Shiho Sugiyama

Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia.

Arsenic trioxide therapy has recently been found to be very effective in relapsed or refractory acute promyelocytic leukemia. It has resulted in complete remission in more than 52% of cases in China and the United States (1, 2). Shen and colleagues (1) have given the most detailed report of adverse events related to arsenic trioxide therapy. Although most of the patients in their study were critically ill, arsenic trioxide was relatively well tolerated. Updated analyses showed that nonlife-threatening cardiac toxicities related to arsenic trioxide occurred in 8 of 47 patients (3). Electrocardiographic abnormalities, such as QRS complex broadening, prolonged QT intervals, ST-segment depression, T-wave flattening, and multifocal ventricular tachycardia, have been reported in acute arsenic poisoning (4-6). Recently, Huang and colleagues (7) found that 1 patient developed complete atrioventricular block during arsenic trioxide therapy and required implantation of a permanent pacemaker. After observing a prolonged QT interval in the first patient with relapsed acute promyelocytic leukemia who received arsenic trioxide in our hospital, we used continuous monitoring to prospectively examine electrocardiograms and echocardiograms and determine the cardiac toxicities of arsenic trioxide in 8 patients with this disease. We observed prolonged QT intervals in all 8 patients and serious arrhythmias in 4 patients. Methods We used arsenic trioxide to treat 8 patients with acute promyelocytic leukemia who had relapse after extensive previous therapy with all-trans retinoic acid and chemotherapy, including anthracycline (Table). Arsenic trioxide was provided by PolaRx Biopharmaceuticals, Inc. (New York, New York). Our protocol, which was the same as that of a phase II study in the United States, was reviewed and approved by the institutional review board of Hamamatsu University School of Medicine in Hamamatsu, Japan. All patients gave written informed consent and were hospitalized while receiving arsenic trioxide (0.15 mg/kg of body weight), which was administered daily by 2-hour infusion for a maximum of 60 days. Treatment was discontinued if patients met conventional criteria for complete remission (cellular bone marrow aspirate with blasts 5%, absolute neutrophil count 1.5 109 cells/L, and platelet count 100 109 cells/L). Patients who achieved complete remission received one additional 25-day course of arsenic trioxide at the same dose between 3 and 6 weeks after induction therapy. Patients were continuously monitored with ambulatory electrocardiography while receiving arsenic trioxide, and standard 12-lead electrocardiography was performed at least once per week. The QT intervals were calculated in the weekly electrocardiograms, were expressed as the mean values in the 12-lead electrocardiograms, and were corrected by heart rates according to the Bazett formula (QTc interval=QT interval/R-R interval) (8). Table. Patient Characteristics and Prolongation of the QTc Interval during Arsenic Trioxide Therapy The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Five patients (63%) achieved complete remission, and 4 patients received the second course of arsenic trioxide as consolidation therapy. Long QTc intervals (>440 ms) had been noted in 4 of 8 patients before arsenic trioxide therapy. Prolonged QT intervals were observed in all patients during induction therapy with arsenic trioxide and in 3 of 4 patients during the second course of therapy after complete remission (Table). The PQ interval and QRS duration were not prolonged in any case. Ventricular premature contractions were seen during 8 of 12 courses of therapy. Four patients developed nonsustained monomorphic ventricular tachycardia ( 3 successive ventricular premature contractions that stopped spontaneously within 30 seconds) and received antiarrhythmic agents (mexiletine HCl and lidocaine HCl). No patients developed sustained ventricular tachycardia or polymorphic ventricular tachycardia. Patient 1 received arsenic trioxide therapy during his second relapse. The QTc interval was prolonged gradually until day 33 and reverted to the pretreatment level after arsenic trioxide was stopped on day 43. The patient had seven successive ventricular premature contractions on day 25 when the QTc interval was 474 milliseconds (Figure). Therefore, mexiletine HCl (150 mg/d) was administered from day 28 to day 148 during arsenic trioxide therapy. The second course of arsenic trioxide with prophylactic mexiletine HCl was started on day 114. Although similar prolonged QT intervals were seen, only isolated ventricular premature contractions, not ventricular tachycardia, were induced. Patient 3 received arsenic trioxide for 46 days as induction therapy during her second relapse. She had five successive ventricular premature contractions on day 5 and three on day 31. She was given amphotericin B and received potassium and calcium supplements because she had low-normal levels of serum potassium and calcium on day 5. The QTc interval was prolonged from 408 to 460 milliseconds until day 50 and decreased to 442 milliseconds on day 87, when the second course was started. The second course again caused a prolonged QT interval. Figure. Electrocardiographic tracing and QT intervals in patient 1 during arsenic trioxide therapy. Patient 6 had two acute myocardial infarctions before developing acute promyelocytic leukemia. He relapsed four times and received large doses of chemotherapy before receiving arsenic trioxide. The ejection fraction was low (0.45) before arsenic trioxide therapy began. The patient had been receiving mexiletine HCl, 300 mg/d, since his second myocardial infarction. On day 38, nonsustained ventricular tachycardia (27 successive beats) was noticed when the QTc interval was prolonged from 443 to 485 milliseconds. Arsenic trioxide was reduced to 0.1 mg/kg per day and was administered intermittently until day 92 with lidocaine HCl or verapamil HCl. However, the patient developed accelerated idioventricular rhythm on day 62 and nonsustained ventricular tachycardia on day 70. He did not achieve complete remission, and arsenic trioxide therapy was discontinued on day 92. Patient 7 had nonsustained ventricular tachycardia before arsenic trioxide therapy in her second relapse, and mexiletine HCl, 150 mg/d, was given prophylactically until day 54. Arsenic trioxide was not effective and was withdrawn on day 40. The QTc interval was prolonged from 448 to 479 milliseconds; however, no serious arrhythmias were induced. Patient 8, who had a second relapse, had four successive ventricular premature contractions on day 23 and day 24 when the QTc interval was 461 milliseconds. Arsenic trioxide was withdrawn on day 23, and mexiletine HCl, 300 mg/d, was given. Thereafter, no ventricular tachycardia developed and arsenic trioxide therapy was restarted on day 26. Complete remission occurred, and arsenic trioxide therapy was stopped on day 41. No patient developed echocardiographic abnormalities (such as contractile dysfunction, cardiac enlargement, or hypertrophy) except the patient with previous myocardial infarctions. Serum electrolyte levels were within normal limits in all patients during the study. Discussion We used continuous monitoring by ambulatory electrocardiography to show prolonged QT intervals in 8 patients receiving arsenic trioxide. Ventricular arrhythmias, including ventricular tachycardia, developed in 5 of 12 courses of therapy and were associated with prolonged QT intervals. Previous reports of cardiographic abnormalities in arsenic trioxide therapy have shown low-flat T-wave, sinus tachycardia, prolonged QT intervals, and atrioventricular blocks, but not ventricular arrhythmias (1, 2, 7). However, multifocal ventricular tachycardia and ventricular fibrillation have been reported in arsenic poisoning (4-6). The tachyarrhythmias in our study were not sustained ventricular tachycardia or torsade de pointes but nonsustained ventricular tachycardia, accelerated idioventricular rhythm, or paroxysmal supraventricular tachycardia. It is unknown why polymorphic ventricular tachycardias and torsade de pointes were not observed. We believe that spatial inhomogeneity (QT dispersion) or abnormal ventricular repolarization might also be related to the arrhythmias. Indeed, in some cases, prolonged QT intervals were accompanied by an increase in the QT dispersion with no change in the QRS duration. It remains unclear why arsenic prolongs the QT interval. The metal is known to affect the peripheral nervous system diffusely (9), and imbalance of the sympathetic nervous system may be involved. Arsenic also causes widespread damage in many organs by combining with sulfhydryl proteins (9). A direct effect of arsenic on the myocardium could also be involved. However, the evidence remains speculative and further study is needed. Because of its remarkable effectiveness, arsenic trioxide will continue to be widely used for relapsed or refractory acute promyelocytic leukemia. Since such patients have been heavily treated with chemotherapeutic agents, including anthracycline and all-trans retinoic acid, cardiac damage is likely to be universal before arsenic trioxide therapy begins. Arsenic trioxide thus might induce arrhythmia. In our study, although the number of patients was small, ventricular arrhythmias were observed, often through careful monitoring. Therefore, we believe that patients taking arsenic trioxide should have frequent electrocardiographic monitoring and, in particular, should be monitored carefully for serious arrhythmias when QT intervals are prolonged. Prophylactic antiarrhythmic drugs that do not prolong the QT interval should be used because previous reports showed an association between fatal ventricular tachycardias and prolonged QT intervals in arsenic intoxication (4-6). Elect

Effects of a selective inhibitor of Na+/Ca2+ exchange, KB-R7943, on reoxygenation-induced injuries in guinea pig papillary muscles.

The effects of a novel agent that is reported to selectively block Ca2+ influx by Na+/Ca2+ exchange (NCX), KB-R7943, on the reoxygenation-induced arrhythmias and the recovery of developed tension after reoxygenation, were investigated in guinea pig papillary muscles. KB-R7943 dose-dependently suppressed the contracture tension during low-sodium (21.9 mM) perfusion (23+/-8% of steady-state developed tension at 10 microM vs. 56+/-11% in control; n = 6, p<0.05), but did not change action potential and contractile parameters. During the reoxygenation period after 60-min substrate-free hypoxia, KB-R7943 (10 microM) significantly decreased the incidence of arrhythmias (44 vs. 100% in control; n = 9, p <0.05) and shortened the duration of arrhythmias (16+/-11 vs. 72+/-14 s; p<0.01). KB-R7943 (10 microM) significantly enhanced the recovery of developed tension after reoxygenation (83+/-4 vs. 69+/-3% in control; p<0.05). We conclude that KB-R7943 (10 microM) selectively inhibits the reverse mode of NCX, and that it attenuates reoxygenation-induced arrhythmic activity and prevents contractile dysfunction in guinea pig papillary muscles. These results suggest that Ca2+ influx by NCX may play a key role in reoxygenation injury.

Heterogeneity and underlying mechanism for inotropic action of endothelin-1 in rat ventricular myocytes

To clarify the mechanisms underlying the positive inotropic action of endothelin‐1 (ET‐1), we investigated the effect of ET‐1 on twitch cell shortening and the Ca2+ transient in rat isolated ventricular myocytes loaded with a fluorescent Ca2+ indicator indo‐1. There was a cell‐to‐cell heterogeneity in response to ET‐1. ET‐1 (100 nm) increased twitch cell shortening in only 6 of 14 cells (44 %) and the increase in twitch cell shortening was always accompanied by an increase in the amplitude of the Ca2+ transient. The ETA‐ and ETB‐receptors antagonist TAK‐044 (100 nm) almost reversed both the ET‐1‐induced increases in twitch cell shortening and in the Ca2+ transient. In the ET‐1 non‐responding cells, the amplitude of the Ca2+ transient never increased. Intracellular pH slightly increased (∼0.08 unit) after 30 min perfusion of ET‐1 in rat ventricular myocytes. However, ET‐1 did not change the myofilament responsiveness to Ca2+, which was assessed by (1) the relationship between the Ca2+ transient amplitude and twitch cell shortening, and by (2) the Ca2+ transient‐cell shortening phase plane diagram during negative staircase. We concluded that there was a cell‐to‐cell heterogeneity in the positive inotropic effect of ET‐1, and that the ET‐receptor‐mediated positive inotropic effect was mainly due to an increase in the Ca2+ transient amplitude rather than to an increase in myofilament responsiveness to Ca2+.

The importance of glycolytically-derived ATP for the Na+/H+ exchange activity in guinea pig ventricular myocytes.

The cardiac subtype of Na+/H+ exchanger (NHE-1) plays an important role in the regulation of intracellular pH (pHi) and also can be a major route for Na+ influx. Although intracellular ATP is required for the optimal function of NHE-1, the regulation of the exchanger by ATP is less well characterized. This study was designed to investigate which intracellular ATP generated by oxidative phosphorylation or by glycolysis is dominant for the activation of NHE-1 in intact cardiac myocytes. Isolated guinea pig ventricular myocytes were loaded with the pHi-sensitive fluorescent indicator, 2′-7′-bis(carboxyl)-5′,6′-carboxy fluorescein (BCECF), and exposed to 20 mM 2-deoxyglucose (2-DG) or 2 mM sodium cyanide (CN) to inhibit glycolysis or oxidative phosphorylation, respectively. The activity of NHE-1 was estimated with pHi recovery following transient application of 15 mM NH4Cl (NH4Cl prepulse). After the NH4Cl prepulse, pHi decreased from 7.00 ± 0.03 (mean ± S.E.) to 6.60 ± 0.06 and recovered to 6.94 ± 0.13 at 10 min (n = 7). The pHi recovery was suppressed in the presence of 2-DG (6.67 ± 0.05, p < 0.01, n = 7), but was not changed in the presence of CN (6.88 ± 0.18, n = 6). Since there was no difference in the intrinsic H+ buffering power, the estimation of the net acid efflux demonstrated that the activity of NHE-1 was significantly depressed in 2-DG. The inhibitory effect of 2-DG was not due to more extensive depletion of global intracellular ATP or secondary to the change in either intracellular Na+ or Ca2+ concentration. We concluded that ATP generated by glycolysis rather than by oxidative phosphorylation is essential to activate NHE-1 in ventricular myocytes.

Regulation of [Na + i and [Ca 2+ ] i during Myocardial Ischemia and Reperfusion in a Single-Cell Model

To study the regulation of [Na+]i and [Ca2+]i during metabolic inhibition (MI) by the perfusion of 3.3 mM amytal and 5 μM CCCP, [Na+]i and [Ca2+], were measured simultaneously using guinea pig ventricular myocytes that were dual-loaded with SBFI/M and fluo-3/AM. It was suggested that 1) [Na+]i increased during MI by both the activated Na+ influx via Na+-H+ exchange and the suppressed Na+ extrusion via the Na+-K+ pump, 2) Na+-Ca2+ exchange was inhibited during MI, causing the dissociation between [Na+]i and [Ca2+]i, 3) Na+-Ca2+ exchange could be reactivated by energy repletion, resulting in an increase of [Ca2+]i and 4) cell contracture during MI was related to rigor due to energy depletion, while cell contracture after energy repletion was likely to be related to Ca2+ overload. We also investigated the regulation of [Na+]i, [Ca2+]i, and pHi during simulated ischemia (MI with extracellular acidosis) and reperfusion. Na+-H+ exchange was active during simulated ischemia. After reperfusion, Na+-H+ exchange was activated further as pHi was recovered, resulting in an additional [Na+]i elevation.