Inheritable Arrhythmia Research Articles

Multisite Validation of a Functional Assay to Adjudicate SCN5A Brugada Syndrome-Associated Variants.

Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification. An in vitro SCN5A-Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function. Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic. This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.

A case involving tooth extraction of upper and lower third molars under general anesthesia in a patient with catecholaminergic polymorphic ventricular tachycardia

AbstractBackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT), an inheritable arrhythmia, poses a grave risk of syncope or cardiac arrest.Case PresentationA 23‐year‐old female with CPVT history and implantable cardioverter‐defibrillator (ICD) implantation sought tooth extraction of her third molars. She underwent the procedure under general anesthesia to mitigate VT risk. Defibrillation function was temporarily halted during anesthesia induction, managed with total intravenous anesthesia. The postoperative course remained uneventful, obviating defibrillation intervention.ConclusionsThis case underscores the efficacy of general anesthesia in averting VT onset during oral surgery for CPVT patients, ensuring a safe and uneventful postoperative recovery.

Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes.

Advances in next-generation sequencing have been exceptionally valuable for identifying variants in medically actionable genes. However, for most missense variants there is insufficient evidence to permit definitive classification of variants as benign or pathogenic. To overcome the deluge of Variants of Uncertain Significance, there is an urgent need for high throughput functional assays to assist with the classification of variants. Advances in parallel planar patch clamp technologies has enabled the development of automated high throughput platforms capable of increasing throughput 10- to 100-fold compared to manual patch clamp methods. Automated patch clamp electrophysiology is poised to revolutionize the field of functional genomics for inheritable cardiac ion channelopathies. In this review, we outline i) the evolution of patch clamping, ii) the development of high-throughput automated patch clamp assays to assess cardiac ion channel variants, iii) clinical application of these assays and iv) where the field is heading.

PO-01-048 FACTORS INFLUENCING SUBCUTANEOUS IMPLANTABLE CARDIOVERTER DEFIBRILLATOR SCREENING SUCCESS IN PAEDIATRIC POPULATION: A TERTIARY HOSPITAL EXPERIENCE

Implantable cardioverter defibrillators (ICD), used to reduce risk from life threatening ventricular arrhythmia, are important treatments. Subcutaneous ICD (SICD) offers a lower risk of endocarditis, lead fracture and vascular complication. Screening is essential to identify the appropriate candidates and reduce inappropriate shocks, however there are limited data available in the paediatric population. To assess the incidence and associated characteristics of SICD screen failure, and the incidence of inappropriate shocks in a paediatric population. All patients screened for SICD from June 2016 to November 2022 were included. Screening failures were identified from supine, standing and exercise in both left and right sternal positions. Those who passed at least two vectors in all conditions were offered an SICD. The incidence of inappropriate shocks on follow up was assessed. From 74 screened patients (baseline characteristics Table 1), 58 (78%) passed supine and standing and 51(69%) on exercise screening. 59 (67%) had Hypertrophic Cardiomyopathy (HCM), 17 (23%) Inherited arrhythmias (IA) and 8 (11%) Other Cardiomyopathies (OC). Overall, 60(81%) had a primary prevention indication. Of the 45 (61%) who passed screening on the left supine, all passed when standing and 43 (96%) passed on exercise. Those screened on the right, 18 (55%) passed supine, 16(88%) of these passed standing and 14(87%) passed on exercise. Those that failed were younger and had HCM (passed vs failed, age 14±2.6 vs 12±3.7, p=0.009, HCM 56% vs 87%, p=0.008). IA patients were more likely to pass (pass vs failed, 35% vs 8%, p=0.02). Weight, height and BMI did not impact on the failure rate (Table 1). Overall, 40 (78%) had an SICD implanted with a mean follow up 21±15 months. Four patients had inappropriate shocks; One for air in the header and three for T wave oversensing. Those who had T wave oversensing had left sided lead implants, two had HCM and one had AI. In this population the screen failure rate for SICD was high, particularly in younger patients with HCM. The addition of exercise further excluded patients however, the number was small. There was no link between weight, height and BMI and screen failure. The incidence of inappropriate shocks was low.Tabled 1Table 1 – Characteristics of patients who passed and failed Subcutaneous Internal Cardioverter Defibrillator ScreeningCharacteristicsPassed (n=51)Failed (n=23)p-valueAge, years mean (SD)14 ± 2.612 ±3.7p=0.009Sex F(%)17 (34)6 (26)p=0.6Weight kg, mean (SD)57 ±16.953 ±(22)p=0.34Height cm mean (SD)156 ±29.6155 ±17.8p=0.88BMI kg/m2 mean (SD)23 ± 10.421 ± 5.5p=0.39HCM n (%)29 (56)20 (87)p=0.008Inherited n (%)15 (29)2 (8)p=0.02Other Cardiomyopathy n (%)7 (14)1 (4)p=0.26 Open table in a new tab

Human-induced pluripotent stem cell-derived cardiomyocytes to study PUFA analogues as a potential treatment of long QT syndrome.

Long QT syndrome (LQTS) is an inheritable ventricular arrhythmia that predisposes patients to torsades de pointes and sudden cardiac death. Mutations in voltage-gated ion channels (VGC) and their regulatory β subunits involved in the cardiac action potential (AP) generate LQTS by prolonging the QT interval of the electrocardiogram. 15 types of LQTS has been described depending on the underlying gene mutated. LQT1 and LQT5 are described as loss-of-function mutations in genes that encode Kv7.1 (alpha pore-forming subunit) and its β-regulatory subunit KCNE1, respectively. Kv7.1/KCNE1 channels elicit one of the main repolarization currents (IKs) involved in the cardiac AP. Therefore, Kv7.1/KCNE1 channel-specific activators might be a potential treatment for LQTS. Polyunsaturated fatty acid (PUFA) analogues can broadly modulate cardiac VGC when applied on isolated channels in a heterologous system. In the present study, we measured the effects of these four compounds, Linoleoyl-taurine (LIN-Tau), docosahexaenoyl-Tau (DHA-Tau), Linoleoyl-Glycine (LIN-Gly), and DHA-Gly, on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). DHA-analogues shortened the hiPSC-CMs AP duration (APD), while LIN-analogues prolonged hiPSC-CMs APD. DHA-analogues were also tested in isogenic hiPSC-CMs lines for two KCNQ1 (Kv7.1 gene) mutations that cause LQT1, R190Q, and G269S. R190Q is an autosomal dominant missense mutation characterized by a 70-80 % reduction of IKs because of a dominant negative traffic defect. Moreover, we also analyzed DHA-analogues in a heterozygous missense KCNQ1 mutation, G269S. G269S mutation shows a net effect of less than 50% reduction of IKs current (haploinsufficiency). We here use a combination of hiPSC-CM monolayers with a high-resolution, all-optical electrophysiology system for screening the anti-arrhythmic properties of diverse PUFA analogues. Moreover, the well-characterized hiPSC-CMs mutants show us whether PUFA analogues might be a potential treatment approach for more than one type of LQT1.

Genetic Profile and Clinical Characteristics of Brugada Syndrome in the Chinese Population.

Brugada syndrome (BrS) is an inheritable arrhythmia syndrome that can lead to sudden cardiac death in patients while the heart structure is normal. However, the genetic background of more than 65% of BrS probands remains unclear. The purpose of this study is to report the variant spectrum in a Chinese cohort with suspected BrS and to analyze their distinct clinical and electrocardiographic features. Patients with suspected BrS from Tongji Hospital between 2008 and 2021 were analyzed retrospectively. A total of 79 probands were included in this study. Patients with type 1 BrS electrocardiogram (ECG) had a prolonged QRS duration compared to patients with type 2/3 BrS ECG. Of them, 59 probands underwent genetic testing. Twenty-five patients (42.37%) showed abnormal genetic testing results, and eight of them (13.56%) carried pathogenic/likely pathogenic (P/LP) mutations. Mutation carriers presented much more prominent depolarization and repolarization abnormalities than non-carriers, including a prolonged P-wave duration, QRS duration, QTc interval, decreased QRS amplitude, and deviation of the electrocardiographic axes (T-wave axis and R-wave axis). Furthermore, our study identified four novel P/LP mutations: Q3508X in TTN, A990G in KCNH2, G1220E, and D372H (in a representative pedigree) in SCN5A. Our study showed the variant spectrum of a suspected Chinese BrS cohort, and we identified four novel P/LP mutations in TTN, KCNH2, and SCN5A.

The SIDECAR project: S-IcD registry in European paediatriC and young Adult patients with congenital heaRt defects.

Subcutaneous-implantable cardiac defibrillators (S-ICDs) are used increasingly to prevent sudden cardiac death in young patients. This study was set up to gain insight in the indications for S-ICD, possible complications, and their predictors and follow-up results. A multicentre, observational, retrospective, non-randomized, standard-of-care registry on S-ICD outcome in young patients with congenital heart diseases (CHDs), inherited arrhythmias (IAs), idiopathic ventricular fibrillation (IVF), and cardiomyopathies (CMPs). Anthropometry was registered as well as implantation technique, mid-term device-related complications, and incidence of appropriate/inappropriate shocks (IASs). Data are reported as median (interquartile range) or mean ± standard deviation. Eighty-one patients (47% CMPs, 20% CHD, 21% IVF, and 12% IA), aged 15 (14-17) years, with body mass index (BMI) 21.8 ± 3.8 kg/m2, underwent S-ICD implantation (primary prevention in 59%). This was performed with two-incision technique in 81% and with a subcutaneous pocket in 59%. Shock and conditional zones were programmed at 250 (200-250) and 210 (180-240) b.p.m., respectively. No intraoperative complications occurred. Follow up was 19 (6-35) months: no defibrillation failure occurred, 17% of patients received appropriate shocks, 13% of patients received IAS (supraventricular tachycardias 40%, T-wave oversensing 40%, and non-cardiac oversensing 20%). Reprogramming, proper drug therapy, and surgical revision avoided further IAS. Complications requiring surgical revision occurred in 9% of patients, with higher risks in patients with three-incision procedures [hazard ratio (HR) 4.3, 95% confidence interval (95% CI) 0.5-34, P = 0.038] and BMI < 20 (HR 5.1, 95% CI 1-24, P = 0.031). This multicentre European paediatric registry showed good S-ICD efficacy and safety in young patients. Newer implantation techniques and BMI > 20 showed better outcome.

Human induce pluripotent stem cell-derived cardiomyocyte model to study PUFA analogs as a potential treatment of long QT syndrome

Long QT syndrome (LQTS) is an inheritable ventricular arrhythmia that predisposes patients to torsades de pointes and sudden cardiac death. Mutations in voltage-gated ion channels and their regulatory β subunits involved in the cardiac action potential (AP) generate LQTS by prolonging the QT interval of the electrocardiogram. 15 types of LQTS (LQT1-15) have been described depending on the underlying gene mutated. The majority of the cases correlate to LQT1-2 which are mutations in voltage-gated potassium channels involved in cardiac AP repolarization.

Inherited Ventricular Arrhythmia in Zebrafish: Genetic Models and Phenotyping Tools.

In the last years, the field of inheritable ventricular arrhythmia disease modelling has changed significantly with a push towards the use of novel cellular cardiomyocyte based models. However, there is a growing need for new in vivo models to study the disease pathology at the tissue and organ level. Zebrafish provide an excellent opportunity for in vivo modelling of inheritable ventricular arrhythmia syndromes due to the remarkable similarity between their cardiac electrophysiology and that of humans. Additionally, many state-of-the-art methods in gene editing and electrophysiological phenotyping are available for zebrafish research. In this review, we give a comprehensive overview of the published zebrafish genetic models for primary electrical disorders and arrhythmogenic cardiomyopathy. We summarise and discuss the strengths and weaknesses of the different technical approaches for the generation of genetically modified zebrafish disease models, as well as the electrophysiological approaches in zebrafish phenotyping. By providing this detailed overview, we aim to draw attention to the potential of the zebrafish model for studying arrhythmia syndromes at the organ level and as a platform for personalised medicine and drug testing.

5206SICD registry in European paediatric and adult patients with congenital heart defects: preliminary results of the SIDECAR project

Abstract Aim Use of the subcutaneous implantable cardioverter-defibrillator (S-ICD) to prevent sudden cardiac death is increasing. Few data exist on S-ICD in young patients. We report preliminary data from a multicenter European registry of paediatric and young adult patients who underwent S-ICD implantation Methods Observational, prospective, non-randomized, standard-of-care study on S-ICD implantation/follow-up in young patients with inherited arrhythmias (IA), cardiomyopathies, and congenital heart defects (CHD). Results 29 patients (12 CHD, 14 Cardiomyopathies, and 3 IA), mean age 17±6 years, 13 of them &lt;18 years, with body mass index (BMI) 23±4, underwent S-ICD implantation (primary prevention 66%). The first 8 patients underwent a three-incision procedure, the following 21 (72%) a two-incision procedure. No intraoperative complications occurred. Over 19 months median follow-up (25th–75th percentiles, 5–37) 5 patients (17%) received appropriate and 2 (7%) inappropriate shocks. Four patients (14%) had device-related complications requiring surgical intervention: three skin erosions at the superior parasternal incision, one pocket infection. A higher risk of complications was seen in patients who underwent standard procedures [hazard ratio (HR) 14.7, 95% confidence interval (CI) 2.34 to 93.03; P=0.001] and those with BMI &lt;20 (HR 11.06, 95% CI 1.01–121.07; P=0.008). Conclusion These preliminary results of a multicenter European paediatric registry suggest that S-ICD is safe and effective with low rates of inappropriate shocks. Improvement of implantation techniques seems associated with better outcome.

First person – Christiaan Veerman

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Christiaan Veerman is first author on ‘Genetic variation in GNB5 causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (IK,Ach)’, published in DMM. Christiaan is a resident in cardiology in the lab of Prof. Bezzina at University of Amsterdam, The Netherlands, investigating pathophysiological mechanisms of inheritable cardiac arrhythmia syndromes using human induced pluripotent stem cells.

Implantable Loop Recorder in Inherited Arrhythmia Diseases

The differential diagnosis between benign syncope common in a young population and life-threatening arrhythmic ones represents a major challenge in the management of patients with inherited arrhythmias (IAs) [(1)][1]. In this population, ventricular arrhythmias can often be hemodynamically tolerated

Subcutaneous implantable cardioverter-defibrillator: is it ready for use in children and young adults? A single-centre study.

Use of the subcutaneous implantable cardioverter-defibrillator (S-ICD) to prevent sudden cardiac death is increasing. Few data exist on S-ICD in young patients. We reviewed our single-centre experience in order to assess the effectiveness and safety of S-ICD implantation, and to identify potential factors associated with complications. Observational, non-randomized, standard-of-care study on S-ICD implantation/follow-up in young patients with inherited arrhythmias (IA), cardiomyopathies, and congenital heart defects (CHD). Fifteen patients (6 CHD, 8 cardiomyopathies, and 1 IA), median age 15 years (25th-75th centiles, 14-28), 10 of them <18 years, with body mass index (BMI) 22.6 ± 3.4, underwent S-ICD implantation (primary prevention 93%). The first six patients underwent a standard implantation procedure (three surgical incisions), the following nine a two-incision procedure. No intraoperative complications occurred. Over 12 (7-24) months follow-up, two patients received appropriate shocks and one (7%) inappropriate shock. Four patients had device-related complications requiring surgical intervention: three skin erosions at the superior parasternal incision, one pocket infection. A higher risk of complications was seen in patients who underwent standard procedures [hazard ratio (HR) 4.98, 95% confidence interval (CI) 1.53-47.36; P = 0.0482] and those with BMI <20 (HR 9.44, 95% CI 0.95-93.23; P = 0.0169). S-ICD implantation was safe and effective in young patients with low rates of inappropriate shock. However, the risk of device-related complications during follow-up remains substantial in patients with low BMI. To prevent possible complications, a two-incision technique should be preferred.

Selecting the right defibrillator in the younger patient: Transvenous, epicardial or subcutaneous?

The advent of the subcutaneous implantable cardioverter-defibrillator (SQ-ICD) provides an alternative to transvenous and epicardial ICD therapy. Particularly germane to the young patient with congenital heart disease or inheritable arrhythmia syndromes, the SQ-ICD may be ideal for those who do not require permanent cardiac pacing. The serious complications associated with transvenous ICD systems are largely driven by the intravascular components of these devices and are avoided by this extravascular technique. Multiple clinical trials have shown that SQ-ICDs are effective in detecting and terminating ventricular arrhythmias, yet nuanced issues must be considered, especially in the context of congenital cardiovascular anomalies. This review aims to contextualize the role of this technology in contrast with traditional ICDs, and provide a logical approach to appropriate device selection.

Brugada syndrome genetic testing: A reliable sanger sequencing protocol

The Brugada syndrome (BrS) is a potentially lethal, inheritable arrhythmia syndrome affecting about 5 in 10,000 people worldwide. This cardiac disorder, triggered by mutations in SCN5A gene (encoding for cardiac sodium channels), results in changes in the onset or propagation of cardiac action potential that can generate arrhythmias, potentially fatal. In the last few years, the genetic studies are performed with next generation sequencing (NGS), obtaining global genomic information. However, this strategy requires capillary electrophoresis data validations. In this study, we developed and optimized a Sanger sequencing workflow for SCN5A gene exons.

Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome

BackgroundShort QT syndrome (SQTS) is a rare inheritable arrhythmia, associated with atrial and ventricular fibrillations, caused by mutations in six cardiac ion channel genes with high penetrance. However, genotype-specific clinical differences between SQTS patients remain to be elucidated. Methods and resultsWe screened five unrelated Japanese SQTS families, and identified three mutations in KCNH2 and KCNQ1. A novel mutation KCNH2-I560T, when expressed in COS-7 cells, showed a 2.5-fold increase in peak current density, and a positive shift (+14mV) of the inactivation curve compared with wild type. Computer simulations recapitulated the action potential shortening and created an arrhythmogenic substrate for ventricular fibrillation. In another family carrying the mutation KCNQ1-V141M, affected members showed earlier onset of manifestation and frequent complications of bradyarrhythmia. To determine genotype-specific phenotypes in SQT1 (KCNH2), SQT2 (KCNQ1), and other subtypes SQT3–6, we analyzed clinical variables in 65 mutation-positive patients among all the 132 SQTS cases previously reported. The age of manifestation was significantly later in SQT1 (SQT1: 35±19years, n=30; SQT2: 17±25years, n=8, SQT3–6: 19±15years, n=15; p=0.011). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75%; non-SQT2: 5/57, 9%; p<0.001) and atrial fibrillation (SQT2: 5/8, 63%; non-SQT2: 12/57, 21%; p=0.012). Of 51 mutation-positive individuals from 16 SQTS families, nine did not manifest short QT, but exhibited other ECG abnormalities such as atrial fibrillation. The resulting penetrance, 82%, was lower than previously recognized. ConclusionWe propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype.

HCN4, Sinus Bradycardia and Atrial Fibrillation.

Based on their established role in the generation of spontaneous activity in pacemaker cells and control of cardiac rate, funny/ hyperpolarisation-activated, cyclic nucleotide gated 4 (HCN4) channels are natural candidates in the search for causes of sinus arrhythmias. Investigation of funny current-related inheritable arrhythmias has led to the identification of several mutations of the HCN4 gene associated with bradycardia and/or more complex arrhythmias. More recently, the search has been extended to include auxiliary proteins such as the minK-related peptide 1 (MiRP1) β-subunit. All mutations described so far are loss-of-function and in agreement with the role of funny channels, the predominant type of arrhythmia found is bradycardia. Funny channel-linked arrhythmias, however, also include atrioventricular (AV) block and atrial fibrillation, in agreement with an emerging new concept according to which defective funny channels have a still unexplored role in impairing AV conduction and triggering atrial fibrillation. Also, importantly, recent work shows that HCN4 mutations can be associated with cardiac structural abnormalities. In this short review I briefly address the current knowledge of funny/HCN4 channel mutations and associated sinus and more complex arrhythmias.

HCN4, Sinus Bradycardia and Atrial Fibrillation

Based on their established role in the generation of spontaneous activity in pacemaker cells and control of cardiac rate, funny/hyperpolarisation-activated, cyclic nucleotide gated 4 (HCN4) channels are natural candidates in the search for causes of sinus arrhythmias. Investigation of funny current-related inheritable arrhythmias has led to the identification of several mutations of the HCN4 gene associated with bradycardia and/or more complex arrhythmias. More recently, the search has been extended to include auxiliary proteins such as the minK-related peptide 1 (MiRP1) β-subunit. All mutations described so far are loss-of-function and in agreement with the role of funny channels, the predominant type of arrhythmia found is bradycardia. Funny channel-linked arrhythmias, however, also include atrioventricular (AV) block and atrial fibrillation, in agreement with an emerging new concept according to which defective funny channels have a still unexplored role in impairing AV conduction and triggering atrial fibrillation. Also, importantly, recent work shows that HCN4 mutations can be associated with cardiac structural abnormalities. In this short review I briefly address the current knowledge of funny/HCN4 channel mutations and associated sinus and more complex arrhythmias.

Recent advances in the understanding and management of long QT syndrome.

The sudden death of a previously healthy young individual is a dreadful occurrence. Identifying those at risk of such a dire outcome, and appropriately managing and counseling them, has been an ongoing challenge, but rapid advances are being made. This review will focus on the long QT syndrome (LQTS), the most common of the potentially lethal inheritable arrhythmias, with specific focus on the genetics relevant to clinical presentation, therapy and response. The past 2 decades have seen tremendous progress in the field of inheritable arrhythmias. Emphasis is given to risk stratification, screening of family members, and the counseling of young athletes, as well as new developments in screening and treatment. For the primary care provider, long QT syndrome should be considered during the evaluation of syncope, near-syncope and seizures, especially in the setting of exercise or with a family history of sudden unexplained death in a first-degree relative. The corrected QT interval (QTc) should be assessed as a routine when obtaining electrocardiograms. If there are concerns on the basis of electrocardiogram findings, medical history or family history, referral to a cardiologist is indicated. Providers need to be cognizant of the challenges of therapy and lifestyle changes for patients and families with long QT syndrome.

Are we able to predict the diagnosis of Brugada syndrome?

This editorial refers to ‘New electrocardiographic criteria to differentiate type 2 Brugada pattern from ECG of healthy athletes with r ′-wave in leads V1/V2’ by Serra et al ., doi:10.1093/europace/euu025. Please let me provide you the answer right away: no, we are not able to predict the diagnosis of Brugada syndrome with 100% certainty … on non-diagnostic electrocardiograms (ECGs). But can we come close? That is the question which Dr Serra together with colleagues from Spain, Canada, Belgium, and Italy asked and wrote about in this issue of the Journal .1 The inheritable arrhythmia syndrome—Brugada syndrome—is characterized on the ECG by a specific coved-type or Type-1 right-precordial J-ST segment and by a propensity for malignant arrhythmias and sudden death. Until recently, this characteristic ECG pattern had to be accompanied by evidence or the suggestion of ventricular arrhythmias and/or familial segregation to make the diagnosis of Brugada syndrome. However, since the latest consensus report2 this prerequisite has been abandoned. With non-diagnostic ECGs in persons in whom the diagnosis is suspected, one may use provocation testing with potent sodium channel blockers (e.g. ajmaline) to confirm or to refute the diagnosis. Treatment is mostly conservative (i.e. avoidance of certain drugs,3 family screening, and long-term follow-up) but may include chronic drug therapy (with quinidine), cardioverter defibrillator implantation, and/or ablation of the arrhythmic substrate. Its prevalence is variable but is about 1 in every 2000 persons4 and its underlying pathophysiological mechanism is disputed but involves depolarization and/or repolarization abnormalities.5 While the Brugada syndrome gained increasing attention since the late 1990s, the number of persons suspected of being affected erupted. It is intuitive that only those persons who have a solid and guideline-approved diagnosis should be regarded as having the Brugada syndrome. However, as we have seen earlier in the long QT syndrome, …