Circulation, Vol 88, 1063-1071, Copyright © 1993 by American Heart Association
PT Sager, P Uppal, C Follmer, M Antimisiaris, C Pruitt and BN Singh
BACKGROUND. In general, antiarrhythmic agents that prolong the action
potential duration (APD) have attenuated effects on repolarization at short
cycle lengths (reverse frequency dependence), and this may limit their
efficacy for controlling ventricular arrhythmias. The frequency- dependent
effects of amiodarone on repolarization may differ from those of other
antiarrhythmic agents and have not been determined in humans. METHODS AND
RESULTS. The frequency-dependent effects of amiodarone on repolarization
and conduction were determined during electrophysiologic study in 19
patients at drug-free baseline and after 11 days of amiodarone loading
(1621 +/- 162 mg/d, group A) and in 15 additional patients after > or =
1 year of chronic amiodarone therapy (380 +/- 56 mg/d, group B). The two
groups were similar in all clinical characteristics. The ventricular APD at
90% repolarization (APD90), right ventricular effective refractory period
(VERP), and QRS duration were determined at paced cycle lengths of 300 to
600 milliseconds. In group A, amiodarone significantly (10% to 13%, P <
.001) increased the APD90 at all paced cycle lengths by approximately 30
milliseconds compared with baseline. Similarly, there were no
frequency-dependent effects on the percent increase in VERP. However, there
was greater amiodarone-induced prolongation of the VERP magnitude at longer
paced cycle lengths than at shorter cycle lengths (P = .04), although the
VERP remained significantly prolonged at the shortest paced cycle length
(300 milliseconds) by 33 +/- 22 milliseconds (16.9% increase from baseline,
P < .001). Amiodarone significantly (P < .01) increased the QRS
duration at paced cycle lengths < or = 500 milliseconds by a maximum of
28% compared with baseline measurements. The increase in ventricular
conduction time was frequency dependent (P < .01), consistent with
significant sodium channel blockade. The VERP/APD90 ratio (determined at
twice diastolic threshold) was significantly prolonged by amiodarone (as
compared with baseline) at cycle lengths > or = 400 milliseconds,
indicative of both time- and voltage-dependent effects on refractoriness.
The increase in induced sustained ventricular tachycardia cycle length in
group A patients after amiodarone loading was significantly correlated with
the increase in VERP (r = .68, P = .044) but not with increases in QRS
duration or APD90. In addition, there were no significant differences in
frequency- dependent effects of amiodarone between groups A and B.
CONCLUSIONS. The frequency-dependent response of the electrophysiologic
effects of amiodarone are similar after 11 days of loading or > or = 1
year of chronic therapy. Amiodarone does not exert frequency-dependent
effects on ventricular repolarization; it prolongs refractoriness by both
time- and voltage-dependent mechanisms and exerts frequency-dependent
effects on ventricular conduction. The absence of amiodarone-induced
reverse frequency-dependent effects on repolarization, together with its
time- dependent effects on refractoriness may account in part for the high
efficacy of the drug and its low propensity to cause torsade de pointes.
ARTICLES
Frequency-dependent electrophysiologic effects of amiodarone in humans
Division of Cardiology, Veterans Affairs Medical Center of West Los Angeles, CA 90073.
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