Ramon Brugada

HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)

Michael J. Ackerman, MD, PhD, Silvia G. Priori, MD, PhD, Stephan Willems, MD, PhD, Charles Berul, MD, FHRS, CCDS, Ramon Brugada, MD, PhD, Hugh Calkins, MD, FHRS, CCDS, A. John Camm, MD, FHRS, Patrick T. Ellinor, MD, PhD, Michael Gollob, MD, Robert Hamilton, MD, CCDS, Ray E. Hershberger, MD, Daniel P. Judge, MD, Hervè Le Marec, MD, William J. McKenna, MD, Eric Schulze-Bahr, MD, PhD, Chris Semsarian, MBBS, PhD, Jeffrey A. Towbin, MD, Hugh Watkins, MD, PhD, Arthur Wilde, MD, PhD, Christian Wolpert, MD, Douglas P. Zipes, MD, FHRS

HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies

This international consensus statement provides the state of genetic testing for the channelopathies and cardiomyopathies. 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 use and role of genetic testing for these potentially heritable cardiac conditions. This document focuses primarily on the state of genetic testing for the 13 distinct entities detailed and the relative diagnostic, prognostic, and therapeutic impact of the genetic test result for each entity. It does not focus on the therapeutic management of the various channelopathies and cardiomyopathies. Treatment/management issues are only discussed for those diseases (i.e., LQTS, HCM, DCM + CCD, RCM) in which the genetic test result could potentially influence treatment considerations.nnWriting recommendations for genetic diseases require adaptation of the methodology normally adopted to prepare guidelines for clinical practice. Documents produced by other scientific societies have acknowledged the need to define the criteria used to rank the strength of recommendation for genetic diseases.1nnThe most obvious difference is that randomized and/or blinded studies do not exist. Instead, most of the available data are derived from registries that have followed patients and recorded outcome information. The authors of this statement have therefore defined specific criteria for Class I, Class IIa or b, and Class III recommendations and have used the conventional language adopted by AHA/ACC/ESC Guidelines to express each class. All recommendations are level of evidence (LOE) C (i.e., based on experts opinions).nnA Class I recommendation ( “is recommended” ) was applied for genetic testing in index cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a genetic test is high (likelihood of positive result >40% and signal/noise ratio >10; Tablexa03), AND/OR when …

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

BACKGROUNDnBrugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.nnnOBJECTIVEnThis study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.nnnMETHODSnMutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.nnnRESULTSnA total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.nnnCONCLUSIONnThis international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.

Síndrome de Brugada

El sindrome de Brugada, descrito por primera vez en 1992, se caracteriza por un patron electrocardiografico caracteristico en precordiales derechas y la predisposicion a presentar arritmias ventriculares y muerte subita. El sindrome de Brugada se incluye entre las canalopatias, trastornos electricos primarios que caracteristicamente no asocian cardiopatia estructural concomitante. En los ultimos anos, gracias a una intensa labor cientifica tanto basica como clinica, hemos podido identificar multiples mutaciones causales, y asimismo comprender cuales son los mecanismos implicados en la aparicion del fenotipo caracteristico y los determinantes del pronostico clinico en los pacientes. Sin embargo, todavia persisten multiples preguntas sin resolver que mantienen activa la investigacion sobre el tema. Este articulo revisa nuestro conocimiento actual sobre el sindrome de Brugada y trata de recoger los principales estudios basicos y clinicos que han contribuido mas significativamente a avanzar en nuestra comprension de esta enfermedad.

Number of electrocardiogram leads displaying the diagnostic coved-type pattern in Brugada syndrome: a diagnostic consensus criterion to be revised

AIMSnAccording to the diagnostic consensus criteria, the electrocardiographic (ECG) diagnosis of Brugada syndrome requires coved-type > or =2 mm ST-segment elevation in >1 right precordial lead (RPL) V1-V3 in the presence or absence of a sodium-channel blocker. However, this consensus has not been evaluated. We aimed to assess the distribution of coved-type ST-segment elevation on RPLs in a large patient cohort to reevaluate the appropriateness of the diagnostic consensus criteria.nnnMETHODS AND RESULTSnWe included 186 individuals with spontaneous and/or drug-induced ECGs of coved-type > or =2 mm ST-segment elevation in at least one RPL. A total of 376 ECGs were analysed for the number, distribution and maximal J-point elevation of diagnostic RPLs. Among all ECGs, 27 (7%) showed a coved-type pattern in 3 RPLs, 205 (55%) in 2 RPLs, and 144 (38%) in only 1 RPL. Leads V1 and V2 were diagnostic in 99% of all ECGs with two diagnostic RPLs. Lead V3 alone was not diagnostic in any ECG. Maximal J-point elevation was significantly higher in lead V2 than V1. Sixty case subjects (32%) had only ECGs with one RPL displaying a coved-type ST-segment elevation. There was no significant difference in clinical presentation and outcome compared with the 126 Brugada patients with ECGs displaying >1 diagnostic RPL. Major arrhythmic events occurred with the same rate (8%) in both groups during a follow-up >5 years.nnnCONCLUSIONnLead V3 does not yield diagnostic information in Brugada syndrome. Individuals with ECGs displaying only one diagnostic RPL have a similar clinical profile and arrhythmic risk as Brugada patients with ECGs displaying >1 diagnostic RPL. Revision of the consensus criteria should be considered.

Heart rate variability analysis indicates preictal parasympathetic overdrive preceding seizure‐induced cardiac dysrhythmias leading to sudden unexpected death in a patient with epilepsy

Evidence for seizure‐induced cardiac dysrhythmia leading to sudden unexpected death in epilepsy (SUDEP) has been elusive. We present a patient with focal cortical dysplasia who has had epilepsy for 19 years and was undergoing presurgical evaluation. The patient did not have any cardiologic antecedents. During long‐term video–electroencephalography (EEG) monitoring, following a cluster of secondarily generalized tonic–clonic seizures (GTCS), the patient had prolonged postictal generalized EEG suppression, asystole, followed by arrhythmia, and the patient died despite cardiopulmonary resuscitation. Analysis of heart rate variability showed a marked increase in the parasympathetic activity during the period preceding the fatal seizures, compared with values measured 1 day and 7 months before, and also higher than the preictal values in a group of 10 patients with GTCS without SUDEP. The duration of the QTc interval was short (335–358 msec). This unfortunate case documented during video‐EEG monitoring indicates that autonomic imbalance and seizure‐induced cardiac dysrhythmias contribute to the pathomechanisms leading to SUDEP in patients at risk (short QT interval).

Genetics of arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a rare clinical entity characterised by fibro-fatty replacement of myocardium, mainly involving right ventricular free wall, leading to malignant electrical instability and sudden cardiac death. The disease is inherited in up to 50% of cases, with incomplete penetrance and variable phenotypic expression. To date, more than 300 pathogenic mutations have been identified in 12 genes, mainly with autosomal dominant inheritance. Here, we focus on recent advances in the genetics of arrhythmogenic right ventricular cardiomyopathy. Despite continuous improvements, current genotype–phenotype studies have not contributed yet to establish a genetic risk stratification of the disease.

New electrocardiographic criteria to differentiate the Type-2 Brugada pattern from electrocardiogram of healthy athletes with r'-wave in leads V1/V2.

AIMSnDiagnosis of Type-2 Brugada pattern remains challenging and it could be confused with other electrocardiogram (ECG) patterns presenting an r-wave in leads V1-V2 like in healthy athletes. This could impact their ability to perform competitive sports. The aim of the study was to evaluate, as a proof of concept, the new ECG criteria to differentiate the Type-2 Brugada pattern from the ECG pattern of healthy athletes depicting an r-wave in leads V1-V2.nnnMETHODS AND RESULTSnSurface ECGs from 50 patients with Brugada syndrome and type-2 Brugada pattern and 58 healthy athletes with an r-wave in leads V1-V2 were analysed. Different criteria based on the characteristics of the triangle formed by the ascendant and descendant arms of the r-wave in leads V1-V2 were compared. The duration of the base of the triangle at 0.5 mV (5 mm) from high take-off ≥160 ms (4 mm) has a specificity (SP) of 95.6%, sensitivity (SE) 85%, positive predictive value (PPV) 94.4%, and negative predictive value (NPV) 87.9%. The duration of the base of the triangle at the isoelectric line ≥60 ms (1.5 mm) in leads V1-V2 has an SP of 78%, SE 94.8%, PPV 79.3%, and NPV 93.5%. The ratio of the base at isoelectric line/height from the baseline to peak of r-wave in leads V1-V2 has an SP of 92.1%, SE 82%, PPV 90.1%, and NPV 83.3%.nnnCONCLUSIONSnThe three new ECG criteria were accurate to distinguish the Type-2 Brugada pattern from the ECG pattern with an r-wave in healthy athletes. The duration of the base of the triangle at 0.5 mV from the high take-off is the easiest to measure and may be used in clinical practice.

Negative autopsy and sudden cardiac death.

Forensic medicine defines the unexplained sudden death as a death with a non-conclusive diagnosis after autopsy. Molecular diagnosis is being progressively incorporated in forensics, mainly due to improvement in genetics. New genetic technologies may help to identify the genetic cause of death, despite clinical interpretation of genetic data remains the current challenge. The identification of an inheritable defect responsible for arrhythmogenic syndromes could help to adopt preventive measures in family members, many of them asymptomatic but at risk of sudden death. This multidisciplinary translational research requires a specialized team.

Sarcomeric gene mutations in sudden infant death syndrome (SIDS).

In developed countries, sudden infant death syndrome (SIDS) represents the most prevalent cause of death in children between 1 month and 1 year of age. SIDS is a diagnosis of exclusion, a negative autopsy which requires the absence of structural organ disease. Although investigators have confirmed that a significant percentage of SIDS cases are actually channelopathies, no data have been made available as to whether other sudden cardiac death-associated diseases, such as hypertrophic cardiomyopathy (HCM), could be responsible for some cases of SIDS. The presence of a genetic mutation in the sarcomeric protein usually affects the force of contraction of the myocyte, whose weakness is compensated with progressive hypertrophy and disarray. However, it is unclear whether in the most incipient forms, that is, first years of life, the lack of these phenotypes still confers a risk of arrhythmogenesis. The main goal of the present study is to wonder whether genetic defects in the sarcomeric proteins, previously associated with HCM, could be responsible for SIDS. We have analysed 286 SIDS cases for the most common genes implicated in HCM in adults. A total of 680 mutations localised in 16 genes were analysed by semi-automated matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDITOF-MS) using the Sequenom MassARRAY(®) System. Ten subjects with completely normal hearts showed mutated alleles at nine of the genetic variants analysed, and one additional novel mutation was detected by conventional sequencing. Therefore, a genetic mutation associated with HCM may cause sudden cardiac death in the absence of an identifiable phenotype.