Torsade de pointes after amiodarone withdrawal; effects of mild hypokalaemia on repolarization

Recurrent atypical ventricular tachycardia, with a long QT interval,was documented in a 56-year-old patient 16 days after discontinuingamiodarone 200 mg and 400 mg on alternate days. Tachycardiaand variable prolongation of myocardial repolarization wereabolished by temporary cardiac pacing and correction of mildhypokalaemia.     

Torsade de pointes induced by short-term oral amiodarone therapy.

Although amiodarone appears to have few pro-arrhythmic effects, torsade de pointes (TdP) has been observed during long-term drug administration, usually in conjunction with electrolyte disturbances, a change in drug dosage, or concomitant drug therapy. We report two cases of amiodarone-induced TdP shortly after administration of a low dose of oral amiodarone, in the absence of predisposing factors.     

Torsade de pointes during loading with amiodarone

Torsade de pointes represents a potential complication of chronicamiodarone therapy. Several reports have emphasized the needfor a loading dose in order to achieve therapeutic blood levelsrapidly. We report a case of torsade de pointes following asingle oral dose of amiodarone (1400 mg or 30 mg kg^–1)administered after short intravenous loading for preventionof paroxysmal atrial flutter. Torsades de pointes were precededand associated with marked QT prolongation and bradycardia.This report suggests that careful monitoring of patients undergoingoral amiodarone loading is necessary.     

临时人工心脏起搏治疗尖端扭转型室性心动过速

本组１０例尖端扭转型室速（Ｔｄｐ），８例为间歇依赖性长ＱＴ间期综合征（ＬＱＴＳ），２例为肾上腺素能依赖性ＬＱＴＳ。前者中有５例为缓慢心律，一入院即行临时人工心脏起搏术，再补钾补镁，余３例为药物治疗无效且出现血流动力学改变时行临时起搏；后者临时起搏术后给予静滴心得安治疗。１０例Ｔｄｐ均中止发作，无一例死亡。     

Torsade de pointes associated with bradycardia and takotsubo cardiomyopathy

Two cases of torsade de pointes associated with bradycardia and takotsubo cardiomyopathy are reported. In both cases, atrioventricular block preceded the occurrence of takotsubo cardiomyopathy. Bradycardia-induced QT interval prolongation seemed to be amplified by the occurrence of takotsubo cardiomyopathy, resulting in torsade de pointes. Temporary ventricular pacing at a high rate decreased the QT interval and prevented the recurrence of torsade de pointes. Because atrioventricular block recurred or persisted even after the resolution of takotsubo cardiomyopathy, the patients received permanent pacemakers.     

Practice and challenges of thorough QT studies

The drug-induced Torsade de Pointes (TdP) tachycardia is a known regulatory problem which led to the concept of the so-called thorough QT (TQT) studies now required for practically every new pharmaceutical compound. This review summarizes the concept of the TQT studies, their statistical evaluation, and related pharmacodynamic /pharmacokinetic modeling. The review also lists suggestions of how to make TQT studies more efficient and how to improve the interpretation of clinical data obtained during drug development to identify drugs prone to TdP induction more effectively.     

Provocation of sudden heart rate oscillation with adenosine exposes abnormal QT responses in patients with long QT syndrome: a bedside test for diagnosing long QT syndrome.

AIMS: As arrhythmias in the long QT syndrome (LQTS) are triggered by heart rate deceleration or acceleration, we speculated that the sudden bradycardia and subsequent tachycardia that follow adenosine injection would unravel QT changes of diagnostic value in patients with LQTS. METHODS AND RESULTS: Patients (18 LQTS and 20 controls) received intravenous adenosine during sinus rhythm. Adenosine was injected at incremental doses until atrioventricular block or sinus pauses lasting 3 s occurred. The QT duration and morphology were studied at baseline and at the time of maximal bradycardia and subsequent tachycardia. Despite similar degree of adenosine-induced bradycardia (longest R-R 1.7+/-0.7 vs. 2.2+/-1.3 s for LQTS and controls, P=NS), the QT interval of LQT patients increased by 15.8+/-13.1%, whereas the QT of controls increased by only 1.5+/-6.7% (P<0.001). Similarly, despite similar reflex tachycardia (shortest R-R 0.58+/-0.07 vs. 0.55+/-0.07 s for LQT patients and controls, P=NS), LQTS patients developed greater QT prolongation (QTc=569+/-53 vs. 458+/-58 ms for LQT patients and controls, P<0.001). The best discriminator was the QTc during maximal bradycardia. Notched T-waves were observed in 72% of LQT patients but in only 5% of controls during adenosine-induced bradycardia (P<0.001). CONCLUSION: By provoking transient bradycardia followed by sinus tachycardia, this adenosine challenge test triggers QT changes that appear to be useful in distinguishing patients with LQTS from healthy controls.     

Serious adverse effects of amiodarone

Amiodarone is an effective antiarrhythmic drug which has been used successfully to treat a variety of cardiac arrhythmias. Early reports emphasized both the striking efficacy of this agent and the relative paucity of side effects necessitating discontinuing treatment with this drug. As amiodarone has been used more widely and in more diverse patient populations, reports of serious thyroid, pulmonary, cardiovascular, and other adverse reactions have appeared in the literature. In this paper, we review the serious adverse effects that have been reported to date. The incidence of these reactions varies considerably in different series, and cannot be explained solely by different doses employed or by varying methods of drug administration. The final role of amiodarone in the therapy of cardiac arrhythmias cannot be determined until the long-term toxicity has been more thoroughly investigated.     

Dofetilide induced torsade de pointes: Mechanism,risk factors and management strategies

Dofetilide is an effective antiarrhythmic agent for conversion of atrial fibrillation and atrial flutter as well as maintenance of sinus rhythm in appropriately selected patients. However, as with other antiarrhythmic agents, proarrhythmia is a known adverse effect. The risk of dofetilide induced torsade de pointes (Tdp) is low when used with strict dosing criteria guided by renal function, QT interval and concomitant drug therapy. Benefit from dofetilide use must be individualized and weighed against the side effects and the role of other available treatment options. In this review, we discuss the underlying mechanism, risk factors and precautionary measures to avoid dofetilide induced QT prolongation and ventricular tachycardia/Tdp. We suggest a scheme for the management of QT prolongation, ventricular arrhythmia and Tdp as well.     

Bepridil对豚鼠心室肌细胞动作电位时程和跨膜离子流的作用

为观察bepridi1对豚鼠单心室肌细胞动作电位时程 (APD)及动作电位形成过程中主要离子流的作用 ,探讨其诱发长QT间期及多形性室性心动过速的电生理机制。采用Nystatin 破膜法研究bepridil对豚鼠单心室肌细胞APD的作用 ,常规全细胞方法研究其对主要跨膜离子流的作用。结果 :在 5Hz剌激频率时 ,0 .1μmol/Lbepridil使APD明显延长 ,APD90 平均延长 18.0l%( 6 2 .40± 7.6 5msvs 5 2 .88± 5 .90ms,P <0 .0 5 )。当bepridil在细胞外液中的浓度增至1或 3μmol/L时 ,APD恢复到用药前水平 ;但当药物浓度进一步提高到 10 μmol/L时 ,APD明显缩短 ,动作电位幅度下降 ,这一作用随着药物浓度的升高而加强。在持续 2 5 0ms和 10 0 0ms至不同膜电位的去极化的实验中 ,bepridil能明显降低延迟整流钾电流 (IK)的尾电流和稳态电流 ,抑制作用呈浓度依赖性。在 3 0 0 0ms、+6 0mV去极化及IK的快成分 (Ikr)被E 40 31完全阻断时 ,bepridil对IK 的慢成分 (Iks)亦具有抑制作用 ,但两种情况下的半抑制浓度 (IC50 )不同 :3 0 0 0ms,+6 0mV去极化bepridil对IK 的IC50 为 1.6 2 μmol/L ,约为在 +2 0mV、10 0 0ms去极化时对IK 尾电流IC50 ( 0 .12 μmol/L)的 13.5倍。在 1Hz频率去极化时 ,该药对钠电流 (INa)和钙电流 (ICa)也具有浓     

Two Cases of Acute Promyelocytic Leukemia Complicated by Torsade de Pointes during Arsenic Trioxide Therapy

We describe 2 patients with acute promyelocytic leukemia (APL) in whom torsade de pointes (TdP) developed during treatment with arsenic trioxide. Patient 1 was a 23-year-old woman with second-relapse APL. Ventricular premature beat bigeminy developed on day 27 of treatment, and episodes of TdP developed on day 28. Patient 2 was a 51-year-old woman with second-relapse APL who had cardiomyopathy due to prior anthracycline treatment. TdP developed on day 17 of treatment. Arsenic trioxide is known to cause electrocardiographic abnormalities, such as ventricular tachycardia and prolongation of QT interval. Patient 1 was given fluconazole as a concomitant drug. Patient 2 had cardiomyopathy and hypokalemia. Careful management is needed during arsenic trioxide therapy because this treatment prolongs the QT interval, possibly inducing episodes of TdP.     

长时间应用盐酸尼非卡兰治疗持续性室性心动过速的安全性与有效性分析

目的分析长时间应用盐酸尼非卡兰（尼非卡兰）治疗持续性室性心动过速（室速）的安全性及有效性。方法顺序入选院内发作持续性室速的患者,分为不同用药时间组观察静脉应用尼非卡兰的复律效果及安全性。结果从2005年9月至2008年11月连续人选16例持续性室速患者,给予负荷量0．5mg／kg后,维持量（0．8mg·kg^-1·h^-1）分为短时组（1h）和长时组（12h）,各8例。维持时间分别为,长时组可以在用药90min后追加第二次负荷量0．25mg／kg。长时组患者左心室射血分数（LVEF）有好于短时组的趋势（0．52±0．14）和（0．39±0．15）,P=0．054。两组各有3例患者在维持用药60min内转复,而长时组另有4例患者在维持量超过60min后转复;用药终止室速即刻患者的QTc均明显长于停药12h后,但转复时两组间QTc差异无统计学意义（P=0．981）。短时组有1例患者出现尖端扭转性室速（Tdp）,其QTc达到了610ms,其他患者未见任何副作用。结论长时间应用尼非卡兰治疗多种疾病并发的室速具有一定的安全性,而且可以明显提高治疗的有效性。但在实际应用中应密切监测QTc以减少Tdp的发生。     

Monophasic versus biphasic waveform shocks for atrial fibrillation cardioversion in patients with concomitant amiodarone therapy.

AIMS: With transthoracic cardioversion of atrial fibrillation (AF), biphasic are more effective than monophasic waveforms. We sought to determine the ideal energy levels for biphasic waveforms. Methods We compared biphasic truncated exponential waveforms with monophasic damped sine waveform defibrillators, in a prospective, single-centre, randomized (1:1 ratio) study. The study included 154 patients receiving concomitant amiodarone; 77 received serial biphasic (50, 100, 150, up to 175 J) and 77 monophasic shocks (100, 200, 300, up to 360 J), as necessary. Results First-shock efficacy was similar in the two groups (57 vs. 55%, P = 0.871, respectively), as were serial-shocks (90 vs. 92%, P = 0.780). Both groups received equal numbers of shocks (1.8 +/- 1.1 vs. 1.7 +/- 1.0, P = 0.921). In both groups, serum creatine kinase levels showed a small but significant increase. The increase was, however, higher in the monophasic group. CONCLUSION: In patients with concomitant amiodarone therapy, biphasic truncated exponential shocks, using half the energy, were as effective as monophasic damped sine shocks. The biphasic scheme was not more efficacious for cardioverting AF. In our population, a first shock of at least 100 J seemed advisable with either waveform. If necessary, escalating shocks must be performed, but ideal levels of increase per shock are still uncertain for biphasic waveforms.     

先天性长QT综合征的临床特点

目的 强调先天性QT综合征（LQTS）患者临床特点的重要性。方法 对4例LQTS患者的临床和心电图特点进行分析。并对其临床诊断,发病机制、治疗及分子遗传学研究加以讨论,并行4例家系调查分析。结果 4例均为女性,家系中除1例外均为女性,QT间期均延长,反复发作性晕厥;4例均为Romano-Ward综合征,结论 LQTS是一个不难诊断的疾病,目前已有有效的治疗措施。应提高诊断率,勿漏诊或误诊。     

特发性长QT综合征QT离散度的临床意义

目的 探讨ＱＴ离散度与特发性长ＱＴ综合征（Ｉｄｉｏｐａｔｈｉｃ ｌｏｎｇ ＱＴ ｓｙｎｄｒｏｍｅ,ＬＱＴ１）发生尖端扭转性室性心动过速的关系。方法 ７８例基因（１１ｐ１５．５）携带者根据晕厥发作的频度和程度分３组;轻度（０￣４次,ｎ＝５９）中度（５￣１００次,ｎ＝１４）和重度（有心脏骤停史,ｎ＝５）。比较（１）３组首次心电图ＱＴ离散度的差异;（２）１８例小于２０岁的中、重度患者长期用β阻滞剂后ＱＴ     

完全性房室传导阻滞患者发生尖端扭转型室性心动过速的危险因素分析

目的　分析完全性房室传导阻滞患者发生尖端扭转型室性心动过速 (Td P)的危险因素。方法　用 logistic回归法分析 116例完全性房室传导阻滞住院患者 Td P的发生率与年龄、性别、治疗前血钾浓度、QT间期、校正的 QT间期 (QTc)、心率 (HR)的相关性。结果　 12例患者 (10 .3% )发生 Td P,其中女性 9例。Td P组血钾浓度为 (3.5 4±0 .5 5 ) m mol/ L ,明显低于未发生 Td P组血钾浓度 (4 .0 1± 0 .5 7) mm ol/ L (P<0 .0 1)。 Td P组 QT间期为 (0 .5 7±0 .0 75 ) s,明显大于未发生 Td P组 QT间期 (0 .4 6 5± 0 .0 93) s,(P<0 .0 1)。 Td P组年龄、HR、QTc与未发生 Td P组无显著差异。女性、血钾浓度和 QT的风险比值 (OR)分别为 5 .6 39、6 .773和 5 .90 5 ;而年龄、HR、QTc的 OR分别为 1.0 12、0 .92 5、1.0 30。结论　完全性房室传导阻滞患者发生 Td P的独立危险因素是低血钾浓度、长 QT间期和女性。对女性完全性房室传导阻滞患者应给予更积极的治疗 ,以免发生 Td P。     

Ketoconazole induced torsades de pointes without concomitant use of QT interval-prolonging drug

Ketoconazole is not known to be proarrhythmic without concomitant use of QT interval-prolonging drugs. We report a woman with coronary artery disease who developed a markedly prolonged QT interval and torsades de pointes (TdP) after taking ketoconazole for treatment of fungal infection. Her QT interval returned to normal upon withdrawal of ketoconazole. Genetic study did not find any mutation in her genes that encode cardiac IKr channel proteins. We postulate that by virtue of its direct blocking action on IKr, ketoconazole alone may prolong QT interval and induce TdP. This calls for attention when ketoconazole is administered to patients with risk factors for acquired long QT syndrome.     

High‐Rate Pacing Reduces Variability of Repolarization and Prevents Repolarization‐Dependent Arrhythmias in Dogs With Chronic AV Block

High‐Rate Pacing Prevents Drug‐Induced Arrhythmias. Introduction: High‐rate pacing may have an inhibitory effect on the initiation of Torsade de Pointes arrhythmias (TdP). However, permanent pacing is only indicated in high‐risk patients. We performed a proof of concept study into automatic overdrive pacing for prevention of drug‐induced TdP, using short‐term variability of repolarization (STV) as a feedback parameter of arrhythmic risk. Methods and Results: The minimal signal sampling frequency required for measuring STV was determined through computer simulation. Arrhythmogenic response to dofetilide (25 μg/kg/5minutes) was tested at two different paced heart rates (60–65 bpm vs 100–110 bpm) in 7 dogs with chronic atrioventricular block, while recording right and left ventricular (LV) monophasic action potential (MAP) and LV electrogram (EGM). Simulations showed a sampling frequency of 500 Hz is sufficient to capture relevant STV values. High‐rate pacing prevented dofetilide‐induced TdP seen at the low rate (low: 6/7 vs high: 1/7). At the low rate, STV from LV MAP duration increased before occurrence of spontaneous, ectopic activity and TdP (1.7 ± 0.6–3.0 ± 1.8 ms, P < 0.05), but at the high‐rate STV did not change significantly (0.9 ± 0.2–1.5 ± 1.4 ms, NS). Regression analysis showed a close relation between STV calculated from LV MAP and from LV EGM (R²= 0.71). Conclusions: High‐rate pacing increases repolarization reserve in dogs with chronic atrioventricular block, preventing dofetilide‐induced TdP. Changes in repolarization reserve are reflected in values of STV. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1384‐1391, December 2010)