N-3-(4-hydroxyphenyl) propionyl Pro-Hyp-Gly-Ala-Gly-OH reduces dispersion of action potential duration during ischemia\/reperfusion in rabbit hearts.","volume":"40","author":"Kj\u00f8lbye","year":"2002","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B31","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1161\/01.CIR.67.6.1356","article-title":"Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations.","volume":"67","author":"Kuo","year":"1983","journal-title":"Circulation"},{"key":"B32","doi-asserted-by":"publisher","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":"B33","doi-asserted-by":"publisher","DOI":"10.5114\/aoms.2012.31385","article-title":"Electrophysiological effect of rotigaptide in rabbits with heart failure.","volume":"10","author":"Liu","year":"2014","journal-title":"Arch. Med. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.2174\/1381612820666141029102443","article-title":"Role of gap junction channel in the development of beat-to-beat action potential repolarization variability and arrhythmias.","volume":"21","author":"Magyar","year":"2015","journal-title":"Curr. Pharm. Design"},{"key":"B35","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":"B36","doi-asserted-by":"crossref","first-page":"H199","DOI":"10.1152\/ajpheart.00387.2012","article-title":"Ca2+\/calmodulin-dependent protein kinase II increases the susceptibility to the arrhythmogenic action potential alternans in spontaneously hypertensive rats.","volume":"307","author":"Mitsuyama","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B37","doi-asserted-by":"crossref","first-page":"H886","DOI":"10.1152\/ajpheart.00298.2016","article-title":"Mild hypothermia preserves myocardial conduction during ischemia by maintaining gap junction intracellular communication and Na+ channel function.","volume":"312","author":"Nassal","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2200","DOI":"10.1152\/japplphysiol.01035.2001","article-title":"Selected contribution: hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis.","volume":"92","author":"Ning","year":"2002","journal-title":"J. Appl. Physiol."},{"key":"B39","doi-asserted-by":"crossref","first-page":"531","DOI":"10.4244\/EIJ-D-17-00279","article-title":"COOL AMI EU pilot trial: a multicentre, prospective, randomised controlled trial to assess cooling as an adjunctive therapy to percutaneous intervention in patients with acute myocardial infarction.","volume":"13","author":"Noc","year":"2017","journal-title":"EuroIntervention"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1161\/01.res.87.12.1157","article-title":"Role of structural barriers in the mechanism of alternans-induced reentry.","volume":"87","author":"Pastore","year":"2000","journal-title":"Circ. Res."},{"key":"B41","doi-asserted-by":"crossref","first-page":"H1762","DOI":"10.1152\/ajpheart.00346.2004","article-title":"Physiology C. Altered connexin43 expression produces arrhythmia substrate in heart failure.","volume":"287","author":"Poelzing","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1161\/01.cir.102.14.1664","article-title":"Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue.","volume":"102","author":"Qu","year":"2000","journal-title":"Circulation"},{"key":"B43","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/j.amjcard.2019.05.055","article-title":"Risk of mortality associated with therapeutic hypothermia among sudden cardiac arrest survivors with known heart failure.","volume":"124","author":"Qureshi","year":"2019","journal-title":"Am. J. Cardiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1016\/j.cardiores.2003.12.007","article-title":"Gap junction alterations in human cardiac disease.","volume":"62","author":"Severs","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1472","DOI":"10.1016\/j.athoracsur.2006.04.061","article-title":"Reduction and redistribution of gap and adherens junction proteins after ischemia and reperfusion.","volume":"82","author":"Tansey","year":"2006","journal-title":"Ann. Thor. Surg."},{"key":"B46","doi-asserted-by":"publisher","first-page":"28197","DOI":"10.1074\/jbc.m102548200","article-title":"Role of sodium channel deglycosylation in the genesis of cardiac arrhythmias in heart failure.","volume":"276","author":"Ufret-Vincenty","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.656516","article-title":"Role of reduced sarco-endoplasmic reticulum Ca2+-ATPase function on sarcoplasmic reticulum Ca2+ alternans in the intact rabbit heart.","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Physiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.hrthm.2008.11.008","article-title":"Heart failure enhances susceptibility to arrhythmogenic cardiac alternans.","volume":"6","author":"Wilson","year":"2009","journal-title":"Heart Rhythm"},{"key":"B49","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1046\/j.1540-8167.2003.02329.x","article-title":"ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs.","volume":"14","author":"Xing","year":"2003","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.642843","article-title":"Effects of therapeutic hypothermia on normal and ischemic heart.","volume":"8","author":"Yamada","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"B51","doi-asserted-by":"crossref","first-page":"H677","DOI":"10.1152\/ajpheart.2000.278.3.H677","article-title":"Physiology C. Beat-to-beat repolarization variability in ventricular myocytes and its suppression by electrical coupling.","volume":"278","author":"Zaniboni","year":"2000","journal-title":"Am. J. Physiol. Heart Circ. Physiol."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.726389\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T05:46:03Z","timestamp":1631511963000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.726389\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,13]]},"references-count":51,"alternative-id":["10.3389\/fphys.2021.726389"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.726389","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,13]]},"article-number":"726389"}}