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

Mei Hwan Wu, Chun Jung Lin, Chi Long Chen, Ming Jai Su, Selma Siu Man Sun, Ann Lii Cheng

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25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)214-220
Number of pages7
JournalToxicology and Applied Pharmacology
Volume189
Issue number3
DOIs
Publication statusPublished - Jun 15 2003
Externally publishedYes

Fingerprint

Arsenicals
Toxicity
Tissue
Rabbits
Ventricular Tachycardia
arsenic trioxide
Perfusion
Acute Promyelocytic Leukemia

Keywords

  • Arsenic trioxide
  • Electrophysiology
  • Heart

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Direct cardiac effects of As2O3 in rabbits : Evidence of reversible chronic toxicity and tissue accumulation of arsenicals after parenteral administration. / Wu, Mei Hwan; Lin, Chun Jung; Chen, Chi Long; Su, Ming Jai; Sun, Selma Siu Man; Cheng, Ann Lii.

In: Toxicology and Applied Pharmacology, Vol. 189, No. 3, 15.06.2003, p. 214-220.

Research output: Contribution to journalArticle

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abstract = "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.",
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AB - 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.

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