Direct cardiac effects of As₂O₃ in rabbits: Evidence of reversible chronic toxicity and tissue accumulation of arsenicals after parenteral administration

Although parenteral administration of As₂O₃ is highly effective in the treatment of acute promyelocytic leukemia, cardiac toxicity has been reported. This study employed Langendorff perfusion to determine the direct effects of As₂O₃ in the electrophysiological properties of rabbit hearts after acute or chronic As₂O₃ treatment (0.2 mg/kg/day iv for 30 days). Tissue accumulations of arsenicals and pathological changes as well as the reversibility of chronic As₂O₃ effects were assessed. We found that cardiac conduction and repolarization were not altered whatsoever after acute As₂O₃ treatment at clinically relevant (1, 3, and 10 μM) and higher (30 μM) doses. Nevertheless, an extremely high concentration of As₂O₃ (300 μM) prolonged the corrected QT interval. Subsequent to chronic As₂O₃ administration and with 30 μM As₂O₃ via Langendorff perfusion, polymorphic ventricular tachycardia was observed (1/7, 14%). Corrected QT interval was prolonged, while basic cycle length was shortened. Significant accumulation of arsenicals in the cardiac tissue was found, but without any pathological changes. After As₂O₃ was discontinued for 30 days, the chronic As₂O₃ -induced electrophysiological changes improved, no ventricular arrhythmia was noted, and the tissue concentration of arsenicals decreased considerably. We therefore conclude that, although no immediate cardiac effects were discemable at clinically relevant doses, an extremely high concentration of As₂O₃ could prolong ventricular repolarization. Chronic As₂O₃ treatment resulted in a prolonged ventricular repolarization, in association with arsenicals accumulation and with risk of ventricular tachycardia. These chronic cardiac toxicities and the tissue accumulation of arsenicals were, however, partially reversible after cessation of As₂O₃.