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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Arking DE, Pulit SL, Crotti L, van der Harst P, Munroe PB, Koopmann TT, Sotoodehnia N, Rossin EJ, Morley M, Wang X, Johnson AD, Lundby A, Gudbjartsson DF, Noseworthy PA, Eijgelsheim M, Bradford Y, Tarasov KV, Dörr M, Müller-Nurasyid M, Lahtinen AM, Nolte IM, Smith AV, Bis JC, Isaacs A, Newhouse SJ, Evans DS, Post WS, Waggott D, Lyytikäinen LP, Hicks AA, Eisele L, Ellinghaus D, Hayward C, Navarro P, Ulivi S, Tanaka T, Tester DJ, Chatel S, Gustafsson S, Kumari M, Morris RW, Naluai ÅT, Padmanabhan S, Kluttig A, Strohmer B, Panayiotou AG, Torres M, Knoflach M, Hubacek JA, Slowikowski K, Raychaudhuri S, Kumar RD, Harris TB, Launer LJ, Shuldiner AR, Alonso A, Bader JS, Ehret G, Huang H, Kao WH, Strait JB, Macfarlane PW, Brown M, Caulfield MJ, Samani NJ, Kronenberg F, Willeit J, CARe Consortium, COGENT Consortium, Smith JG, Greiser KH, Meyer Zu Schwabedissen H, Werdan K, Carella M, Zelante L, Heckbert SR, Psaty BM, Rotter JI, Kolcic I, Polašek O, Wright AF, Griffin M, Daly MJ, DCCT/EDIC, Arnar DO, Hólm H, Thorsteinsdottir U, eMERGE Consortium, Denny JC, Roden DM, Zuvich RL, Emilsson V, Plump AS, Larson MG, O'Donnell CJ, Yin X, Bobbo M, D'Adamo AP, Iorio A, Sinagra G, Carracedo A, Cummings SR, Nalls MA, Jula A, Kontula KK, Marjamaa A, Oikarinen L, Perola M, Porthan K, Erbel R, Hoffmann P, Jöckel KH, Kälsch H, Nöthen MM, HRGEN Consortium, den Hoed M, Loos RJ, Thelle DS, Gieger C, Meitinger T, Perz S, Peters A, Prucha H, Sinner MF, Waldenberger M, de Boer RA, Franke L, van der Vleuten PA, Beckmann BM, Martens E, Bardai A, Hofman N, Wilde AA, Behr ER, Dalageorgou C, Giudicessi JR, Medeiros-Domingo A, Barc J, Kyndt F, Probst V, Ghidoni A, Insolia R, Hamilton RM, Scherer SW, Brandimarto J, Margulies K, Moravec CE, del Greco M F, Fuchsberger C, O'Connell JR, Lee WK, Watt GC, Campbell H, Wild SH, El Mokhtari NE, Frey N, Asselbergs FW, Mateo Leach I, Navis G, van den Berg MP, van Veldhuisen DJ, Kellis M, Krijthe BP, Franco OH, Hofman A, Kors JA, Uitterlinden AG, Witteman JC, Kedenko L, Lamina C, Oostra BA, Abecasis GR, Lakatta EG, Mulas A, Orrú M, Schlessinger D, Uda M, Markus MR, Völker U, Snieder H, Spector TD, Ärnlöv J, Lind L, Sundström J, Syvänen AC, Kivimaki M, Kähönen M, Mononen N, Raitakari OT, Viikari JS, Adamkova V, Kiechl S, Brion M, Nicolaides AN, Paulweber B, Haerting J, Dominiczak AF, Nyberg F, Whincup PH, Hingorani AD, Schott JJ, Bezzina CR, Ingelsson E, Ferrucci L, Gasparini P, Wilson JF, Rudan I, Franke A, Mühleisen TW, Pramstaller PP, Lehtimäki TJ, Paterson AD, Parsa A, Liu Y, van Duijn CM, Siscovick DS, Gudnason V, Jamshidi Y, Salomaa V, Felix SB, Sanna S, Ritchie MD, Stricker BH, Stefansson K, Boyer LA, Cappola TP, Olsen JV, Lage K, Schwartz PJ, Kääb S, Chakravarti A, Ackerman MJ, Pfeufer A, de Bakker PI, Newton-Cheh C
(2014) Nat Genet 46: 826-36
MeSH Terms: Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide
Show Abstract · Added June 26, 2014
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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17 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
Personalized medicine to treat arrhythmias.
Roden DM
(2014) Curr Opin Pharmacol 15: 61-7
MeSH Terms: Animals, Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Humans, Precision Medicine
Show Abstract · Added June 26, 2014
The efficacy of antiarrhythmic drug therapy is incomplete, with responses ranging from efficacy to no effect to severe adverse effects, including paradoxical drug-induced arrhythmia. Most antiarrhythmic drugs were developed at a time when the mechanisms underlying arrhythmias were not well understood. In the last decade, a range of experimental approaches have advanced our understanding of the molecular and genomic contributors to the generation of an arrhythmia-prone heart, and this information is directly informing targeted therapy with existing drugs or the development of new ones. The development of inexpensive whole genome sequencing holds the promise of identifying patients susceptible to arrhythmias in a presymptomatic phase, and thus implementing preventive therapies.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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5 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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1 Members
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29 MeSH Terms
Pulseless electrical activity in a pediatric patient: a case report and review of causative factors and treatment.
Newman J
(2013) AANA J 81: 459-64
MeSH Terms: Anesthesia, General, Arrhythmias, Cardiac, Bronchoscopy, Cardiopulmonary Resuscitation, Female, Heart Arrest, Humans, Infant, Pulse
Show Abstract · Added March 20, 2014
Pulseless electrical activity, an arrhythmia that leads to cardiac arrest, is defined as the presence of organized electrical activity without a palpable pulse or arterial blood pressure. When this arrhythmia presents during anesthesia, it has become routine practice to initiate advanced cardiac life support according to the American Heart Association guidelines. This arrhythmia is usually associated with a poor prognosis unless a reversible cause is investigated and treated immediately. The purpose of this article is to summarize the causative factors of pulseless electrical activity and its treatment modalities. This case report describes the successful resuscitation of a pediatric patient who presented with pulseless electrical activity during anesthesia for a rigid bronchoscopy.
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9 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
Is a palpable pulse always restored during cardiopulmonary resuscitation in a patient with a left ventricular assist device?
Haglund NA, Schlendorf K, Keebler M, Gupta C, Maltais S, Ely EW, Lenihan D
(2014) Am J Med Sci 347: 322-7
MeSH Terms: Adult, Algorithms, Arrhythmias, Cardiac, Cardiopulmonary Resuscitation, Delirium, Heart Arrest, Heart Failure, Heart-Assist Devices, Hemodynamics, Humans, Male
Show Abstract · Added May 27, 2014
End-stage heart failure patients are being supported with continuous flow left ventricular assist devices (CF-LVAD) in increasing numbers. The severe physiologic and pharmacologic derangements associated with end-stage heart failure therapies predispose these patients to delirium. During a delirious episode, a patient may inadvertently disconnect CF-LVAD equipment, which may have dangerous consequences. Unfortunately, it is not yet routine to use readily available clinical monitoring tools to allow early detection of delirium in this high-risk population. The authors present a case of acute hyperactive delirium leading to pump power disconnection and cardiopulmonary arrest occurring 7 days after CF-LVAD implantation. The case highlights the need for delirium awareness in the cardiovascular intensive care unit and the unique challenges associated with resuscitation of CF-LVAD patients. The authors propose that cardiovascular intensive care unit patients undergo at least twice daily delirium monitoring and provide a novel resuscitation algorithm for patients who have CF-LVADs.
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1 Members
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11 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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2 Members
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21 MeSH Terms
The Lambeth Conventions (II): guidelines for the study of animal and human ventricular and supraventricular arrhythmias.
Curtis MJ, Hancox JC, Farkas A, Wainwright CL, Stables CL, Saint DA, Clements-Jewery H, Lambiase PD, Billman GE, Janse MJ, Pugsley MK, Ng GA, Roden DM, Camm AJ, Walker MJ
(2013) Pharmacol Ther 139: 213-48
MeSH Terms: Animals, Arrhythmias, Cardiac, Biomedical Research, Humans, Research Design
Show Abstract · Added March 7, 2014
The 'Lambeth Conventions' is a guidance document, written in 1987 (Walker et al., 1988), intended to be of practical value in the investigation of experimental arrhythmias induced by ischaemia, infarction, and reperfusion. This is an update, expanded to include guidance on the study of supraventricular arrhythmias, drug-induced arrhythmias, heritable arrhythmias, and advances in our knowledge in core areas since 1987. We have updated the guidance on the design and execution of experiments and the definition, classification, quantification, and analysis of all types of arrhythmias. Investigators are encouraged to adopt the conventions and test their validity in the hope that this will improve uniformity and interlaboratory comparisons, aid clinical research, facilitate antiarrhythmic drug discovery and safety assessment, and improve antiarrhythmic drug deployment for different cardiac conditions. We note that there is a gap between some definitions proposed here and their conventional clinical counterparts, and encourage the research necessary to bridge that translational gap. A web link offers the chance to vote and comment on the new conventions (https://bscr.wufoo.com/forms/z7x0x5/).
Copyright © 2013 Elsevier Inc. All rights reserved.
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1 Members
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5 MeSH Terms
Induced pluripotent stem cell-derived cardiomyocytes: boutique science or valuable arrhythmia model?
Knollmann BC
(2013) Circ Res 112: 969-76; discussion 976
MeSH Terms: Arrhythmias, Cardiac, Humans, Induced Pluripotent Stem Cells, Myocytes, Cardiac
Show Abstract · Added February 12, 2015
This article reviews the strengths and limitations of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) as models of cardiac arrhythmias. Specifically, the article attempts to answer the following questions: Which clinical arrhythmias can be modeled by iPSC-CM? How well can iPSC-CM model adult ventricular myocytes? What are the strengths and limitations of published iPSC-CM arrhythmia models? What new mechanistic insight has been gained? What is the evidence that would support using iPSC-CM to personalize antiarrhythmic drug therapy? The review also discusses the pros and cons of using the iPSC-CM technology for modeling specific genetic arrhythmia disorders, such as long QT syndrome, Brugada Syndrome, or Catecholaminergic Polymorphic Ventricular Tachycardia.
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4 MeSH Terms