Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors

The present study aimed to investigate the causative medications and underlying risk factors that predispose to drug-induced QT interval prolongation. Twenty-one patients with drug-induced long QT (90% females, mean age 64.3 ± 14.1 years) were included in the study. Transthoracic echocardiography as well as continuous or ambulatory 48-h electrocardiographic monitoring was carried out in all patients during their hospitalization. The mean corrected QT (QTc) interval was 542 ± 56.8 ms. Known cardiac agents (mainly class III antiarrhythmics) were implicated in 13/21 (62%), antipsychotics in 8/21 (38%), and antibiotics in 5/21 patients (24%). Potential drug-interactions through inhibition of cytochrome P450 isoenzymes were considered responsible in 5/21 cases (24%). The underlying cardiovascular diseases included hypertension (57%) with left ventricular hypertrophy (29%), paroxysmal atrial tachyarrhytmias (48%), heart failure (14%), valvular heart disease (10%), and coronary artery disease (5%). Torsade de pointes (TdP) was recorded in 6/21 of patients, and cardiac arrest necessitating resuscitation occurred in five of them. A significant correlation was observed between administration of cardiac agents and TdP events (P < 0.05). TdP and cardiac arrest events were both associated with a QTc interval >510 ms (P < 0.05). Advanced age (>60 years), female gender, hypertension and paroxysmal atrial tachyarrhytmias were the most common identifiable pre-existing factors for drug-induced long QT in our patient cohort. Marked QTc interval prolongation should be considered of prognostic significance for TdP and cardiac arrest events.     

The preclinical assessment of the risk for QT interval prolongation

Some drugs have been reported to induce severe ventricular arrhythmias, including torsades de pointes, and have been responsible in some cases for sudden death of patients. Although the mechanisms of these arrhythmias are not well understood, they are often, but not always, associated with QT interval prolongation. Regulatory authorities (CPMP in Europe) have recently pointed out the necessity to assess most carefully the potential, especially of non-cardiovascular drugs, for QT interval prolongation. Different methodological approaches are presented in this paper and experimental protocols are suggested; limitations and advantages of the presently available in vitro and in vivo models are discussed. It appears that both in vitro and in vivo approaches are complementary. In particular it is pointed out that only the in vitro models using isolated cardiac tissues (Purkinje fibres or papillary muscles) enable assessment of the drug properties under low cardiac rhythm conditions. This model allows us to mimic pathological situations of long QT interval (such as acquired or congenital long QT syndrome) in which most of the major clinical problems are encountered. Finally, a strategy for the preclinical assessment of the potential of a molecule for QT interval prolongation is presented.     

儿童室性期前收缩QT间期离散度和心率变异性的研究

目的：研究儿童室性期前收缩与QT间期离散度的变化以及心率变异性的关系。方法：选取2012年1月到2014年1月至成都市妇女儿童中心医院进行体检的50例正常儿童作为对照组，选取成都市妇女儿童中心医院小儿心内科于2012年1月到2014年1月收治的147例室性期前收缩患儿作为临床研究对象，并根据Lown分级结果将这147例患儿分为良性组（LownⅠ、Ⅱ）90例和恶性组（LownⅢ、ⅣA、ⅣB、V级）57例，对比3组患儿的QT间期离散度和心率变异性的各项指标。结果：（1）良性组患儿与对照组儿童的QT间期离散度无统计学差异（P＞0．05），恶性组患儿的QT间期离散度要明显高于功能组与对照组，差异具有显著的统计学意义（P＜0．001）；（2）根据试验结果可知，恶性组患儿的NN间期标准差（SDNN）、NN间期均值标准差（SDANN）、NN间期标准差指数（SDNN index）、相邻NN间期差值均方根（rMSSD）、相邻NN间期差值超过50ms心搏数百分率（PNN50）等数据均要明显低于良性组和对照组，差异具有统计学意义（P＜0．01）；良性组患儿的SDNN、SDANN、SDNN index要明显低于对照组，差异具有统计学意义（P＜0．05）。结论：恶性室性期前收缩的患儿心率变异性显著降低，QT间期离散度显著增高，QT间期离散度以及心率变异性检测可以有效地预测儿童室性期前收缩的危险程度。     

Single-dose ziprasidone associated with QT interval prolongation

Ziprasidone has been rarely associated with QT prolongation especially in patients (1) with no underlying cardiac or metabolic disorders, (2) who are receiving no concomitant medications known to prolong the QT interval, and (3) whom therapy is being initiated at a low dose. We report a 47-year-old patient who was agitated with suicidal ideation. He had a history of cocaine use, the last time being 72 hours before emergency department (ED) presentation. His electrocardiogram (ECG) on arrival in the ED showed a QT of 484 milliseconds and a QTc of 475 milliseconds with a pulse of 58 beats per minute. The patient was given 20 mg intramuscular (IM) ziprasidone for agitation. He reported feeling palpitations and weakness 45 minutes after receiving ziprasidone. His QT interval was prolonged on ECG and returned to baseline after 72 hours. Clinicians should consider obtaining an ECG before ziprasidone administration.     

Relevance of in vitro SCREENIT results for drug-induced QT interval prolongation in vivo: a database review and analysis

INTRODUCTION: The use of an isolated rabbit heart model (SCREENIT) to predict drug-induced QTc prolongation in animals was assessed using hERG and telemetry data. PURPOSE: We compiled data from (i) hERG assay (IC50s), (ii) SCREENIT assay (APD60) and (iii) in vivo non-rodent telemetry studies (QTc interval) and evaluated the reliability of APD60 to fit with IC50s and QTc prolongation using the ratio to free plasma level (FPL). Eighty-two compounds were separated into three classes based on hERG IC50s (class I: IC50s< or =1 microM, n=7; class II: IC50s>1 microM to < or =10 microM, n=15; class III: IC50s>10 microM, n=60). RESULTS: Three class I compounds did not prolong QTc at the FPL equivalent to their IC50s (43% hERG false positives). There were no false positives in SCREENIT. Six class II compounds prolonged the QTc interval. Results showed 40% hERG false negatives and no SCREENIT false negatives. Nine compounds had no effect on QTc, and two prolonged APD60 at an equivalent concentration/FPL (13% false positives). Three class III compounds prolonged QTc at an FPL lower than maximum SCREENIT concentrations (5% false negatives). Four other compounds generated SCREENIT false positive results (7%). CONCLUSION: SCREENIT increased the predictability of preclinical results for QTc prolongation without generating any false positive results in class I (13% in class II). Making decisions without isolated heart data increases the risk for eliminating efficient drugs displaying hERG inhibition.     

Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine

The Food and Drug Administration recently banned the sale of ephedra alkaloids because of their association with arrhythmic sudden death, myocardial infarction, and stroke. This has resulted in the emergence of formulations marketed for weight loss and performance enhancement that are "ephedra free" but contain other sympathomimetic substances, the safety of which has not been established. We report a case of exercise-induced syncope in a healthy 22-year-old woman that occurred 1 hour after she took the second dose of Xenadrine EFX, an ephedra-free weight-loss supplement. Electrocardiography revealed prolongation of the QT interval (corrected QT, 516 milliseconds); this resolved in 24 hours. Results of echocardiography and exercise stress testing were normal. Nine months of monitoring with an implanted loop recorder revealed no arrhythmias in the absence of Xenadrine EFX. Although this product contains a number of compounds whose pharmacologic effect is poorly characterized, notable quantities of phenylephrine are present, and the proarrhythmic potential of this compound in the setting of exercise is discussed.     

The imprecision in heart rate correction may lead to artificial observations of drug induced QT interval changes

Because of the known limitations of the Bazett and other heart rate correction formulas, it has been proposed that studies of drug induced QT interval changes should use several different heart rate correction formulas and that the consistency of findings by a majority of such formulas should be considered as valid. The aim of this article was to show that such an approach is inappropriate. Using the database of the EMIAT trial, data of QT and RR intervals were taken from electrocardiograms of the first postrandomization visit of 1,402 patients. Of these, 309 were on amiodarone and beta-blockers, 395 on amiodarone and off beta-blockers, 318 on beta-blockers and off amiodarone, and 380 off amiodarone and off beta-blockers. An investigation of drug induced QT interval changes was modeled by evaluating the corrected QT (QTc) interval differences between patients on and off amiodarone, and on and off beta-blockers. A set of 31 previously published heart rate correction formulas was used. In addition to calculating the QTc difference between on and off drug for each formula, the success of heart rate correction was judged by computing correlation coefficients between QTc and RR intervals (ideally corrected QTc values should be independent of heart rate). The difference between on and off drug QT intervals was also evaluated by logarithmic regression models between uncorrected QT and RR intervals in data taken from patients on and off treatment. The QTc interval prolongation on amiodarone was confirmed by all heart rate correction formulas but the extent of the prolongation differed from formula to formula and ranged from 13.6 to 30.9 ms. Of the 31 formulas, 3 reported QTc interval shortening on beta-blockers (up to -11.8 ms) and 28 reported QTc interval prolongation (up to +16.8 ms). The distribution of the results provided by the different formulas suggested that beta-blocker treatment led to a QTc interval prolongation by approximately 7 ms (e.g., +7.4 ms by the Fridericia formula, P = 0.002). The on treatment QTc changes obtained by different formulas were closely correlated to their correction success. Formulas that provided QTc intervals almost independent of the RR intervals estimated approximately 20 ms QTc prolongation on amiodarone and no QTc change on beta-blockers. QT/RR regression analysis confirmed that while amiodarone led to substantial QT prolongation, there was no change of QT interval on beta-blockers beyond the change in heart rate. The study showed that the concept of "majority voting" by different heart rate correction formulas is inappropriate and may lead to erroneous conclusions.     

平板运动试验QT频率适应性降低诊断冠心病的价值研究

目的评价平板运动试验QTc间期频率适应性变化对冠心病及早期冠状动脉病变的诊断价值。方法选择新疆医科大学第一附属医院先后行平板运动试验和冠状动脉造影的148例患者,根据冠状动脉造影结果,以频率适应性QTc间期(RAQTc)延长(≥420 ms)为阳性判定标准,进行回顾性病例对照研究。结果 (1)运动中,CAG阳性和CAG阴性两组的QT间期变化不同;(2)RAQTc延长诊断冠心病的敏感性、特异性、准确性、阳性预测值,均高于ST段改变标准;(3)两指标(RAQTc延长和ST段改变)联用可提高冠心病诊断的准确性;(4)经Spearman秩相关分析显示,RAQTc与冠状动脉病变程度呈正相关,有统计学显著差异(r=0.51,P<0.05);(5)与无冠状动脉病变组比较,冠状动脉病变<50%组的RAQTc变化无统计学差异。结论平板运动试验中RAQTc延长可作为诊断冠心病的一个参考指标。早期冠状动脉病变患者运动中QTc间期的频率适应性尚可,RAQTc无明显延长。     

Effect kinetics of N-acetylprocainamide-induced QT interval prolongation

We attempted to correlate clinical response with the effects of N-acetylprocainamide (NAPA) on the QT interval in five patients with stable chronic ventricular arrhythmias. A 15 mg/kg dose of NAPA was administered and a pharmacokinetic-pharmacodynamic model was used to relate plasma NAPA concentrations to changes in corrected QT interval (QTc). NAPA volume of distribution, elimination clearance, and elimination half-life averaged 1.37 +/- 0.19 L/kg, 174 +/- 63 ml/min, and 8.2 +/- 1.4 hours, respectively (mean +/- SD), and NAPA renal clearance averaged 1.9 +/- 0.6 times creatinine clearance. QTc prolongation was characterized by a linear-effect model in the first four patients and averaged 2.4 msec for every microgram per milliliter NAPA in a hypothetic biophase. QTc prolongation in patient 5 was exaggerated and was analyzed with an Emax model. Nonetheless, NAPA did not control this patient's arrhythmia. Conversely, patient 1 subsequently developed torsade de pointes even though QTc prolongation in this patient was comparable to that in patients 2 through 4, who responded satisfactorily to NAPA. We conclude that QT interval changes during initial NAPA administration do not reliably predict subsequent clinical response.     

Prenatal diagnosis of QT prolongation by magnetocardiography

Magnetocardiography constitutes a new tool for monitoring fetal cardiac activity. The fetal magnetocardiogram (FMCG) recorded noninvasively over the maternal abdomen is detectable with high temporal resolution and permits analysis of all parts of the PQRST waveform. In this way measurements of cardiac time intervals, including the QT interval, become possible. The following article constitutes the first report of antenatal detection of QT prolongation in two fetuses by FMCG.     

支架置入与冠状动脉粥样硬化性心脏病患者QT离散度及校正QT离散度变化

目的:探讨支架置入临床应用特点及其对冠状动脉粥样硬化性心脏病患者QT离散度及校正QT离散度的影响.方法:应用万方数据库和中国期刊全文数据库(CNKI),由第一作者以支架置入,QT离散度,校正QT离散度等检索1998/2010时限内与支架置入对冠状动脉粥样硬化性心脏病患者QT离散度影响有关的文献.排除重复研究或较陈旧文献.结果:依据纳入排除标准共保留文献22篇.常用支架为金属裸支架与药物支架.金属裸支架置入操作简便易行,并具有形状记忆效应及良好的生物相容性等临床应用优势,但术后早期再狭窄发生率高;药物支架有效降低术后再狭窄发生率,但远期安全性尚不明确.同时因经济投入高、置放技术要求严格等不易进行临床推广.从临床应用效果来看,支架置入显著缩短冠心病患者QT离散度以及校正QT离散.结论:支架置入显著缩短QT离散度以及校正QT离散,有效改善心肌再灌注,降低恶性心血管事件发生率,改善患者长期预后.但不同类型支架置入引起QT离散度的对应性变化,尚需进一步研究.     

西咪替丁对过敏性紫癜患儿心率、QT间期及心率校正的QT间期的影响

目的：观察西咪替丁佐治小儿过敏性紫癜对心率及 QT间期、心率校正的 QT 间期（linear corrected QT,QTLc）的影响并探讨其临床意义。方法采用随机对照的研究方法,选择腹型过敏性紫癜患儿83例,随机分为观察组和对照组。对照组37例,给予地塞米松、维生素C、钙剂综合治疗;观察组46例,在综合治疗基础上加用西咪替丁。观测心电图心率及 QT间期、QTLc情况。结果用药后心率及 QT间期、QTLc两组间比较差异有统计学意义,在综合治疗的基础上加用西咪替丁的观察组较对照组心率减慢,QT间期及 QTLc延长。结论临床小儿使用西咪替丁治疗期间须监测心电图心率及 QT间期、QTLc变化,避免室性心律失常的发生。     

Digital Holter measurement of QT prolongation in ziprasidone overdose

Objective. QT prolongation is an important complication in drug overdose, particularly with some antidepressants and antipsychotics. There are problems with the accurate measurement of the QT interval and determining for what QT interval patients should be monitored, because of the risk of torsades des pointes (TdP). We report a case of ziprasidone overdose with QT prolongation, demonstrating different methods of measuring the QT interval. Case report. A 47-year-old female presented after taking 1.2 g of ziprasidone and 250 mg of diazepam. She was taking propranolol and venlafaxine therapeutically. She developed bradycardia and QT prolongation (540 msec). She was transferred to a telemetry bed and observed for 48 h until her QT interval returned to normal (460 msec). QT intervals were extracted from (1) 12-lead digital Holter recordings (gold standard); (2) automated measurements on standard electrocardiograms (ECGs); and (3) manual measurements on standard ECGs, and compared on a QT versus time plot. An abnormal QT was determined based on the QT nomogram. Manual QT measurements showed a clear temporal association between ziprasidone overdose and a long QT, consistent with accurate QT measurements using continuous 12-lead Holter recordings with automatic QT measurements. However, standard automated measurements did not indicate an abnormal QT. Conclusions. Manual measurement of the QT interval appeared to be similar to the more accurate measurement of the QT by automated digital Holter recordings and better than standard automated measurements. Manual QT measurements would be more appropriate in clinical assessment of patients.     

Dynamics of corrected QT interval and heart rate in patients with early postinfarction angina

The subjects of the study were 135 patients with acute Q-wave and non-Q-wave myocardial infarction (MI) aged 36 to 78 years (mean 62.4 +/- 11.2 years). 59 patients (main group) developed early postinfarction angina (EPA). 76 patients (control group) had no stenocardia attacks within the entire period of hospital treatment. In the patients with EPA corrected QT interval dispersion was greater within the entire period of hospital treatment: 81.2 +/- 7.6 and 67.1 +/- 4.6 ms1/2 on the first day, 74.6 +/- 6.0 and 70.3 +/- 4.7 ms1/2 on the third day, 82.1 +/- 6.5 and 71.6 +/- 6.2 ms1/2 on the seventh day, 88.7 +/- 6.2 and 69.4 +/- 8.2 ms1/2 on the 28th day, respectively. Heart rate entropy decreased in both groups, but before discharge (mean 28th day) the patients with EPA demonstrated its significant reduction compared to the patients without EPA (3.89 +/- 0.16 and 4.13 +/- 0.09 bits, respectively, p < 0.05). Thus, recurrent myocardial ischemia in patients with MI, manifesting by EPA attacks, leads to the increase of QT interval dispersion and to heart rate rigidity which apparently mirrors greater probability of myocardial electric instability and increased risk of fatal arrhythmias in such patients.