Circulation, Vol 83, 536-545, Copyright © 1991 by American Heart Association
C Funck-Brentano, Y Kibleur, F Le Coz, JM Poirier, A Mallet and P Jaillon
Studies in animals have shown that drug-induced action potential
prolongation with class III antiarrhythmic agents increases with slow
pacing rates. We studied the physiological rate dependence of sotalol
effects on ventricular repolarization, measured as QT interval duration on
the surface electrocardiogram at rest and during a maximal exercise test,
in 10 normal volunteers. In a randomized, crossover study, three dosages of
sotalol (160 mg/24 hr, 320 mg/24 hr, and 640 mg/24 hr) were administered
during 4 days to each subject. In a control period, no drug was
administered. During each period, 50-100 QT intervals were measured over a
wide range of RR intervals recorded at rest and during the course of a
maximal exercise test. Plasma sotalol concentration and beta-adrenoceptor
blockade (percent reduction in peak exercise heart rate from control) were
also measured. The QT-versus-RR relation was fitted to several formulas,
and the overall best fit was used to calculate QT interval duration
normalized for a heart rate of 60 beats/min (QTc) and to analyze the rate
dependence of QT prolongation with sotalol. Sotalol-induced
beta-adrenoceptor blockade and QTc prolongation were dose and concentration
dependent. Sotalol reduced peak exercise heart rate by 13.8 +/- 7% at the
dosage of 320 mg/24 hr and by 25.4 +/- 8% at the dosage of 640 mg/24 hr
(both p less than 0.01). Sotalol prolonged QTc interval by 5.8 +/- 3.7% and
11.8 +/- 3% at these respective dosages (both p less than 0.01). The
concentration of sotalol required to produce minimal (mean QTc
prolongation, 5.6%; confidence interval, 0-11.2%) QTc prolongation (680
ng/ml) tended to be lower than that required for minimal (mean percent
reduction in maximal exercise heart rate, 13.9%; confidence interval,
0-27.8%) beta-blockade (840 ng/ml). QT prolongation with sotalol increased
with increasing RR intervals (i.e., decreasing heart rate) at all dosages.
QT prolongation became statistically significant for RR of 800 msec or more
at all dosages and for RR intervals of 600 msec or more at the dosage of
640 mg/24 hr. This rate dependence altered the relation between QT interval
duration and sotalol plasma concentrations. These results suggest that
sotalol prolongs QTc interval in humans at dosages and concentrations
similar to those required to produce beta-adrenoceptor blockade, QT
prolongation with sotalol is more pronounced when heart rate decreases and
is not apparent during exercise-induced tachycardia, and the relation
between QT prolongation with sotalol and plasma concentrations of the drug
depends on the heart rate at which measurements are made.
ARTICLES
Rate dependence of sotalol-induced prolongation of ventricular repolarization during exercise in humans
Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
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