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

Background Arsenic trioxide (As_2O_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_2O_3. Methods and Results Standard 12-lead ECGs were monitored throughout As_2O_3 therapy in 20 APL patients. As_2O_3 (0.15mg/kg) significantly prolonged the corrected QT interval (QTc: 445±7 to 517±17ms, 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_2O_3 perfusion (350μmol/L). The action potential duration was prolonged (APD_<90>: 150±11 to 195±12ms at 60min, p<0.01, n=5) and perfusion of As_2O_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_2O_3 induced muscle contracture, after-contractions, triggered activities and electromechanical alternans. Tetrodotoxin or butylated hydroxytoluene partially prevented the As_2O_3-induced prolongation of APD. Conclusions The prolonged QTc and spatial heterogeneity are responsible for the As_2O_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_2O_3.