Beat-to-Beat variability of repolarization determines proarrhythmic outcome in dogs susceptible to drug-induced torsades de pointes.
OBJECTIVE
We investigated whether increasing or decreasing beat-to-beat variability of repolarization (BVR) would change drug-induced proarrhythmic outcome accordingly.


BACKGROUND
Increased variability of repolarization has been suggested as a prelude to proarrhythmic circumstances in experimental and clinical situations.


METHODS
The non-cardiovascular, I(Kr)-blocking drug sertindole was administered to anesthetized dogs with chronic atrioventricular block. Three interventions were used to prevent or suppress sertindole-induced torsades de pointes (TdP).


RESULTS
Supratherapeutic doses of sertindole (1.0 mg/kg intravenously) induced TdP in 10 of 13 dogs whereas 0.2 mg/kg induced no TdP, despite increases in QT intervals by both doses. The BVR, quantified as short-term variability (STV) from Poincaré plots, was the only parameter that predicted TdP outcome (1.0 mg/kg sertindole: 2.3 +/- 0.7 ms to 5.1 +/- 2.1 ms, p < 0.05; 0.2 mg/kg sertindole: 2.3 +/- 0.8 ms to 3.2 +/- 1.1 ms, p= NS).


METHODS
1) KCl, intravenous, reduced the incidence of sertindole-induced TdP from 6 of 7 to 1 of 7 dogs (p<0.05) and prevented sertindole-related increase of STV: 3.0 +/- 1.1 ms vs. 4.5 +/- 1.3 ms (p < 0.05); 2) levcromakalim (I(K,ATP) activator) reduced sertindole-induced TdP and decreased STV from 4.9 +/- 2.1 ms to 2.6 +/- 0.9 ms (p < 0.05); 3) steady-state ventricular pacing (60 beats/min) abolished sertindole-induced TdP and decreased STV from 4.9 +/- 1.5 to 3.2 +/- 1.0 (p < 0.05). Torsades de pointes reappeared upon return to non-paced idioventricular rhythm. None of the 3 interventions reduced the sertindole-induced prolonged QT interval.


CONCLUSIONS
Proarrhythmic intervention is related to an increase in BVR, whereas antiarrhythmic treatment is associated with a decrease in BVR. The BVR is superior to QT interval prolongation in the prediction and prevention of drug-induced TdP in this experimental model.
Thomsen
Morten B
MB
Department of Medical Physiology, Heart Lung Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
Volders
Paul G A
PG
Beekman
Jet D M
JD
Matz
Jørgen
J
Vos
Marc A
MA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002304:Cardiac Pacing, Artificial; D019806:Cromakalim / Q000494:pharmacology; D004198:Disease Susceptibility; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D009994:Osmolar Concentration; D011188:Potassium / Q000097:blood; D026902:Potassium Channel Blockers / Q000008:administration & dosage; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D012008:Recurrence; D016171:Torsades de Pointes / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology* / Q000517:prevention & control; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D007211:Indoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019806:Cromakalim; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; C066304:sertindole; D011188:Potassium