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.
abstract: BACKGROUND
  Therapeutic hypothermia (TH) may increase the susceptibility to ventricular arrhythmias by decreasing ventricular conduction velocity (CV) and facilitating arrhythmogenic spatially discordant alternans (SDA).
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that rotigaptide, a gap junction enhancer, can increase ventricular CV, delay the onset of SDA, and decrease the susceptibility to pacing-induced ventricular fibrillation (PIVF) during TH.
  
  
  METHODS
  Langendorff-perfused isolated rabbit hearts were subjected to 30-minute moderate hypothermia (33°C) followed by 20-minute treatment with rotigaptide (300 nM, n = 8) or vehicle (n = 5). The same protocol was also performed at severe hypothermia (30°C; n = 8 for rotigaptide, n = 5 for vehicle). Using an optical mapping system, epicardial CV and SDA threshold were evaluated by S1 pacing. Ventricular fibrillation inducibility was evaluated by burst pacing for 30 seconds at the shortest pacing cycle length (PCL) that achieved 1:1 ventricular capture.
  
  
  RESULTS
  Rotigaptide increased ventricular CV during 33°C (PCL 300 ms, from 76 ± 6 cm/s to 84 ± 7 cm/s, P = .039) and 30°C (PCL 300 ms, from 62 ± 6 cm/s to 68 ± 4 cm/s, P = .008). Rotigaptide decreased action potential duration dispersion at 33°C (P = .01) and 30°C (P = .035). During 30°C, SDA thresholds (P = .042) and incidence of premature ventricular complexes (P = .025) were decreased by rotigaptide. PIVF inducibility was decreased by rotigaptide at 33°C (P = .039) and 30°C (P = .042). Rotigaptide did not change connexin43 expressions and distributions during hypothermia.
  
  
  CONCLUSIONS
  Rotigaptide protects the hearts against ventricular arrhythmias by increasing ventricular CV, delaying the onset of SDA, and reducing repolarization heterogeneity during TH. Enhancing cell-to-cell coupling by rotigaptide might be a novel approach to prevent ventricular arrhythmias during TH.
authors.affiliation: Cardiovascular Center, Taichung Veterans General Hospital and Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Financial and Computational Mathematics, Providence University, Taichung, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Cardiovascular Center, Taichung Veterans General Hospital and Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Jiunn-Cherng
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Cardiovascular Center, Taichung Veterans General Hospital and Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chen-Ying
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Cardiovascular Center, Taichung Veterans General Hospital and Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Cheng-Hung
authors.initials: CH
authors.lastname: Li
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Institute of Biomedical Engineering, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Departments of Internal Medicine and Medical Research, Mackay Memorial Hospital, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Yeh
authors.affiliation: Cardiovascular Center, Taichung Veterans General Hospital and Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Huang
authors.affiliation: Department of Financial and Computational Mathematics, Providence University, Taichung, Taiwan.
authors.forename: Chu-Pin
authors.initials: CP
authors.lastname: Lo
authors.affiliation: Department of Cardiology, Roskilde University Hospital, Roskilde, Denmark.
authors.forename: Ketil
authors.initials: K
authors.lastname: Haugan
authors.affiliation: Zealand Pharma A/S, Glostrup, Denmark.
authors.forename: Bjarne D
authors.initials: BD
authors.lastname: Larsen
authors.affiliation: Cardiovascular Center, Taichung Veterans General Hospital and Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address: tjwu@vghtc.gov.tw.
authors.forename: Tsu-Juey
authors.initials: TJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D018031:Connexin 43 / Q000378:metabolism*; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D007036:Hypothermia, Induced / Q000009:adverse effects*; D008955:Models, Cardiovascular; D009842:Oligopeptides / Q000494:pharmacology*; D011817:Rabbits; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D056969:Voltage-Sensitive Dye Imaging / Q000379:methods
chemical_list: D000889:Anti-Arrhythmia Agents; D018031:Connexin 43; C500216:GJA1 protein, human; D009842:Oligopeptides; C477643:rotigaptide
keywords: Cardiac alternans; Conduction velocity; Gap junction; Hypothermia; Optical mapping