title: Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation.
abstract: OBJECTIVE
  Acquired long-QT syndrome in combination with increased beat-to-beat variability of repolarisation duration (BVR) is associated with lethal torsades de pointes arrhythmias (TdP) in dogs with remodelled heart after atrioventricular block (AVB). We evaluated the relative contributions of bradycardia and ventricular remodelling to proarrhythmic BVR with and without pharmacological I(Kr) block in order to identify the individual at risk.
  
  
  METHODS
  Three groups of dogs were used: sinus rhythm dogs (n = 12), dogs with acute AVB (n = 8), and dogs with >3 weeks chronic AVB (n = 27). Under anaesthesia, ECG and monophasic action potential duration (MAPD) were measured. Local BVR was quantified as short-term variability from 30 consecutive left ventricular MAPD (STV = summation absolute value(D(n(i)-D(n+1))/[30 x square root of 2])). All dogs received dofetilide iv.
  
  
  RESULTS
  The slower ventricular rate acutely after AVB affected neither QTc nor STV (288+/-18 to 293+/-38 ms and 0.7+/-0.1 to 0.7+/-0.1 ms, respectively; P = NS for both), whereas ventricular remodelling increased both (to 376+/-46 and 2.3+/-0.6 ms, respectively; P < 0.05 for both). Neither dogs in sinus rhythm nor acute AVB showed any TdP, whereas dofetilide induced TdP in 74% of the chronic-AVB dogs. Dofetilide increased the QTc interval in all groups (19-24%; P < 0.05 for all groups), whereas STV was elevated in chronic-AVB dogs only (to 4.2+/-1.5 ms; P < 0.05) and further confined to inducible chronic-AVB dogs (5.0+/-0.8 versus 1.9+/-0.4 ms for resistant dogs; P < 0.05). Variability of the idioventricular rate was increased directly after AVB and did not influence BVR.
  
  
  CONCLUSIONS
  Under drug-free circumstances, a persistent high BVR in chronic-AVB dogs is remodelling dependent rather than a direct consequence of bradycardia acutely after AVB. Variability of this slower rate does not influence BVR. Dofetilide causes a transient increase in BVR only in proarrhythmic dogs. Thus, BVR may aid the identification of the TdP-susceptible patient.
authors.affiliation: Department of Medical Physiology, Yalelaan 50, NL-3584 CM Utrecht, The Netherlands.
authors.forename: Morten B
authors.initials: MB
authors.lastname: Thomsen
authors.forename: Avram
authors.initials: A
authors.lastname: Oros
authors.forename: Marieke
authors.initials: M
authors.lastname: Schoenmakers
authors.forename: Jurren M
authors.initials: JM
authors.lastname: van Opstal
authors.forename: Joep N
authors.initials: JN
authors.lastname: Maas
authors.forename: Jet D M
authors.initials: JD
authors.lastname: Beekman
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000200:Action Potentials; D000208:Acute Disease; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006327:Heart Block / Q000503:physiopathology; D006329:Heart Conduction System / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D010627:Phenethylamines / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D016171:Torsades de Pointes / Q000503:physiopathology; D020257:Ventricular Remodeling
chemical_list: D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide