title: Drug-induced torsade de pointes arrhythmias in the chronic AV block dog are perpetuated by focal activity.
abstract: BACKGROUND
  The electrically remodeled canine heart after chronic AV block (CAVB) has a high susceptibility for drug-induced torsade de pointes (TdP) arrhythmias. Although focal mechanisms have been considered for initiation, there is still controversy about whether reentry is the dominant mechanism for perpetuation of TdP. In this animal model with known nonuniform prolongation of repolarization, the mechanism of perpetuation of TdP arrhythmia was explored.
  
  
  RESULTS
  Seventeen TdP-sensitive CAVB and 10 sinus rhythm (SR) dogs were studied. In 6 animals, 66 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Activation times and activation recovery intervals were determined before and during ibutilide-induced TdP. In 12 CAVB and 9 SR dogs, left ventricular (LV) and right ventricular (RV) epicardial electrograms were recorded with a 208-point multiterminal grid electrode allowing conduction velocity (CV) and ventricular effective refractory period (VERP) measurements. Biopsy specimens were processed for connexin43 (Cx43) expression and collagen content. Ventricular myocytes were isolated to determine sodium current (I(Na)) density and cell dimensions. Computer simulations were used to assess the effects of changes therein. In CAVB, VERP and ARI were increased, whereas CV was unaltered in LV. Transversal but not longitudinal CV was increased in RV. I(Na) was reduced by 37% in LV but unaltered in RV. LV and RV cell size were increased, but collagen and Cx43 content remained unchanged. Simulations showed increase in CV of RV as a consequence of increased cell size at normal I(Na). Ibutilide increased ARI, ERP, and maximal transmural dispersion of ERP (45 ± 25 to 120 ± 65 ms; P < 0.05). Twenty-eight of 47 episodes of self-terminating TdP (43 ± 72 beats) were analyzed. The majority (> 90%) of beats were focal; reentry was observed only occasionally.
  
  
  CONCLUSIONS
  Focal activity is the dominant mechanism involved in perpetuation of ibutilide-induced TdP in CAVB dogs based on detailed 3D mapping. This conclusion is in line with unaltered conduction and documented increase in VERP.
authors.affiliation: Department of Medical Physiology and Department of Cardio-Thoracic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boulaksil
authors.forename: Jerome G
authors.initials: JG
authors.lastname: Jungschleger
authors.forename: Gudrun
authors.initials: G
authors.lastname: Antoons
authors.forename: Marien J C
authors.initials: MJ
authors.lastname: Houtman
authors.forename: Teun P
authors.initials: TP
authors.lastname: de Boer
authors.forename: Ronald
authors.initials: R
authors.lastname: Wilders
authors.forename: Jet D
authors.initials: JD
authors.lastname: Beekman
authors.forename: Jos G
authors.initials: JG
authors.lastname: Maessen
authors.forename: Ferenc F
authors.initials: FF
authors.lastname: van der Hulst
authors.forename: Marcel A G
authors.initials: MA
authors.lastname: van der Heyden
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D054537:Atrioventricular Block / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D022062:Electrophysiologic Techniques, Cardiac; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy; D012032:Refractory Period, Electrophysiological; D015222:Sodium Channels / Q000378:metabolism; D013449:Sulfonamides / Q000009:adverse effects*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*; D018497:Ventricular Dysfunction, Right / Q000503:physiopathology*
chemical_list: D000889:Anti-Arrhythmia Agents; D018031:Connexin 43; D015222:Sodium Channels; D013449:Sulfonamides; C067192:ibutilide; D003094:Collagen