FREQUENCY-DEPENDENT ELECTROPHYSIOLOGIC EFFECTS OF AMIODARONE IN HUMANS

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 tho se of other antiarrhythmic agents and have not been determined in huma ns. Methods and Results. The frequency-dependent effects of amiodarone on repolarization and conduction were determined during electrophysio logic 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 pat ients after greater-than-or-equal-to 1 year of chronic amiodarone ther apy (380+/-56 mg/d, group B). The two groups were similar in all clini cal characteristics. The ventricular APD at 90% repolarization (APD90) , right ventricular effective refractory period (VERP), and QRS durati on were determined at paced cycle lengths of 300 to 600 milliseconds. In group A, amiodarone significantly (10% to 13%, P<.001) increased th e APD90 at all paced cycle lengths by approximately 30 milliseconds co mpared with baseline. Similarly, there were no frequency-dependent eff ects on the percent increase in VERP. However, there was greater amiod arone-induced prolongation of the VERP magnitude at longer paced cycle lengths than at shorter cycle lengths (P=.04), although the VERP rema ined significantly prolonged at the shortest paced cycle length (300 m illiseconds) by 33+/-22 milliseconds (16.9% increase from baseline, P< .001). Amiodarone significantly (P<.01) increased the QRS duration at paced cycle lengths less-than-or-equal-to 500 milliseconds by a maximu m of 28% compared with baseline measurements. The increase in ventricu lar conduction time was frequency dependent (P<.01), consistent with s ignificant sodium channel blockade. The VERP/APD90 ratio (determined a t twice diastolic threshold) was significantly prolonged by amiodarone (as compared with baseline) at cycle lengths greater-than-or-equal-to 400 milliseconds, indicative of both time- and voltage-dependent effe cts on refractoriness. The increase in induced sustained ventricular t achycardia cycle length in group A patients after amiodarone loading w as significantly correlated with the increase in VERP (r=.68, P=.044) but not with increases in QRS duration or APD90. In addition, there we re no significant differences in frequency-dependent effects of amioda rone between groups A and B. Conclusions. The frequency-dependent resp onse of the electrophysiologic effects of amiodarone are similar after 11 days of loading or greater-than-or-equal-to 1 year of chronic ther apy. Amiodarone does not exert frequency-dependent effects on ventricu lar repolarization; it prolongs refractoriness by both time- and volta ge-dependent mechanisms and exerts frequency-dependent effects on vent ricular conduction. The absence of amiodarone-induced reverse frequenc y-dependent effects on repolarization, together with its time-dependen t effects on refractoriness may account in part for the high efficacy of the drug and its low propensity to cause torsade de pointes.