Frequency-dependent electrophysiologic effects of amiodarone in humans.
Authors: Sager P T , Uppal P , Follmer C , Antimisiaris M , Pruitt C , Singh B N 
Published: June 2012

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.