title: Intrathecal clonidine reduces the incidence of ischemia-provoked ventricular arrhythmias in a canine postinfarction heart failure model.
abstract: BACKGROUND
  Intrathecal clonidine (ITC) is used clinically to manage neuropathic pain but frequently causes hypotension and bradycardia due to centrally mediated sympatholytic effects.
  
  
  OBJECTIVE
  The purpose of this study was to evaluate the cardiac electrophysiologic effects of thoracic ITC and its effects on ischemia-provoked ventricular arrhythmias.
  
  
  METHODS
  Twelve mongrel dogs with healed myocardial infarctions and heart failure were evaluated. ITC was delivered locally via catheter to the T2-T4 spinal segments and was dosed to reduce heart rate (HR) by >20% to 25%. Electrophysiologic testing was performed before and after ITC. Transient (4-minute) myocardial ischemia was induced via left circumflex coronary artery occlusion on two separate occasions to provoke ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]). Ischemic episodes were separated by 1 to 2 days, and dogs were randomly assigned to receive ITC or intrathecal saline flush (control) prior to the first or the second ischemic episode.
  
  
  RESULTS
  ITC produced significant decrease in HR (31%) and increases in PR interval (22%), Wenckebach cycle length (122%), and atrial and ventricular effective refractory periods (19% and 9%, respectively) but had no significant effect on systemic blood pressure. The occurrence of VT/VF was reduced from 9 of 12 to 3 of 12 dogs when ITC was administered prior to transient myocardial ischemia (P = .04). ITC also blunted ischemia-induced HR increase by 74%.
  
  
  CONCLUSIONS
  ITC reduced ischemia-induced VT/VF in a canine model of healed myocardial infarction with superimposed heart failure and acute ischemia. Results from electrophysiologic testing were consistent with a clonidine-induced reduction in cardiac sympathetic activity from the spinal cord. These data suggest that ITC administration may be a novel approach to treating ventricular arrhythmias.
authors.affiliation: Krannert Institute of Cardiology, Indiana University, Indianapolis, Indiana 46202, USA.
authors.forename: Ziad F
authors.initials: ZF
authors.lastname: Issa
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ujhelyi
authors.forename: Keith R
authors.initials: KR
authors.lastname: Hildebrand
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhou
authors.forename: Josh
authors.initials: J
authors.lastname: Rosenberger
authors.forename: William J
authors.initials: WJ
authors.lastname: Groh
authors.forename: John M
authors.initials: JM
authors.lastname: Miller
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Zipes
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004285:Dogs; D022062:Electrophysiologic Techniques, Cardiac; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006339:Heart Rate / Q000187:drug effects; D007278:Injections, Spinal; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D010138:Pacemaker, Artificial; D017180:Tachycardia, Ventricular / Q000503:physiopathology / Q000517:prevention & control*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000628:therapy; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000316:Adrenergic alpha-Agonists; D003000:Clonidine