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Journal of Cardiovascular... Apr 2004Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the... (Review)
Review
Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits.
Topics: Anti-Arrhythmia Agents; Drugs, Investigational; Electrocardiography; Electrophysiology; Humans; Long QT Syndrome; Risk Assessment; Torsades de Pointes
PubMed: 15090000
DOI: 10.1046/j.1540-8167.2004.03534.x -
Journal of the American College of... Mar 2010
Review
Topics: Cardiology Service, Hospital; Critical Care; Electrocardiography; Humans; Monitoring, Physiologic; Societies, Medical; Societies, Nursing; Torsades de Pointes; United States
PubMed: 20185054
DOI: 10.1016/j.jacc.2010.01.001 -
Japanese Journal of Pharmacology May 2000A progressively increasing number of cardiac and noncardiac drugs prolong the ventricular action potential duration (QT interval of the electrocardiogram) and cause a... (Review)
Review
A progressively increasing number of cardiac and noncardiac drugs prolong the ventricular action potential duration (QT interval of the electrocardiogram) and cause a distinctive polymorphic ventricular tachycardia termed torsades de pointes (TdP) that can degenerate into ventricular fibrillation and sudden cardiac death. Drugs prolong the QT interval and cause TdP by blocking cardiac K+ channels in general and selectively blocking the rapidly activating delayed rectifier channel IKr. Coassembly of HERG (human-ether-a-go-go-related gene) alpha-subunits and MiRP1 (MinK-related peptide 1) beta-subunits recapitulate the behavior of native human IKr and mutations of HERG and MiRP1 decrease the repolarizing current, delay ventricular repolarization and prolong the QT. Thus, drug-induced QT prolongation and TdP might represent an iatrogenic reproduction of the congenital LQTS. In patients with silent forms of the congenital LQTS associated with mutations in IKr, arrhythmic symptoms developed almost exclusively after exposure to QT-prolonging drugs. This review centers on the possible cellular mechanisms underlying drug-induced QT prolongation and TdP, the description of specific drugs and risk factors facilitating the development of TdP, and the recommendations for preventing and treating this potentially fatal arrhythmia.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Anti-Infective Agents; Humans; Long QT Syndrome; Potassium Channels; Psychotropic Drugs; Risk Factors; Torsades de Pointes
PubMed: 10887935
DOI: 10.1254/jjp.83.1 -
Circulation Apr 2017Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications....
BACKGROUND
Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known.
METHODS
We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration.
RESULTS
The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (=0.55; 95% confidence interval, 0.09-0.81; =0.02), 23% in response to quinidine (=0.48; 95% confidence interval, -0.03 to 0.79; =0.06), and 27% in response to ranolazine (=0.52; 95% confidence interval, 0.05-0.80; =0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (=12%, =1×10).
CONCLUSIONS
We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01873950.
Topics: Adult; Arrhythmias, Cardiac; Female; Genome-Wide Association Study; Humans; Long QT Syndrome; Male; Pilot Projects; Polymorphism, Single Nucleotide; Risk Assessment; Torsades de Pointes
PubMed: 28213480
DOI: 10.1161/CIRCULATIONAHA.116.023980 -
Computer Methods and Programs in... Dec 2023In silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models... (Review)
Review
BACKGROUND AND OBJECTIVE
In silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models tended not to account for inter-individual response variability due to demographic covariates, such as sex, or physiologic covariates, such as renal function, which may be crucial when predicting TdP. This study aims to compare the effects of drugs in male and female populations with normal and impaired renal function using in silico methods.
METHODS
Pharmacokinetic models considering sex and renal function as covariates were implemented from data published in pharmacokinetic studies. Drug effects were simulated using an electrophysiologically calibrated population of cellular models of 300 males and 300 females. The population of models was built by modifying the endocardial action potential model published by O'Hara et al. (2011) according to the experimentally measured gene expression levels of 12 ion channels.
RESULTS
Fifteen pharmacokinetic models for CiPA drugs were implemented and validated in this study. Eight pharmacokinetic models included the effect of renal function and four the effect of sex. The mean difference in action potential duration (APD) between male and female populations was 24.9 ms (p<0.05). Our simulations indicated that women with impaired renal function were particularly susceptible to drug-induced arrhythmias, whereas healthy men were less prone to TdP. Differences between patient groups were more pronounced for high TdP-risk drugs. The proposed in silico tool also revealed that individuals with impaired renal function, electrophysiologically simulated with hyperkalemia (extracellular potassium concentration [K] = 7 mM) exhibited less pronounced APD prolongation than individuals with normal potassium levels. The pharmacokinetic/electrophysiological framework was used to determine the maximum safe dose of dofetilide in different patient groups. As a proof of concept, 3D simulations were also run for dofetilide obtaining QT prolongation in accordance with previously reported clinical values.
CONCLUSIONS
This study presents a novel methodology that combines pharmacokinetic and electrophysiological models to incorporate the effects of sex and renal function into in silico drug simulations and highlights their impact on TdP-risk assessment. Furthermore, it may also help inform maximum dose regimens that ensure TdP-related safety in a specific sub-population of patients.
Topics: Female; Humans; Male; Arrhythmias, Cardiac; Sulfonamides; Torsades de Pointes; Potassium; DNA-Binding Proteins
PubMed: 37844488
DOI: 10.1016/j.cmpb.2023.107860 -
Journal of Cardiothoracic and Vascular... Jan 2022
Review
Topics: Anesthesiologists; Electrocardiography; Humans; Long QT Syndrome; Torsades de Pointes
PubMed: 33495078
DOI: 10.1053/j.jvca.2020.12.011 -
Annals of Noninvasive Electrocardiology... Jul 2022Hypoparathyroidism predisposes patients to hypocalcemia. Patients with hypoparathyroidism are thus at risk of electrocardiographic abnormalities, including T-wave...
Hypoparathyroidism predisposes patients to hypocalcemia. Patients with hypoparathyroidism are thus at risk of electrocardiographic abnormalities, including T-wave alternans. T-wave alternans is poorly understood and lacks uniform diagnostic criteria. Its presence suggests myocardial electrical instability, and it has become an important sign for identifying patients at high risk of malignant arrhythmias and sudden cardiac death. We report a rare case of T-wave alternans with torsade de pointes due to hypocalcemia. The etiology of T-wave alternans may easily be overlooked. It should thus be thoroughly investigated to avoid misdiagnosis and poor outcomes.
Topics: Arrhythmias, Cardiac; Electrocardiography; Humans; Hypocalcemia; Hypoparathyroidism; Torsades de Pointes
PubMed: 35146844
DOI: 10.1111/anec.12939 -
Journal of Pharmacological Sciences Aug 2023We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant...
Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.
We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization.
Topics: Dogs; Animals; Rats; Atrial Fibrillation; Torsades de Pointes; Isoflurane; Anti-Arrhythmia Agents
PubMed: 37344055
DOI: 10.1016/j.jphs.2023.05.003 -
Sports Health 2016The congenital long QT syndrome (LQTS) is an inherited channelopathy known for its electrocardiographic manifestations of QT prolongation and its hallmark arrhythmia,... (Review)
Review
CONTEXT
The congenital long QT syndrome (LQTS) is an inherited channelopathy known for its electrocardiographic manifestations of QT prolongation and its hallmark arrhythmia, torsades de pointes (TdP). TdP can lead to syncope or sudden death and is often precipitated by triggers such as physical exertion or emotional stress. Given that athletes may be at particular risk for adverse outcomes, those suspected of having LQTS should be evaluated, risk stratified, treated, and receive appropriate counseling by providers with sufficient expertise according to the latest guidelines.
EVIDENCE ACQUISITION
The following keywords were used to query MEDLINE and PubMed through 2016: LQTS, LQT1, LQT2, LQT3, long QT, long QTc, prolonged QT, prolonged QTc, QT interval, QTc interval, channelopathy, channelopathies, athletes, torsades de pointes, and sudden cardiac death. Selected articles within this primary search, in addition to relevant references from those articles, were reviewed for relevant information and data. Articles with pertinent information regarding pathophysiology, evaluation, diagnosis, genetic testing, treatment, and guidelines for athletes were included, particularly those published in the prior 2 decades.
STUDY DESIGN
Clinical review.
LEVEL OF EVIDENCE
Level 3.
RESULTS
Diagnosis of LQTS involves eliciting the patient's family history, clinical history, and evaluation of electrocardiographic findings. Genetic testing for common mutations can confirm suspected cases. β-Blockers represent the mainstay of treatment, though interventions such as implantable cardioverter-defibrillator placement or left cardiac sympathetic denervation may be required. Properly evaluated and treated athletes with LQTS have a low risk of cardiac events.
CONCLUSION
Detection and management of LQTS in the athletic population is crucial given the possibility of adverse outcomes with the stress of athletic participation. Preparticipation screening examinations should include a thorough clinical and family history. Screening electrocardiograms may display key findings consistent with LQTS while genetic testing can confirm the diagnosis. Formerly considered a strict contraindication to athletic participation, LQTS is now an increasingly manageable entity with proper evaluation and treatment by qualified and experienced providers.
Topics: Athletes; Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Health Knowledge, Attitudes, Practice; Humans; Long QT Syndrome; Practice Guidelines as Topic; Risk Assessment; Sports Medicine; Torsades de Pointes
PubMed: 27480102
DOI: 10.1177/1941738116660294 -
Scientific Reports Jul 2020There is conflicting evidence regarding the impact of propofol on cardiac repolarization and the risk of torsade de pointes (TdP). The purpose of this study was to...
There is conflicting evidence regarding the impact of propofol on cardiac repolarization and the risk of torsade de pointes (TdP). The purpose of this study was to elucidate the risk of propofol-induced TdP and to investigate the impact of propofol in drug-induced long QT syndrome. 35 rabbit hearts were perfused employing a Langendorff-setup. 10 hearts were perfused with increasing concentrations of propofol (50, 75, 100 µM). Propofol abbreviated action potential duration (APD) in a concentration-dependent manner without altering spatial dispersion of repolarization (SDR). Consequently, no proarrhythmic effects of propofol were observed. In 12 further hearts, erythromycin was employed to induce prolongation of cardiac repolarization. Erythromycin led to an amplification of SDR and triggered 36 episodes of TdP. Additional infusion of propofol abbreviated repolarization and reduced SDR. No episodes of TdP were observed with propofol. Similarly, ondansetron prolonged cardiac repolarization in another 13 hearts. SDR was increased and 36 episodes of TdP occurred. With additional propofol infusion, repolarization was abbreviated, SDR reduced and triggered activity abolished. In this experimental whole-heart study, propofol abbreviated repolarization without triggering TdP. On the contrary, propofol reversed prolongation of repolarization caused by erythromycin or ondansetron, reduced SDR and thereby eliminated drug-induced TdP.
Topics: Action Potentials; Animals; Disease Models, Animal; Electrocardiography; Erythromycin; Heart; Heart Ventricles; Propofol; Rabbits; Risk; Torsades de Pointes
PubMed: 32699382
DOI: 10.1038/s41598-020-69193-7