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Hypogonadism as a Reversible Cause of Torsades de Pointes in Men.
Salem JE, Waintraub X, Courtillot C, Shaffer CM, Gandjbakhch E, Maupain C, Moslehi JJ, Badilini F, Haroche J, Gougis P, Fressart V, Glazer AM, Hidden-Lucet F, Touraine P, Lebrun-Vignes B, Roden DM, Bachelot A, Funck-Brentano C
(2018) Circulation 138: 110-113
MeSH Terms: Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Androgen Antagonists, Biomarkers, Cross-Sectional Studies, Databases, Factual, Electronic Health Records, Heart Rate, Hormone Replacement Therapy, Humans, Hypogonadism, Male, Middle Aged, Paris, Pharmacovigilance, Prospective Studies, Risk Assessment, Risk Factors, Testosterone, Torsades de Pointes
Added October 1, 2018
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1 Members
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21 MeSH Terms
Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors.
Grouthier V, Lebrun-Vignes B, Glazer AM, Touraine P, Funck-Brentano C, Pariente A, Courtillot C, Bachelot A, Roden DM, Moslehi JJ, Salem JE
(2018) Heart 104: 1859-1863
MeSH Terms: Action Potentials, Adolescent, Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Aromatase Inhibitors, Cardiotoxicity, Databases, Factual, Europe, Female, Heart Conduction System, Heart Rate, Humans, Long QT Syndrome, Middle Aged, Prognosis, Risk Assessment, Risk Factors, Selective Estrogen Receptor Modulators, Tamoxifen, Torsades de Pointes, Young Adult
Show Abstract · Added October 1, 2018
OBJECTIVE - A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.
METHODS - We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.
RESULTS - SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs.
CONCLUSIONS - SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.
TRIAL REGISTRATION NUMBER - NCT03259711.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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23 MeSH Terms
Finding a Needle in a QT Interval Big Data Haystack: The Role for Orthogonal Datasets.
Roden DM, Mosley JD, Denny JC
(2016) J Am Coll Cardiol 68: 1765-1768
MeSH Terms: Ether-A-Go-Go Potassium Channels, Humans, Long QT Syndrome, Potassium Channels, Voltage-Gated, Torsades de Pointes
Added March 14, 2018
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5 MeSH Terms
QT Prolongation and Oncology Drug Development.
Fradley MG, Moslehi J
(2015) Card Electrophysiol Clin 7: 341-55
MeSH Terms: Antineoplastic Agents, Cardiotoxins, Electrocardiography, Humans, Long QT Syndrome, Torsades de Pointes
Show Abstract · Added March 6, 2016
Many pharmaceutical agents interact with cardiac ion channels resulting in abnormal ventricular repolarization and prolongation of the QT interval. In rare circumstances, this has resulted in the development of the potentially life-threatening arrhythmia, torsades de pointes. It is recognized, however, that accurate measurement of the QT interval is challenging, and it is a poor predictor for the development of this arrhythmia. Nevertheless, QT interval monitoring is an essential part of pharmaceutical development, and significant increases in the QT interval may prevent a drug from gaining approval.
Copyright © 2015 Elsevier Inc. All rights reserved.
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6 MeSH Terms
Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.
Yang T, Chun YW, Stroud DM, Mosley JD, Knollmann BC, Hong C, Roden DM
(2014) Circulation 130: 224-34
MeSH Terms: 4-Aminopyridine, Action Potentials, Animals, CHO Cells, Cells, Cultured, Cricetinae, Cricetulus, Drug Evaluation, Preclinical, Female, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Models, Animal, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Phenethylamines, Phosphatidylinositol 3-Kinases, Potassium Channel Blockers, Proto-Oncogene Proteins c-akt, Risk Factors, Signal Transduction, Sulfonamides, Torsades de Pointes, Transfection
Show Abstract · Added June 5, 2014
BACKGROUND - New drugs are routinely screened for IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway.
METHODS AND RESULTS - Acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2 to 48 hours of exposure to the drug generated arrhythmogenic afterdepolarizations and ≥15-fold increases in INa-L. Including phosphatidylinositol 3,4,5-trisphosphate, a downstream effector for the phosphoinositide 3-kinase pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by phosphatidylinositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem cell-derived cardiomyocytes and in Chinese hamster ovary cells transfected with SCN5A, encoding sodium current. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr-blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, and erythromycin) to little or no effect (haloperidol, moxifloxacin, and verapamil).
CONCLUSIONS - Some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the phosphoinositide 3-kinase pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.
© 2014 American Heart Association, Inc.
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26 MeSH Terms
Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome.
Weeke P, Mosley JD, Hanna D, Delaney JT, Shaffer C, Wells QS, Van Driest S, Karnes JH, Ingram C, Guo Y, Shyr Y, Norris K, Kannankeril PJ, Ramirez AH, Smith JD, Mardis ER, Nickerson D, George AL, Roden DM
(2014) J Am Coll Cardiol 63: 1430-7
MeSH Terms: Adult, Aged, Alleles, Case-Control Studies, Drug-Related Side Effects and Adverse Reactions, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Incidence, KCNQ1 Potassium Channel, Long QT Syndrome, Male, Middle Aged, Potassium Channels, Potassium Channels, Voltage-Gated, Predictive Value of Tests, Reference Values, Risk Assessment, Sequence Analysis, Protein, Torsades de Pointes
Show Abstract · Added February 28, 2014
OBJECTIVES - The aim of this study was to test the hypothesis that rare variants are associated with drug-induced long QT interval syndrome (diLQTS) and torsades de pointes.
BACKGROUND - diLQTS is associated with the potentially fatal arrhythmia torsades de pointes. The contribution of rare genetic variants to the underlying genetic framework predisposing to diLQTS has not been systematically examined.
METHODS - We performed whole-exome sequencing on 65 diLQTS patients and 148 drug-exposed control subjects of European descent. We used rare variant analyses (variable threshold and sequence kernel association test) and gene-set analyses to identify genes enriched with rare amino acid coding (AAC) variants associated with diLQTS. Significant associations were reanalyzed by comparing diLQTS patients with 515 ethnically matched control subjects from the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project.
RESULTS - Rare variants in 7 genes were enriched in the diLQTS patients according to the sequence kernel association test or variable threshold compared with drug-exposed controls (p < 0.001). Of these, we replicated the diLQTS associations for KCNE1 and ACN9 using 515 Exome Sequencing Project control subjects (p < 0.05). A total of 37% of the diLQTS patients also had 1 or more rare AAC variants compared with 21% of control subjects (p = 0.009), in a pre-defined set of 7 congenital long QT interval syndrome (cLQTS) genes encoding potassium channels or channel modulators (KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, AKAP9).
CONCLUSIONS - By combining whole-exome sequencing with aggregated rare variant analyses, we implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS. Moreover, diLQTS patients were more burdened by rare AAC variants in cLQTS genes encoding potassium channel modulators, supporting the idea that multiple rare variants, notably across cLQTS genes, predispose to diLQTS.
Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.
Behr ER, Ritchie MD, Tanaka T, Kääb S, Crawford DC, Nicoletti P, Floratos A, Sinner MF, Kannankeril PJ, Wilde AA, Bezzina CR, Schulze-Bahr E, Zumhagen S, Guicheney P, Bishopric NH, Marshall V, Shakir S, Dalageorgou C, Bevan S, Jamshidi Y, Bastiaenen R, Myerburg RJ, Schott JJ, Camm AJ, Steinbeck G, Norris K, Altman RB, Tatonetti NP, Jeffery S, Kubo M, Nakamura Y, Shen Y, George AL, Roden DM
(2013) PLoS One 8: e78511
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Child, European Continental Ancestry Group, Female, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Torsades de Pointes
Show Abstract · Added March 7, 2014
Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.
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21 MeSH Terms
QT variability during initial exposure to sotalol: experience based on a large electronic medical record.
Weeke P, Delaney J, Mosley JD, Wells Q, Van Driest S, Norris K, Kucera G, Stubblefield T, Roden DM
(2013) Europace 15: 1791-7
MeSH Terms: Adrenergic beta-Antagonists, Aged, Anti-Arrhythmia Agents, Electronic Health Records, Female, Heart Conduction System, Humans, Linear Models, Logistic Models, Long QT Syndrome, Male, Middle Aged, Multivariate Analysis, Odds Ratio, Risk Assessment, Risk Factors, Sotalol, Time Factors, Torsades de Pointes
Show Abstract · Added February 28, 2014
AIMS - A prolonged QT interval is associated with increased risk of Torsades de pointes (TdP) and may be fatal. We sought to investigate the extent to which clinical covariates affect the change in QT interval among 'real-world' patients treated with sotalol and followed in an electronic medical record (EMR) system.
METHODS AND RESULTS - We used clinical alerts in our EMR system to identify all patients in whom a new prescription for sotalol was written (2001-11). Rate-corrected QT (QTc) was calculated by Bazett's formula. Correlates of sotalol-induced change in the QTc interval and sotalol discontinuation were examined using linear and logistic regression, respectively. Overall, 541 sotalol-exposed patients were identified (n = 200 women, 37%). The mean first sotalol dose was 86 ± 39 mg, age 64 ± 13 years, and BMI 30 ± 7 kg/m(2). Atrial fibrillation/flutter was the predominant indication (92.2%). After initial exposure, the change in the QTc interval from baseline was highly variable: ΔQTc after 2 h = 3 ± 42 ms (P = 0.17) and 11 ± 37 ms after ≥48 h (P < 0.001). Multivariable linear regression analysis identified female gender and age, reduced left ventricular ejection fraction, high sotalol dose, hypertrophic cardiomyopathy, and loop diuretic co-administration as correlates of increased ΔQTc at ≥48 h (P < 0.05 for all). Within 3 days of initiation, 12% discontinued sotalol of which 31% were because of exaggerated QTc prolongation. One percent developed TdP.
CONCLUSION - In this EMR-based cohort, the increase in QTc with sotalol initiation was highly variable, and multiple clinical factors contributed. These data represent an important step in ongoing work to identify real-world patients likely to tolerate long-term therapy and reinforces the utility of EMR-based cohorts as research tools.
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19 MeSH Terms
Drug-induced arrhythmia: pharmacogenomic prescribing?
Behr ER, Roden D
(2013) Eur Heart J 34: 89-95
MeSH Terms: Anti-Arrhythmia Agents, Electrocardiography, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Ion Channels, Long QT Syndrome, Polymorphism, Genetic, Risk Factors, Torsades de Pointes
Show Abstract · Added June 26, 2014
Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from www.qtdrugs.org up to January 2012, case reports and articles from www.pubmed.com up to January 2012, and the British National Formulary edition at www.bnf.org.
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10 MeSH Terms
The International Serious Adverse Events Consortium (iSAEC) phenotype standardization project for drug-induced torsades de pointes.
Behr ER, January C, Schulze-Bahr E, Grace AA, Kääb S, Fiszman M, Gathers S, Buckman S, Youssef A, Pirmohamed M, Roden D
(2013) Eur Heart J 34: 1958-63
MeSH Terms: Adverse Drug Reaction Reporting Systems, Anti-Arrhythmia Agents, Anti-Infective Agents, Antipsychotic Agents, Consensus, Consensus Development Conferences as Topic, Drug-Related Side Effects and Adverse Reactions, Genetic Markers, Genetic Testing, Histamine Antagonists, Humans, Interprofessional Relations, Phenotype, Risk Factors, Sex Factors, Torsades de Pointes
Added June 26, 2014
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16 MeSH Terms