Published online before print December 22, 2003, doi: 10.1161/01.CIR.0000109484.00668.CE
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(Circulation. 2004;109:26-29.)
© 2004 American Heart Association, Inc.
Brief Rapid Communications |
Unusual Effects of a QT-Prolonging Drug, Arsenic Trioxide, on Cardiac Potassium Currents
From the Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Professor of Medicine and Pharmacology, Director, Division of Clinical Pharmacology, 532 Robinson Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232. E-mail dan.roden{at}vanderbilt.edu
Received October 8, 2003; revision received November 4, 2003; accepted November 14, 2003.
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Abstract |
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Background— Cases of QT prolongation, torsades de pointes, and sudden death have been reported with arsenic trioxide (As2O3), a highly effective agent for acute promyelocytic leukemia. In this study, we evaluated the effects of As2O3 on repolarizing cardiac ion currents.
Methods and Results— In HERG- or KCNQ1+KCNE1-transfected CHO cells (n=32; total), As2O3 caused concentration-dependent block of both IKr and IKs, with an IC50 for tail current block of 0.14±0.01 µmol/L for IKr and 1.13±0.06 µmol/L for IKs. In contrast to other QT-prolonging drugs, As2O3 also activated a time-independent current that additional experiments identified as IK-ATP.
Conclusions— As2O3 blocks both IKr and IKs at clinically relevant concentrations. On the other hand, it also activates IK-ATP, which maintains normal repolarization. We infer that variability in the extent of QT interval prolongation and onset of ventricular arrhythmias during arsenic therapy represents competing effects to block and activate multiple repolarizing potassium currents.
Key Words: torsades de pointes • drugs • ion channels
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Introduction |
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Approximately 20% to 30% of patients with acute promyelocytic leukemia (APL) relapse with current standard all-trans retinoic acid and anthracycline-based chemotherapy regimen.1 In the mid-1990s, studies from China reported that arsenic trioxide (As2O3) achieved complete remission in as many as 90% of patients with APL,2,3 and additional trials have confirmed these results.4,5 However, treatment has also been associated with QT prolongation, torsades de pointes, and sudden death.4,6–8 Because most of the patients receiving As2O3 have been exposed to cardiotoxic chemotherapy, cardiac dysfunction is thought to be universal before As2O3 therapy begins.6,9 In addition, hypokalemia and hypomagnesemia are among the most common As2O3-related side effects.1 Thus, it has been proposed that QT prolongation and ventricular arrhythmias associated with arsenic could be exacerbated by concurrent electrolyte disturbances or previous chemotherapy-induced cardiac damage.4,6–8
Recently, clinically relevant concentrations of As2O3 (1 to 10 µmol/L) have been reported to prolong the action potential duration in guinea pig papillary muscle.9 In another study using rabbit hearts, polymorphic ventricular tachycardia was observed with As2O3 30 µmol/L.10 In this study, we therefore investigated the effects of As2O3 on cardiac repolarizing currents and identified an unexpectedly complex profile that may underlie variability in the arrhythmogenic potential of arsenic.
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Methods |
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Experiments were performed in CHO cells transfected with 2 µg (each) of HERG, KCNQ1+KCNE1, or Kir6.2+SUR2A cDNAs. Kir6.2 and SUR2A cDNAs were kindly provided by Dr Joseph Bryan, Baylor College of Medicine, Houston, Tex. Cells were transfected using FuGENE 6 (Roche Applied Science). Green fluorescent protein (GFP) was coexpressed to identify transfected cells. All whole cell currents were recorded at 22°C to 23°C. Cells were held at -80 mV and pulsed to -40 to +60 mV for 1 second (HERG) or 5 seconds (KCNQ1+KCNE1), and tail currents were measured at -40 mV. The maximal tail current amplitudes were sampled after the capacitive transient in a 20-ms window. The composition of extracellular and internal pipette solutions for the HERG and KCNQ1+KCNE1 experiments were as described previously.11 For the Kir6.2+SUR2A experiments, cells were held at 0 mV and pulsed to -100 to +50 mV for 100 ms. The composition of solutions for these experiments was as described previously.12 As2O3 solutions of the extracellular buffer (30 nmol/L to 10 µmol/L) were prepared daily. Glibenclamide and pinacidil solutions in DMSO were prepared daily. The same concentration of DMSO (0.1% vol/vol) was also present in baseline and washout buffer solutions. As2O3, glibenclamide, and pinacidil were obtained from Sigma.
Statistical Analysis
Data are presented as mean±SEM. Concentration-dependent block of HERG or KCNQ1+KCNE1 tail current was tested by the Hotelling t2 test. P<0.05 was considered statistically significant.
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Results |
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Figure 1A shows currents elicited in a HERG-transfected cell under baseline conditions and after 20 minutes of As2O3 100 nmol/L (Figure 1B). In this cell, As2O3 100 nmol/L caused a 60% reduction of the tail current. Unexpectedly, however, there was also an increase in time-independent outward current (Figure 1B, arrow). Figures 1C and 1D show currents elicited before and during As2O3 1 µmol/L. In this cell, As2O3 1 µmol/L caused a 92% reduction of the tail current and clear activation of this time-independent outward current (Figure 1D). Figure 1E shows concentration dependence of the effect on IKr tail current, with an IC50 of 0.14±0.01 µmol/L. Figures 1F through 1J show a similar concentration-dependent block of IKs (assessed by reduction of tail currents) and, again, activation of a time-independent outward current. IKs was
1 order of magnitude less sensitive to block, with an IC50 of 1.13±0.06 µmol/L. Nearly all drugs that cause QT prolongation and torsades de pointes block IKr, and some (eg, quinidine and azimilide) also block IKs, often with somewhat higher IC50 values.13,14 However, activation of an outward current, as in Figure 1, has not been reported previously. Because this effect may reflect activation of a current endogenous to CHO cells, we next step-studied cells transfected with GFP only. Figure 2A shows currents elicited in a GFP-transfected cell under baseline conditions, and Figure 2B shows currents elicited after 20 minutes of As2O3 1 µmol/L. This gating pattern is reminiscent of IK-ATP, and Figure 2C shows that the current was blocked by subsequent exposure to the IK-ATP blocker glibenclamide 10 µmol/L. Figures 2D through 2F show near-identical behaviors with the IK-ATP activator pinacidil 10 µmol/L (Figure 2E) and 10 minutes after the addition of glibenclamide 10 µmol/L (Figure 2F). To additionally test the hypothesis that As2O3 activates IK-ATP, we studied Kir6.2+SUR2A-transfected CHO cells. Figures 2G through 2I show results similar to those in Figures 2A through 2C, demonstrating activation of IK-ATP by As2O3 1 µmol/L. Figures 2J through 2L show that pinacidil 10 µmol/L activates a similar current and glibenclamide 10 µmol/L blocks this current, as expected.
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Discussion |
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Our results show that As2O3 is a potent blocker of IKr (IC50, 0.14±0.01 µmol/L) and IKs (IC50, 1.13±0.06 µmol/L). It has been shown that IKr block may lead to triggered tachyarrhythmias and sudden death.15 Moreover, adding the effect of an IKs blocker on an already-compromised IKr has been shown to additionally decrease the repolarization reserve, potentiating the action potential–prolonging effect of the IKr blocker.16 These concentrations are well within the therapeutically relevant range. In one study of 8 patients with relapsed APL, mean peak plasma arsenic concentration was 6.85 µmol/L (range, 5.54 to 7.30 µmol/L), and after 10 hours, it was 1 µmol/L.2
Unexpectedly, our data also showed that exposure of HERG- or KCNQ1+KCNE1-transfected CHO cells to As2O3 activates a time-independent outward current. This IK-ATP-like current was also activated to a similar extent in GFP-transfected CHO cells exposed to As2O3 and could be reversed by adding glibenclamide 10 µmol/L, an IK-ATP blocker.17 Indeed, the effects of As2O3 in GFP-transfected CHO cells were comparable to those of the IK-ATP activator pinacidil.17 Interestingly, one of the most common non–life-threatening side effects of As2O3 is hyperglycemia, observed in up to 45% of patients.4 This effect has also been associated with other IK-ATP activators, such as diazoxide.17 Moreover, depletion of intracellular ATP, as seen for example during cardiac ischemia, has been shown to activate IK-ATP.17 Interestingly, arsenic is also recognized to uncouple cardiac mitochondrial oxidative phosphorylation.18 The mechanism is thought to be related to competitive substitution of arsenic for inorganic phosphate in the formation of ATP.18 As a result, arsenic-induced reduction of cardiac phosphorylation likely causes depletion of intracellular ATP and thus activation of cardiac IK-ATP.
Therefore, while blocking both IKr and IKs at therapeutic concentrations, thereby producing a severe lesion in repolarization reserve, As2O3 also activates IK-ATP, which may partially restore repolarization reserve and thus contribute to variability in the extent of QT-interval prolongation and onset of ventricular arrhythmias during arsenic therapy.
Conclusions
As2O3 is a potent blocker of both IKr and IKs. On the other hand, it also activates cardiac IK-ATP, which may blunt QT prolongation and arrhythmia risk by restoring repolarization reserve. The risk of torsades de pointes can be reduced by adherence to guidelines for safe use of the drug. In addition, variability in the extent of QT effects among patients may reflect this unusual combination of potassium channel actions.
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Acknowledgments |
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Supported by the United States Public Health Service (HL46681, HL49989). Dr Roden holds the William Stokes Chair in Experimental Therapeutics, a gift of the Dai-ichi Corporation. Benoit Drolet is the recipient of a postdoctoral fellowship award from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. The authors also thank Donna Choate for technical assistance.
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References |
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1. Rust DM, Soignet SL. Risk/benefit profile of arsenic trioxide. The Oncologist. 2001; 6: 29–32.
2. 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.
3. Zhang P, Wang S, Hu X. Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol. 1996; 17: 58–62.
4. 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.
5. 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.
6. 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.
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17. Terzic A, Vivaudou M. Molecular pharmacology of ATP-sensitive K+ channels: how and why? In: Archer SL, Rusch NJ, eds. Potassium Channels in Cardiovascular Biology. New York: Kluwer Academic/Plenum Publishers; 2001: 257–277.
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