Dynamic analysis of dofetilide-induced changes in ventricular repolarization.
OBJECTIVE
To use dynamic electrocardiographic (ECG) techniques to study the influence of heart rate on dofetilide-induced QT prolongation among healthy volunteers.


BACKGROUND
The extent to which heart rate modulates QT prolongation induced by the new class III antiarrhythmic drug dofetilide is a matter of debate.


METHODS
Ten healthy volunteers underwent two 24-hour ECG recordings, one in the absence of dofetilide and the other after a single oral dose of 0.5 mg dofetilide. Two 4-hour periods were defined during the second recording: Dh, which corresponded to stable high concentration of the drug, and D1, which corresponded to low concentration of the drug. Corresponding baseline recording periods, Ch and C1, matched by time with Dh and D1 were selected from the control ECG recording in the absence of dofetilide. QT versus R-R relations were compared in the presence and absence of dofetilide. The QT versus R-R relation slope was used as an index of the rate dependence QT prolongation. Rate-independent changes in QT duration were also analyzed.


RESULTS
During Dh, dofetilide induced a mean 12% lengthening of ventricular repolarization. Dynamic ECG analysis showed that this prolongation increased as R-R cycles became longer, a phenomenon known as reverse rate dependence. However, QT prolongation persisted at the shortest (600 ms) R-R cycle length that could be analyzed. During D1, dynamic ECG analysis showed a persistent, although small, effect of dofetilide on both QT prolongation (3%) and reverse rate dependence of this effect.


CONCLUSIONS
Dofetilide prolongs QT duration, and this class III effect is influenced by heart rate. Although dofetilide-induced QT prolongation decreases when the R-R cycle shortens, this reverse rate dependence is only partial because marked QT prolongation persists at an R-R cycle of 600 ms. The results of our study indicated that dynamic ECG techniques can be useful in detection of subtle, drug-induced changes in the duration of ventricular repolarization.
Department of Cardiology, Lariboisière Hospital, Paris, France.
G
G
Lande
P
P
Maison-Blanche
J
J
Fayn
M
M
Ghadanfar
P
P
Coumel
C
C
Funck-Brentano
D000284:Administration, Oral; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D010627:Phenethylamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide