{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T21:42:18Z","timestamp":1776894138253,"version":"3.51.2"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology of Taiwan","doi-asserted-by":"crossref","award":["109-2314-B-075 -076 -MY3, 111-2314-B-075 -007 -MY3"],"award-info":[{"award-number":["109-2314-B-075 -076 -MY3, 111-2314-B-075 -007 -MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Amiodarone is commonly used during therapeutic hypothermia (TH) following cardiac arrest due to ventricular arrhythmias. However, electrophysiological changes and proarrhythmic risk after amiodarone treatment have not yet been explored in TH.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Epicardial high-density bi-ventricular mapping was performed in pigs under baseline temperature (BT), TH (32\u201334\u00b0C), and amiodarone treatment during TH. The total activation time (TAT), conduction velocity (CV), local electrogram (LE) duration, and wavefront propagation from pre-specified segments were analyzed during sinus rhythm (SR) or right ventricular (RV) pacing (RVP), along with tissue expression of connexin 43. The vulnerability to ventricular arrhythmias was assessed.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Compared to BT, TH increased the global TAT, decreased the CV, and generated heterogeneous electrical substrate during SR and RVP. During TH, the CV reduction and LE duration prolongation were greater in the anterior mid RV than in the other areas, which changed the wavefront propagation in all animals. Compared to TH alone, amiodarone treatment during TH further increased the TAT and LE duration and decreased the CV. Heterogeneous conduction was partially attenuated after amiodarone treatment. After TH and amiodarone treatment, the connexin 43 expression in the anterior mid RV was lower than that in the other areas, compatible with the heterogeneous CV reduction. The animals under TH and amiodarone treatment had a higher incidence of inducible ventricular arrhythmias than those under BT or TH without amiodarone.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Electrical heterogeneity during amiodarone treatment and TH was associated with vulnerability to ventricular arrhythmias.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0282943","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T18:08:13Z","timestamp":1682014093000},"page":"e0282943","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epicardial electrical heterogeneity after amiodarone treatment increases vulnerability to ventricular arrhythmias under therapeutic hypothermia"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3282-7523","authenticated-orcid":true,"given":"Chin-Yu","family":"Lin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting-Yung","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5715-2070","authenticated-orcid":true,"given":"Yu-Feng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Cheng","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Jen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-I","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yenn-Jiang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shih-Lin","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Wei","family":"Lo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tze-Fan","family":"Chao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fa-Po","family":"Chung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo-Nan","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ta-Chuan","family":"Tuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shih-Ann","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,4,20]]},"reference":[{"key":"pone.0282943.ref001","doi-asserted-by":"crossref","first-page":"S465","DOI":"10.1161\/CIR.0000000000000262","article-title":"Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care","volume":"132","author":"CW Callaway","year":"2015","journal-title":"Circulation"},{"key":"pone.0282943.ref002","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1056\/NEJMoa003289","article-title":"Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia","volume":"346","author":"SA Bernard","year":"2002","journal-title":"N Engl J Med"},{"key":"pone.0282943.ref003","doi-asserted-by":"crossref","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":"pone.0282943.ref004","doi-asserted-by":"crossref","first-page":"e016676","DOI":"10.1161\/JAHA.120.016676","article-title":"Effect of Amiodarone and Hypothermia on Arrhythmia Substrates During Resuscitation","volume":"10","author":"JS Piktel","year":"2021","journal-title":"J Am Heart Assoc"},{"key":"pone.0282943.ref005","first-page":"228","article-title":"Effects of hypothermia on the repolarization duration of ventricular myocytes in rats and its mechanism","volume":"36","author":"XK Fu","year":"2020","journal-title":"Zhongguo Ying Yong Sheng Li Xue Za Zhi"},{"key":"pone.0282943.ref006","first-page":"325","article-title":"Transient outward potassium current and repolarization of cardiac cells","volume":"182","author":"E Coraboeuf","year":"1998","journal-title":"Bull Acad Natl Med"},{"key":"pone.0282943.ref007","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":"YC Hsieh","year":"2011","journal-title":"Circ J"},{"key":"pone.0282943.ref008","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.cardiores.2003.09.016","article-title":"Reduced reactive O2 species formation and preserved mitochondrial NADH and [Ca2+] levels during short-term 17 degrees C ischemia in intact hearts","volume":"61","author":"ML Riess","year":"2004","journal-title":"Cardiovasc Res"},{"key":"pone.0282943.ref009","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0008-6363(97)00114-4","article-title":"Cellular electropharmacology of amiodarone","volume":"35","author":"I Kodama","year":"1997","journal-title":"Cardiovasc Res"},{"key":"pone.0282943.ref010","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/00005344-199407000-00020","article-title":"Chronic versus acute effects of amiodarone on the Vmax-conduction velocity relationship and on the space constant in canine myocardium","volume":"24","author":"RA Quinteiro","year":"1994","journal-title":"J Cardiovasc Pharmacol"},{"key":"pone.0282943.ref011","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1161\/01.CIR.78.3.684","article-title":"Mechanisms of depressed conduction from long-term amiodarone therapy in canine myocardium","volume":"78","author":"JH Levine","year":"1988","journal-title":"Circulation"},{"key":"pone.0282943.ref012","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1161\/01.CIR.100.19.2025","article-title":"Evidence-based analysis of amiodarone efficacy and safety","volume":"100","author":"SJ Connolly","year":"1999","journal-title":"Circulation"},{"key":"pone.0282943.ref013","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1093\/cvr\/cvy305","article-title":"Hypothermia and cardiac electrophysiology: a systematic review of clinical and experimental data","volume":"115","author":"ES Dietrichs","year":"2019","journal-title":"Cardiovasc Res"},{"key":"pone.0282943.ref014","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1097\/00005344-199012000-00006","article-title":"Effects of amiodarone on cardiac electrophysiology and inducibility of arrhythmias in chronically infarcted dogs: late arrhythmias, haemodynamics, and sympatholytic actions","volume":"16","author":"E Winslow","year":"1990","journal-title":"J Cardiovasc Pharmacol"},{"key":"pone.0282943.ref015","doi-asserted-by":"crossref","first-page":"82G","DOI":"10.1016\/S0002-9149(97)00717-0","article-title":"Proarrhythmia with class III antiarrhythmic drugs: types, risks, and management.","volume":"80","author":"SH Hohnloser","year":"1997","journal-title":"Am J Cardiol"},{"key":"pone.0282943.ref016","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1093\/europace\/eup233","article-title":"Amiodarone use in therapeutic hypothermia following cardiac arrest due to ventricular tachycardia and ventricular fibrillation.","volume":"11","author":"JN Khan","year":"2009","journal-title":"Europace."},{"key":"pone.0282943.ref017","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.hrthm.2015.07.030","article-title":"A swine model of infarct-related reentrant ventricular tachycardia: Electroanatomic, magnetic resonance, and histopathological characterization","volume":"13","author":"CM Tschabrunn","year":"2016","journal-title":"Heart Rhythm"},{"key":"pone.0282943.ref018","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.hrthm.2010.10.044","article-title":"Accuracy of combined endocardial and epicardial electroanatomic mapping of a reperfused porcine infarct model: a comparison of electrofield and magnetic systems with histopathologic correlation","volume":"8","author":"R Tung","year":"2011","journal-title":"Heart Rhythm"},{"key":"pone.0282943.ref019","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1053\/j.jvca.2012.11.026","article-title":"Therapeutic hypothermia for out-of-hospital ventricular fibrillation survivors: a feasibility study comparing time to achieve target core temperature using conventional conductive cooling versus combined conductive plus pericranial convective cooling.","volume":"27","author":"CT Wass","year":"2013","journal-title":"J Cardiothorac Vasc Anesth"},{"key":"pone.0282943.ref020","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1097\/00005344-199909000-00019","article-title":"A comparison of the antifibrillatory effects of desethylamiodarone to amiodarone in a swine model","volume":"34","author":"L Zhou","year":"1999","journal-title":"J Cardiovasc Pharmacol"},{"key":"pone.0282943.ref021","first-page":"347","article-title":"QRS duration and dispersion for predicting ventricular arrhythmias in early stage of acute myocardial infraction.","volume":"41","author":"E Chavez-Gonzalez","year":"2017","journal-title":"Med Intensiva"},{"key":"pone.0282943.ref022","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1136\/hrt.63.6.342","article-title":"QT dispersion: an indication of arrhythmia risk in patients with long QT intervals","volume":"63","author":"CP Day","year":"1990","journal-title":"Br Heart J"},{"key":"pone.0282943.ref023","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1016\/j.jacc.2005.12.049","article-title":"Tpeak-Tend and Tpeak-Tend dispersion as risk factors for ventricular tachycardia\/ventricular fibrillation in patients with the Brugada syndrome","volume":"47","author":"J Castro Hevia","year":"2006","journal-title":"J Am Coll Cardiol"},{"key":"pone.0282943.ref024","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1161\/CIRCEP.113.000833","article-title":"Novel algorithmic methods in mapping of atrial and ventricular tachycardia.","volume":"7","author":"M El Haddad","year":"2014","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"pone.0282943.ref025","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1161\/CIRCULATIONAHA.119.042423","article-title":"Targeted Ablation of Ventricular Tachycardia Guided by Wavefront Discontinuities During Sinus Rhythm: A New Functional Substrate Mapping Strategy","volume":"140","author":"Z Aziz","year":"2019","journal-title":"Circulation"},{"key":"pone.0282943.ref026","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.hrthm.2009.04.030","article-title":"EHRA\/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA).","volume":"6","author":"EM Aliot","year":"2009","journal-title":"Heart Rhythm."},{"key":"pone.0282943.ref027","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1016\/j.hrthm.2017.08.016","article-title":"The identification of conduction gaps after pulmonary vein isolation using a new electroanatomic mapping system","volume":"14","author":"M Masuda","year":"2017","journal-title":"Heart Rhythm"},{"key":"pone.0282943.ref028","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1161\/hc0402.102975","article-title":"Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association","volume":"105","author":"MD Cerqueira","year":"2002","journal-title":"Circulation"},{"key":"pone.0282943.ref029","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.117.006472","article-title":"Hypothermia Modulates Arrhythmia Substrates During Different Phases of Resuscitation From Ischemic Cardiac Arrest","volume":"6","author":"JS Piktel","year":"2017","journal-title":"J Am Heart Assoc"},{"key":"pone.0282943.ref030","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1161\/CIRCEP.110.960658","article-title":"Prolonged Tpeak-to-tend interval on the resting ECG is associated with increased risk of sudden cardiac death.","volume":"4","author":"R Panikkath","year":"2011","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"pone.0282943.ref031","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/0002-8703(84)90451-4","article-title":"Electrophysiologic effects of amiodarone: experimental and clinical observation relative to serum and tissue drug concentrations","volume":"108","author":"N Ikeda","year":"1984","journal-title":"Am Heart J"},{"key":"pone.0282943.ref032","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/S0735-1097(86)80273-X","article-title":"Acute and chronic effects of amiodarone on ventricular refractoriness, intraventricular conduction and ventricular tachycardia induction","volume":"7","author":"F Morady","year":"1986","journal-title":"J Am Coll Cardiol"},{"key":"pone.0282943.ref033","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1161\/01.CIR.91.2.451","article-title":"Pharmacokinetics and regional electrophysiological effects of intracoronary amiodarone administration","volume":"91","author":"JN Nanas","year":"1995","journal-title":"Circulation"},{"key":"pone.0282943.ref034","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0735-1097(85)80272-2","article-title":"Rate-dependent effects of intravenous lidocaine, procainamide and amiodarone on intraventricular conduction","volume":"6","author":"F Morady","year":"1985","journal-title":"J Am Coll Cardiol"},{"key":"pone.0282943.ref035","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1152\/physrev.00025.2003","article-title":"Basic mechanisms of cardiac impulse propagation and associated arrhythmias","volume":"84","author":"AG Kleber","year":"2004","journal-title":"Physiol Rev"},{"key":"pone.0282943.ref036","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":"FG Akar","year":"2007","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"pone.0282943.ref037","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1093\/cvr\/cvz309","article-title":"Moderate but not severe hypothermia causes pro-arrhythmic changes in cardiac electrophysiology","volume":"116","author":"ES Dietrichs","year":"2020","journal-title":"Cardiovasc Res"},{"key":"pone.0282943.ref038","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/S0735-1097(98)00330-1","article-title":"Amiodarone reduces transmural heterogeneity of repolarization in the human heart","volume":"32","author":"E Drouin","year":"1998","journal-title":"J Am Coll Cardiol"},{"key":"pone.0282943.ref039","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1038\/s41467-022-28418-1","article-title":"Heterogeneous repolarization creates ventricular tachycardia circuits in healed myocardial infarction scar.","volume":"13","author":"K Kelemen","year":"2022","journal-title":"Nat Commun"},{"key":"pone.0282943.ref040","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0092-8674(01)00243-4","article-title":"Molecular and cellular mechanisms of cardiac arrhythmias","volume":"104","author":"MT Keating","year":"2001","journal-title":"Cell"},{"key":"pone.0282943.ref041","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.hrthm.2011.11.046","article-title":"The peak-to-end of the T wave in the limb ECG leads reflects total spatial rather than transmural dispersion of ventricular repolarization in an anthopleurin-A model of prolonged QT interval","volume":"9","author":"D Izumi","year":"2012","journal-title":"Heart Rhythm"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0282943","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T18:08:43Z","timestamp":1682014123000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0282943"}},"subtitle":[],"editor":[{"given":"Tomohiko","family":"Ai","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,4,20]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0282943","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,20]]}}}