Premium
Dynamic analysis of dofetilide‐induced changes in ventricular repolarization
Author(s) -
Lande Gilles,
MaisonBlanche Pierre,
Fayn Jocelyne,
Ghadanfar Mathieu,
Coumel Philippe,
FunckBrentano Christian
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90180-1
Subject(s) - dofetilide , ventricular repolarization , repolarization , cardiology , medicine , qt interval , electrophysiology
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: D h , which corresponded to stable high concentration of the drug, and D 1 , which corresponded to low concentration of the drug. Corresponding baseline recording periods, C h and C 1 , matched by time with D h and D 1 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 of QT prolongation. Rate‐independent changes in QT duration also were analyzed. Results During D h , 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 D 1 , 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. Clinical Pharmacology & Therapeutics (1998) 64 , 312–321; doi: