title: Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired torsade de pointes arrhythmias: a comparison between almokalant and d-sotalol using the dog as its own control.
abstract: OBJECTIVE
  We sought to further elucidate the role of early afterdepolarizations (EADs) and interventricular dispersion of repolarization (deltaAPD) in the genesis of acquired torsade de pointes (TdP) arrhythmias.
  
  
  BACKGROUND
  Administration of class III agents can be associated with TdP. We developed a dog model in which TdP can be reproducibly induced by pacing after d-sotalol. This model shows reproducible results over weeks.
  
  
  METHODS
  In 14 anesthetized dogs with chronic complete atrioventricular block, two separate experiments were performed in which d-sotalol (2 mg/kg body weight) or almokalant (0.12 mg/kg) was administered. Monophasic action potentials were simultaneously recorded from the endocardium of the right and left ventricle to register EADs and to measure the action potential duration (APD). DeltaAPD was defined as the APD of the left ventricle minus that of the right ventricle.
  
  
  RESULTS
  Baseline conditions were identical in the serially performed experiments. The cycle length and QT time increased by 16% and 26% after d-sotalol and by 15% and 31% after almokalant, respectively. After both drugs the action potential of the left ventricle prolonged more than that of the right ventricle, thereby increasing deltaAPD (almokalant [mean +/- SD]: 110 +/- 60 ms; d-sotalol: 80 +/- 45 ms, p < 0.05). The incidence of EADs (18 of 22 vs. 11 of 24, p < 0.05) and single ectopic beats (EBs) (1.5 +/- 2 vs. 24 +/- 32, p < 0.01) was more frequently observed after almokalant than after d-sotalol. Moreover, multiple EBs only occurred after almokalant. These beats interfered with the basic rhythm, leading to dynamic changes in left ventricular APD and to additional increases in deltaAPD. Spontaneous TdP was observed in 9 of 14 dogs after almokalant and could be increased to 12 of 14 with programmed electrical stimulation. After d-sotalol, TdP could only be induced by programmed electrical stimulation (5 of 14, p < 0.05).
  
  
  CONCLUSIONS
  In the same dog, almokalant induced more delay in repolarization, more EADs, multiple EBs and more ventricular inhomogeneity in APD than d-sotalol. These changes were related to a higher incidence of TdP and thereby confirm a strong association of the occurrence of EADs, multiple EBs and deltaAPD in the genesis of TdP. These findings also show the possible value of our model for evaluating the proarrhythmic potential of different drugs.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute, University of Limburg, Maastricht, The Netherlands.
authors.forename: S C
authors.initials: SC
authors.lastname: Verduyn
authors.forename: M A
authors.initials: MA
authors.lastname: Vos
authors.forename: J
authors.initials: J
authors.lastname: van der Zande
authors.forename: A
authors.initials: A
authors.lastname: Kulcsàr
authors.forename: H J
authors.initials: HJ
authors.lastname: Wellens
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D008297:Male; D011412:Propanolamines; D012044:Regression Analysis; D013015:Sotalol; D016171:Torsades de Pointes / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D013015:Sotalol; C074334:almokalant