Development Of Torsade De Pointes Research Articles

Clarithromycin induced torsade de pointes

Clarithromycin is a commonly used macrolide antibiotic. It is known to cause QT prolongation. Medication induced QT prolongation is a major risk factor for the development of torsade de pointes. A 79-year-old lady presented with frequent episodes of torsade de pointes following commencement of clarithromycin. This was noted to be in association with a prolongation of the QT interval. Knowledge of medications which prolong the QT interval is important to minimize the risk of ventricular arrhythmias, which may lead to sudden death. This is essential in patients with a congenitally long QT interval.

QT prolongation and Torsades de Pointes in patients previously treated with Anthracyclines

Anthracyclines reduce myocardial repolarization reserve and might increase the risk for Torsades de Pointes a long time after treatment. We studied all the publications concerning Torsades de Pointes in patients previously treated with anthracyclines to investigate the clinical circumstances leading to this rare life-threatening complication. Our literature search yielded nine reports of 11 patients who had developed Torsades de Pointes anywhere from weeks to years following treatment with anthracyclines. One of the patients was hospitalized in our medical center. Risk factors and triggers for Torsades de Pointes, among other clinical aspects, were analyzed in each report. Most patients (n=10; 90.9%) were previously treated with anthracyclines owing to acute leukemias: acute myelogenous leukemia (n=5), acute lymphocytic leukemia (n=3) and acute promyelocytic leukemia (n=2). One patient was previously treated with anthracyclines owing to Hodgkin's lymphoma. Most patients were women (n=9; 81.8%). The most prevalent triggers for Torsades de Pointes were the administration of a QT-prolonging agent (n=10; 90.9%) and hypokalemia (n=9; 81.8%). Azole derivatives were the most prevalent of the QT-prolonging agents that triggered Torsades de Pointes (n=5; 45.5%). Although four patients suffered from anthracycline-induced left ventricular dysfunction and five other patients had only one or two questionable triggers for Torsades de Pointes, in only two of these cases the authors considered previous treatment with anthracyclines as a risk factor for Torsades de Pointes. Previous treatment with anthracycline is an underestimated risk factor for Torsades de Pointes. Possible triggers includes azole derivatives, other QT-prolonging agents and hypokalemia. Women patients are particularly at risk.

Proarrhythmia as a Class Effect of Quinolones: Increased Dispersion of Repolarization and Triangulation of Action Potential Predict Torsades de Pointes

Numerous noncardiovascular drugs prolong repolarization and thereby increase the risk for patients to develop life-threatening tachyarrhythmias of the torsade de pointes (TdP) type. The development of TdP is an individual, patient-specific response to a repolarization-prolonging drug, depending on the repolarization reserve. The aim of the present study was to analyze the underlying mechanisms that discriminate hearts that will develop TdP from hearts that will not develop TdP. We therefore investigated the group of quinolone antibiotics that reduce repolarization reserve via I(Kr) blockade in an intact heart model of proarrhythmia. In 47 Langendorff-perfused, AV-blocked rabbit hearts, ciprofloxacin (n = 10), ofloxacin (n = 14), levofloxacin (n = 10), and moxifloxacin (n = 13) in concentrations from 100 microM to 1,000 microM were infused. Eight monophasic action potentials (MAPs) and an ECG were recorded simultaneously. After incremental pacing at cycle lengths from 900 ms to 300 ms to compare the action potential duration, potassium concentration was lowered to provoke TdP. All antibiotics led to a significant increase in QT interval and MAP duration, and exhibited reverse-use dependence. Eight simultaneously recorded MAPs demonstrated an increase in dispersion of repolarization in the presence of all antibiotics. MAP triangulation (ratio: MAP(90/50)) and fluctuation of consecutive action potentials were increased for all tested drugs at high concentrations. In the presence of low potassium concentration, all quinolones led to TdP: ciprofloxacin, 4 out of 10 (40%); ofloxacin, 3 out of 14 (21%); moxifloxacin, 9 out of 13 (69%); and levofloxacin, 2 out of 10 (20%). Hearts that developed TdP demonstrated a significant greater influence on dispersion of repolarization and on triangulation as compared with hearts without TdP. Quinolone antibiotics may be proarrhythmic due to a significant effect on myocardial repolarization. The individual response of a heart to develop TdP in this experimental model is characterized by a greater effect on dispersion of repolarization and on triangulation of action potential as compared with hearts that do not develop TdP.

Moxifloxacin and Torsade de Pointes

To report a case of torsade de pointes in a patient receiving moxifloxacin. An 87-year-old woman was admitted to the hospital for pneumonia, and antibiotic therapy with intravenous moxifloxacin 400 mg/day was initiated. The patient was noted to have significant QTc interval prolongation 2 hours after administration of moxifloxacin and developed torsade de pointes 8-10 hours after moxifloxacin administration. She was converted back to normal sinus rhythm after a precordial thump. Moxifloxacin was discontinued, and the woman's QTc interval subsequently returned to baseline. Torsade de pointes is a life-threatening arrhythmia that has previously been associated with the use of fluoroquinolones. Minimal information is available regarding the risk of torsade de pointes with moxifloxacin. According to the Naranjo probability scale, the episode in this case was probably related to administration of intravenous moxifloxacin. In patients with underlying risk factors for a prolonged QT interval, the use of moxifloxacin can lengthen the interval further and ultimately trigger episodes of torsade de pointes. Moxifloxacin administration in these patients therefore should be administered and monitored judiciously.

Preclinical cardio-safety assessment of torsadogenic risk and alternative methods to animal experimentation: The inseparable twins

The last decade has been marked by the withdrawal from the market of several medicines whose use in patients has been associated with the development of torsade de pointes (TdP), a potentially life-threatening polymorphic tachycardia. In a few cases, TdP can degenerate into ventricular fibrillation and lead to sudden death, thus constituting a real problem of public health. The recently finalized ICH S7B guideline defines the prolongation of the QT interval on the electrocardiogram as the best biomarker for predicting the torsadogenic risk of a given compound. However, a growing body of evidence suggests that drugs' torsadogenic potential may not necessarily be proportional to their ability to prolong the QT interval. It is a dynamic combination of multiple predisposing factors and components rather than a single particular event that can trigger this particular tachycardia. Following recommendations of the guideline, pharmaceutical companies have intensively implemented methodologies to assess the possible risk of QT prolongation and TdP in humans. The main problem in cardiac safety pharmacology is how best to combine the capabilities of different methodologies with their strengths and limitations in order to detect the potential of one molecular entity to induce a lethal arrhythmia of very low clinical incidence. This publication will review the current methodologies, focusing on the alternative methods to animal experimentation, including an overview of cardiac modeling.

A severely obese patient surviving cardiopulmonary arrest and exhibiting an interesting relationship between excessive weight loss and electrocardiographic QT interval prolongation

We report a patient with severe obesity who suffered cardiopulmonary arrest (CPA) after drastic weight loss but successfully survived with cardiopulmonary resuscitation and critical care in the ICU. We describe the patient's care and discuss the relationship between drastic weight loss and secondary prolongation of corrected QT interval (long QT syndrome) with development of torsades de pointes (Tdp). The corrected QT interval (QTc) observed upon the first visit of the patient to the outpatient unit was 0.475 sec, with a body mass index (BMI) of 67.5. QTc was prolonged to 0.507 sec after drastic weight reduction to achieve a BMI of 60.8. That was further prolonged to 0.608 sec upon ICU admission following resuscitation. Postresuscitation treatment in the ICU was successful, and she was discharged from the ICU on the 7th day. Strict medical weight control after discharge from the ICU successfully shortened QTc within the normal range. The relationship between BMI and QTc observed in the present case suggests that severe obesity and excessive weight loss caused prolongation of QTc and CPA. These findings contribute to elucidation of the pathology of sudden death in the severe obese population.

Amiodarone-Associated Torsades de Pointes

A 42 year old female presented with epigastric pain of one day duration, 5 days after starting erythromycin for cellulitis. In the ER, she had a cardiopulmonary arrest. During resuscitation she developed recurrent ventricular fibrillation requiring conversion with more than 3 D/C shocks for which she was started on IV amiodarone. Baseline, and current electrocardiograms showed QT prolongation, with hypokalemia and hypomagnesemia on blood tests (immediately supplemented). However, patient developed torsades de pointes (TDP) associated with seizures and hypotension, responding to D/C cardioversion every 1-2 hours. The amiodarone drip was stopped due to worsening QT prolongation, and Isoproterenol infusion was started to maintain a HR of 100 beats/min. Subsequently a transvenous pacemaker was inserted terminating the TDP, pending implantable cardioverterdefibrillator (ICD) insertion.

Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes

Reduction of drug-induced adverse events may be achievable through a better understanding of the underlying causes of such events. Identifying phenotypes and genotypes that allow event prediction would provide greater safety margins for new therapeutics. Torsades de pointes (TdP) is one such life-threatening adverse event and can arise from excessive lengthening of the QT interval. This study was designed to better understand the role of genetics in the development of TdP and to determine whether genotypes can be used to predict susceptibility and thus reduce adverse events. Seven known familial long QT syndrome genes were scanned for sequence variations in 34 patients with TdP. This group of patients is the largest such cohort ever assembled for this type of analysis. The allele frequencies for novel and known polymorphisms in these patients were compared with those in healthy control subjects. Six novel mutations--4 in ANK2, 1 in KCNQ1, and 1 in SCN5A--were found in the patients with TdP. Two mutations were also found in 595 healthy control subjects, whereas the others were unique to patients with TdP. Two common single nucleotide polymorphisms may be associated with the risk of TdP. The entire ANK2 gene had not been screened in a population this large previously. Genotypes alone could not be used to completely predict susceptibility to TdP, even when used with phenotypes. The best model using genotypic and phenotypic variables was unable to predict all events. It is unclear what other risk genes or environmental effects might be necessary to predict such cases.

Development of torsade de pointes caused by exacerbation of QT prolongation during clipping of cerebral artery aneurysm in a patient with subarachnoid haemorrhage

We report the case of a 79-yr-old woman with subarachnoid haemorrhage (SAH) in whom torsade de pointes (TdP) caused by worsening the QT prolongation occurred during clipping of cerebral artery aneurysm. This patient shows a potential risk of occurrence of life-threatening tachyarrhythmia, TdP by prolonging the QT interval during surgery in patients with SAH even with no additional factors that predispose to TdP. Therefore, a proper monitoring of the QT interval is necessary as a predictor of TdP. When ventricular tachyarrhythmia occurs, recognition of TdP is important because antiarrhythmic drug therapy for TdP is different from that for ventricular tachyarrhythmias that is not TdP.

T-wave alternans during cardiac resynchronization therapy

Biventricular (BV) pacing has been shown to be effective in selected patients with left ventricular (LV) dysfunction. However, BV pacing does not necessarily decrease sudden cardiac death. Recent studies have shown that epicardial LV pacing may lead to the prolongation of the QT interval and the development of torsade de pointes. On the other hand, microvoltage T-wave alternans (TWA) has been shown to be associated with increased susceptibility to ventricular tachyarrhythmias. The purpose of this study was to examine the effectiveness of right ventricular (RV), LV, and BV pacings on the TWA. Methods: T-wave alternans was measured during each pacing mode incrementally from 70 to 120 bpm in 6 patients with a mean ejection fraction of 33% F 9%. T-wave alternans was considered positive if the alternans voltage was higher than 1.9 lVand the alternans ratio was higher than 3.0 lV for at least 1 minute. Results: The mean alternans voltage values during BV, RV, and LV pacings were 2.2 F 0.5, 0.96 F 0.2, and 1.45 F 0.6 lV, respectively ( P b .01 vs RV). The mean alternans ratios during BV, RV, and LV pacings were 14.5 F 6.5, 6.3 F 2.7, and 6.5 F 1.1 lV, respectively. Positive TWA was observed in 83%, 50%, and 60% during BV, RV, and LV pacings, respectively. Conclusion: Biventricular pacing may increase the inhomogeneity of ventricular repolarization, which may lead to the development of ventricular tachyarrhythmias.

Psychotropic drugs and sudden death

Sudden death associated with psychotropic drugs is an issue in clinical practice which is currently debated worldwide in the literature. The objective of this work is to review recent literature on the issue (up to the end of 2004). The literature focuses mainly on the association between unexplained sudden death and antipsychotics and, to a lesser degree, tricyclic antidepressants; there are few references to other classes of psychotropic drugs. Over the last few decades various causal mechanisms have been proposed. However, recent literature refers mostly to sudden cardiac death induced by arrhythmias, and discusses, as a possible mechanism, the prolongation of the QTc interval due to the inhibition of potassium channels, leading to the risk of developing torsade de pointes which can result in sudden death. Although these cases of sudden death are rare, associated risk factors are also discussed because it is believed that a combination of several of these factors may increase the risk. We go on to consider recommendations to diminish the risk of sudden death. Finally, we review sudden death cases that have occurred in the last 5 years in the Acute Psychiatric Ward of S. Francisco Xavier Hospital (January 1999 to December 2004).

Long QTc Interval and Torsade de Pointes Caused by Fluconazole

To describe a patient who developed torsade de pointes while being treated with fluconazole. A 33-year-old woman with a 5 year history of systemic lupus erythematosus was admitted to the intensive care unit because of respiratory insufficiency due to Candida albicans pneumonia. Therapy with intravenous fluconazole 200 mg/day, with dose later adjusted according to her renal function, was started. Prolongation of the QTc interval and torsade de pointes occurred. Initially, domperidone, which had been initiated the day before fluconazole, was suspected as the possible cause and was discontinued; ultimately, both drugs were discontinued. However, torsade de pointes recurred several weeks later when the patient was treated with fluconazole for a second time and disappeared again on withdrawal of the drug. According to the Naranjo probability scale, this adverse reaction was highly probable. The risk of torsade de pointes does not correlate in a linear fashion with prolongation of the QTc interval, but an interval beyond 500 msec is considered a significant risk factor. Given that both fluconazole and domperidone are metabolized by the cytochrome P450 system, they may intensify each other's proarrhythmic effects, particularly in patients with concurrent renal dysfunction. These risks are of particular concern in patients whose baseline QTc interval is prolonged for any reason. From the case history, as well as use of the Naranjo scale, we concluded that fluconazole was the highly probable cause of the development of torsade de pointes in our patient.

The Action Potential of the Purkinje Fiber: An In Vitro Model for Evaluation of the Proarrhythmic Potential of Cardiac and Noncardiac Drugs

The proarrhythmic potential of new chemical entities can be investigated using in vitro electrophysiological techniques measuring the cardiac action potential in isolated Purkinje fibers. Different types of arrhythmias may occur as early afterdepolarizations (EADs), which are favored by action potential duration lengthening and bradycardia, or as delayed afterdepolarizations (DADs), which are facilitated by tachycardia. The effects of a test compound on the occurrence of these arrhythmias, thought to be responsible for the development of torsades de pointes in the clinic can be studied using the experimental protocols described in this unit.

Use of a Failing Rabbit Heart as a Model to Predict Torsadogenicity

Humans with underlying cardiovascular disease are at greater risk than humans with normal hearts for developing torsade de pointes (TdP) following exposure to some drugs that prolong ventricular repolarization. This study was designed to test the hypothesis that rabbits with ischemic myocardial failure are at similarly increased risk of developing QTc prolongation and TdP following exposure to escalating doses of drugs, which is known to have a capacity to induce TdP in humans. Coronary artery ligation was performed in 28 rabbits, causing significant (p < 0.05) reduction in left ventricular shortening fraction and systolic myocardial dysfunction 4 weeks after ligation in all operated animals compared to 38 normal, nonoperated controls. All studies were performed on rabbits anesthetized with ketamine (35 mg/kg) and xylazine (5 mg/kg). Rabbits were exposed to escalating doses of amiodarone (3, 10, 30 mg/kg/10 min), cisapride (0.10, 0.25, 0.50 mg/kg/10 min), clofilium (0.1, 0.2, 0.4 mg/kg/10 min), dofetilide (0.005, 0.01, 0.02, 0.04 mg/kg/10 min), quinidine (3, 10, 30 mg/kg/10 min), and verapamil (0.25, 0.5, 1.0 mg/kg/10 min). A greater percentage of rabbits with failing hearts developed TdP following intravenous infusion of escalating doses of dofetilide (85%), clofilium (100%), or cisapride (50%) than did normal rabbits exposed to the same drug protocol (20, 33, and 0%, respectively). None of the rabbits in either group developed TdP when exposed to escalating doses of amiodarone, verapamil, or quinidine. Two out of four test articles lengthened QTc more in rabbits with myocardial failure than in normals, and TdP occurred in 13 out of 28 rabbits with myocardial failure as opposed to only four out of 38 rabbits with normal myocardial function.

The Role of Sodium Channel Current in Modulating Transmural Dispersion of Repolarization and Arrhythmogenesis

Ventricular myocardium in larger mammals is composed of three distinct cell types: epicardial, M, and endocardial cells. Epicardial and M cell, but not endocardial cell, action potentials have a prominent I(to)-mediated notch. M cells are distinguished from the other cell types in that they display a smaller I(Ks), but a larger late I(Na) and I(Na-Ca). These ionic differences may account for the longer action potential duration (APD) and steeper APD-rate relationship of the M cell. The difference in the time course of repolarization of phase 1 and phase 3 contributes to the inscription of the electrocardiographic J wave and T wave, respectively. These repolarization gradients are modulated by electrotonic interactions, [K(+)](o), and agents or mutations that alter net repolarizing current. An increase in late I(Na), as occurring under a variety of pathophysiological states or in response to certain toxins, leads to a preferential prolongation of the M cell action potential, thus prolonging the QT interval and increasing transmural dispersion of repolarization (TDR), which underlies the development of torsade de pointes (TdP) arrhythmias. Agents that reduce late I(Na) are effective in reducing TDR and suppressing TdP. A reduction in peak I(Na) or an increase in net repolarizing current in the early phases of the action potential can lead to a preferential abbreviation of the action potential of epicardium in the right ventricle, and thus the development of a large TDR, phase 2 reentry, and polymorphic ventricular tachycardia associated with the Brugada syndrome.

Droperidol’s Effect on QT Interval

The Food and Drug Administration (FDA) issued a letter to health care providers on December 4, 2001, concerning the medication, droperidol. The purpose of the warning was to alert health care providers to the possible role of droperidol in the development of torsades de pointes (TdP) in susceptible patients. The purpose of this article is to explore the role of droperidol in the development of TdP in susceptible patients and current recommendations for the use of droperidol as an antiemetic.

Torsade de pointes during sevoflurane anesthesia in a child with congenital long QT syndrome

We present a case of congenital long QT syndrome which developed torsade de pointes during sevoflurane anesthesia for implantation of an internal cardioverter-defibrillator. The diagnosis, implications and treatment are discussed.

Volatile Anesthetics and the Long QT Syndrome

*University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. stefan.rasche@uniklinikum-dresden.deWith much interest we read the article by Susan J. Kies et al. regarding patients with congenital long QT syndrome (LQTS). We congratulate the authors on their excellent review but would like to discuss several aspects. As stated in the introduction, patients with LQTS often show a “delayed cellular repolarization and heterogeneity in dispersion of repolarization, which … can lead to early after-depolarization, further dispersion of repolarization, and the formation of reentry circuits.”It becomes increasingly apparent that the QT interval prolongation per se is not the crucial pathology in LQTS. The delayed cellular repolarization in LQTS represents either impaired rapid or slow delayed rectifier potassium currents (iKr or iKs) or inappropriately inactivated sodium currents (iNa). The main arrhythmogenic substrate resulting from these altered ion currents is an increase in transmural repolarization heterogeneity. This heterogeneity favors the development of torsade de pointes, which is triggered by early after-depolarizations. More than 300 mutations in six genes encoding cardiac ion channel subunits and ankyrin B have been identified in patients with LQTS. According to the affected ion channel subunit, LQTS is classified into six subtypes with partially different clinical courses and triggers of torsade de pointes. Hence, the clinical and electrophysiologic presentations of the syndrome are considerably heterogeneous, and the effects of different drugs may be unpredictable.The QT interval obtained by a 12-lead electrocardiogram is only a rough measure of the repolarization time. Diagnosis based solely on summation vectors projected to the body surface is therefore neither sensitive nor specific. Accordingly, studies that only focus on drug effects on the QT interval may produce premature conclusions regarding potential safety or risk of these drugs in LQTS. This explains the contradicting results of numerous investigations, which report different effects of drugs on QT interval. Kies et al. recommend isoflurane as volatile anesthetic of choice in LQTS patients. In our opinion, to date, such recommendation cannot be supported. The reported effects of volatile anesthetics on QT interval are inconsistent or even conflicting. Only few studies have focused on QT heterogeneity or ion channel physiology, and it seems that all volatile anesthetics—including isoflurane—interact directly with cardiac delayed rectifier potassium channels.8,9,10,11 We therefore propose to avoid this class of anesthetics and would prefer propofol as the anesthetic of choice until more information is available from pharmacologic studies that focus on ion channel physiology and transmural heterogeneity of repolarization. These studies should ideally differentiate between LQTS subtypes.*University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. stefan.rasche@uniklinikum-dresden.de

QT Interval Prolongation: And the Beat Goes on

Consideration of QT interval prolongation and the risk for developing torsade de pointes is a critical issue in the evaluation of new bioactive agents. Over the past several years, there has been a dramatic increase in understanding the I(Kr) channel and its role in the duration of the action potential and cardiac repolarization. Furthermore, a variety of factors and situations have been identified that can increase the risk of QT interval prolongation. In this brief summary, an overview of the hERG channel and QT prolongation will be presented. The basic electro-physiology of the heart, the related action potentials, and pre-clinical assays is reviewed. Further, an introduction to the current status of in silico efforts in predicting potential hERG blockers is discussed. Lastly, the strengths and weaknesses of each modeling method is presented along with insight to the appropriate use of each model.

Use of preclinical assays to predict risk of drug-induced torsades de pointes

Numerous medications, including drugs prescribed for noncardiac indications, can induce electrophysiologic changes that trigger the rare, malignant polymorphic ventricular tachyarrhythmia known as torsades de pointes (TdP). Although the exact relationship between electrophysiologic events and the development of TdP is not defined, prolongation of the QT interval and inhibition of the rapidly activating potassium current I(Kr) by drugs may be associated with an increased risk of TdP. The ability of a drug to reduce I(Kr) and prolong the QT interval often is considered to predict the likelihood that the drug will cause TdP in humans. However, these surrogate measures of the drug-induced risk of causing TdP, and therefore of drug safety, now are recognized to be imperfect predictors of drug safety. New preclinical models should be used to assess drug risk, including preparations, conditions, and measurements used by basic research scientists to produce ventricular polymorphic arrhythmias in the laboratory. In this review, we discuss the task of assessing the arrhythmogenic potential of a drug. Assays of drug effect to induce early afterdepolarizations and ectopic beats and/or to increase the dispersion of ventricular repolarization when "repolarization reserve" is reduced appear to be the best predictors of the drug-induced risk of TdP. Current experimental models and protocols, especially those using conditions wherein the net repolarizing current is reduced, can detect the potential for a drug to induce TdP, even when the potential is extremely low.