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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.
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.
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.
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.
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.
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.
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.
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.
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.