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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
Transcription factor ETV1 is essential for rapid conduction in the heart.
Shekhar A, Lin X, Liu FY, Zhang J, Mo H, Bastarache L, Denny JC, Cox NJ, Delmar M, Roden DM, Fishman GI, Park DS
(2016) J Clin Invest 126: 4444-4459
MeSH Terms: Animals, DNA-Binding Proteins, Heart Atria, Heart Conduction System, Heart Ventricles, Homeobox Protein Nkx-2.5, Humans, Mice, Mice, Transgenic, Myocardium, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Transcription Factors
Show Abstract · Added March 14, 2018
Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart.
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13 MeSH Terms
Forward problem of electrocardiography: is it solved?
Bear LR, Cheng LK, LeGrice IJ, Sands GB, Lever NA, Paterson DJ, Smaill BH
(2015) Circ Arrhythm Electrophysiol 8: 677-84
MeSH Terms: Action Potentials, Animals, Body Surface Potential Mapping, Electrocardiography, Epicardial Mapping, Heart Conduction System, Models, Animal, Models, Cardiovascular, Pericardium, Predictive Value of Tests, Reproducibility of Results, Signal Processing, Computer-Assisted, Swine
Show Abstract · Added April 26, 2016
BACKGROUND - The relationship between epicardial and body surface potentials defines the forward problem of electrocardiography. A robust formulation of the forward problem is instrumental to solving the inverse problem, in which epicardial potentials are computed from known body surface potentials. Here, the accuracy of different forward models has been evaluated experimentally.
METHODS AND RESULTS - Body surface and epicardial potentials were recorded simultaneously in anesthetized closed-chest pigs (n=5) during sinus rhythm, and epicardial and endocardial ventricular pacing (65 records in total). Body surface potentials were simulated from epicardial recordings using experiment-specific volume conductor models constructed from magnetic resonance imaging. Results for homogeneous (isotropic electric properties) and inhomogeneous (incorporating lungs, anisotropic skeletal muscle, and subcutaneous fat) forward models were compared with measured body surface potentials. Correlation coefficients were 0.85±0.08 across all animals and activation sequences with no significant difference between homogeneous and inhomogeneous solutions (P=0.85). Despite this, there was considerable variance between simulated and measured body surface potential distributions. Differences between the body surface potential extrema predicted with homogeneous forward models were 55% to 78% greater than observed (P<0.05) and attenuation of potentials adjacent to extrema were 10% to 171% greater (P<0.03). The length and orientation of the vector between potential extrema were also significantly different. Inclusion of inhomogeneous electric properties in the forward model reduced, but did not eliminate these differences.
CONCLUSIONS - These results demonstrate that homogeneous volume conductor models introduce substantial spatial inaccuracies in forward problem solutions. This probably affects the precision of inverse reconstructions of cardiac potentials, in which this assumption is made.
© 2015 American Heart Association, Inc.
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13 MeSH Terms
Clinical characteristics and outcomes associated with the natural history of early repolarization in a young, biracial cohort followed to middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
Ilkhanoff L, Soliman EZ, Prineas RJ, Walsh JA, Ning H, Liu K, Carr JJ, Jacobs DR, Lloyd-Jones DM
(2014) Circ Arrhythm Electrophysiol 7: 392-9
MeSH Terms: Adult, African Continental Ancestry Group, Age Factors, Arrhythmias, Cardiac, Brugada Syndrome, Cardiac Conduction System Disease, Cardiovascular Diseases, Cause of Death, Cohort Studies, Confidence Intervals, Echocardiography, Electrocardiography, European Continental Ancestry Group, Female, Follow-Up Studies, Heart Conduction System, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Assessment, Sex Factors, Survival Rate, Time Factors, Young Adult
Show Abstract · Added October 10, 2014
BACKGROUND - Early repolarization (ER), a common electrocardiographic phenotype, has been associated with increased mortality risk in middle-aged adults. Data are sparse on long-term follow-up and outcomes associated with ER in younger adults.
METHODS AND RESULTS - We prospectively examined 5039 participants (mean age, 25 years at baseline, 40% black) from the Coronary Artery Disease Risk in Adults (CARDIA) cohort for 23 years. Twelve-lead ECGs were recorded and analyzed at years 0, 7, and 20 and coded as definite or probable ER using a standardized algorithm. Cox regression was used, and models were adjusted for important baseline and clinical covariates. Kaplan-Meier curves were created for presence of ER and total mortality and cardiovascular mortality. Participants with ER were more likely to be black, male, smoke, have higher systolic blood pressure, lower heart rate and body mass index, higher exercise duration, and longer PR, QRS, and QT intervals. ER was associated with total mortality (hazard ratio, 1.77; confidence interval, 1.38-2.28; P<0.01) and cardiovascular mortality (hazard ratio, 1.59; confidence interval, 1.01-2.50; P=0.04) in unadjusted analyses, but adjustment for age, sex, and race attenuated associations almost completely. Sex-race stratified analyses showed no significant associations between ER and outcome for any of the subgroups except blacks.
CONCLUSIONS - The presence of ER at any time point during 23 years of follow-up was not associated with adverse outcomes. Black race and male sex confound the unadjusted association of ER and outcomes, with no race-sex interactions noted. Additional studies are necessary to understand the factors associated with heightened risk of death in those who maintain ER into and beyond middle age.
© 2014 American Heart Association, Inc.
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27 MeSH Terms
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW, American College of Cardiology/American Heart Association Task Force on Practice Guidelines
(2014) J Am Coll Cardiol 64: e1-76
MeSH Terms: Anti-Arrhythmia Agents, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Autonomic Nervous System, C-Reactive Protein, Cardiac Output, Low, Catheter Ablation, Comorbidity, Defibrillators, Implantable, Echocardiography, Transesophageal, Electric Countershock, Electrocardiography, Fibrinolytic Agents, Heart Atria, Heart Conduction System, Humans, Inflammation, Natriuretic Peptide, Brain, Oxidative Stress, Pacemaker, Artificial, Platelet Aggregation Inhibitors, Renin-Angiotensin System, Risk Assessment, Risk Factors, Septal Occluder Device, Stroke, Thromboembolism, Ventricular Remodeling
Added May 27, 2014
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29 MeSH Terms
Heart rate-corrected QT interval is an independent predictor of all-cause and cardiovascular mortality in individuals with type 2 diabetes: the Diabetes Heart Study.
Cox AJ, Azeem A, Yeboah J, Soliman EZ, Aggarwal SR, Bertoni AG, Carr JJ, Freedman BI, Herrington DM, Bowden DW
(2014) Diabetes Care 37: 1454-61
MeSH Terms: Adult, Arrhythmias, Cardiac, Brugada Syndrome, Cardiac Conduction System Disease, Cardiovascular Diseases, Cause of Death, Diabetes Mellitus, Type 2, Electrocardiography, Female, Heart Conduction System, Heart Rate, Humans, Incidence, Male, Middle Aged, Prognosis, Risk, Risk Factors, United States
Show Abstract · Added October 10, 2014
OBJECTIVE - Heart rate-corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.
RESEARCH DESIGN AND METHODS - We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.
RESULTS - At baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03-1.36]) and 29% increased risk for CVD mortality (1.29 [1.05-1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95-3.15]; CVD mortality 2.86 [1.35-6.08]).
CONCLUSIONS - Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.
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19 MeSH Terms
Common SCN10A variants modulate PR interval and heart rate response during atrial fibrillation.
Delaney JT, Muhammad R, Shi Y, Schildcrout JS, Blair M, Short L, Roden DM, Darbar D
(2014) Europace 16: 485-90
MeSH Terms: Action Potentials, Aged, Atrial Fibrillation, Electrocardiography, Female, Genetic Predisposition to Disease, Heart Conduction System, Heart Rate, Humans, Male, Middle Aged, NAV1.8 Voltage-Gated Sodium Channel, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Registries, Risk Assessment, Risk Factors, Tennessee, Time Factors
Show Abstract · Added March 7, 2014
AIMS - SCN10A encodes the sodium channel Nav1.8 implicated by genome-wide association studies as a modulator of atrioventricular conduction (PR interval). In a cohort of patients with atrial fibrillation (AF), we examined whether there was an association between common variants in SCN10A and both the PR interval during normal sinus rhythm and the heart rate response during AF.
METHODS AND RESULTS - Patients prospectively enrolled in the Vanderbilt AF registry with electrocardiograms in normal sinus rhythm and/or AF within 1 year of enrollment were genotyped for two common SCN10A variants rs6795970 and rs12632942. Both variants were associated with the PR interval duration in a gene-dose effect on unadjusted analysis; after adjustment for the covariates age, gender, body mass index, hypertension, congestive heart failure, and medication usage, the association remained for rs6795970 only (P = 0.012, partial R(2) = 0.0139). On unadjusted analysis, heart rate response during AF was associated with rs6795970 (P = 0.035, partial R(2) = 0.015), but not with rs12632942 (P = 0.89), and neither association was significant after adjustment for covariates.
CONCLUSION - The common variant rs6795970 in SCN10A is associated with the PR interval duration among healthy patients and those with AF. In addition, this single nucleotide polymorphism trended towards an association with heart rate response during AF indicating the importance of this common SCN10A polymorphism as a marker of atrioventricular conduction.
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20 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
Genetic mechanisms of atrial fibrillation: impact on response to treatment.
Darbar D, Roden DM
(2013) Nat Rev Cardiol 10: 317-29
MeSH Terms: Animals, Anti-Arrhythmia Agents, Atrial Fibrillation, Genetic Predisposition to Disease, Genetic Testing, Heart Conduction System, Humans, Patient Selection, Pharmacogenetics, Phenotype, Precision Medicine, Predictive Value of Tests, Treatment Outcome
Show Abstract · Added March 7, 2014
Atrial fibrillation (AF) is the most-common sustained arrhythmia observed in clinical practice, but response to therapy is highly variable between patients. Current drug therapies to suppress AF are incompletely and unpredictably effective and carry substantial risk of proarrhythmia and noncardiac toxicities. The limited success of therapy for AF is partially the result of heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to therapies in individual patients. In this Review, we discuss the evidence that variability in response to drug therapy is also conditioned by the underlying genetic substrate for AF. Increased susceptibility to AF is mediated through diverse genetic mechanisms, including modulation of the atrial action-potential duration, conduction slowing, and impaired cell-to-cell communication, as well as novel mechanisms, such as regulation of signalling proteins important in the pathogenesis of AF. However, the translation of genetic data to the care of the patients with AF has been limited because of poor understanding of the underlying mechanisms associated with common AF-susceptibility loci, a dearth of prospective, adequately powered studies, and the challenges associated with determining efficacy of antiarrhythmic drugs. What is apparent, however, is the need for appropriately designed, genotype-directed clinical trials.
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13 MeSH Terms
Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk.
Ritchie MD, Denny JC, Zuvich RL, Crawford DC, Schildcrout JS, Bastarache L, Ramirez AH, Mosley JD, Pulley JM, Basford MA, Bradford Y, Rasmussen LV, Pathak J, Chute CG, Kullo IJ, McCarty CA, Chisholm RL, Kho AN, Carlson CS, Larson EB, Jarvik GP, Sotoodehnia N, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) QRS Group, Manolio TA, Li R, Masys DR, Haines JL, Roden DM
(2013) Circulation 127: 1377-85
MeSH Terms: Adult, Aged, Aged, 80 and over, Arrhythmias, Cardiac, Female, Genetic Markers, Genome-Wide Association Study, Heart Conduction System, Heart Rate, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Risk Factors
Show Abstract · Added December 10, 2013
BACKGROUND - ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias.
METHODS AND RESULTS - We performed a genome-wide association study to identify genomic markers of QRS duration in 5272 individuals without cardiac disease selected from electronic medical record algorithms at 5 sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium QRS genome-wide association study meta-analysis. Twenty-three single-nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 single-nucleotide polymorphisms were in the chromosome 3 SCN5A and SCN10A loci, where the most significant single-nucleotide polymorphisms were rs1805126 in SCN5A with P=1.2×10(-8) (eMERGE) and P=2.5×10(-20) (CHARGE) and rs6795970 in SCN10A with P=6×10(-6) (eMERGE) and P=5×10(-27) (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies on variants in these 5 loci in 13859 European Americans to search for diagnoses associated with these markers. Phenome-wide association study identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5272 "heart-healthy" study population.
CONCLUSIONS - We conclude that DNA biobanks coupled to electronic medical records not only provide a platform for genome-wide association study but also may allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The phenome-wide association study approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
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15 MeSH Terms