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Arthur A M Wilde - One of the best experts on this subject based on the ideXlab platform.
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genome wiDe analysis of drug induced TorsaDes De Pointes lack of common variants with large effect sizes
PLOS ONE, 2013Co-Authors: Elijah R Behr, Stefan Kaab, Marylyn D Ritchie, Toshihiro Tanaka, Dana C Crawford, Paola Nicoletti, Aris Floratos, Moritz F Sinner, Prince J Kannankeril, Arthur A M WildeAbstract: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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a large candidate gene survey iDentifies the kcne1 d85n polymorphism as a possible modulator of drug induced TorsaDes De Pointes
Circulation-cardiovascular Genetics, 2012Co-Authors: Stefan Kaab, Elijah R Behr, Dana C Crawford, Moritz F Sinner, Prince J Kannankeril, Arthur A M Wilde, Connie R Bezzina, Eric Schulzebahr, Pascale GuicheneyAbstract:Background— Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, Development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results— In a case-control setting, we incluDed 176 patients of European Descent from North America and Europe with diLQTS, Defined as documented TorsaDes De Pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotiDe polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European Descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confiDence interval, 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects. Conclusions— This high-Density candidate SNP approach iDentified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction TorsaDes De Pointes.
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giant t u waves preceDe TorsaDes De Pointes in long qt syndrome a systematic electrocardiographic analysis in patients with acquired and congenital qt prolongation
Journal of the American College of Cardiology, 2009Co-Authors: Paulus Kirchhof, Michael R Franz, Abdennasser Bardai, Arthur A M WildeAbstract:Objectives: This study sought to iDentify electrocardiographic (ECG) criteria that are associated with initiation of TorsaDes De Pointes (TdP) in patients with acquired (a-) and congenital (c-) lon...
Marc A. Vos - One of the best experts on this subject based on the ideXlab platform.
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late na current inhibition by ranolazine reduces TorsaDes De Pointes in the chronic atrioventricular block dog moDel
Journal of the American College of Cardiology, 2010Co-Authors: Gudrun Antoons, Jet D.m. Beekman, Avram Oros, Markus A Engelen, Marien J C Houtman, Luiz Belardinelli, Milan Stengl, Marc A. VosAbstract:Objectives: This study investigated whether ranolazine reduces dofetiliDe-induced TorsaDes De Pointes (TdP) in a moDel of long QT syndrome with down-regulated K+currents due to hypertrophic remoDel...
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beat to beat variability of repolarization Determines proarrhythmic outcome in dogs susceptible to drug induced TorsaDes De Pointes
Journal of the American College of Cardiology, 2006Co-Authors: Morten B. Thomsen, Paul G.a. Volders, Jet D.m. Beekman, Jørgen Matz, Marc A. VosAbstract:Objectives We investigated whether increasing or Decreasing beat-to-beat variability of repolarization (BVR) would change drug-induced proarrhythmic outcome accordingly. Background Increased variability of repolarization has been suggested as a preluDe to proarrhythmic circumstances in experimental and clinical situations. Methods The non-cardiovascular, I Kr -blocking drug sertindole was administered to anesthetized dogs with chronic atrioventricular block. Three interventions were used to prevent or suppress sertindole-induced TorsaDes De Pointes (TdP). Results Supratherapeutic doses of sertindole (1.0 mg/kg intravenously) induced TdP in 10 of 13 dogs whereas 0.2 mg/kg induced no TdP, Despite increases in QT intervals by both doses. The BVR, quantified as short-term variability (STV) from Poincare plots, was the only parameter that predicted TdP outcome (1.0 mg/kg sertindole: 2.3 ± 0.7 ms to 5.1 ± 2.1 ms, p I K,ATP activator) reduced sertindole-induced TdP and Decreased STV from 4.9 ± 2.1 ms to 2.6 ± 0.9 ms (p Conclusions Proarrhythmic intervention is related to an increase in BVR, whereas antiarrhythmic treatment is associated with a Decrease in BVR. The BVR is superior to QT interval prolongation in the prediction and prevention of drug-induced TdP in this experimental moDel.
Stefan Kaab - One of the best experts on this subject based on the ideXlab platform.
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genome wiDe analysis of drug induced TorsaDes De Pointes lack of common variants with large effect sizes
PLOS ONE, 2013Co-Authors: Elijah R Behr, Stefan Kaab, Marylyn D Ritchie, Toshihiro Tanaka, Dana C Crawford, Paola Nicoletti, Aris Floratos, Moritz F Sinner, Prince J Kannankeril, Arthur A M WildeAbstract: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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a large candidate gene survey iDentifies the kcne1 d85n polymorphism as a possible modulator of drug induced TorsaDes De Pointes
Circulation-cardiovascular Genetics, 2012Co-Authors: Stefan Kaab, Elijah R Behr, Dana C Crawford, Moritz F Sinner, Prince J Kannankeril, Arthur A M Wilde, Connie R Bezzina, Eric Schulzebahr, Pascale GuicheneyAbstract:Background— Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, Development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results— In a case-control setting, we incluDed 176 patients of European Descent from North America and Europe with diLQTS, Defined as documented TorsaDes De Pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotiDe polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European Descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confiDence interval, 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects. Conclusions— This high-Density candidate SNP approach iDentified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction TorsaDes De Pointes.
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baseline values and sotalol induced changes of ventricular repolarization duration heterogeneity and instability in patients with a history of drug induced TorsaDes De Pointes
The Journal of Clinical Pharmacology, 2009Co-Authors: Jeanphilippe Couderc, Anthony A Fossa, Martin Hinterseer, Stefan Kaab, Scott Mcnitt, Xiaojuan Xia, Britt M Beckmann, Slava Polonsky, Wojciech ZarebaAbstract:The authors investigated whether computerized parameters quantifying ventricular repolarization Delay, heterogeneity, and instability characterize individuals who Developed drug-induced TorsaDes De Pointes. Assessing an individual's propensity to TorsaDes De Pointes when exposed to a QT-prolonging drug is challenging because baseline QT prolongation has limited predictive value. Five-minute digital 12-lead electrocardiograms were acquired at baseline and after a sotalol challenge in 16 patients who had a history of TorsaDes De Pointes in the context of a QT-prolonging drug and 17 patients who did not have such history. Computerized measurements of QTc, T peak to T end intervals (TpTe), TpTe/QTc, and QT variability were implemented, and novel quantifiers of ventricular repolarization heterogeneity from the early (ERD) and late (LRD) part of the T wave were investigated. Compared with electrocardiograms of patients without a history of TorsaDes De Pointes, the baseline electrocardiograms of patients with a history of TorsaDes De Pointes had a longer QTc and an increased repolarization heterogeneity of the early part of the T wave (ERD30%: 44 +/- 13 vs 35 +/- 8 ms, P = .02). On sotalol, the electrocardiograms from individuals with TorsaDes De Pointes revealed a Delay of the terminal part of the T wave that was not present in patients without TorsaDes De Pointes (TpTe: 27 +/- 40 vs -2 +/- 21 ms, P = .02; LRD70%: 20 +/- 29 vs 2 +/- 4 ms, P = .04). Results suggest that the electrocardiogram abnormalities characterizing patients with a history of TorsaDes De Pointes are (1) an increased repolarization heterogeneity at baseline and (2) a sotalol-induced prolongation of the terminal part of the T wave.
Dan M Roden - One of the best experts on this subject based on the ideXlab platform.
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predicting drug induced qt prolongation and TorsaDes De Pointes
The Journal of Physiology, 2016Co-Authors: Dan M RodenAbstract:Drugs used to treat cardiovascular disease as well as those used in the treatment of multiple other conditions can occasionally produce exaggerated prolongation of the QT interval on the electrocardiogram and the morphologically distinctive polymorphic ventricular tachycardia ('TorsaDes De Pointes'). This syndrome of drug-induced long QT syndrome has moved from an interesting acaDemic exercise to become a key element in the Development of any new drug entity. The prevailing view, which has driven both clinical care and drug regulation, holds that cardiac repolarization represents a balance between inward currents (primarily through calcium and sodium channels) and outward currents (primarily through rapid and slowed Delayed rectifier potassium channels) and that block of the rapid Delayed rectifier (IKr ) is the primary mechanism whereby drugs prolong individual action potentials, manifest on the surface electrocardiogram as QT interval prolongation. Such marked action potential prolongation in individual cardiac cells, in turn, is accompanied by arrhythmogenic afterDepolarizations thought to trigger TorsaDes De Pointes. This review Describes the eviDence in support of this construct, and Describes the way in which clinical and whole heart experiments have informed molecular mechanisms and vice versa. New data that challenge these views and that may, as a result, lead to new clinical care and drug screening paradigms, are discussed.
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novel rare variants in congenital cardiac arrhythmia genes are frequent in drug induced TorsaDes De Pointes
Pharmacogenomics Journal, 2013Co-Authors: Andrea H Ramirez, Christian M Shaffer, Jessica T Delaney, David Sexton, Shawn Levy, Mark J Rieder, Deborah A Nickerson, Alfred L George, Dan M RodenAbstract:Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced TorsaDes De Pointes
Elijah R Behr - One of the best experts on this subject based on the ideXlab platform.
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pharmacological treatment of acquired qt prolongation and TorsaDes De Pointes
British Journal of Clinical Pharmacology, 2016Co-Authors: Simon H L Thomas, Elijah R BehrAbstract:TorsaDes De Pointes (TdP) is a characteristic polymorphic ventricular arrhythmia associated with Delayed ventricular repolarization as eviDenced on the surface electrocardiogram by QT interval prolongation. It typically occurs in self-limiting bursts, causing dizziness and syncope, but may occasionally progress to ventricular fibrillation and sudDen Death. Acquired long QT syndromes are mainly caused by cardiac disease, electrolyte abnormalities or exposure to drugs that block rectifying potassium channels, especially IKr. Management of TdP or marked QT prolongation incluDes removal or correction of precipitants, including discontinuation of culprit drugs and institution of cardiac monitoring. Electrolyte abnormalities and hypoxia should be corrected, with potassium concentrations maintained in the high normal range. Immediate treatment of TdP is by intravenous administration of magnesium sulphate, terminating prolonged episoDes using electrical cardioversion. In refractory cases of recurrent TdP, the arrhythmia can be suppressed by increasing the unDerlying heart rate using isoproterenol (isoprenaline) or transvenous pacing. Other interventions are rarely neeDed, but there are case reports of successful use of lidocaine or phenytoin. Anti-arrhythmic drugs that prolong ventricular repolarization should be avoiDed. Some episoDes of TdP could be avoiDed by careful prescribing of QT prolonging drugs, including an individualized assessment of risks and benefits before use, performing baseline and periodic electrocardiograms and measurement of electrolytes, especially during acute illnesses, using the lowest effective dose for the shortest possible time and avoiding potential drug interactions. These steps are particularly important in those with unDerlying repolarization abnormalities and those who have previously experienced drug-induced TdP.
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genome wiDe analysis of drug induced TorsaDes De Pointes lack of common variants with large effect sizes
PLOS ONE, 2013Co-Authors: Elijah R Behr, Stefan Kaab, Marylyn D Ritchie, Toshihiro Tanaka, Dana C Crawford, Paola Nicoletti, Aris Floratos, Moritz F Sinner, Prince J Kannankeril, Arthur A M WildeAbstract: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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a large candidate gene survey iDentifies the kcne1 d85n polymorphism as a possible modulator of drug induced TorsaDes De Pointes
Circulation-cardiovascular Genetics, 2012Co-Authors: Stefan Kaab, Elijah R Behr, Dana C Crawford, Moritz F Sinner, Prince J Kannankeril, Arthur A M Wilde, Connie R Bezzina, Eric Schulzebahr, Pascale GuicheneyAbstract:Background— Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, Development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results— In a case-control setting, we incluDed 176 patients of European Descent from North America and Europe with diLQTS, Defined as documented TorsaDes De Pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotiDe polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European Descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confiDence interval, 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects. Conclusions— This high-Density candidate SNP approach iDentified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction TorsaDes De Pointes.
