Frequency-dependent electrophysiologic effects of amiodarone in humans.
Frequency-dependent electrophysiologic effects of amiodarone in humans.
复制标题
胺碘酮对人体的频率依赖性电生理效应。
作者：
P. T. Sager;P. Uppal;Christopher Follmer;M. Antimisiaris;Clara Pruitt;Bramahn . Singh
背景
一般而言，延长动作电位时程（APD）的抗心律失常药物在短周期长度下对复极的影响减弱（反向频率依赖性），这可能限制其控制室性心律失常的疗效。胺碘酮对复极的频率依赖性效应可能不同于其他抗心律失常药物，尚未在人体中确定。
方法和结果
在19例患者的电生理研究中，在无药物基线和胺碘酮负荷11天后（1621 +/- 162 mg/d，A组）以及在胺碘酮长期治疗≥ 1年后（380 +/- 56 mg/d，B组）的另外15例患者中，测定了胺碘酮对复极和传导的频率依赖性效应。两组在所有临床特征方面相似。在300至600毫秒的起搏周期长度下测定心室90%复极化时的APD（APD 90）、右心室有效不应期（VERP）和QRS时限。在A组中，胺碘酮显著（10%至13%，P <0.001）增加了APD 90在所有起搏周期长度与基线相比约30毫秒。同样，对VERP的百分比增加没有频率依赖性影响。然而，在较长的起搏周期长度下胺碘酮诱导的VERP幅度延长大于较短的周期长度（P = .04），尽管在最短的起搏周期长度（300毫秒）下VERP仍显著延长33 +/- 22毫秒（较基线增加16.9%，P < .001）。与基线测量值相比，胺碘酮显著（P <0.01）增加了起搏周期长度≤ 500毫秒时的QRS时限，最多增加28%。心室传导时间的增加是频率依赖性的（P <0.01），与显著的钠通道阻滞一致。胺碘酮（与基线相比）在周期长度>或= 400毫秒时显著延长VERP/APD 90比值（在两倍舒张阈值下测定），表明对不应性的时间和电压依赖性效应。胺碘酮负荷后A组患者诱导的持续性室性心动过速周期长度增加与VERP增加显著相关（r = 0.68，P = 0.044），但与QRS时限或APD 90增加无关。此外，胺碘酮的频率依赖性效应在A组和B组之间无显著差异。
结论
负荷治疗11天或长期治疗≥ 1年后，胺碘酮电生理效应的频率依赖性反应相似。胺碘酮对心室复极不产生频率依赖性作用;它通过时间和电压依赖性机制抑制不应性，并对心室传导产生频率依赖性作用。胺碘酮诱导的对复极的反向频率依赖性效应的缺失及其对不应期的时间依赖性效应可能部分解释了该药物的高疗效及其引起尖端扭转型室性心动过速的低倾向。
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.
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