title: Characterization of an anesthetized dog model of transient cardiac ischemia and rapid pacing: a pilot study for preclinical assessment of the potential for proarrhythmic risk of novel drug candidates.
abstract: BACKGROUND
  Preclinical proarrhythmic risk assessment of drug candidates is focused predominantly on arrhythmias arising from repolarization abnormalities. However, drug-induced cardiac conduction slowing is associated with significant risk of life-threatening ventricular arrhythmias, particularly in a setting of cardiac ischemia. Therefore, we optimized and characterized an anesthetized dog model to evaluate the potential proarrhythmic risk of drug candidates in ischemic heart disease patients.
  
  
  METHODS
  Anesthetized dogs were instrumented with atrial and ventricular epicardial electrodes for pacing and measurement of conduction times, and a balloon occluder and flow probe placed around the left anterior descending coronary artery (LAD) distal to the first branch. Conduction times, ECG intervals and incidence of arrhythmias were assessed serially at the end of each dose infusion (flecainide: 0.32, 0.63, 1.25, 2.5 and 5mg/kg, i.v.; dofetilide:1.25, 2.5, 5, 10 and 20 μg/kg, i.v.; or vehicle; n=6/group) both during normal flow (with and without rapid pacing) and during 5-min LAD occlusion (with and without rapid pacing). Compound X, a development candidate with mild conduction slowing activity, was also evaluated.
  
  
  RESULTS
  Flecainide produced pronounced, dose-dependent slowing of conduction that was exacerbated during ischemia and rapid pacing. In addition, ventricular tachycardia (VT) and fibrillation (VF) occurred in 4 of 6 dogs (3 VF @ 0.63 mg/kg; 1VT @ 2.5mg/kg). In contrast, no animals in the vehicle group developed arrhythmias. Dofetilide, a potent IKr blocker that does not slow conduction, prolonged QT interval but did not cause further conduction slowing during ischemia with or without pacing and there were no arrhythmias. Compound X, like flecainide, produced marked conduction slowing and arrhythmias (VT, VF) during ischemia and pacing.
  
  
  CONCLUSIONS
  This model may be useful to more accurately define shifts in safety margins in a setting of ischemia and increased cardiac demand for drugs that slow conduction.
authors.affiliation: Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Research and Development, LLC 1400 McKean Rd, Spring House, PA, USA. Electronic address: bdamiano@its.jnj.com.
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.affiliation: Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, Belgium.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: van der Linde
authors.affiliation: Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Van Deuren
authors.affiliation: Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Somers
authors.affiliation: Nonclinical Biostatistics, Janssen Research and Development, LLC 1400 McKean Rd, Spring House, PA, USA.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Lubomirski
authors.affiliation: Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, Belgium.
authors.forename: Ard
authors.initials: A
authors.lastname: Teisman
authors.affiliation: Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, Belgium.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000008:administration & dosage / Q000009:adverse effects*; D006329:Heart Conduction System / Q000187:drug effects; D017202:Myocardial Ischemia / Q000473:pathology*; D010627:Phenethylamines / Q000008:administration & dosage / Q000009:adverse effects*; D010865:Pilot Projects; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D005424:Flecainide; C063533:dofetilide
keywords: Arrhythmia; Cardiac conduction; Cardiovascular safety; Dofetilide; Dog; Flecainide; Ischemia; Methods; Pacing