Showing papers by "Elijah R. Behr published in 2013"
New York University1, University of Amsterdam2, Shiga University of Medical Science3, Kyungpook National University4, St George's, University of London5, Children's National Medical Center6, Leiden University7, University of Barcelona8, University of Oulu9, Vanderbilt University10, University of British Columbia11, University of Paris12, University of Rochester13, University of Pavia14, Nippon Medical School15, Johns Hopkins University16, Washington University in St. Louis17
TL;DR: Developed in partnership with the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology, and the Asia Pacific Heart Rhythm society (APHRS).
1,569 citations
University of Pavia1, Shiga University2, Kyungpook National University Hospital3, St George's, University of London4, Children's National Medical Center5, Leiden University Medical Center6, University of Barcelona7, University of Oulu8, Monroe Carell Jr. Children's Hospital at Vanderbilt9, University of British Columbia10, University of Rochester Medical Center11, Nippon Medical School12, Johns Hopkins University13, Washington University in St. Louis14
TL;DR: This international consensus statement is the collaborative effort of three medical societies representing electrophysiology in North America, Europe, and Asian-Pacific area and summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature.
Abstract: This international consensus statement is the collaborative effort of three medical societies representing electrophysiology in North America, Europe, and Asian-Pacific area: the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the Asia Pacific Heart Rhythm Society. The objective of the consensus document is to provide clinical guidance for diagnosis, risk stratification, and management of patients affected by inherited primary arrhythmia syndromes. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the clinical data on patients affected by channelopathies.
This document does not address the indications of genetic testing in patients affected by inherited arrhythmias and their family members. Diagnostic, prognostic, and therapeutic implications of the results of genetic testing are also not included in this document because this topic has been covered by a recent publication1 coauthored by some of the contributors of this consensus document, and it remains the reference text on this topic. Guidance for the evaluation of patients with idiopathic ventricular fibrillation, sudden arrhythmic death …
555 citations
University of Amsterdam1, University of Nantes2, French Institute of Health and Medical Research3, Centre national de la recherche scientifique4, University of Pavia5, Pierre-and-Marie-Curie University6, Paris Diderot University7, Heidelberg University8, St George's, University of London9, Copenhagen University Hospital10, National Research Foundation of South Africa11, Ludwig Maximilian University of Munich12, Vanderbilt University13, Niigata University14, Shiga University of Medical Science15, Nagasaki University16, Nippon Medical School17, Imperial College London18, university of lille19, Pasteur Institute20, University of Paris-Sud21, IRSA22, University of Würzburg23
TL;DR: The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia and indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
Abstract: Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
467 citations
TL;DR: The current status of gene discovery and the associations between phenotype and genotype in the cardiac channelopathies and cardiomyopathies are described.
Abstract: Over the past 2 decades, investigators in the field of cardiac genetics have evolved a complex understanding of the pathophysiological basis of inherited cardiac diseases, which predispose individuals to sudden cardiac death. In this Review, we describe the current status of gene discovery and the associations between phenotype and genotype in the cardiac channelopathies and cardiomyopathies. The various indications for genetic testing and its utility in the clinic are assessed in relation to diagnosis, cascade testing, guiding management, and prognosis. Some common problems exist across all phenotypes: the variable penetrance and expressivity of genetic disease, and the difficulty of assessing the functional and clinical effects of novel mutations. These issues will be of particular importance as the next-generation sequencing technologies are used by genetics laboratories to provide results from large panels of genes. The accurate interpretation of these results will be the main challenge for the future.
159 citations
New York University1, Shiga University2, Kyungpook National University Hospital3, St George's, University of London4, Children's National Medical Center5, Leiden University Medical Center6, University of Barcelona7, University of Oulu8, Monroe Carell Jr. Children's Hospital at Vanderbilt9, University of British Columbia10, University of Rochester Medical Center11, University of Pavia12, Nippon Medical School13, Johns Hopkins University14, Washington University in St. Louis15
TL;DR: The management of patients with Inherited Primary Arrhythmia Syndromes Silvia G. Priori and Minoru Horie, MD, PhD, (APHRS Chairperson), Yongkeun Cho, MD , (APH RS Chairperson) and Elijah R. Behr, MA, MBBS,MD, FRCP are involved.
156 citations
TL;DR: In this article, the authors explored the hypothesis that sudden cardiac deaths represent sudden arrhythmic death syndrome (SADS) and found that a similar proportion of primary arrhythmogenic syndromes to a contemporary series of SADS.
Abstract: Background— The sudden death of young individuals is commonly attributed to inherited cardiac disorders, and familial evaluation is advocated. The identification of pathognomonic histopathologic findings, or the absence of cardiac pathology (sudden arrhythmic death syndrome [SADS]) at postmortem, directs familial evaluation targeting structural disorders or primary arrhythmogenic syndromes, respectively. In a proportion of autopsies, structural abnormalities of uncertain significance are reported. We explored the hypothesis that such sudden cardiac deaths represent SADS.
Methods and Results— Families (n=340) of index cases of sudden cardiac deaths who underwent postmortem evaluation were evaluated in specialist cardiogenetics clinics. Families in whom the deceased exhibited structural abnormalities of uncertain significance (n=41), such as ventricular hypertrophy, myocardial fibrosis, and minor coronary artery disease, were included in the study. Results were compared with 163 families with normal postmortem (SADS). Relatives underwent comprehensive cardiac evaluation. Twenty-one families (51%) with autopsy findings of uncertain significance received a diagnosis based on the identification of an inherited cardiac condition phenotype in ≥1 relatives: 14 Brugada syndrome; 4 long-QT syndrome; 1 catecholaminergic polymorphic ventricular tachycardia; and 2 cardiomyopathy. A similar proportion of families (47.2%) received a diagnosis in the SADS cohort ( P =0.727). An arrhythmogenic syndrome was the predominant diagnosis in both cohorts (46% versus 45%; P =0.863).
Conclusions— Familial evaluation after sudden cardiac deaths with autopsy findings of uncertain significance identified a similar proportion of primary arrhythmogenic syndromes to a contemporary series of SADS. Our study highlights the need for accurate interpretation of autopsy findings to avoid erroneous diagnoses, with potentially devastating implications.
117 citations
TL;DR: Electrocardiographic voltage criteria for RVH are frequently fulfilled in healthy athletes without underlying RV pathology, and should not prompt further evaluation if observed in isolation.
Abstract: Aims Pre-participation cardiovascular screening of young athletes may prevent sports-related sudden cardiac deaths. Recognition of physiological electrocardiography (ECG) changes in healthy athletes has improved the specificity of screening while maintaining sensitivity for disease. The study objective was to determine the clinical significance of electrocardiographic right ventricular hypertrophy (RVH) in athletes.
Methods and results Between 2010 and 2012, 868 subjects aged 14–35 years (68.8% male) were assessed using ECG and echocardiography (athletes; n = 627, sedentary controls; n = 241). Results were compared against patients with established right ventricular (RV) pathology (arrhythmogenic right ventricular cardiomyopathy, n = 68; pulmonary hypertension, n = 30). Sokolow-Lyon RVH (R[V1]+S[V5orV6] > 1.05 mV) was more prevalent in athletes than controls (11.8 vs . 6.2%, P = 0.017), although RV wall thickness (RVWT) was similar (4.0 ± 1.0 vs . 3.9 ± 0.9 mm, P = 0.18). Athletes exhibiting electrocardiographic RVH were predominantly male (95.9%), and demonstrated similar RV dimensions and function to athletes with normal electrocardiograms (RVWT; 4.0 ± 1.1 vs . 4.0 ± 0.9 mm, P = 0.95, RV basal dimension; 42.7 ± 5.2 vs . 42.1 ± 5.9 mm, P = 0.43, RV fractional area change; 40.6 ± 7.6 vs . 42.2 ± 8.1%, P = 0.14). Sensitivity and specificity of Sokolow-Lyon RVH for echocardiographic RVH (>5 mm) were 14.3 and 88.2%, respectively. Further evaluation including cardiac magnetic resonance imaging did not diagnose right ventricular pathology in any athlete. None of the cardiomyopathic or pulmonary hypertensive patients exhibited voltage RVH without additional ECG abnormalities.
Conclusion Electrocardiographic voltage criteria for RVH are frequently fulfilled in healthy athletes without underlying RV pathology, and should not prompt further evaluation if observed in isolation. Recognition of this phenomenon should reduce the burden of investigations after pre-participation ECG screening without compromising sensitivity for disease.
79 citations
TL;DR: The problem, predisposing factors, and the underlying genetic predisposition as it is understood currently, including the future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed.
Abstract: Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from www.qtdrugs.org up to January 2012, case reports and articles from www.pubmed.com up to January 2012, and the British National Formulary edition at www.bnf.org.
78 citations
TL;DR: This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk.
Abstract: Background
Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden.
61 citations
St George's, University of London1, Vanderbilt University2, Pennsylvania State University3, Tokyo Medical and Dental University4, Ludwig Maximilian University of Munich5, Columbia University6, University of Amsterdam7, University of Münster8, French Institute of Health and Medical Research9, University of Miami10, University of Nantes11, Stanford University12, University of Chicago13
TL;DR: It is argued that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.
Abstract: 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 ≥27 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: 15-26) 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
57 citations
TL;DR: A genetic predisposition for AF has long been recognized, but its manifestation in patients likely involves a combination of rare and common genetic variants, which would represent a significant breakthrough for understanding the mechanisms that associate with disease.
Abstract: R231H Causes a High Penetrance for Familial AF
Background
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease.
Method and Results
Candidate gene sequencing in 5 unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage-gated K+ channel that conducts the slowly activating delayed rectifier K+ current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (IKCNQ1) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in IKCNQ1 following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage-dependent gating.
Conclusions
The R231H variant causes a high penetrance for interfamilial early-onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1. We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF.
TL;DR: Two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes are compared, with PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short- read sequencing (Hyb-SR).
Abstract: Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and “hot spots” in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs. In the next iteration of these assays we anticipate sensitivity above 97 % for all LQT genes. NGS assays will soon replace conventional sequencing for LQT diagnostics and molecular pathology.
TL;DR: The latest research replicates and extends the existing knowledge regarding epidemiology and familial evaluation of SADS, whilst genetic studies support a role for the molecular autopsy.
Abstract: Purpose of review Unexplained sudden death and the sudden arrhythmic death syndrome (SADS) affect a small but significant proportion of young and apparently healthy individuals. This review revisits the causes underlying such deaths and the investigational strategies that identify surviving family who may be at risk. Recent findings Recent epidemiological data is available from case series or government records. The yield from familial cardiological evaluation for inherited conditions has been supported by additional small series. The greatest advance has come with molecular autopsy studies, which have utilized various methodologies and candidate genes to investigate SADS cases and their families. Summary The latest research replicates and extends the existing knowledge regarding epidemiology and familial evaluation of SADS, whilst genetic studies support a role for the molecular autopsy.
TL;DR: It is suggested that long–QT syndrome (LQTS) is considered a provisional entity because no association has ever been found between LQTS and isolated CAV3 mutations, and mutations inCAV3 are rare in LQ TS.
Abstract: Background— Mutations in CAV3 , coding for caveolin-3, the major constituent scaffolding protein of cardiac caveolae, have been associated with skeletal muscle disease, cardiomyopathy, and most recently long–QT syndrome (LQTS) and sudden infant death syndrome. We examined the occurrence of CAV3 mutations in a large cohort of patients with LQTS.
Methods and Results— Probands with LQTS (n=167) were screened for mutations in CAV3 using direct DNA sequencing. A single proband (0.6%) was found to be a heterozygous carrier of a previously described missense mutation, caveolin-3:p.T78M. The proband was also a heterozygous carrier of the trafficking-deficient Kv11.1:p.I400N mutation. The caveolin-3:p.T78M mutation was found isolated in 3 family members, none of whom had a prolonged QTc interval. Coimmunoprecipitations of caveolin-3 and the voltage-gated potassium channel subunit (Kv11.1) were performed, and the electrophysiological classification of the Kv11.1 mutant was carried out by patch-clamp technique in human embryonic kidney 293 cells. Furthermore, the T-wave morphology was assessed in mutation carriers, double mutation carriers, and nonmutation carriers by applying a morphology combination score. The morphology combination score was normal for isolated caveolin-3:p.T78M carriers and of LQT2 type in double heterozygotes.
Conclusions— Mutations in CAV3 are rare in LQTS. Furthermore, caveolin-3:p.T78M did not exhibit a LQTS phenotype. Because no association has ever been found between LQTS and isolated CAV3 mutations, we suggest that LQTS9 is considered a provisional entity.
St George's, University of London1, University of Wisconsin-Madison2, University of Cambridge3, Ludwig Maximilian University of Munich4, Center for Drug Evaluation and Research5, Food and Drug Administration6, Takeda Pharmaceutical Company7, University of Liverpool8, Vanderbilt University Medical Center9
TL;DR: The consensus phenotype definition for the relatively rare but potentially life-threatening ADR of drug-induced torsades de pointes (DITdP), the syndrome of polymorphic ventricular tachycardia (VT) associated with QT-interval prolongation and T-wave abnormalities is described.
Abstract: Serious adverse drug reactions (ADRs) represent an important problem for clinicians and for the drug development process. Since these are rare, case series for the analysis of risk are generally accrued across multiple institutions. Thus, a key step in this process is the development of standard phenotype definitions. To facilitate this, the International Severe Adverse Event Consortium (iSAEC) has initiated a phenotype standardization project to improve case ascertainment of different types of serious ADRs.1 For each ADR phenotype, a group of investigators with expertise in relevant disciplines (clinical and basic science; regulatory affairs) was convened to develop, in a pragmatic fashion, a standardized case definition with the goal of enhancing the recruitment and usability of data sets for future genomic analysis.
This manuscript describes the consensus phenotype definition for the relatively rare but potentially life-threatening ADR of drug-induced torsades de pointes (DITdP), the syndrome of polymorphic ventricular tachycardia (VT) associated with QT-interval prolongation and T-wave abnormalities. Torsades de pointes (TdP) may be self-limited arrhythmia or progress to ventricular fibrillation (VF) and cardiac arrest. It is most often caused by the use of QT-prolonging anti-arrhythmic drugs (e.g. quinidine, sotalol, dofetilide, and ibutilide),2,3 but can also occur with a wide variety of non-cardiovascular drugs including antibiotics/anti-infectives (erythromycin, clarithromycin, pentamidine), antipsychotics (thioridazine, haloperidol), and antihistamines (terfenadine, astemizole).2,3 A comprehensive list of drugs with a known or potential risk for TdP is maintained at www.QTdrugs.org. Approximately 1–5% of patients treated with QT-prolonging anti-arrhythmic drugs will develop TdP.2,3 The overall incidence of DITdP with ‘non-cardiovascular’ drugs, however, seems much smaller and has not been accurately determined due in part to the fact that most cases reported are not well characterized or are mainly derived from epidemiological and post-marketing surveillance studies4 and therefore have …
TL;DR: ER with horizontal/descending ST-segment morphology in the inferior or inferolateral leads that persists during exercise is more common in patients with prior unexplained syncope and may identify patients at higher risk of arrhythmic events.
TL;DR: This review highlights the current state-of-the-art therapies and their controversies of Brugada syndrome, with a lack of drug therapy and high complication rates from implantable cardioverter defibrillators.
Abstract: More than 20 years have passed since the description of Brugada syndrome as a clinical entity. The original case series depicted patients who all had coved ST-segment elevation in the right precordial leads, associated with a high risk of sudden death and no apparent structural heart disease. As subsequent registry data were published, it became apparent that the spectrum of risk is wide, with the majority of patients classified as low risk. Two consensus documents have been published that will continue to be updated. Despite intense research efforts, many controversies still exist over its pathophysiology and the risk stratification for sudden death. Management continues to be challenging with a lack of drug therapy and high complication rates from implantable cardioverter defibrillators. In this review, we highlight the current state-of-the-art therapies and their controversies.
TL;DR: Tasha E Fingerlin, Elissa Murphy, Weiming Zhang, Anna L Peljto, Kevin K Brown, Mark P Steele, James E Loyd, Gregory P Cosgrove, David Lynch, Steve Groshong, Harold R Collard, Paul J Wolters, Williamson Z Bradford, Karl Kossen, Scott D Seiwert, Roland M du Bois, Christine Kim Garcia, Megan S Devine, Gunnar Gudmundsson.
Abstract: Tasha E Fingerlin, Elissa Murphy, Weiming Zhang, Anna L Peljto, Kevin K Brown, Mark P Steele, James E Loyd, Gregory P Cosgrove, David Lynch, Steve Groshong, Harold R Collard, Paul J Wolters, Williamson Z Bradford, Karl Kossen, Scott D Seiwert, Roland M du Bois, Christine Kim Garcia, Megan S Devine, Gunnar Gudmundsson, Helgi J Isaksson, Naftali Kaminski, Yingze Zhang, Kevin F Gibson, Lisa H Lancaster, Joy D Cogan, Wendi R Mason, Toby M Maher, Philip L Molyneaux, Athol U Wells, Miriam F Moffatt, Moises Selman, Annie Pardo, Dong Soon Kim, James D Crapo, Barry J Make, Elizabeth A Regan, Dinesha S Walek, Jerry J Daniel, Yoichiro Kamatani, Diana Zelenika, Keith Smith, David McKean, Brent S Pedersen, Janet Talbert, Raven N Kidd, Cheryl R Markin, Kenneth B Beckman, Mark Lathrop, Marvin I Schwarz & David A Schwartz Nat. Genet. 45, 613–620 (2013); published online 14 April 2013; corrected after print 1 October 2013
01 Jan 2013
TL;DR: The current knowledge on the genetics of Brugada syndrome is summarized, focusing on SCN5A, and its use as a biomarker for diagnosis, prognosis and treatment is discussed.
Abstract: Brugada syndrome is an inherited arrhythmia syndrome predisposing to sudden cardiac death. Six years after its initial description as a clinical entity, the first mutations in SCN5A encoding the cardiac sodium channel Nav1.5 were reported. Over 300 mutations in SCN5A have since been described in addition to mutations in genes encoding Nav1.5 auxiliary units, potassium and calcium channels. This review summarizes the current knowledge on the genetics of Brugada syndrome, focusing on SCN5A, and discusses its use as a biomarker for diagnosis, prognosis and treatment.
TL;DR: The complex nature of familial cardiomyopathies is incompletely understood, and recent data suggests that some patients may have more than one mutation or variant contributing to disease.
Abstract: The complex nature of familial cardiomyopathies is incompletely understood. The effective management of patients and their relatives therefore requires a multidisciplinary approach involving a specialist genetic counselling service. Genetic testing is clinically available, and our knowledge in this area continues to grow with developments in new technologies. Many of the genes associated are not specific to a particular type of cardiomyopathy, and recent data suggests that some patients may have more than one mutation or variant contributing to disease. Developments in next generation sequencing have enabled us to accurately and efficiently sequence these areas of interest, but the current capacity to analyse and interpret this data (bioinformatics) remains a major limitation. Genetic guided therapies have the potential to revolutionise our management of affected patients in the future but this is far from being a clinical reality at the current time.
TL;DR: Family-based cardiac screening in relatives of victims of sudden arrhythmic death syndrome and the experience at a single tertiary referral centre in the Republic of Ireland of familial evaluation following SADS-death is reported.
Abstract: This editorial refers to ‘Family-based cardiac screening in relatives of victims of sudden arrhythmic death syndrome’ by C. McGorrian et al ., on page 1050.
Sudden arrhythmic death syndrome (SADS) defines a sudden unexpected death that remains unexplained after comprehensive postmortem examination, histology, and toxicology studies. It accounts for up to 500 deaths in the UK every year, corresponding to an annual incidence of 1.34/100 000 population.1,2 International estimates vary partly due to different populations and inclusion criteria. The incidence of SADS in other Caucasian populations ranges from 0.81/100 000 (Danish) to 1.2/100 000 (USA). South-east Asia demonstrates the highest annual incidence of unexplained sudden death with 38 per 100 000 men.3
A significant proportion of SADS cases have been demonstrated to be due to inherited channelopathies and cardiomyopathies. These have been identified through studies on familial cardiological evaluation and/or the mutation analysis of SADS victims' DNA, the ‘molecular autopsy’, and have laid the groundwork for much of our current clinical practice.4–8
In this issue of the Journal , McGorrian et al .9 report on their experience at a single tertiary referral centre in the Republic of Ireland of familial evaluation following SADS-death. They studied 262 relatives from 73 families over 4 years from 2007 to 2011 and employed a standard screening protocol similar to that reported by our group in 2008; beginning with a review of clinical and family history followed by first-line investigations consisting a 12-lead electrocardiogram (ECG), 24 h Holter monitor, exercise stress test, and echocardiogram. Further testing with a signal-averaged ECG, cardiac magnetic resonance imaging, and ajmaline provocation were performed if deemed necessary.4
They identified an inheritable cardiac condition in 36 relatives (13.7%), leading to diagnoses in 22 families—representing a yield of 30.1% from the family screening. Channelopathies …
TL;DR: It is indicated that common genetic variation may have a strong impact on predisposition to BrS and a new gene involved in the pathogenesis of the disease is identified.
Patent•
11 Dec 2013
TL;DR: In this article, an electrocardiography apparatus and method based on using bipolar chest leads showing the difference in potential between a precordial electrode and a limb electrode of a standard 12-lead ECG arrangement was provided.
Abstract: There is provided an electrocardiography apparatus and method based on using bipolar chest leads showing the difference in potential between a precordial electrode and a limb electrode of a standard 12-lead electrocardiography arrangement.