High risk of QT interval prolongation and torsades de pointes associated with intravenous quinidine used for treatment of resistant malaria or babesiosis

Cardiac toxicity may be associated with drugs used for malaria. Torsades de pointes (TdP) is a well-known adverse effect of quinidine when used for atrial fibrillation. Intravenous quinidine doses for resistant malaria are 2 to 3 times higher than those used for arrhythmias. Among 6 patients receiving quinidine for malaria or babesiosis, 4 developed QT interval prolongation and 2 experienced TdP. Clinicians should be aware that recommended doses of quinidine for malaria carry a high TdP risk.     

Torsades de Pointes Ventricular Tachycardia Induced by Clarithromycin and Disopyramide in the Presence of Hypokalemia

We report a 76-year-Old woman who developed TdP ventricular tachycardia induced by combined use of clarithromycin and disopyramide. She had a history of myocardial infarction 5 years earlier and has taken disopyramide for supraventricular arrhythmias. In addition, she had taken clarithromycin for upper respiratory tract infection. On admission, an ECG showed prolongation of QTc interval to 0.71 seconds and self-terminating TdP occurred several times. Disopyramide was metabolized by the cytochrome enzyme CYP3A4 and clarithromycin competitively inhibits this enzyme, probably resulting in an increase in plasma concentration of disopyramide. We should consider this possibility when prescribing clarithromycin in combination with antiarrhythmic agent disopyramide.     

Nicorandil, a Potassium Channel Opener, Abolished Torsades de Pointes in a Patient with Complete Atrioventricular Block

TdP is a serious complication of AV block. We report a case of complete AV block with QT prolongation who had bouts of TdP resistant to lidocaine and isoproterenol. Temporary pacing could not be performed, because insertion of a pacing lead triggered TdP that deteriorated into ventricular fibrillation. Nicorandil, a potassium channel opener, shortened the QT interval and abolished TdP. This may suggest that potassium channel opening drugs are clinically effective against TdP associated with bradycardia-dependent QT prolongation.     

Drug-induced arrhythmias

Drug-induced arrhythmias are commonly described as proarrhythmia, arrhythmogenesis or aggravation of arrhythmias. A variety of drugs including cardiotonic drugs (antiarrhythmics, digitalis, cathecholamines), psychiatric drugs(phenothiazines, antidepressants), and macrolide antibiotics would worsen or induce arrhythmias. Among them are bradyarrhythmias and tachyarrhythmias, especially torsade de pointes(TdP) resulting from QT prolongation. There exist some predisposing factors which could potentiate proarrhythmic effect of drugs. They include age, congestive heart failure, ischemic heart disease, renal or hepatic dysfunction, electrolyte disturbance and previous history of proarrhythmia. It should be, therefore, very cautious when drugs with potentially proarrhythmic effect are given to subjects with predisposing factors. Correction of these factors and prevention of bradycardia are important in the management of proarrhythmia and TdP can be treated by infusion of magnesium.     

The anaesthetised methoxamine-sensitised rabbit model of torsades de pointes

Current guidelines describe strategies on how the potential of non-antiarrhythmic drugs to delay ventricular repolarisation should be assessed. However, the non-clinical guidelines recommend repolarisation assays only and do not advocate experimental models that express the proarrhythmia of concern, torsades de pointes (TdP). Although the repolarisation assays may predict QT interval prolongation in man they cannot alone sufficiently predict proarrhythmia risk. Furthermore, there is also a need for more robust surrogate markers of drug-induced proarrhythmia and such validated markers are on the horizon as a result of the availability of sensitive animal models of TdP. This review will describe the methoxamine-sensitised rabbit model of TdP, one of the most frequently used proarrhythmia models, and present some of it characteristics, its pros and cons and how it historically has been used for assessing proarrhythmia liability of drugs.     

Prolonged Q-T interval following astemizole overdose.

Astemizole overdose has been reported to cause torsades-de-pointes and in the present case it caused prolongation of the Q-T interval. Astemizole overdoses should be managed in a similar way to overdose with other cardiotoxic drugs.     

Heart block and prolonged Q-Tc interval following muscle relaxant reversal: a case report

Heart block and Q-Tc interval prolongation have been reported with several agents used in anesthesia, and the US Food and Drug Administration mandates evaluation of the Q-T interval with new drugs. Drug-induced Q-T interval prolongation may precipitate life-threatening arrhythmias, is considered a precursor for torsades de pointes, and may predict cardiovascular complications. In the patient described in this article, heart block occurred and the Q-Tc interval became prolonged after muscle relaxant reversal with neostigmine; both were considered to be related to the combination of agents used in the case, as well as to other predisposing factors such as morbid obesity. The agents used that affected cardiac conduction were neostigmine, desflurane, droperidol, dolasetron, and dexmedetomidine. Although the heart block was resolved after 2 doses of atropine, prolonged P-R and Q-Tc intervals persisted into the immediate postoperative period but returned to baseline within 4 hours. Clinical implications of this report include increasing awareness of the multitude of factors affecting Q-T interval prolongation during anesthesia.     

Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes

A number of non-cardiovascular drugs have been withdrawn from clinical use due to unacceptable adverse cardiac side-effects involving drug-induced Torsades de Pointes (TdP)--a rare, life-threatening polymorphic ventricular tachycardia associated with prolongation of the action potential duration of ventricular myocytes and, hence, prolongation of the QT interval, of the electrocardiogram (ECG), which measures the total time for activation of the ventricles and their recovery to the resting state. Research has suggested that women are more prone to develop TdP than men during administration of medicines that share the potential to prolong the QT interval, with 65-75% of drug-induced TdP occurring in women. Clinical and experimental studies show that female sex demonstrate differences in the electrocardiographic pattern of ventricular repolarization in human and other animal species and is associated with a longer rate-corrected QT (QTc) interval at baseline than males. Reports of a similar propensity towards drug-induced TdP in both premenopausal and postmenopausal women support factors in addition to those of female sex hormones eliciting sex-based differences in ventricular repolarization. However, conflicting evidence suggests sex hormones may have a role in increasing the susceptibility of women or ultimately reducing the susceptibility of men to TdP. Cyclical variations in hormone levels during the menstrual cycle have been associated with an increased and reduced risk of TdP. In contradiction to this finding, the male sex hormone is thought to be beneficial. Modulation of the ventricular repolarization by testosterone may explain why the QTc interval shortens at puberty, and might account for the tendency towards an age-dependent reduction in the incidence of drug-induced TdP in men. Mechanisms underlying these differences are not fully understood but a case for the involvement of gonadal steroids is obviously strong. Therefore, further non-clinical/clinical investigations ought to be a necessary step to elucidate any sex differences in cardiac repolarization characteristics, QT interval prolongation and susceptibility to cardiac arrhythmias. This may have implications for the development of the safest medicinal products and for the clinical management of cardiac arrhythmias.     

Modulation of the Q-T Interval by the Autonomic Nervous System

Recent investigations have clarified some of the effects of the autonomic nervous system on duration and spatial distribution of the Q-T interval in humans. The use of atrial pacing to fix heart rate or 24-hour continuous electrocardiographic recording to develop a regression formula for individual patients has provided a means to interpret the effects of an intervention that alters both the heart rate and the Q-T interval. Drugs that affect Ihe autonomic nervous system can influence Q-T interval directly or by changing rate. Bazett's formula to correct for rate may be misleading after certain drug interventions. For example, the Q-T interval during sinus rhythm or afrial pacing and the ventricular effective refractory period shorten after atropine plus propranolol, but corrected Q-T interval using Bazetf's formula does not change. No change occurs in the Q-T interval during sinus rhythm or atrial pacing, or in ventricular effective refractory period after administration of propranolol although corrected Q-T interval using Bazett's formula markedly shortens. Q-T interval during sinus rhythm and atrial pacing and ventricular effective refractory period decrease after atropine but correct Q-T interval lengthens. To define further the relationship of the autonomic nervous system on the duration of the Q-T interval we studied the effects of sleep. Fifteen patients receiving no drugs underwent 3–6 days of continuous electrocardiography recordings. The duration of the Q-T interval was longer during sleep in all 15 patients independent of heart rate change. This prolongation of the Q-T interval during sleep may reflect increased parasympathetic tone or decreased sympathetic tone on the ventricle. Further investigation of the relation of the autonomic nervous system to ventricular depolarization and repolarization may delineate some of Ihe trigger mechanisms for the development of lethal ventricular arrhythmias in humans.     

Drugs for men and women - how important is gender as a risk factor for TdP?

The cardiac arrhythmia known as torsade de pointes (TdP), which is a very rare but potentially lethal side effect of a variety of drugs, occurs approximately twice as often in women as it does in men. Most drugs that have this adverse effect prolong the repolarization phase of the cardiac action potential which can be detected by a lengthening of the QT interval on the ECG. The gender difference in susceptibility to TdP only appears after puberty suggesting that sex hormones are contributory factors. Studies in patients indicate that testosterone-induced shortening of action potential duration may account for the shorter rate-corrected QT interval in men rather than any effect of estradiol in women, whereas drug-induced QT prolongation can be potentiated by estradiol. Experimental investigations suggest that sex hormones may alter either Ca(2+) currents, K(+) currents, or both and that actions on these ionic currents may account for the gender differences in cardiac repolarization. Although estradiol exacerbated drug-induced TdP in an in vivo model, no similar information is available for progesterone or testosterone. Further studies are required to clarify the influence of these sex hormones and to investigate the importance of the balance between sex hormones in both genders. Such information would assist in risk:benefit analysis and may allow the development of "drugs for men" and "drugs for women".     

Brady Cardie-Dependent Early Afterdepolarizations in a Patient with QTU Prolongation and Torsade de Pointes in Association with Marked Bradycardia and Hypokalemia

Endocardial monophasic action potentials (MAPs) were recorded at the right ventricular apex in a patient with QTU prolongation and torsade de pointes (TdP) in association with marked bradycardia and hypokalemia. There was a distinct hump on phase 3 repolarization of the MAPs characteristic of early afterdepolarizations (EADs), which was associated with marked prolongation of the QTU interval on the surface electrocardiogram. EAD amplitude was bradycardia dependent, and there was a strong correlation (r = 0.91) between the preceding RR interval and the amplitude of the EAD (percent of MAP amplitude). Intravenous administration of lidocaine or right ventricular pacing suppressed the ventricular premature complexes and TdP in association with the suppression of the EADs on the MAPs. Furthermore, these EADs were not recorded on the MAPs 1 month later when the QTU prolongation and TdP had disappeared. These findings suggest that the TU abnormality and QTU prolongation responsible for TdP were due to bradycardia-dependent EADs.     

Long Q-T syndrome precipitated by atropine and hypokalemia

In a small child successfully treated with atropine sulfate and other drugs because of pesticide poisoning, a prolongation of the Q-T interval, extrasystolic ventricular tachyarrhythmia complicated by ventricular fibrillation and cardiac syncope, was observed. At the time of this incident the child was hypokalemic. After compensation of hypokalemia, reduction of atropine dose and subsequent discontinuation of the drug, the changes in the patient's follow-up ECG records disappeared. Thus, the use of atropine in the presence of hypokalemia should be included in the list of factors releasing the long Q-T syndrome.     

Torsades de pointes episode in a woman with high-grade fever and inflammatory activation: A case report

BACKGROUNDQT interval prolongation can induce torsades de pointes (TdP), a potentially fatal ventricular arrhythmia. Recently, an increasing number of non-cardiac drugs have been found to cause QT prolongation and/or TdP onset. Moreover, recent findings have demonstrated the key roles of systemic inflammatory activation and fever in promoting long-QT syndrome (LQTS) and TdP development.CASE SUMMARYA 30-year-old woman was admitted with a moderate to high-grade episodic fever for two weeks. The patient was administered with multiple antibiotics after hospitalization but still had repeating fever and markedly elevated C-reactive protein. Once after a high fever, the patient suddenly lost consciousness, and electrocardiogram (ECG) showed transient TdP onset after frequent premature ventricular contraction. The patient recovered sinus rhythm and consciousness spontaneously, and post-TdP ECG revealed a prolonged QTc interval of 560 ms. The patient’s clinical manifestations and unresponsiveness to the antibiotics led to the final diagnosis of adult-onset Still’s disease (AOSD). There was no evidence of cardiac involvement. After the AOSD diagnosis, discontinuation of antibiotics and immediate initiation of intravenous dexamethasone administration resulted in the normal temperature and QTc interval. The genetic analysis identified that the patient and her father had heterozygous mutations in KCNH2 (c.1370C>T) and AKAP9 (c.7725A>C). During the 2-year follow-up period, the patient had no recurrence of any arrhythmia and maintained normal QTc interval.CONCLUSIONThis case study highlights the risk of systemic inflammatory activation and antibiotic-induced TdP/LQTS onset. Genetic analysis should be considered to identify individuals at high risk of developing TdP.     

Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes

Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.     

Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease

BACKGROUND: In recent years there has been ain increase in the use of class III antiarrhythmic drugs such as sotalol, amiodarone, and the so-called pure class III compound for the control of cardiac arrhythmias. It appears there has been a corresponding increase in the frequency of torsades de pointes (TdP). METHODS AND RESULTS: The case reported here, a patient on daily renal dialysis for end-stage renal disease, has important implications for class III agents, which are excreted largely by the kidneys. A relatively low dose of sotalol administered for the prevention of recurrences of atrial fabrillation, with a fast ventricular response producing angina, led to modest increases in the QT interval and moderate bradycardia. This culminated in the development of TdP, which deteriorated into ventricular fibrillation, from which the patient could be resuscitated with considerable difficulty. Dialysis after the occurrence of TdP led to further and striking prolongation of the QT interval associated with numerous episodes of TdP for several days before control was achieved. The atrial fibrillation and recurrences of TdP were eventually controlled with oral amiodarone. CONCLUSIONS: This case emphasizes that in the absence of significant renal function, use of sotalol may not be safe because drug accumulation may not be controlled adequately with renal dialysis. In view of this, in patients with end-stage renal disease, the use of sotalol for arrhythmia control appears contraindicated and alternative agents, the excretion of which does not occur by the renal route, should be used.     

The Long QT Syndrome and Torsade De Pointes

The LQTS is a prime example of how molecular biology, ion channel, cellular, and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and acquired LQTS are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying cardiac repolarization. In this review, the continually unraveling molecular biology of congenital LQTS is discussed. The various pharmacological agents associated with the acquired LQTS are listed. Although it is difficult to predict which patients are at risk for TdP, careful assessment of the risk-benefit ratio is important before prescribing drugs known to be able to cause QT prolongation. The in vivo electrophysiological mechanism of TdP in the LQTS is described using, as a paradigm, the anthopleurin-A canine model, a surrogate for LQT3. In the LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization. Prolongation of repolarization also acts as a primary step for the generation of EADs. The focal EAD induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant VT, sometimes having the characteristic twisting QHS configuration known as TdP. The review concludes by discussion of the clinical manifestations and current management of both the congenital and acquired LQTS. The initial therapy of choice for the large majority of patients with the congenital LQTS is a beta-blocking drug. This therapy seems to be effective in LQT1 and LQT2 patients, but may not be as effective in LQT3 patients. Other therapeutic options include pacemakers, cervicothoracic sympathectomy, and the implantable cardioverter defibrillator. Recent molecular genetic studies have suggested several genotype specific therapies; however, long-term efficacy data are not available.     

Preclinical assessment of drug-induced proarrhythmias: role of the arterially perfused rabbit left ventricular wedge preparation

Drug-induced torsade de pointes (TdP) is a rare but lethal side effect of many cardiovascular and non-cardiovascular drugs. It has led to black box warnings or even withdrawal of many useful compounds from the market and is one of the major stumbling blocks for new drug development. The critical need for a better test that can predict the TdP liability of a candidate drug has led to the development of multiple preclinical models. Each of these models has it own merits and limitations in preclinical testing for TdP liability; however, most of these models have not been adequately validated, so their precise sensitivity and specificity remain largely unknown. Recent blinded validation studies have demonstrated that the rabbit left ventricular wedge preparation can predict drug-induced TdP with an extremely high sensitivity and specificity. As a matter of fact, the wedge technique was initially developed primarily for studying the electrical heterogeneity of myocardium and the cellular basis of QT prolongation and TdP. Naturally then, the electrophysiological data obtained from the wedge takes into account every critical factor associated with the development of TdP. The TdP scores generated using the wedge technique have been shown to assess the torsadogenic potential of the drugs in a predictable fashion. This review elaborates on the current and prospective role of the rabbit left ventricular wedge preparation in preclinical assessment of drug-induced proarrhythmias including but not limited to TdP.     

QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development

Prolongation of the QT interval of the electrocardiogram is a typical effect of Class III antiarrhythmic drugs, achieved through blockade of potassium channels. In the past decade, evidence has accrued that several classes of drugs used for non-cardiovascular indications may prolong the QT interval with the same mechanism (namely, human ether-a-go-go-related gene (hERG) K(+) channel blockade). The great interest in QT prolongation is because of several reasons. First, drug-induced QT prolongation increases the likelihood of a polymorphous ventricular arrhythmia (namely, torsades de pointes, TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death. Second, the fact that several classes of drugs, such as antihistamines, fluoroquinolones, macrolides, and neuroleptics may cause the long QT syndrome (LQTS) raises the question whether this is a class effect (e.g., shared by all agents of a given pharmacological class) or a specific effect of single agents within a class. There is now consensus that, in most cases, only a few agents within a therapeutic class share the ability to significantly affect hERG K(+) channels. These compounds should be identified as early as possible during drug development. Third, QT prolongation and interaction with hERG K(+) channels have become surrogate markers of cardiotoxicity and have received increasing regulatory attention. This review briefly outlines the mechanisms leading to QT prolongation and the different strategies that can be followed to predict this unwanted effect. In particular, it will focus on the approaches recently proposed for the in silico screening of new compounds.     

Emergency department approach to QTc prolongation

QTc prolongation has been associated with increased risk of developing ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). QTc prolongation is influenced by many factors including congenital causes, heart rate, metabolic imbalances, and pharmacotherapy. Several commonly used medications in the emergency department (ED), such as antipsychotics and antiemetics, are known to prolong the QT interval. In addition, ED patients may present with conditions that may predispose them to QTc prolongation, such as drug overdose or hypokalemia, which can further complicate management. ED providers should not only be aware of which medications have these effects, but must also thoroughly investigate any pertinent patient history that may contribute to QTc prolongation. This review discusses commonly encountered medications that are associated with QTc prolongation, the mechanisms by which they prolong the QTc interval, and other factors that may influence ED medication administration and management.