title: Beat-to-Beat Variability in Preload Unmasks Latent Risk of Torsade de Pointes in Anesthetized Chronic Atrioventricular Block Dogs.
abstract: BACKGROUND
  Beat-to-beat variability in ventricular repolarization (BVR) associates with increased arrhythmic risk. Proarrhythmic remodeling in the dog with chronic AV-block (CAVB) compromises repolarization reserve and associates with increased BVR, which further increases upon dofetilide infusion and correlates with Torsade de Pointes (TdP) arrhythmias. It was hypothesized that these pro-arrhythmia-associated increases in BVR are induced by beat-to-beat variability in preload.
  
  
  RESULTS
  Left ventricular monophasic action potential duration (LVMAPD) was recorded in acute (AAVB) and CAVB dogs, before and after dofetilide infusion. BVR was quantified as short-term variability of LVMAPD. The PQ-interval was controlled by pacing: either a constant or an alternating preload pattern was established, verified by PV-loop. The effect of the stretch-activated channel blocker, streptomycin, on BVR was evaluated in a second CAVB group. At alternating preload only, BVR was increased after proarrhythmic remodeling (0.45±0.14 ms AAVB vs. 2.2±1.1 ms CAVB, P<0.01). At CAVB, but not at AAVB, dofetilide induced significant proarrhythmia. Preload variability augmented the dofetilide-induced BVR increase at CAVB (+1.5±0.8 ms vs. +0.9±0.9 ms, P=0.058). In the second group, the increase in baseline BVR by alternating preload (0.3±0.03 ms to 1.0±0.8 ms, P<0.01) was abolished by streptomycin (0.5±0.2 ms, P<0.05).
  
  
  CONCLUSIONS
  In CAVB dogs, the inverse relation between BVR and repolarization reserve originates from an augmented sensitivity of ventricular repolarization to beat-to-beat preload changes. Stretch-activated channels appear to be involved in the mechanism of BVR. (Circ J 2016; 80: 1336-1345).
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center.
authors.forename: Thom Rg
authors.initials: TR
authors.lastname: Stams
authors.forename: Peter
authors.initials: P
authors.lastname: Oosterhoff
authors.forename: Atty
authors.initials: A
authors.lastname: Heijdel
authors.forename: Albert
authors.initials: A
authors.lastname: Dunnink
authors.forename: Jet Dm
authors.initials: JD
authors.lastname: Beekman
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Harold Vm
authors.initials: HV
authors.lastname: van Rijen
authors.forename: Marcel Ag
authors.initials: MA
authors.lastname: van der Heyden
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D054537:Atrioventricular Block / Q000503:physiopathology*; D004285:Dogs; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology; D012306:Risk; D013307:Streptomycin / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D016171:Torsades de Pointes / Q000503:physiopathology*
chemical_list: D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide; D013307:Streptomycin