Arrhythmogenic Effects of Arsenic Trioxide in Patients With Acute Promyelocytic Leukemia and an Electrophysiological Study in Isolated Guinea Pig Papillary Muscles

Keisuke Yamazaki, Hajime Terada, Hiroshi Satoh, Kensuke Naito, Akihiro Takeshita, Akihiko Uehara, Hideki Katoh, Kazunori Ohnishi, Hideharu Hayashi
2006 Circulation Journal  
ecently, arsenic trioxide (As2O3) has been shown to induce complete remission of acute promyelocytic leukemia (APL) 1 and both the USA Food and Drug Administration (FDA) and the Ministry of Health, Labor and Welfare of Japan have approved As2O3 for the treatment of APL. However, As2O3 is also a poison that causes multiple organ failure. Toxic effects on the cardiac system include: torsades de pointes (TdP), T-U wave alternans, ST-T change and QT interval prolongation. [2] [3] [4] The FDA
more » ... d that the incidence of QT interval prolongation was 40%, and recommended particular attention be paid to QT interval prolongation. We previously reported that QT interval prolongation occurred in all of 8 APL patients treated with As2O3, and recent studies in isolated guinea pig papillary muscles have also shown that As2O3 prolongs the action potential duration (APD) in a reverse frequency-dependent way, as well as blocking both Ikr and Iks in HERGor KCNQ1 + KCNE1-transfected CHO cells. 5,6 However, Methods ECG Changes This investigation conforms to the principles outlined in the Declaration of Helsinki (Cardiovascular Research 1997; 35: 2-4). Twenty patients with APL who had relapsed after previous extensive therapies with all-trans retinoic acid and other chemotherapies were treated with As2O3 (0.15 mg· kg -1 ·day -1 ). The 12-lead ECG and chest X-ray were recorded once a week and telemetry ECG was monitored throughout the admission period. The following parameters Background Arsenic trioxide (As2O3) 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 As2O3. Methods and Results Standard 12-lead ECGs were monitored throughout As2O3 therapy in 20 APL patients. As2O3 (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 As2O3 perfusion (350 mol/L). The action potential duration was prolonged (APD90: 150±11 to 195±12 ms at 60 min, p<0.01, n=5) and perfusion of As2O3 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 As2O3 induced muscle contracture, aftercontractions, triggered activities and electromechanical alternans. Tetrodotoxin or butylated hydroxytoluene partially prevented the As2O3-induced prolongation of APD. Conclusions The prolonged QTc and spatial heterogeneity are responsible for the As2O3-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 As2O3. (Circ J 2006; 70: 1407 -1414
doi:10.1253/circj.70.1407 pmid:17062962 fatcat:bhlcc3vl3ra3jne36mbfhsaf3i