Effects of Arsenic Trioxide on Electrocardiography

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1 Original Article Acta Cardiol Sin 2004;20:1 6 Electrophysiology Effects of Arsenic Trioxide on Electrocardiography Tu-Ying Liu, 1 Hsiang-Ning Luk, 2 Tsui-Min Wang, 3 Philip Yu-An Ding 1 and Chern-En Chiang 1 Background: Arsenic trioxide 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 arsenic trioxide. However, the effects on other electrocardiogram (ECG) have not been determined. Methods: Three-channel ECG (leads II, V1 and V5) was recorded from adult Hartley guinea pigs ( gm). The P wave, PR interval and QRS duration were measured at baseline condition just before the administration of various doses (,, and ) of arsenic trioxide or water (control group) via nasogastric tube, and every 30 minutes until 3 hours. The effect of intravenous arsenic trioxide was also tested. Arsenic trioxide, 0.15 mg/kg,, and, were infused for duration of 2 hours. The control group received equivalent volume of saline. The ECG parameters were measured immediately before infusion, at 10 minutes after, and every 30 minutes after infusion for a total of 2 hours. Results: Both oral and intravenous arsenic trioxide increased P wave, PR interval and QRS duration in guinea pigs. The percent increase was dose-dependent and time-dependent, and was more prominent in PR interval compared with those in the P wave and QRS duration. There was no change in the control group. Atrioventricular block was observed in high-dose group. Conclusions: We have demonstrated that oral and intravenous arsenic trioxide prolonged P wave, PR interval and QRS duration. Routine regular ECG follow-up in patients receiving arsenic trioxide therapy may be indicated, especially in patients who already have prolongation of P wave, PR interval, or bundle branch block, or receiving concomitant administration of sodium channel blockers. Key Words: Arsenic trioxide Guinea pig Electrocardiogram INTRODUCTION Acute promyelocytic leukemia (APL) is characterized by chromosome translocation t(15;17) and a poor prognosis. 1 Treatment with all-trans retinoic acid (ATRA) Received: August 6, 2002 Accepted: October 15, Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei; 2 Department of Anesthesiology, Chang-Gung Memorial Hospital, Taipei; 3 Graduate Institute of Medical Science, Taipei Medical University, Taipei, Taiwan. Address correspondence and reprint requests to: Dr. Chern-En Chiang, Division of Cardiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan. Tel: ; Fax: ; cechiang@vghtpe.gov.tw has not only opened a new approach in cancer treatment, but also produced complete remission in most APL patients. 2 In spite of these advances, 30% to 40% of patients relapsed within 5 years after complete remission. Most of these patients lost sensitivity to ATRA and died shortly thereafter. Recently, investigators from China reported that arsenic trioxide could induce complete remissions in patients with relapsed APL. 3 However, there are several articles reporting prolongation of QT interval in patients receiving arsenic trioxide for relapsed APL. 4,5 We recently found that arsenic trioxide prolonged action potential duration and QT interval in guinea pig heart. 6 Since arsenic trioxide has been widely used in patients 1 Acta Cardiol Sin 2004;20:1 6

2 Tu-Ying Liu et al. with acute leukemia, more detailed characterization of its effect on electrophysiology, especially on the electrocardiogram (ECG), is indicated. In the present study, we used oral and intravenous arsenic trioxide to study the effects on the ECG parameters in guinea pigs. METHODS ECG recording Adult Hartley guinea pigs ( gm) were anesthetized with intraperitoneal urethane (1.2 gm/kg). Twenty-seven gauge needles were fixed subcutaneously in each limb and in correct positions on the chest. Three channel ECG (leads II, V1 and V5) was recorded for off-line measurement. The P wave duration was measured from the beginning of the P wave to the end of the P wave, the PR interval from the beginning of the P wave to the beginning of the QRS complex, and QRS duration from the beginning of the QRS complex to the end of the QRS complex. 7,8 The changes of QT and QTc intervals have been reported. 6 These ECG parameters were recorded at baseline condition just before the administration of various doses (,, and ) of arsenic trioxide or water (control group) via nasogastric tube, and every 30 minutes until 3 hours. Our pilot study showed that arsenic trioxide with doses more than 100 mg/kg killed guinea pigs before the end of the 3-hour recording period. Lead II is used to measure these ECG parameters because its P wave is usually larger and more discrete. 7 The effect of intravenous arsenic trioxide was also tested. Arsenic trioxide,, a commonly used dose in human, 1,3,9 was infused for a duration of 2 hours. To test the dose-dependent effect, higher doses (0.45 mg/kg, and ) were also used. The control group received equivalent volume of saline. The ECG parameters were measured immediately before infusion, at 10 minutes after, and every 30 minutes after infusion for a total of 2 hours. 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 difference was considered statistically significant when p value was less than RESULTS Oral arsenic trioxide increased P wave, PR interval and QRS duration in guinea pigs Low-dose arsenic trioxide () had no effect on P wave duration. However, higher doses of arsenic trioxide ( and ) exhibited time-dependent and dose-dependent prolongation of P wave duration (Figure 1 and Table 1). There was no change in the group for total observation period of 180 min. The changes in the PR interval are shown in Figure 2 and Table 2. Arsenic trioxide produced time-dependent and dose-dependent block in all 3 groups. The effects were time-dependent and dose-dependent. One guinea pig in the high-dose () group developed 2:1 atrioventricular block. The percent prolongation of PR interval was larger than that of P wave duration. For instance, for the group, the largest percent prolongation of PR interval was % which was significantly more than that of P wave duration (19.7 Table 1. Changes in P wave duration in the oral feeding group Pwave(ms) 0 min min min min min * 150 min * * 180 min * # Figure 1. Changes in P wave duration in the oral feeding group. Acta Cardiol Sin 2004;20:1 6 2

3 Arsenic and ECG Table 2. Changes in PR interval in the oral feeding group PR interval (ms) 0min min min min * * 120 min * * 150 min * * # 180 min * # *p < 0.05 vs control; # p <0.01vscontrol; p <0.001vscontrol. 3.8%, p < 0.05). Likewise, for the group, there was % prolongation in PR interval vs % in the P wave duration (p < 0.05). The changes in the QRS duration were similar to those of P wave duration to have dose-dependent and time-dependent prolongation (Figure 3 and Table 3). Similarly, the percent prolongation of QRS duration was less than that of PR interval (largest prolongation = % in the group; largest prolongation = % in the group; both p <0.05vs those of PR interval). Figure 2. Changes in PR interval in the oral feeding group. Intravenous arsenic trioxide prolonged P wave, PR interval and QRS duration in guinea pigs The conventional dose of intravenous arsenic trioxide for humans () did not prolong P wave duration for 2 hours (Table 4). But higher doses did prolong P wave duration (Figure 4 and Table 4). The degree of prolongation was dose-dependent and time-dependent. The changes in the PR interval by intravenous arsenic trioxide are shown in Figure 5 and Table 5. The prolongation also showed dose-dependency and time-dependency. Table 3. Changes in QRS duration in the oral feeding group QRS (ms) 0min min min min min min * * 180 min * * Table 4. Changes in P wave duration in the intravenous group Pwave(ms) 0 min min min * 60 min * 90 min * # 120 min * # Figure 3. Changes in QRS duration in the oral feeding group. Figure 4. Changes in P wave duration in the intravenous group. 3 Acta Cardiol Sin 2004;20:1 6

4 Tu-Ying Liu et al. Table 5. Changes in PR interval in the intravenous group PR interval (ms) 0 min min * 30 min * * # 60 min * * # 90 min * # min * # *p < 0.05 vs control; # p <0.01vscontrol; p < vs control. Table 6. Changes in QRS duration in the intravenous group QRS (ms) 0min min min * 60 min * 90 min * # 120 min * # Figure 5. Changes in PR interval in the intravenous group. Figure 6. 2:1 atrioventricular block in high-dose intravenous group. Arrow: P waves. Figure 7. In the highest-dose group (), one guinea pig developed 2:1 atrioventricular block and one developed complete atrioventricular block (Figure 6). Similar to the findings in the oral feeding group, the changes in PR interval were more marked than those in the P waves because with a dose of there was already prolongation of PR interval since 30 minutes. The highest percent prolongations for and were % and %, respectively, significantly higher than those of P waves ( % and %, respectively, both p < 0.05). QRS duration was prolonged by higher doses of arsenic trioxide ( and ), but not by lower dose () (Figure 7 and Table 6). The prolongation showed dose-dependency and time-dependency. The percent prolongation of QRS duration was less than that of PR interval in the group receiving (largest prolongation = %; p <0.05 vs that of PR interval). DISCUSSION Changes in QRS duration in the intravenous group. The major finding in this paper is that arsenic trioxide, administered orally or intravenously, prolonged P wave and QRS duration, but to a lesser extent than that in the PR interval. Furthermore, high dose of arsenic trioxide produced atrioventricular block, suggesting the necessity of regular ECG follow-up in patients receiving arsenic trioxide. In our previous study, we demonstrated that arsenic Acta Cardiol Sin 2004;20:1 6 4

5 Arsenic and ECG trioxide did not change the heart rate, but had direct membrane effect, and dose-dependently prolonged QTc interval and APD 90 in guinea pig hearts. 6 From the particular finding of reverse frequency-dependent effect by arsenic trioxide in our previous report, it is suggested that arsenic trioxide might be able to block the rapid component of the delayed rectifier K + channel, 10 like other QT-prolonging agents. 11 In the present study, arsenic trioxide prolonged P wave duration and QRS duration, suggesting that arsenic might be able to block the fast sodium channel as well. It has also been shown in this study that the effect of arsenic trioxide on the PR interval is more prominent than those on the P wave and QRS complex. Conduction through the atrioventricular node accounts for the greatest part of the PR interval, and for the L-type calcium channel being responsible for the atrioventricular nodal conduction. It is possible that the blocking effect of arsenic trioxide on the L-type calcium channel is more potent than its effect on the fast sodium channel. However, the exact mechanism remains to be determined. In the present study, 2:1 and complete atrioventricular block were observed. Routine regular ECG check-up in patients receiving arsenic therapy may be indicated. In addition, patients who already have prolongation of P wave or bundle branch block should be carefully monitored if the administration of arsenic trioxide is necessary. We also recommend that concomitant administration of sodium channel blockers, such as Class I antiarrhythmic agents, might have to be withheld. Limitation of study Although the effects on guinea pig ECG may be different from those from human, it is not ethical to directly test the effect of such a toxic drug in humans. ACKNOWLEDGMENTS The authors gratefully acknowledge TTY Biopharm Company for kindly providing intravenous arsenic trioxide to us. Supported in part by the Taiwan Society of Cardiology, Institutional Research Grants from Taipei Veterans General Hospital (VGH and VGH ), and the National Science Council (NSC B ). REFERENCES 1. 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: Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia: I. Clinical results. Blood 1990;76: 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: 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: Unnikrishnan D, Dutcher JP, Varshneya N, et al. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001;97: Chiang CE, Luk HN, Wang TM, et al. Prolongation of cardiac repolarization by arsenic trioxide. Blood 2002;100: Chou TC. Normal electrocardiogram. In: Chou TC, ed. Electrocardiography in Clinical Practice. Philadelphia: W.B. Saunders Company, 1996: Suzuki M, Nishizaki M, Arita M, et al. Increased QT dispersion in patients with vasospastic angina. Circulation 1998;98: 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: 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: Camm AJ, Janse MJ, Roden DM, et al. Congenital and acquired long QT syndrome. Eur Heart J 2000;21: Acta Cardiol Sin 2004;20:1 6