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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
Arrhythmia genetics: Not dark and lite, but 50 shades of gray.
Roden DM, Glazer AM, Kroncke B
(2018) Heart Rhythm 15: 1231-1232
MeSH Terms: Arrhythmias, Cardiac, Humans, Long QT Syndrome, Phenotype, Potassium Channels, Voltage-Gated
Added March 26, 2019
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MeSH Terms
Exploiting ion channel structure to assess rare variant pathogenicity.
Kroncke BM, Yang T, Kannankeril P, Shoemaker MB, Roden DM
(2018) Heart Rhythm 15: 890-894
MeSH Terms: Adolescent, Adult, Body Surface Potential Mapping, DNA, DNA Mutational Analysis, ERG1 Potassium Channel, Female, Humans, KCNQ1 Potassium Channel, Long QT Syndrome, Mutation, Pedigree, Phenotype
Show Abstract · Added March 26, 2019
BACKGROUND - A 27-year-old woman was seen for long QT syndrome. She was found to be a carrier of 2 variants, KCNQ1 Val162Met and KCNH2 Ser55Leu, and both were classified as "pathogenic" by a diagnostic laboratory, in part because of sequence proximity to other known pathogenic variants.
OBJECTIVE - The purpose of this study was to assess the relationship between both the KCNQ1 and KCNH2 variants and clinical significance using protein structure, in vitro functional assays, and familial segregation.
METHODS - We used co-segregation analysis of family, patch clamp in vitro electrophysiology, and structural analysis using recently released cryo-electron microscopy structures of both channels.
RESULTS - The structural analysis indicates that KCNQ1 Val162Met is oriented away from functionally important regions while Ser55Leu is positioned at domains critical for KCNH2 fast inactivation. Clinical phenotyping and electrophysiology study further support the conclusion that KCNH2 Ser55Leu is correctly classified as pathogenic but KCNQ1 Val162Met is benign.
CONCLUSION - Proximity in sequence space does not always translate accurately to proximity in 3-dimensional space. Emerging structural methods will add value to pathogenicity prediction.
Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
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Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance.
Li B, Mendenhall JL, Kroncke BM, Taylor KC, Huang H, Smith DK, Vanoye CG, Blume JD, George AL, Sanders CR, Meiler J
(2017) Circ Cardiovasc Genet 10:
MeSH Terms: Databases, Genetic, Female, Genetic Variation, Humans, KCNQ1 Potassium Channel, Long QT Syndrome, Male, Predictive Value of Tests, Protein Domains
Show Abstract · Added March 14, 2018
BACKGROUND - An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity.
METHODS AND RESULTS - In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein. We found that conserved subdomains generally are critical for channel function and are enriched with dysfunctional variants. Using this experimentally validated data set, we trained a neural network, designated Q1VarPred, specifically for predicting the functional impact of KCNQ1 variants of unknown significance. The estimated predictive performance of Q1VarPred in terms of Matthew's correlation coefficient and area under the receiver operating characteristic curve were 0.581 and 0.884, respectively, superior to the performance of 8 previous methods tested in parallel. Q1VarPred is publicly available as a web server at http://meilerlab.org/q1varpred.
CONCLUSIONS - Although a plethora of tools are available for making pathogenicity predictions over a genome-wide scale, previous tools fail to perform in a robust manner when applied to KCNQ1. The contrasting and favorable results for Q1VarPred suggest a promising approach, where a machine-learning algorithm is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools.
© 2017 American Heart Association, Inc.
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9 MeSH Terms
Regulation of KCNQ/Kv7 family voltage-gated K channels by lipids.
Taylor KC, Sanders CR
(2017) Biochim Biophys Acta Biomembr 1859: 586-597
MeSH Terms: Amino Acid Sequence, Binding Sites, Cell Membrane, Epilepsy, Benign Neonatal, Fatty Acids, Unsaturated, Hearing Loss, Bilateral, Humans, Hydrophobic and Hydrophilic Interactions, KCNQ1 Potassium Channel, Long QT Syndrome, Membrane Lipids, Models, Molecular, Phosphatidylinositol 4,5-Diphosphate, Protein Binding, Protein Isoforms, Protein Structure, Secondary
Show Abstract · Added November 21, 2018
Many years of studies have established that lipids can impact membrane protein structure and function through bulk membrane effects, by direct but transient annular interactions with the bilayer-exposed surface of protein transmembrane domains, and by specific binding to protein sites. Here, we focus on how phosphatidylinositol 4,5-bisphosphate (PIP) and polyunsaturated fatty acids (PUFAs) impact ion channel function and how the structural details of the interactions of these lipids with ion channels are beginning to emerge. We focus on the Kv7 (KCNQ) subfamily of voltage-gated K channels, which are regulated by both PIP and PUFAs and play a variety of important roles in human health and disease. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
Copyright © 2016 Elsevier B.V. All rights reserved.
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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
Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks.
Gomez-Hurtado N, Boczek NJ, Kryshtal DO, Johnson CN, Sun J, Nitu FR, Cornea RL, Chazin WJ, Calvert ML, Tester DJ, Ackerman MJ, Knollmann BC
(2016) Circ Arrhythm Electrophysiol 9:
MeSH Terms: Action Potentials, Adult, Animals, Calmodulin, DNA Mutational Analysis, Electrocardiography, Exercise Test, Female, Genotype, Humans, Long QT Syndrome, Male, Mice, Phenotype, Ryanodine, Tachycardia, Ventricular
Show Abstract · Added April 18, 2017
BACKGROUND - Calmodulin (CaM) mutations are associated with severe forms of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). CaM mutations are found in 13% of genotype-negative long QT syndrome patients, but the prevalence of CaM mutations in genotype-negative CPVT patients is unknown. Here, we identify and characterize CaM mutations in 12 patients with genotype-negative but clinically diagnosed CPVT.
METHODS AND RESULTS - We performed mutational analysis of CALM1, CALM2, and CALM3 gene-coding regions, in vitro measurement of CaM-Ca(2+) (Ca)-binding affinity, ryanodine receptor 2-CaM binding, Ca handling, L-type Ca current, and action potential duration. We identified a novel CaM mutation-A103V-in CALM3 in 1 of 12 patients (8%), a female who experienced episodes of exertion-induced syncope since age 10, had normal QT interval, and displayed ventricular ectopy during stress testing consistent with CPVT. A103V modestly lowered CaM Ca-binding affinity (3-fold reduction versus WT-CaM), but did not alter CaM binding to ryanodine receptor 2. In permeabilized cardiomyocytes, A103V-CaM (100 nmol/L) promoted spontaneous Ca wave and spark activity, a cellular phenotype of ryanodine receptor 2 activation. Even a 1:3 mixture of A103V-CaM:WT-CaM activated Ca waves, demonstrating functional dominance. Compared with long QT syndrome D96V-CaM, A103V-CaM had significantly less effects on L-type Ca current inactivation, did not alter action potential duration, and caused delayed afterdepolarizations and triggered beats in intact cardiomyocytes.
CONCLUSIONS - We discovered a novel CPVT mutation in the CALM3 gene that shares functional characteristics with established CPVT-associated mutations in CALM1. A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via ryanodine receptor 2 dysregulation, which explains the autosomal dominant inheritance.
© 2016 American Heart Association, Inc.
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16 MeSH Terms
Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes.
Pipilas DC, Johnson CN, Webster G, Schlaepfer J, Fellmann F, Sekarski N, Wren LM, Ogorodnik KV, Chazin DM, Chazin WJ, Crotti L, Bhuiyan ZA, George AL
(2016) Heart Rhythm 13: 2012-9
MeSH Terms: Action Potentials, Calmodulin, Child, Preschool, Electrocardiography, Genetic Predisposition to Disease, Humans, Infant, Long QT Syndrome, Male, Mutation, Myocytes, Cardiac, Switzerland
Show Abstract · Added April 18, 2017
BACKGROUND - Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS).
OBJECTIVE - The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias.
METHODS - The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations.
RESULTS - A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation.
CONCLUSION - Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.
Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G.
Boczek NJ, Gomez-Hurtado N, Ye D, Calvert ML, Tester DJ, Kryshtal D, Hwang HS, Johnson CN, Chazin WJ, Loporcaro CG, Shah M, Papez AL, Lau YR, Kanter R, Knollmann BC, Ackerman MJ
(2016) Circ Cardiovasc Genet 9: 136-146
MeSH Terms: Amino Acid Sequence, Animals, Calmodulin, Demography, Female, Humans, Long QT Syndrome, Male, Mice, Inbred C57BL, Mutation, Missense, Prevalence, Young Adult
Show Abstract · Added April 18, 2017
BACKGROUND - Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca(2+) and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants.
METHODS AND RESULTS - Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca(2+)-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release.
CONCLUSIONS - Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.
© 2016 American Heart Association, Inc.
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12 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