Drug-induced QT dispersion: does it predict the risk of torsade de pointes?

Drug-induced delay in ventricular repolarization and proarrhythmias have attracted considerable regulatory attention. The measure of delayed ventricular repolarization most frequently used clinically is the ability of the new chemical entity (NCE) to prolong the QTc interval on surface electrocardiogram. Before they can be approved, new chemical entities with systemic bioavailability require characterization for their potential to prolong the QTc interval. Inevitably, QTc interval prolongation has come to be recognized as a surrogate marker of the risk of torsade de pointes (TdP)--a unique form of potentially fatal polymorphic ventricular tachycardia. Although it is the best and the simplest clinical measure that is available at present, QTc interval is not a reliable surrogate of TdP. Intramyocardial dispersion of repolarization appears to play a more important role both in electrical stability of the ventricles and in arrhythmogenesis. The potential importance of myocardial dispersion of refractoriness in arrhythmogenesis has led to a number of attempts to assess it from the surface electrocardiogram. This review summarizes the evidence for and against the predictive value of one of these attempts-measurement of the so-called QT dispersion. Although the concept of QT dispersion is the best known and most widely investigated, it has also proved to be the least successful in predicting the risks of drug-induced TdP.     

Drugs that cause torsades de pointes and increase the risk of sudden cardiac death

Torsades de pointes (TdP) is a potentially life-threatening arrhythmia associated with not only antiarrhythmic drugs, but noncardiac drugs of many different classes. All these drugs prolong the QT interval by their blocking of the potassium channel IKr, and many are metabolized by the cytochrome P450 isoenzyme CYP3A4. Polypharmacy with other drugs utilizing the same enzyme, or inhibiting CYP3A4, can lead to TdP. A consistent finding of all the QT-prolonging drugs is predominance of TdP in women. Other risk factors for QT prolongation and TdP include hypokalemia, congestive heart failure, and structural heart disease. Knowledge of potential drug interactions and other risk factors for TdP can help in reducing the number of adverse events associated with the use of QT-prolonging drugs.     

Citalopram induced torsade de pointes, a rare life threatening side effect

Acquired Long QT syndrome is a disorder caused by medications, electrolyte imbalances, and drug interactions. This syndrome is associated with an increased risk of a characteristic life-threatening cardiac arrhythmia, known as torsade de pointes (TdP). In the setting of Long QT syndrome (LQTS), selective serotonin reuptake inhibitors (SSRIs) can precipitate TdP. We report the first case of LQTS and TdP induced by citalopram in the United States. After discontinuation of citalopram, the QT/QTc interval normalized after 3 days and resolved further episodes of TdP. Patients on citalopram should be monitored closely for QT/QTc interval to prevent torsade de pointes.     

Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: a case control pilot study.

AIMS: Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT intervals. Here, we evaluate variability of QT intervals in patients with a history of drug-induced long QT syndrome (dLQTS) and TdP in absence of a mutation in any of the major LQTS genes. METHODS AND RESULTS: Twenty patients with documented TdP under drugs with QT-prolonging potential were compared with 20 matched control individuals. An observer blinded to diagnosis manually measured lead-II, RR, and QT intervals from 30 consecutive beats. BVR was determined from Poincaré plots of QT intervals as short-term variability (STV(QT) = Sigma|QT(n)(+1) - QT(n)|/[30 x radical2]). QRS interval and cycle length was comparable between study groups and controls. No difference was found in QTc between dLQTS and controls (428 +/- 25 vs. 421 +/- 34 ms, P = 0.26), whereas STV(QT) was significantly higher in dLQTS when compared with controls (8.1 +/- 3.7 vs. 3.6 +/- 1.3 ms, P = 0.001). Proarrhythmic predictive power of STV(QT) was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI: 0.79-0.99 vs. 0.39-0.75). CONCLUSION: In the absence of QTc prolongation, baseline STV(QT) characterized patients with documented drug-induced proarrhythmia. STV(QT) could prove to be a useful non-invasive, easily obtainable parameter aiding the identification of the patient at risk for potentially life threatening arrhythmia in the context of drugs with QT prolonging potential.     

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.     

Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T-wave, incriminates safe drugs, and misses profibrillatory drugs

Drug-induced QT prolongation has such a strong correlation with torsade de pointes (TdP) that it comes to serve as a surrogate for TdP. As a result, drugs that prolong QT by as little as a few ms, even without any evidence of TdP, may get dropped from development or blocked from approval. However, measurement of QT with ms accuracy may be impossible to achieve. Worse, some drugs that lengthen the QT interval are not only not proarrhythmic, they may even be antiarrhythmic; while some that shorten the QT can be strongly proarrhythmic. Indeed, proarrhythmia related to repolarization disturbances is caused by triangulation, reverse use dependence, instability, and dispersion (TRIaD). When TRIaD is present with QT prolongation it commonly yields TdP, but when TRIaD is combined with QT shortening it preferentially leads to VF instead. While TdP is lethal in less than 20% of instances, VF is much more morbid. Worse, available evidence suggests that there is more death from drug-induced fibrillation than TdP. Thus, QT prolongation alone is not very useful. Instead, the T-wave should be used in alternate ways: extraction of TRIaD.     

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。     

The morphology of the QT interval predicts torsade de pointes during acquired bradyarrhythmias.

OBJECTIVES: The purpose of this study was to define the electrocardiographic (ECG) predictors of torsade de pointes (TdP) during acquired bradyarrhythmias. BACKGROUND: Complete atrioventricular block (CAVB) might lead to downregulation of potassium channels, QT interval prolongation, and TdP. Because potassium-channel malfunction causes characteristic T-wave abnormalities in the congenital long QT syndrome (LQTS), we reasoned that T-wave abnormalities like those described in the congenital LQTS would identify patients at risk for TdP during acquired bradyarrhythmias. METHODS: In a case-control study, we compared 30 cases of bradyarrhythmias complicated by TdP with 113 cases of uncomplicated bradyarrhythmias. On the basis of the criteria used for the congenital LQTS, T waves were defined as LQT1-like (long QT interval with broad T waves), LQT2-like (notched T waves), and LQT3-like (small and late) T waves. RESULTS: Neither the ventricular rate nor the QRS width at the time of worst bradyarrhythmia predicted the risk of TdP. However, the QT, corrected QT (QTc), and T(peak)-T(end) intervals correlated with the risk of TdP. The best single discriminator was a T(peak)-T(end) of 117 ms. LQT1-like and LQT3-like morphologies were rare during bradyarrhythmias. In contrast, LQT2-like "notched T waves" were observed in 55% of patients with TdP but in only 3% of patients with uncomplicated bradyarrhythmias (p < 0.001). A 2-step model based on QT duration and the presence of LQT2-like T waves identified patients at risk for TdP with a positive predictive value of 84%. CONCLUSIONS: Prolonged QT interval, QTc interval, and T(peak)-T(end) correlate with increased risk for TdP during acquired bradyarrhythmias, particularly when accompanied by LQT2-like notched T waves.     

QT interval prolongation associated with venlafaxine administration

A significant number of non-antiarrhythmic drugs including psychotropic agents have been shown to prolong cardiac repolarization increasing the risk for torsade de pointes ventricular tachycardia. We briefly describe a 60-year-old woman who admitted to the hospital due to hypertension and mild dyspnea having a prolonged QT interval (QTc: 582 ms). The patient had a known history of depression treated with venlafaxine. The QT interval normalised a few days after cessation of the antidepressant agent. This is the first report of venlafaxine-induced QT interval prolongation.     

尖端扭转型室性心动过速与TP—TE时间及Q—T间期比值关系的研究

目的探讨长Q—T间期患者T波峰末时间（TP-TE时间）、TP-TE／Q—T与尖端扭转型室性心动过速（TdP）发生的相关性。方法选择长Q—T间期患者29例,将其分为伴TdP组（发作期或稳定期）和不伴TdP组两组,通过常规心电图和动态心电图分析测量并比较Q—T间期、校正的Q—T间期（Q—Tc间期）、TP-TE时间和TP-TE／Q—Tc结果伴TdP组稳定期患者TP-TE时间、TP—TE／Q—T（14157±37．33ms、0．27±0．05）和发作期（154．29±42ms、0．29±0．06）均较不伴TdP组（97．60±5．51ms、0．19±0．13）延长或增大。差异均有统计学意义（均P〈0．05）;在预测TdP发生风险时,伴TdP组稳定期和发作期TP-TE时间、TP-TE／Q—T均较Q—T间期更敏感（Wald值分别为1247、15．77和5．77、6．23）,差异均有统计学意义（P〈O．05）。结论TP-TE时间TP-TE／Q—T比值有助于预测长Q—T间期患者发生TdP的风险。     

Antibiotic‐induced Cardiac Arrhythmias

This review aims to clarify the underlying risk of arrhythmia associated with the use of macrolides and fluoroquinolones antibiotics. Torsades de pointes (TdP) is a rare potential side effect of fluoroquinolones and macrolide antibiotics. However, the widespread use of these antibiotics compounds the problem. These antibiotics prolong the phase 3 of the action potential and cause early after depolarization and dispersion of repolarization that precipitate TdP. The potency of these drugs, as potassium channel blockers, is very low, and differences between them are minimal. Underlying impaired cardiac repolarization is a prerequisite for arrhythmia induction. Impaired cardiac repolarization can be congenital in the young or acquired in adults. The most important risk factors are a prolonged baseline QTc interval or a combination with class III antiarrhythmic drugs. Modifiable risk factors, including hypokalemia, hypomagnesemia, drug interactions, and bradycardia, should be corrected. In the absence of a major risk factor, the incidence of TdP is very low. The use of these drugs in the appropriate settings of infection should not be altered because of the rare risk of TdP, except among cases with high‐risk factors.     

Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society

The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.     

Relationships between preclinical cardiac electrophysiology,clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development

OBJECTIVE: To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. METHODS: Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. RESULTS: Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. CONCLUSIONS: The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.     

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

BACKGROUND: The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP. METHODS AND RESULTS: Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as T(p-e)/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C(max). CONCLUSIONS: Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP.     

Arrhythmogenic foods – A growing medical problem

Arrhythmogenic ingredients in our diet such as mushrooms, licorice, toxic honey, liquid protein drinks, etc. have long been recognized as rare but important considerations in the differential diagnosis of arrhythmias. Anecdotal reports of torsades de pointes (TdP), arrhythmias and/or sudden death and small studies in normal subjects have suggested that simple ingredients such as grapefruit juice or ingredients in energy drinks marketed as dietary supplements could have direct arrhythmogenic actions, especially in patients with congenital long QT syndrome (cLQTS). Two recent studies that employed the industry-standard “thorough QT” trial design leave no doubt that grapefruit juice and some energy drinks can prolong the QTc interval and to exceed 500 msec. in some patients with cLQTS, a threshold known to signal imminent danger. These reports raise numerous clinically important questions such as which other patients may be at risk of arrhythmias. For example, patients with multiple clinical risk factors for TdP (hypokalemia, bradycardia, female sex, etc.) may be at risk from these and possibly other dietary ingredients ingested by millions of people each day. It is essential that further research evaluate the safety of these and similar food products and that vulnerable patients, especially those with cLQTS, be warned of this serious and emerging threat.     

Physician-induced torsade de pointes--therapeutic implications

Torsade de pointes (TdP) is a clinico-electrocardiographic syndrome characterized by an abnormally prolonged QT interval and the occurrence of potentially life-threatening ventricular tachyarrhythmias. Two mayor causes can be distinguished: congenital and acquired long QT syndrome. Whereas the former has recently been identified as an ion channelopathy, the mechanisms underlying acquired long QT syndrome are far from being understood. It has been suggested that patients with the acquired form of the disease may suffer from a clinically hidden form of the congenital variant. However, recent studies have yielded only a small number of individual cases in whom genetic analyses revealed the presence of an ion channel gene mutation.Since acquired long QT syndrome is most often induced by drugs prolonging myocardial repolarization, it is largely an iatrogenic disease. In order to prevent unwitting exposure to risk, physicians prescribing agents that may prolong repolarization need to be aware of the typical clinico-electrocardiographic characteristics of drug-induced TdP, and its diagnosis and management. A clearer delineation of the risk factors predisposing to abnormal prolongation of repolarization, and a more precise quantification of the torsadogenic potency of individual drugs appear mandatory in order to prevent or at least minimize the occurrence of this potentially fatal adverse effect of certain drugs.     

Torsade de pointes induced by intravenous and long-term oral amiodarone therapy in a patient with dilated cardiomyopathy

A 70-year-old woman with dilated cardiomyopathy and ventricular tachyarrhythmia was initially treated in 1990 with intravenous amiodarone (240 mg). She developed a junctional escape rhythm (48 beats/min) with QT prolongation (QT: 0.68 s) and 8 h later developed torsade de pointes (TdP). Because other antiarrhythmic drugs did not suppress the arrhythmia, oral amiodarone (100 mg/day) was started in 1995, 7 weeks before she presented with congestive heart failure. The QT prolongation (QTc: 0.64) increased after administration of dopamine, and TdP again developed. This case suggests that amiodarone induces proarrhythmias by different mechanisms when administered intravenously or orally.     

Beta-blocker decreases the increase in QT dispersion and transmural dispersion of repolarization induced by bepridil.

Bepridil is effective for intractable cardiac arrhythmia, but in rare cases will induce torsades de pointes (TdP) associated with QT interval prolongation. Beta-blockers will effectively prevent TdP in some clinical settings, so the effect of beta-blocker on the change in QT interval, QT dispersion and transmural dispersion of repolarization (TDR) induced by bepridil was investigated in 10 patients (7 male, 3 female; 62+/-6 years old) with intractable paroxysmal atrial fibrillation. The QTc interval, QTc dispersion and TDR were measured before and after 1 month of administration of bepridil, and then a beta-blocker was added and the QTc interval, QTc dispersion and TDR re-measured 1 month later. Bepridil significantly prolonged the QTc interval (0.42+/-0.05 to 0.50+/-0.08; p<0.01), and increased both the QT dispersion (0.07+/-0.05 to 0.14+/-0.08; p<0.01) and TDR (0.10+/-0.04 to 0.16+/-0.05; p<0.01). The addition of a beta-blocker decreased the QTc interval (0.50+/-0.08 to 0.47+/-0.04; p=0.09) and significantly decreased both the QTc dispersion (0.14 +/-0.08 to 0.06+/-0.02; p<0.01) and TDR (0.16+/-0.05 to 0.11+/-0.04; p<0.001). Compared with the control, the combination therapy significantly prolonged the QTc interval, but did not increase either QTc dispersion or TDR, and so was effective in all patients with intractable AF. The findings suggest that beta-blocker reduces the increase in QT dispersion and TDR induced by bepridil, and combined therapy with bepridil and beta-blocker might thus be useful for intractable atrial fibrillation.