SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2002-02-0598. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-02-0598v1 100/6/2249    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chiang, C.-E. Articles by Ding, P. Y.-A. Search for Related Content PubMed PubMed Citation Articles by Chiang, C.-E. Articles by Ding, P. Y.-A. Related Collections Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2002, Vol. 100, No. 6, pp. 2249-2252 BRIEF REPORT Prolongation of cardiac repolarization by arsenic trioxide Chern-En Chiang, Hsiang-Ning Luk, Tsui-Ming Wang, and Philip Yu-An Ding From the Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University; Department of Anesthesiology, Chang-Gung Memorial Hospital; and Graduate Institute of Medical Science, Taipei Medical University, Taiwan.     Abstract Top Abstract Introduction Study design Results and discussion References Arsenic trioxide (As2O3; ATO) has recently been found to be very effective for relapsed acute promyelocytic leukemia. Several articles reported prolongation of QT interval or ventricular arrhythmias in patients receiving ATO. However, the QT-prolonging effect has not been confirmed and the direct membrane effect of ATO has never been studied. In the present investigation, using conventional action potential recording technique, we found that ATO dose dependently prolonged action potential duration (APD) in guinea pig papillary muscle with a slow pacing frequency. Parenteral administration of ATO prolonged QT interval and APD in guinea pig hearts. Intravenous infusion of clinically relevant doses of ATO prolonged QT interval and APD dose dependently. These studies suggest that ATO has a direct effect on cardiac repolarization. Patients who are receiving ATO should avoid concomitant administration of other QT-prolonging agents or conditions in favor of delaying cardiac repolarization. (Blood. 2002;100:2249-2252) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Arsenic trioxide (As2O3; ATO) has recently been found to be very effective in relapsed or refractory acute promyelocytic leukemia (APL).1-3 Several articles have reported prolongation of the QT interval in patients receiving ATO for relapsed APL.4,5 However, the conclusive evidence for ATP to prolong cardiac repolarization is lacking. Some of the reported cases with torsade de pointes have hypokalemia or hypomagnesemia or both.4-6 Most of the patients with APL receiving ATO have been heavily treated with chemotherapeutic agents, including anthracycline and all-trans-retinoic acid. Thus, cardiac damage is likely to be universal before ATO therapy begins.2,4,6 Some reported cases have monomorphic ventricular tachycardia instead of polymorphic tachycardia, which is a prototypical arrhythmia of QT prolongation.4 Shen and colleagues did not report QT prolongation in 15 patients receiving ATO.1 Thus, the causal relationship of the use of ATO and prolongation of QT interval is questionable.7-8 There is a need to unravel the effect of ATO on cardiac repolarization. In the present study, we demonstrated that ATO prolonged action potential duration (APD) and QT interval in guinea pig heart. This is the first comprehensive study of effect of ATO on cardiac repolarization.     Study design Top Abstract Introduction Study design Results and discussion References Action potential recording The care and handling of the animals in this study was in full compliance with the American Association for the Accreditation of Laboratory Animal Care. Adult Hartley guinea pigs (weighing 400-500 g) of either sex were used. Action potentials were recorded with conventional intracellular recording technique.9 The action potential duration at 90% repolarization (APD90) was measured. This is the most commonly measured parameter of action potential for the purpose of studying the effect of QT-prolonging agents10-12 because this time period encompasses the interval from the beginning of phase 0 depolarization to the late repolarization, and the prolongation of the ADP90 was usually accompanied by a parallel lengthening of the effective refractory period.13 Effects of different concentrations of ATO (1, 10, and 25 µM) under different stimulation frequencies (0.1, 1, and 2 Hz) were examined. ATO was purchased from Sigma (St Louis, MO). Electrocardiographic recording Adult guinea pigs were anesthetized with intraperitoneal urethane (1.2 g/kg). Needles (27-gauge) were fixed subcutaneously in each limb and in correct positions on the chest. Three-channel electrocardiograms (ECGs; lead II, V1, and V5) were recorded for off-line measurement done by another person who was blinded to the experimental procedures. The QT interval was measured from the beginning of the QRS complex to the end of the T wave, which was defined as the return to the TP baseline (between the end of the T wave and the following P wave).14-16 When the heart rate was rapid, the QT interval was estimated by extrapolating the downslope of the T wave.14 The QT interval was recorded at baseline condition just before the administration of various doses of ATO (10, 30, and 50 mg/kg) or water (control group) via nasogastric tube, and every 30 minutes until 3 hours (acute feeding group). Our pilot study showed that ATO with doses more than 100 mg/kg killed guinea pigs before the end of the 3-hour recording period. For the chronic feeding group, arsenic ATO, 5 mg/kg, or water (control group) was administered (via nasogastric tube) every other day for 4 times until the eighth day. We did not administer higher doses of ATO nor administer the drug every day because guinea pigs could not survive to the end of the eighth day with either method. The QT interval was measured every other day immediately before the administration of ATO. The corrected QT interval (QTc) was calculated with the Bazett formula17: QTc = QT/(RR)1/2, an accepted method for correcting QT interval for rate in guinea pigs.18 Lead II is used to measure QT interval because its T wave ending is usually discrete.16,19 For the chronic feeding group, guinea pigs were killed at the eighth day immediately after the measurement the QT interval. The action potentials of right ventricular papillary muscles were measured. The effect of intravenous ATO was also tested. ATO, 0.15 mg/kg, a dose commonly used in humans,2,3,6 was infused for 2 hours. To test the dose-dependent effect, higher doses (0.45 and 1.5 mg/kg) were also used. The control group received equivalent volume of saline. The QT interval was measured immediately before infusion, at 10 minutes after, and every 30 minutes after infusion for a total of 2 hours. Guinea pigs were killed thereafter and action potential was recorded. Intravenous ATO was a gift from TTY Biopharm (Taiwan). The data are expressed as mean ± SEM. Paired t test was used for the comparison of the effect in the experimental group versus the control group. The intraobserver and interobserver agreement was verified with the Bland-Altman method.20 The difference was considered statistically significant with P < .05.     Results and discussion Top Abstract Introduction Study design Results and discussion References ATO prolonged cardiac action potential Arsenic trioxide prolonged action potential duration when the stimulation frequency was slow (0.1 Hz). As shown in Figure 1A, this effect was not significantly different when the stimulation frequencies were faster. The APD-prolonging effect was-dose dependent. Furthermore, the percent prolongation was greater when the stimulation frequency was 0.1 Hz compared with that of 1 Hz (4.8% ± 0.3% versus 1.3% ± 0.2% for 10 µM, P < .01; 8.6% ± 1.2% versus 2.2% ± 0.3% for 25 µM, P < .01), suggesting a reverse frequency-dependent effect. Figure 1B shows a typical example of the original action potential tracings. View larger version (27K): [in this window] [in a new window]   Figure 1. ATO prolonged cardiac action potentials. (A) Dose-dependent and frequency-dependent prolongation of APD. After action potential was stably stimulated with a frequency of 1 Hz in control condition, ATO (1 µM) was perfused and the effects were recorded. The stimulation frequency was then changed to 0.1 Hz, and then to 2 Hz. The perfusate was then shifted to that containing 10 µM ATO. The changes induced by 3 different stimulation frequencies were recorded. Finally the effect of 25 µM ATO was tested in the same way. Using conventional action potential recording technique, we demonstrated dose-dependent prolongation of APD90 in guinea pig papillary muscle by ATO when the muscle was stimulated with a frequency of 0.1 Hz. The changes in APD90 by faster frequencies (1 and 2 Hz) did not reach statistical significance. *P < .05 versus control; #P < .01 versus control. (B) A typical illustration of action potentials. ATO dose dependently prolonged action potential duration. The stimulation frequency was 0.1 Hz. Enteral (or oral) ATO prolonged QTc and APD Acute feeding of ATO did not significantly change the heart rate (Table 1). But the QT interval showed time-dependent and dose-dependent prolongation (Table 1). As shown in Figure 2A, during the 3-hour observation, QTc progressively prolonged and was significantly longer than that in the control ones after 60 minutes; the magnitude of prolongation was dose-dependent as well.                                View this table: [in this window] [in a new window]   Table 1. The changes in heart rate and QT interval in the acute feeding group View larger version (19K): [in this window] [in a new window]   Figure 2. Parenteral ATO prolonged QTc and APD. (A) Acute feeding of ATO resulted in progressive dose-dependent prolongation of QTc. *P < .05 versus control; #P < .01 versus control; +P < .001 versus control. (B) Chronic feeding of ATO produced time-dependent prolongation of QTc. *P < .05 versus control; #P < .01 versus control. (C) APD of papillary muscle after eighth day chronic feeding of ATO, showing longer APD90 in ATO-treated ones. #P < .01 versus control; +P < .001 versus control. Table 2 shows the changes in the heart rate and the QT interval in the chronic feeding group. The heart rate did not change significantly, but the QT interval progressively prolonged. QTc also progressively prolonged (Figure 2B). Figure 2C demonstrates the APD90 of papillary muscle at the eighth day. APD90 was significantly longer than that in the control group for all the stimulation frequencies being used. Again, the degree of prolongation suggested reverse frequency-dependent relationship (35.4% for 0.1 Hz, 32.8% for 1 Hz, and 30.3% for 2 Hz).                                View this table: [in this window] [in a new window]   Table 2. Changes in heart rate and QT interval in the chronic feeding group Intravenous ATO prolonged QTc and APD Intravenous ATO did not change the heart rate, but prolonged the QT interval dose dependently and time dependently (Table 3). Figure 3A shows that QTc also progressively prolonged in the 2-hour period of intravenous infusion of ATO. The prolongation was dose-dependent. When the APD90 was measured in the papillary muscle after the guinea pigs were killed after 2 hours, it was shown that APD90 was longer in the drug-treatment group than that in the control group (Figure 3B). The prolongation was dose-dependent and reverse frequency-dependent.                                View this table: [in this window] [in a new window]   Table 3. Changes in heart rate and QT interval by intravenous ATO View larger version (28K): [in this window] [in a new window]   Figure 3. Intravenous ATO prolonged QTc and APD. (A) Continuous ECG monitoring revealed progressive prolongation of QTc by intravenous ATO in a dose-dependent manner. *P < .05 versus control; #P < .01 versus control; +P < .001 versus control. (B) APD after 2-hour drug infusion. The prolongation was dose-dependent. *P < .05 versus control; #P < .01 versus control; +P < .001 versus control. Both the intraobserver and the interobserver agreement in the measurement of QTc were excellent. The mean intraobserver difference in the measurement of QTc (n = 426) was 0 ± 3 ms and 95% CI was between 1 and 1 ms. The mean interobserver difference was 0 ± 4 ms and 95% CI was between 1 and 1 ms. In the present study, we have demonstrated that ATO has direct membrane effect, and dose dependently prolonged QTc and APD90 in guinea pig hearts. This report provides direct evidence that ATO delays cardiac repolarization and the rationale for the occurrence of torsade de pointes in susceptible patients.4,5 Patients who are receiving ATO for relapsed APL should avoid concomitant administration of other QT-prolonging agents, or conditions in favor of delaying cardiac repolarization, such as bradycardia, hypokalemia, or hypomagnesemia. It is unclear why ATO prolongs cardiac repolarization. Although examination of the effects on APD90 of guinea pig papillary muscle is a common strategy to look for the QT-prolonging effects of drugs,12,21 there are still differences between human and guinea pig repolarizing currents. From the particular finding of reverse frequency-dependent effect by ATO, it is suggested that ATO might be able to block the rapid component of the delayed rectifier K+ channel (IKr),22 like other QT-prolonging agents.23 The structural uniqueness enables IKr the most common target for drugs capable of delaying cardiac repolarization.24 Future study on the ionic mechanisms will be needed to unravel the mechanism of its QT prolongation.     Acknowledgments The authors gratefully acknowledge TTY Biopharm Company for kindly providing intravenous arsenic trioxide to us.     Footnotes Submitted February 25, 2002; accepted May 13, 2002. Prepublished online as Blood First Edition Paper, May 24, 2002; DOI 10.1182/blood-2002-02-0598. Supported, in part, by Taiwan Society of Cardiology, institutional research grants from Taipei Veterans General Hospital (VGH 90-067 and VGH 90-300), and National Science Council (NSC 90-2314-B-075-041). The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Chern-En Chiang, Division of Cardiology, Taipei Veterans General Hospital 201, Section 2, Shih-Pai Rd, Taipei 112, Taiwan; e-mail: cechiang{at}vghtpe.gov.tw.     References Top Abstract Introduction Study design Results and discussion References 1. Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL), II: clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354-3360[Abstract/Free Full Text]. 2. Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341-1348[Abstract/Free Full Text]. 3. Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94:3315-3324[Abstract/Free Full Text]. 4. Ohnishi K, Yoshida H, Shigeno K, et al. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med. 2000;133:881-885[Abstract/Free Full Text]. 5. Unnikrishnan D, Dutcher JP, Varshneya N, et al. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood. 2001;97:1514-1516[Abstract/Free Full Text]. 6. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852-3860[Abstract/Free Full Text]. 7. Barbey JT, Singer JW, Unnikrishnan D, et al. Cardiac toxicity of arsenic trioxide. Blood. 2001;98:1632-1634[Free Full Text]. 8. Barbey JT, Soignet S. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med. 2001;135:842-843[Free Full Text]. 9. Chen CC, Lin YC, Chen SA, et al. Shortening of cardiac action potentials in endotoxic shock in guinea pigs is caused by an increase in nitric oxide activity and activation of the adenosine triphosphate-sensitive potassium channel. Crit Care Med. 2000;28:1713-1720[CrossRef][Medline] [Order article via Infotrieve]. 10. Yang T, Tande PM, Lathrop DA, Refsum H. Class III antiarrhythmic action by potassium channel blockade: dofetilide attenuates hypoxia induced electromechanical changes. Cardiovasc Res. 1992;26:1109-1115[Abstract/Free Full Text]. 11. MacKenzie I, Saville VL, Waterfall JF. Differential class III and glibenclamide effects on action potential duration in guinea-pig papillary muscle during normoxia and hypoxia/ischaemia. Br J Pharmacol. 1993;110:531-538[Medline] [Order article via Infotrieve]. 12. Gjini V, Korth M, Schreieck J, Weyerbrock S, Schomig A, Schmitt C. Differential class III antiarrhythmic effects of ambasilide and dofetilide at different extracellular potassium and pacing frequencies. J Cardiovasc Pharmacol. 1996;28:314-320[CrossRef][Medline] [Order article via Infotrieve]. 13. Groh WJ, Gibson KJ, McAnulty JH, Maylie JG. -Adrenergic blocking property of d, l-sotalol maintains class III efficacy in guinea pig ventricular muscle after isoproterenol. Circulation. 1995;91:262-264[Abstract/Free Full Text]. 14. Chou T-C. Normal electrocardiogram. In: Chou T-C, ed. Electrocardiography in Clinical Practice. Philadelphia: Saunders; 1996:3-22. 15. Suzuki M, Nishizaki M, Arita M, et al. Increased QT dispersion in patients with vasospastic angina. Circulation. 1998;98:435-440[Abstract/Free Full Text]. 16. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol. 2000;36:1-12[Abstract/Free Full Text]. 17. Bazette HC. An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353-370. 18. Hayes E, Pugsley MK, Penz WP, Adaikan G, Walker MJ. Relationship between QaT and RR intervals in rats, guinea pigs, rabbits, and primates. J Pharmacol Toxicol Methods. 1994;32:201-207[CrossRef][Medline] [Order article via Infotrieve]. 19. Ackerman MJ. The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc. 1998;73:250-269[Abstract]. 20. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1:307-310[CrossRef][Medline] [Order article via Infotrieve]. 21. Shuba LM, Kasamaki Y, Jones SE, Ogura T, McCullough JR, McDonald TF. Action potentials, contraction, and membrane currents in guinea pig ventricular preparations treated with the antispasmodic agent terodiline. J Pharmacol Exp Ther. 1999;290:1417-1426[Abstract/Free Full Text]. 22. Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J. 2000;21:1216-1231[Free Full Text]. 23. Camm AJ, Janse MJ, Roden DM, Rosen MR, Cinca J, Cobbe SM. Congenital and acquired long QT syndrome. Eur Heart J. 2000;21:1232-1237[Free Full Text]. 24. Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A. 2000;97:12329-12333[Abstract/Free Full Text]. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Guglin, M. Aljayeh, S. Saiyad, R. Ali, and A. B. Curtis Introducing a new entity: chemotherapy-induced arrhythmia Europace, December 1, 2009; 11(12): 1579 - 1586. [Abstract] [Full Text] [PDF] I. Mordukhovich, R. O. Wright, C. Amarasiriwardena, E. Baja, A. Baccarelli, H. Suh, D. Sparrow, P. Vokonas, and J. Schwartz Association Between Low-Level Environmental Arsenic Exposure and QT Interval Duration in a General Population Study Am. J. Epidemiol., September 15, 2009; 170(6): 739 - 746. [Abstract] [Full Text] [PDF] J. M. Carbrey, L. Song, Y. Zhou, M. Yoshinaga, A. Rojek, Y. Wang, Y. Liu, H. L. Lujan, S. E. DiCarlo, S. Nielsen, et al. Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice PNAS, September 15, 2009; 106(37): 15956 - 15960. [Abstract] [Full Text] [PDF] A. N. Katchman, J. Koerner, T. Tosaka, R. L. Woosley, and S. N. Ebert Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1098 - 1106. [Abstract] [Full Text] [PDF] M. W Lai, E. W Boyer, M. E Kleinman, N. M Rodig, and M. B. Ewald Acute Arsenic Poisoning in Two Siblings Pediatrics, July 1, 2005; 116(1): 249 - 257. [Abstract] [Full Text] [PDF] E. Ficker, Y. A. Kuryshev, A. T. Dennis, C. Obejero-Paz, L. Wang, P. Hawryluk, B. A. Wible, and A. M. Brown Mechanisms of Arsenic-Induced Prolongation of Cardiac Repolarization Mol. Pharmacol., July 1, 2004; 66(1): 33 - 44. [Abstract] [Full Text] [PDF] B. Drolet, C. Simard, and D. M. Roden Unusual Effects of a QT-Prolonging Drug, Arsenic Trioxide, on Cardiac Potassium Currents Circulation, January 6, 2004; 109(1): 26 - 29. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2002-02-0598v1 100/6/2249    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chiang, C.-E. Articles by Ding, P. Y.-A. Search for Related Content PubMed PubMed Citation Articles by Chiang, C.-E. Articles by Ding, P. Y.-A. Related Collections Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020