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(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).


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).
Yamazaki
Keisuke
K
Department of Internal Medicine III, Division of Cardiology, Hamamatsu University School of Medicine, Handayama, Hamamatsu 431-3192, Japan.
Terada
Hajime
H
Satoh
Hiroshi
H
Naito
Kensuke
K
Takeshita
Akihiro
A
Uehara
Akihiko
A
Katoh
Hideki
H
Ohnishi
Kazunori
K
Hayashi
Hideharu
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006168:Guinea Pigs; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000502:physiology; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D010087:Oxides / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology*; D011042:Poisons / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D001152:Arsenicals; D010087:Oxides; D011042:Poisons; D017382:Reactive Oxygen Species; D002084:Butylated Hydroxytoluene; D013779:Tetrodotoxin; D000077237:Arsenic Trioxide