Arrhythmogenic effects of arsenic trioxide in patients with acute promyelocytic leukemia and an electrophysiological study in isolated guinea pig papillary muscles.
Arrhythmogenic effects of arsenic trioxide in patients with acute promyelocytic leukemia and an electrophysiological study in isolated guinea pig papillary muscles.
复制标题
DOI：
10.1253/circj.70.1407
复制
发表时间：
2006-11
期刊：
影响因子：
--
通讯作者：
K. Yamazaki;H. Terada;H. Satoh;K. Naito;A. Takeshita;A. Uehara;H. Katoh;K. Ohnishi;H. Hayashi
中科院分区：
文献类型：
--
作者：
K. Yamazaki;H. Terada;H. Satoh;K. Naito;A. Takeshita;A. Uehara;H. Katoh;K. Ohnishi;H. Hayashi
三氧化二砷（As（2）O（3））是治疗急性早幼粒细胞白血病（APL）复发的一种新的有希望的方案，但会导致危及生命的心律失常。本研究旨在探讨三氧化二砷（As（2）O（3））致心律失常的发生率及其机制。方法和结果20例APL患者在As 2 O3治疗期间监测标准12导联ECG。As（2）O（3）（0.15 mg/kg）显著延长校正的QT间期（QTc：445+/-7至517+/-17 ms，平均值+/-SE，p<0.01），并增加QTc离散度和跨室壁复极离散度。4例患者发生非持续性室性心动过速，1例患者发生尖端扭转型室性心动过速。在豚鼠乳头肌灌流As（2）O（3）（350 μ mol/L）的过程中，测量了动作电位和等长收缩。动作电位时程延长（APD（90）：60 min时为150+/-11至195+/-12 ms，p<0.01，n=5），低钾溶液低刺激率灌注As（2）O（3）可延长APD，并引起早期后除极和触发活动。长期暴露于As（2）O（3）可引起肌肉挛缩、后收缩、触发活动和电机械交替。河豚毒素或二丁基羟基甲苯可部分阻止As（2）O（3）引起的APD延长。结论QTc延长和空间异质性是As 2 O3诱发室性心律失常的重要原因。As（2）O（3）引起的电生理异常除了APD延长外，还可能与细胞内Ca（2+）超载和脂质过氧化有关。
BACKGROUND Arsenic trioxide (As(2)O (3)) is a new promising regimen for patients with a relapse of acute promyelocytic leukemia (APL), but causes life-threatening arrhythmias. This study aimed to investigate the incidence and mechanism of arrythmogenesis caused by As(2)O(3). METHODS AND RESULTS Standard 12-lead ECGs were monitored throughout As(2)O(3) therapy in 20 APL patients. As(2)O (3) (0.15 mg/kg) significantly prolonged the corrected QT interval (QTc: 445+/-7 to 517+/-17 ms, means+/-SE, p<0.01), and also increased the QTc dispersion and transmural dispersion of repolarization. Non-sustained ventricular tachycardias and torsades de pointes occurred in 4 and 1 patients, respectively. The action potentials and isometric contraction were measured in guinea pig papillary muscles during As(2)O (3) perfusion (350 micromol/L). The action potential duration was prolonged (APD(90): 150+/-11 to 195+/-12 ms at 60 min, p<0.01, n=5) and perfusion of As(2)O(3) in a low K(+) solution with a low stimulation rate augmented the prolongation of APD, and provoked early after-depolarizations and triggered activities. The prolonged exposure to As(2)O(3) induced muscle contracture, aftercontractions, triggered activities and electromechanical alternans. Tetrodotoxin or butylated hydroxytoluene partially prevented the As(2)O(3)-induced prolongation of APD. CONCLUSIONS The prolonged QTc and spatial heterogeneity are responsible for the As(2)O(3)-induced ventricular tachyarrhythmias. In addition to prolongation of the APD, cellular Ca(2+) overload and lipid peroxidation might contribute to the electrophysiological abnormalities caused by As(2)O(3).