Understanding drug-induced torsades de pointes: a genetic stance

Drugs may produce a variety of arrhythmias, but drug-induced QT prolongation and the risk of the polymorphic ventricular tachycardia torsades de pointes (drug-induced long QT syndrome) has garnered the most attention. The wide array of drugs with potential for QT prolongation, the correspondingly large number of patients exposed to such drugs, the difficulty in predicting an individual's risk, and the potentially fatal outcome, make drug-induced long QT syndrome an important public health problem for clinicians, researchers, drug development programs, and regulatory agencies. This review focuses on the genetic risk factors and mechanisms underlying QT prolongation and proarrhythmia. The post-genomic era hints at an improved understanding (and prediction) of how the gene-environment interaction produces this particular adverse drug response.     

抗新型冠状病毒药物致QT间期延长的文献复习及药学监护

本文对新型冠状病毒肺炎患者临床用药方案涉及的抗病毒药物致QT间期延长的文献报道情况进行复习。根据目前文献复习结果可知,洛匹那韦/利托那韦和磷酸氯喹存在引起QT间期延长进而引发尖端扭转型室速的潜在风险。在新型冠状病毒肺炎患者中使用此类药物需关注由此带来的用药风险,熟悉临床上常用的可引起QT间期延长的药物,提高识别患者QT间期延长的易感因素和药物相互作用的能力,重视心电图、电解质管理来预防临床潜在的药物致急性心律失常事件,以降低新型冠状病毒肺炎患者的药物不良反应,避免药源性损害。     

Drug induced QT prolongation: lessons from congenital and acquired long QT syndromes

Recent developments regarding the underlying genetic and intracardiac ion channel causes of congenital long QT syndrome have shed new light in the area of repolarization disorders and their resultant cardiac arrhythmias. Drug induced or acquired QT prolongation often represents a latent form of congenital long QT syndrome, though the genetic basis of this has not been elucidated in the majority of cases. Understanding this has lead to a new concept of repolarization reserve, a measure of inherent susceptibility to repolarization-mediated arrhythmias. The majority of pharmacologic agents that cause significant QT prolongation have potassium channel blocking characteristics, predominantly affecting the rapidly activating current I(Kr). The list of agents known to affect I(Kr)continues to grow, best monitored through several websites that collate reports of drug-induced QT prolongation and arrhythmias. Discontinuation of the offending agent and supportive care are often all that is necessary when clinical arrhythmias arise.     

Acute hypokalemia may not be an effective way to sensitize the in situ canine heart for sparfloxacin-induced long QT syndrome

Extents of the sparfloxacin (3 - 10 mg/kg, i.v.)-induced QT interval prolongation under normokalemic and hypokalemic conditions were assessed in halothane-anesthetized beagle dogs (n = 5). The hypokalemic condition was induced by an oral administration of furosemide (200 mg/kg per day) for 3 days, which decreased the serum potassium concentration from 3.65 +/- 0.13 to 2.35 +/- 0.13 mM (P < 0.05). However, the decrease of potassium concentration by itself did not affect the extent of the sparfloxacin-induced QT interval prolongation. These results indicate that acute hypokalemia may not severely sensitize the in situ heart for drug-induced long QT syndrome as previously thought.     

Microminipig, a non-rodent experimental animal optimized for life science research: in vivo proarrhythmia models of drug-induced long QT syndrome: development of chronic atrioventricular block model of microminipig

A new in vivo proarrhythmia model of drug-induced long QT syndrome was developed using the Microminipig, an incredibly small minipig established by Fuji Micra Inc. (Shizuoka). The atrioventricular (AV) node of the Microminipig of either sex weighing approximately 6 - 7 kg was ablated under halothane anesthesia, and proper care was taken for them. Proarrhythmic effects of drugs were assessed at >2 months after the onset of AV block using a Holter recording system. Oral administration of dl-sotalol (10 mg/kg) to the AV-block Microminipig prolonged the QT interval; moreover, it frequently induced dangerous ventricular premature beats, whereas no arrhythmia was detected after the vehicle administration (n = 4). Such dl-sotalol-induced ventricular arrhythmias were not detected in the intact Microminipig with sinus rhythm, although significant QT prolongation was observed (n = 4). Thus, the sensitivity and specificity of the AV-block Microminipig for detecting the drug-induced long QT syndrome can be considered to be comparable to previously established AV-block animal models of dogs and monkeys.     

An update on risk factors for drug-induced arrhythmias

A variety of drugs, either anti-arrhythmics or non-antiarrhythmics, have been associated with drug-induced arrhythmias. Drug-induced arrhythmias are usually observed in the presence of long QT interval or Brugada electrocardiographic pattern. Clinical risk factors, such as female gender, structural heart disease, metabolic and electrolyte abnormalities, bradycardia and conduction disease, increased drug bioavailability, and silent channelopathies act as ‘‘effect amplifiers’’ which can make an otherwise relatively safe drug dangerous with regard to risk for polymorphic ventricular tachycardia in the setting of QT interval prolongation. A drug-induced type 1 electrocardiographic pattern of Brugada syndrome is considered highly proarrhythmic. Specific electrocardiographic markers including the corrected QT interval, QRS duration, T_peak–T_end/QT ratio, and others may predict the risk of arrhythmias in both situations. The present review highlights on the current clinical and electrocardiographic risk factors for prediction of drug-induced arrhythmias.     

Drug-induced long QT in isolated rabbit Purkinje fibers: importance of action potential duration,triangulation and early afterdepolarizations

In the present study, we investigated three drug-induced long-QT syndromes in isolated rabbit Purkinje fibers in order to identify the relationship of action potential duration (APD), triangulation of action potentials (APD(90)-APD(40)) and early afterdepolarizations. Isolated rabbit Purkinje fibers were superperfused in Tyrode solution with solvent, indapamide (1 x 10 (-4) M, an I(ks) blocker mimicking long QT1), dofetilide (1 x 10 (-9), 1 x 10 (-8) or 1 x 10 (-7) M, an I(kr) blocker mimicking long QT2) or anthopleurin (1 x 10 (-8) M, an inhibitor of the inactivation of the I(Na(+)) current mimicking long QT3) (n=8 per group) for 25 min, and stimulated at 1 Hz for 20 min and at 0.2 Hz for another 5 min. Indapamide did not change APD and triangulation or elicit early afterdepolarizations even in the presence of beta-adrenergic stimulation with isoproterenol. Dofetilide concentration-dependently prolonged APD(90), increased triangulation and elicited early afterdepolarizations. Anthopleurin markedly increased APD(90) as well as triangulation and elicited early afterdepolarizations. The induction of early afterdepolarizations by dofetilide and anthopleurin was associated with a prolongation of APD(90) or an increase in triangulation, but not with a change in APD(40). Moreover, the degree of the increase in the triangulation was larger than that of APD(90) in long QT2 (dofetilide-induced) and long QT3 (anthopleurin-induced) models in isolated rabbit Purkinje fibers. Our present study indicates that rabbit Purkinje fibers can be used as long QT2 (dofetilide-mimicking) and LQT3 (anthopleurin-mimicking) syndrome models, and confirms that drug-induced long QT1 (indapamide-mimicking) is absent. Our present study also shows the relationship between a prolongation of APD(90) or increase in triangulation and the induction of early afterdepolarizations with dofetilide (I(kr) blocker) and anthopleurin (I(Na) modulator) in isolated rabbit Purkinje fibers.     

Facts,fancies and follies of drug-induced QT/QTc interval shortening

Parallels exist between drug-induced QT/QTc prolongation and shortening. However, these parallels are largely superficial and the experience with drug-induced QTc prolongation and its potential proarrhythmic link cannot be directly applied to drug-related QTc shortening. The congenital short QT syndrome (SQTS) is clearly much less prevalent than congenital, long QT syndrome, possibly some 1000 times. If the same discrepancy exists between arrhythmic susceptibility to drug-induced QTc prolongation and shortening, it is questionable whether regulatory burden should be imposed on drugs that might cause serious arrhythmia, once in many millions of exposures. Further, majority of torsadegenic drugs block the I_Kr current which is susceptible to the drug blockade because of the corresponding channel geometry. There is no parallel known for drug-induced QTc shortening. Also, all drugs that prolong QTc interval massively cause torsade de pointes tachycardia in more than exceptional isolated instances. On the contrary, digitalis that causes substantial QTc shortening is not known to trigger frequently ventricular arrhythmias. Moreover, most available population QTc data were obtained with Bazett''s correction which produces erroneous QTc shortening at slow heart rates. Safety limits derived from such data are inappropriate. Because practically all new drugs undergo the so-called thorough QT study, drug-induced QTc shortening will not go unnoticed for any new pharmaceutical. Describing drug-related QTc shortening in the label seems sufficient to avoid treatment of the rare SQTS subjects. Intensive investigations of QTc-shortening drugs (similar to those of drugs with positive thorough QT studies) do not seem to be warranted.This article is a commentary on Shah, pp. 58–69 of this issue and is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis

Torsade de pointes is a rare but potentially fatal ventricular arrhythmia associated with drug-induced delayed repolarization and prolongation of the QT interval. To determine if the arrhythmogenic potential of noncardiac drugs can be assessed in vitro, we evaluated the effects of 12 drugs on the action potential duration (APD) of cardiac Purkinje fibers and compared results with clinical observations. APD changes in canine and porcine fibers were evaluated under physiologic conditions (37 degrees C, [K+]0 = 4 mM) using standard microelectrode techniques. Six of seven drugs associated with QT prolongation or torsade de pointes in man (cisapride, erythromycin, grepafloxacin, moxifloxacin, sertindole, and sotalol) affected concentration-dependent prolongation of the APD in canine fibers during slow stimulation (2-s basic cycle length), attaining greater than 15% prolongation at high concentrations (> or = 10-fold clinically encountered plasma levels). Each of five drugs not linked clinically to QT prolongation and torsade de pointes (azithromycin, enalaprilat, fluoxetine, indomethacin, and pinacidil) failed to attain 15% prolongation, with fluoxetine, indomethacin, and pinacidil abbreviating the APD. Drugs eliciting the greatest prolongation also demonstrated prominent reverse rate-dependent effects. The antihistamine terfenadine (linked to dose-dependent QT prolongation and torsade de pointes clinically) only minimally prolonged the APD in canine and porcine fibers (and exerted no effect on midmyocardial fibers from left ventricular free wall) at supratherapeutic concentrations. On the basis of concentration-dependent APD prolongation and reverse rate-dependent effects, this Purkinje fiber model detects six of seven drugs linked clinically to acquired long QT syndrome and torsade de pointes, and clears each of five drugs not associated with repolarization abnormalities (overall 92% accuracy), validating the utility of this Purkinje fiber model in the preclinical evaluation of QT prolongation and proarrhythmic risk by noncardiac drugs.     

Drug- and non-drug-associated QT interval prolongation

Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene–drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene–drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted.     

Pharmacogenetics of cardiac K(+) channels

A number of commonly prescribed drugs belonging to various therapeutic classes (antiarrhythmic, antibiotic, antifungal, antihistamine, antipsychotic, prokinetic drugs…) possess, in common, the adverse property to prolong cardiac repolarization [prolonged QT interval duration on surface electrocardiogram (ECG)], exposing patients to a risk of torsade-de-pointes arrhythmias, syncope, and sudden death. Arrhythmias related to drug-induced QT prolongation do not occur in every patient treated with these drugs but most likely occur in a subset of susceptible patients. These patients have a high risk of recurrence of arrhythmias upon exposure to any of the other drugs that broaden the QT interval. It is currently suspected (though not yet proven) that susceptible individuals carry a silent mutation in one of the genes responsible for the congenital long QT syndrome. Indeed, it appears more and more clear that a large proportion of congenital long QT syndrome gene carriers, have a normal QT interval and a normal phenotype and therefore, remain undiagnosed. Therefore, a much larger than previously thought proportion of the general population may be affected by asymptomatic mutations in cardiac ion channel encoding genes. No routine technology is currently available in identifying these patients preventively.     

药物导致的获得性长QT综合征诊断与治疗

药物导致的获得性长QT综合征是由药物引起的可逆性的QT间期延长的综合征,其主要机制是药物通过对IKr的阻断作用,导致动作电位3期快速复极延迟,表现为QT间期延长。在临床上,许多结构上无关的药物,包括抗精神病药物均可以导致QT间期的延长。药物导致的获得性长QT综合征容易导致尖端扭转性室性心动过速（TdP）,临床上可以通过Tp-e和Tp-e/QT比值、巨大T-U波、QRS缓慢上升支和QT间期短期变异可以预测TdP的风险。治疗获得性长QT综合征,最根本的是识别和停用导致QT间期延长的药物并积极的纠正代谢异常,如低钾血症或低镁血症。大多数TdP的发作是短暂的,并可自行终止。然而,长时间发作会导致血流动力学紊乱,需要立即进行电复律。     

Comparison of the QT interval response during sinus and paced rhythm in conscious and anesthetized beagle dogs

INTRODUCTION: The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles. METHOD: Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration-time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic-pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms). RESULTS: In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording. DISCUSSION: All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug-induced QT interval prolongation.     

A new preclinical biomarker for risk of Torsades de Pointes: drug-induced reduction of the cardiac electromechanical window

Evaluation of new therapeutic agents for their potential to cause QT interval prolongation and drug-induced ventricular arrhythmia, like Torsades de Pointes (TdP), is a critical activity during drug development. The QT interval has been used as a surrogate biomarker to assess ventricular repolarization effects caused by drug-induced blockade of cardiac repolarizing currents, mainly I_Kr, but is imperfect in predicting proarrhythmia. Evidence suggests that left ventricular mechanical dysfunction may also contribute to ventricular arrhythmias; thus, electrical and mechanical alterations may have a role in drug-induced TdP. The electromechanical window (EMw) represents the time difference between the end of electrical systole (i.e. the QT interval) and the completion of ventricular relaxation (i.e. the QLVP_end interval), and appears to be a new potential biomarker for TdP risk. A reduction in the EMw (to negative values) has now been shown to be associated with the onset of TdP in an anaesthetized dog model of long QT1 syndrome. Therefore, the EMw represents a novel indicator of TdP risk that may add predictive value beyond assay of drug-induced QT interval prolongation.

LINKED ARTICLE

This article is a commentary on van der Linde et al., pp. 1444–1454 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2010.00934.x     

Clinical relevance and management of drug-related QT interval prolongation

Much attention recently has focused on drugs that prolong the QT interval, potentially leading to fatal cardiac dysrhythmias (e.g., torsade de pointes). We provide a detailed review of the published evidence that supports or does not support an association between drugs and their risk of QT prolongation. The mechanism of drug-induced QT prolongation is reviewed briefly, followed by an extensive evaluation of drugs associated with QT prolongation, torsade de pointes, or both. Drugs associated with QT prolongation are identified as having definite, probable, or proposed associations. The role of the clinician in the prevention and management of QT prolongation, drug-drug interactions that may occur with agents known to affect the QT interval, and the impact of this adverse effect on the regulatory process are addressed.     

Acquired QT interval prolongation and HERG: implications for drug discovery and development

Putative interactions between the Human Ether-a-go-go Related Gene (HERG), QT interval prolongation and Torsades de Pointes (TdP) are now integral components of any discussion on drug safety. HERG encodes for the inwardly rectifying potassium channel (I_Kr), which is essential to the maintenance of normal cardiac function. HERG channel mutations are responsible for one form of familial long QT syndrome, a potentially deadly inherited cardiac disorder associated with TdP. Moreover, drug-induced (acquired) QT interval prolongation has been associated with an increase in the incidence of sudden unexplained deaths, with HERG inhibition implicated as the underlying cause. Subsequently, a number of non-cardiovascular drugs which induce QT interval prolongation and/or TdP have been withdrawn. However, a definitive link between HERG, QT interval prolongation and arrhythmogenesis has not been established. Nevertheless, this area is subject to ever increasing regulatory scrutiny. Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening.     

Calculation of QT shift in non clinical safety pharmacology studies

IntroductionDrug-induced QT interval prolongation is a major concern in new drug candidate development. This study presents a method of assessment of drug-induced QT interval prolongation without need for QT correction in conscious Beagle dogs and Cynomolgus monkeys monitored by telemetry. Accuracy and reliability are analysed by comparison with a reference QT correction method (Holzgrefe) from experiments performed with reference substances terfenadine, thioridazine and sotalol.MethodsThe QT shift method principle is assessment of any drug-induced QT interval shift directly from the individual QT/RR relationship. The individual QT/RR relationship is built from a treatment-free 24-hour recording period. QT and RR intervals are determined from a beat-to-beat analysis. A probabilistic method is used to define the individual QT/RR relationships. Checks were performed to compare results obtained with the QT shift method and the QT correction methods. The robustness of the QT shift method was tested under various conditions of drug-induced heart rate change (i.e. normal, bradycardia and tachycardia).ResultsThe extent of agreement with the used reference QT correction method, Holzgrefe formula, was excellent (3–4 ms) in both animal species under the various drug induced effects on heart rate. The statistical sensitivity threshold for detection of QT prolongation according to a standard safety pharmacology study design was 7–8 ms.DiscussionWhen combined with the probabilistic determination of individual QT/RR relationships, this simple method provides a direct assessment of a drug-induced effect on QT interval, without any curve fitting or application of correction formula. Despite noticeably different shapes in QT/RR relationships, the QT shift method is applicable to both Beagle dogs and Cynomolgus monkeys. It is likely that the QT shift method will be particularly helpful in problematic cases, enabling detection of drug-induced prolongation of less than 10 ms.     

西酞普兰致QT间期延长的研究综述

目的综述了西酞普兰致QT间期延长的研究进展。西酞普兰通过阻断心脏相关离子通道，可剂量依赖性地引起QT间期延长，大剂量时可引起致命性的尖端扭转型室性心动过速。西酞普兰应用大剂量、女性、65岁以上人群、电解质紊乱、先天性长QT间期综合症是产生QT间期延长的风险因素。为安全合理地应用西酞普兰，应对其安全性进行持续的监测和评价。     

A method for QT correction based on beat-to-beat analysis of the QT/RR interval relationship in conscious telemetred beagle dogs

INTRODUCTION: Drug-induced QT prolongation is a major clinical risk factor for arrhythmia induction, particularly torsades de pointes. QT interval is rate dependent, and many formulae exist that attempt to correct QT for changes in heart rate. Most correction factors are acknowledged to overcorrect at high heart rates, undercorrect at low heart rates, and tend to be species specific. Data collected from computerised data acquisition systems are normally reported as means over a given logging period, and so extremes of heart rate are averaged out. Therefore, the aim of this study was to develop a technique for assessing drug-induced changes in the QT/RR relationship, which is simple, suitable for small group sizes, and better able to determine rate-dependent effects of drugs. METHODS: Telemetred beagle dogs (n=4) instrumented for the measurement of electrocardiogram (ECG) were monitored for four separate 20-h periods to define the control QT/RR relationship. Data were binned by RR interval, in 10 ms bins, to produce a control curve. Each dog was treated with vehicle and sotalol (4, 8, 32 mg/kg) in a crossover design to determine whether drug-induced changes in the QT/RR relationship could be detected using the data binning technique. RESULTS: The control QT/RR relationship was curvilinear with a steep section for RR intervals below 580 ms, and was much less steep after this point. Sotalol produced QT prolongation and bradycardia-Fridericia's correction (QTf) reduced the magnitude of this prolongation. The data analysed by the binning technique showed a larger prolongation in QT than was suggested by QTf, and an inverse frequency-dependent response. DISCUSSION: Beat-to-beat analysis and binning allows accurate determination of the QT/RR relationship and assessment of QT prolongation without recourse to mathematical modelling. It also highlights the importance of assessing QT effects in well-trained animals over a range of heart rates.