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Aims In patients with Brugada syndrome (BrS) but without spontaneous Type-1 electrocardiogram, several electrocardiographic characteristics have been studied, including the β-angle. Previous studies suggested that the β-angle might be useful in distinguishing BrS-patients from patients with only suggestive repolarization patterns without performing sodium channel blocker provocation testing. In this study, we aimed to determine the diagnostic value of the β-angle in patients suspected of BrS. Methods and results A large cohort (n = 1430) of consecutive patients who underwent provocation testing was evaluated. β-angles were measured in leads V1, V2, and their corresponding positions over the second and third intercostal space. Receiver-operating characteristic curves were constructed and the diagnostic accuracy of previously reported β-angle cut-offs were calculated and evaluated. The importance of the β-angle for predicting the provocation test outcome was determined using a prediction model constructed with logistic regression. The optimum β-angle cut-off in our cohort for ruling out a positive provocation test was 15°; sensitivities were 80–98% and negative predictive values were 79–96% among the right precordial leads. Previously reported β-angle cut-offs performed less well, indicated by lower Youden indices. In the optimism-corrected prediction model [C-statistic: 0.78 (95% CI: 0.75–0.81)], the β-angle had large value (Z-score: 2.1–10.3) and aided construction of a nomogram to predict test outcome. Conclusion To predict the outcome of provocation testing for BrS, the β-angle alone does not demonstrate strong diagnostic characteristics. However, the β-angle is an important variable to predict provocation test outcome and thus has added value.

Brugada syndrome (BrS) is an inherited cardiac disorder, characterised by a typical ECG pattern and an increased risk of arrhythmias and sudden cardiac death (SCD). BrS is a challenging entity, in regard to diagnosis as well as arrhythmia risk prediction and management. Nowadays, asymptomatic patients represent the majority of newly diagnosed patients with BrS, and its incidence is expected to rise due to (genetic) family screening. Progress in our understanding of the genetic and molecular pathophysiology is limited by the absence of a true gold standard, with consensus on its clinical definition changing over time. Nevertheless, novel insights continue to arise from detailed and in-depth studies, including the complex genetic and molecular basis. This includes the increasingly recognised relevance of an underlying structural substrate. Risk stratification in patients with BrS remains challenging, particularly in those who are asymptomatic, but recent studies have demonstrated the potential usefulness of risk scores to identify patients at high risk of arrhythmia and SCD. Development and validation of a model that incorporates clinical and genetic factors, comorbidities, age and gender, and environmental aspects may facilitate improved prediction of disease expressivity and arrhythmia/SCD risk, and potentially guide patient management and therapy. This review provides an update of the diagnosis, pathophysiology and management of BrS, and discusses its future perspectives.

Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype–phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.

Background: Adult long QT syndrome (LQTS) patients have inadequate corrected QT interval (QTc) shortening and an abnormal T-wave response to the sudden heart rate acceleration provoked by standing. In adults, this knowledge can be used to aid an LQTS diagnosis and, possibly, for risk stratification. However, data on the diagnostic value of the standing test in children are currently limited.Objective: To determine the potential value of the standing test to aid LQTS diagnostics in children.Methods: In a prospective cohort including children (≤18 years) who had a standing test, comprehensive analyses were performed including manual and automated QT interval assessments and determination of T-wave morphology changes.Results: We included 47 LQTS children and 86 control children. At baseline, the QTc that identified LQTS children with a 90% sensitivity was 435 ms, which yielded a 65% specificity. A QTc ≥ 490 ms after standing only slightly increased sensitivity (91%, 95% confidence interval [CI]: 80%-98%) and slightly decreased specificity (58%, 95% CI: 47%-70%). Sensitivity increased slightly more when T-wave abnormalities were present (94%, 95% CI: 82%-99%; specificity 53%, 95% CI: 42%-65%). When a baseline QTc ≥ 440 ms was accompanied by a QTc ≥ 490 ms and T-wave abnormalities after standing, sensitivity further increased (96%, 95% CI: 85%-99%) at the expense of a further specificity decrease (41%, 95% CI: 30%-52%). Beat-to-beat analysis showed that 30 seconds after standing, LQTS children had a greater increase in heart rate compared to controls, which was more evidently present in LQTS boys and LQTS type 1 children.Conclusion: In children, the standing test has limited additive diagnostic value for LQTS over a baseline electrocardiogram, while T-wave abnormalities after standing also have limited additional value. The standing test for LQTS should only be used with caution in children.

Failure of drugs and catheter ablation procedures for the treatment of ventricular arrhythmias is still extremely relevant. Recently, stereotactic body radiotherapy has been introduced to treat therapy refractory patients. In this systematic review (International Prospective Register of Systematic Reviews, CRD42019133212), we aimed to summarize electrophysiological and histopathological effects of radioablation in animals, patients, and extracted and perfused hearts. A systematic search was performed in OVID MEDLINE, OVID Embase, the Cochrane Central Register of Controlled Trials, Web of Science, Google Scholar, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) from inception to September 2019. Identified records were independently screened for eligibility by 2 reviewers. Risk of bias and methodological quality were assessed using the SYRCLE, ROBINS-I, or Murad tool and tailored to the different study designs. We included 13 preclinical and 10 clinical publications. Large heterogeneity in study designs prompted a narrative synthesis approach. Baseline, (pre-)procedural details, outcome, target tissue analyses, and safety data were extracted and summarized. In animal studies evaluating electrophysiological parameters, radioablation induced a reduction in voltage/potential amplitude or bidirectional block in target areas in 93.2% of animals. Atrioventricular block (first to third degree) was induced in 78.3% of animals, and in studies evaluating ventricular arrhythmia inducibility, 75% reduction was achieved. In patients, predominantly ventricular tachycardias were targeted with >85% reduction in arrhythmia episodes during follow-up with an encouraging short-term safety profile. Preclinical and clinical evidence on the efficacy and safety of radioablation is limited in both quantity and quality. The results of radioablation for therapy refractory patients with ventricular tachycardia are promising, but further research is needed.

BACKGROUND Diagnosing long QT syndrome (LQTS) remains challenging because of a considerable overlap in QT interval between patients with LQTS and healthy subjects. Characterizing T-wave morphology might improve LQTS diagnosis.OBJECTIVE The purpose of this study was to improve LQTS diagnosis by combining new polynomial-based T-wave morphology parameters with the corrected QT interval (QTc), age, and sex in a model.METHODS A retrospective cohort consisting of 333 patients with LQTS and 345 genotype-negative family members was used in this study. For each patient, a linear combination of the first 2 Hermite-Gauss (HG) polynomials was fitted to the STT segments of an average complex of all precordial leads and limb leads I and II. The weight coefficients as well as the error of the best fit were used to characterize T-wave morphology. Subjects were classified as patients with LQTS or controls by clinical QTc cutoffs and 3 support vector machine models fed with different features. An external cohort consisting of 72 patients and 45 controls was finally used to check the robustness of the models.RESULTS Baseline QTc cutoffs were specific but had low sensitivity in diagnosing LQTS. The model with T-wave morphology features, QTc, age, and sex had the best overall accuracy (84%), followed by a model with QTc, age, and sex (79%). The model with T-wave morphology features especially performed better in LQTS type 3 patients (69%).CONCLUSION T-wave morphologies can be characterized by fitting a linear combination of the first 2 Hermite-Gauss polynomials. Adding T-wave morphology characterization to age, sex, and QTc in a support vector machine model improves LQTS diagnosis.

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Background: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event. Methods: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed. Results: The study group comprised 392 probands: 92 (23.5%) SCN5A+ (44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A−. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (SCN5A− (11.4% versus 3%, P =0.023). The proportion of females was higher among patients with P/LP compared with SCN5A − (18.2% versus 6.3%, P =0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A − (41.9% versus 16.8%, P SCN5A− (87.5% versus 47%, P P P =0.009) were independent variables associated with P/LP genotype following logistic regression. Conclusions: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A− . In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce.Methods and results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy.

Background: Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with sudden onset of ventricular fibrillation of unidentified origin. New diagnostic tools that can detect subtle abnormalities are needed to diagnose and treat patients with an underlying substrate. Objective: The purpose of this study was to explore echocardiographic deformation characteristics in IVF patients. Methods: Echocardiograms were analyzed with deformation imaging by 2-dimensional speckle tracking. Global and regional measurements of the left ventricle (LV) and right ventricle (RV) were performed. Regional LV deformation patterns were evaluated for the presence of postsystolic shortening. Regional RV deformation patterns were classified as type I (normal) or type II/III (abnormal). Results: In total, 47 IVF patients (mean age 45 years; left ventricular ejection fraction [LVEF] 56%) and 47 healthy controls (mean age 41 years; LVEF 60%) were included. IVF patients showed more global deformation abnormalities as indicated by lower LV global longitudinal strain (18.5% ± 2.6% vs 21.6% ± 1.8%; P

Funding Acknowledgements Type of funding sources: None. Introduction An aberrant DPP6 mutation haplotype on chromosome 7 is associated with familial idiopathic ventricular fibrillation in severely affected Dutch families with numerous cases of sudden cardiac death (SCD) So far, no clinical parameters could be linked to predict SCD risk other than this genetic predisposition. In various other cardiac disease, global longitudinal strain (GLS) and mechanical dispersion (MD), both markers of left ventricular (LV) dysfunction, are predictive tools for patients at risk for ventricular arrhythmias (VA) and SCD. The goal of the current study was to investigate whether LV dysfunction, detected by GLS and MD, is present in patients with DPP6 haplotype. Method DPP6 risk-haplotype carriers with sufficient echocardiographic images were included as cases (n = 31, 15 males mean age 41 ± 11 years) and individuals evaluated during cascade screening who were tested but appeared not to be affected as controls (n = 14, 7 males, mean age 39 ± 12 years). Echocardiographic bi-plane ejection fraction (LVEF), GLS and MD of the left ventricular were determined. Results LVEF was similar between DPP6 cases (57.3%) and controls (60.5%, p = 0.07). In contrast, the GLS of the LV (-18.0%) of DPP6 cases was significant lower compared to controls (-21.1%, p Conclusion DPP6 risk- haplotype carriers have similar LVEF, but significant lower LV-GLS and higher mechanical dispersion than controls. These findings can be used for clinical discrimination. Whether these markers can be used for prediction of clinical events has to be determined after a longer follow up. echocardiographic characteristics controls DPP6 p-value LVEF (%) 60.5 57.3 0.07 GLS LV (%) -21.2 -18.0 0.0001 MD ( ms) 26.7 43.4 0.0001

Background Medical castration, gonadotropin-releasing hormone agonists, and antiandrogens have been widely applied as a treatment for prostate cancer. Sex steroid hormones influence cardiac ion channels. However, few studies have examined the proarrhythmic properties of medical castration. Methods and Results This study included 149 patients who underwent medical castration using gonadotropin-releasing hormones with/without antiandrogen for prostate cancer. The changes in the ECG findings during the therapy and associations of the electrocardiographic findings with malignant arrhythmias were studied. The QT and corrected QT (QTc) intervals prolonged during the therapy compared with baseline (QT, 394±32 to 406±39 ms [

Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation and (2) to evaluate its cause, using the insights that could be derived from vectorcardiograms. Hence, from a large cohort of patients who underwent ajmaline provocation testing (n = 1430), we selected patients in whom a type-1 BrS-ECG was evoked (n = 345). Depolarization and repolarization parameters were analyzed for reconstructed vectorcardiograms and were compared between patients with and without a &gt, 30&deg, leftward axis shift. We found (1) that the prevalence of a left axis deviation during provocation testing was 18% and (2) that this left axis deviation was not explained by terminal conduction slowing in the right ventricular outflow tract (4th QRS-loop quartile: +17 &plusmn, 14 ms versus +13 &plusmn, 15 ms, nonsignificant) but was associated with a more proximal conduction slowing (1st QRS-loop quartile: +12[8, 18] ms versus +8[4, 12] ms, p &lt, 0.001 and 3rd QRS-loop quartile: +12 &plusmn, 10 ms versus +5 &plusmn, 7 ms, p &lt, 0.001). There was no important heterogeneity of the action potential morphology (no difference in the ventricular gradient), but a left axis deviation did result in a discordant repolarization (spatial QRS-T angle: 122[59, 147]&deg, versus 44[25, 91]&deg, p &lt, 0.001). Thus, although the development of the type-1 BrS-ECG is characterized by a terminal conduction delay in the right ventricle, BrS-patients with a left axis deviation upon sodium channel blocker provocation have an additional proximal conduction slowing, which is associated with a subsequent discordant repolarization. Whether this has implications for risk stratification is still undetermined.

Background A Brugada syndrome (BrS) diagnosis is made upon documenting its characteristic type-1 ECG abnormality, being either spontaneously present or provoked by drug challenge, in the absence of co-morbidities resulting in similar ECG characteristics. In patients without type-1 ECG but in whom a suspicion of BrS exists, several ECG characteristics have been proposed that could aid in distinguishing BrS from non-BrS, particularly in individuals with incomplete right bundle branch block. Purpose To validate the diagnostic value of ECG characteristics that were previously proposed. Methods For this retrospective study, ECGs were evaluated from consecutive patients suspected of BrS who underwent ajmaline testing (n=1392). Baseline ECG and peak-effect ECG were analyzed with the MEANS software. Parameters considered were P, PR, QRS, S, JT, QT and QTc durations (all in ms), J and S amplitudes (both in mV), and QRS and T axes (both in °). ECG evaluations also included b-angles (in °) and duration of the base of a triangle (DBT) at 0.5 mV from the r' (in ms) in right precordial leads (V1, V2, V1ic3, V2ic3). Results Diagnostic type-1 ECGs were uncovered in 345 subjects and 1047 subjects had a negative test. Patients with BrS had significantly more atrial and ventricular conduction abnormalities (P, PR, QRS, and S duration) at baseline; these differences, except in PR duration, were aggravated upon ajmaline administration. In particular, the b-angle (e.g., V1: 28° [20; 46.5] versus 18° [12; 24], p15°, negative predictive values ranged from 78.6–95.5 and sensitivities ranged from 80–98.1% among different leads. Conclusions Patients with BrS show more baseline ECG abnormalities and display more conduction slowing upon ajmaline infusion. The b-angle and DBT do not demonstrate strong enough diagnostic characteristics to serve as a stand-alone diagnostic tool. Drug provocation tests remain necessary for diagnosing BrS in patients without a spontaneous type-1 ECG. Funding Acknowledgement Type of funding source: None

ObjectivesMajor ECG abnormalities have been associated with increased risk of cardiovascular disease (CVD) burden in asymptomatic populations. However, sex differences in occurrence of major ECG abnormalities have been poorly studied, particularly across ethnic groups. The objectives were to investigate (1) sex differences in the prevalence of major and, as a secondary outcome, minor ECG abnormalities, (2) whether patterns of sex differences varied across ethnic groups, by age and (3) to what extent conventional cardiovascular risk factors contributed to observed sex differences.DesignCross-sectional analysis of population-based study.SettingMulti-ethnic, population-based Healthy Life in an Urban Setting cohort, Amsterdam, the Netherlands.Participants8089 men and 11 369 women of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin aged 18–70 years without CVD.Outcome measuresAge-adjusted and multivariable logistic regression analyses were performed to study sex differences in prevalence of major and, as secondary outcome, minor ECG abnormalities in the overall population, across ethnic groups and by age-groups (18–35, 36–50 and >50 years).ResultsMajor and minor ECG abnormalities were less prevalent in women than men (4.6% vs 6.6% and 23.8% vs 39.8%, respectively). After adjustment for conventional risk factors, sex differences in major abnormalities were smaller in ethnic minority groups (OR ranged from 0.61 in Moroccans to 1.32 in South-Asian Surinamese) than in the Dutch (OR 0.49; 95% CI 0.36 to 0.65). Only in South-Asian Surinamese, women did not have a lower odds than men (OR 1.32; 95% CI 0.96 to 1.84). The pattern of smaller sex differences in ethnic minority groups was more pronounced in older than in younger age-groups.ConclusionsThe prevalence of major ECG abnormalities was lower in women than men. However, sex differences were less apparent in ethnic minority groups. Conventional risk factors did not contribute substantially to observed sex differences.

Ever since the first case was reported at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) has become a serious threat to public health globally in short time. At this point in time, there is no proven effective therapy. The interactions with concomitant disease are largely unknown, and that may be particularly pertinent to inherited arrhythmia syndrome. An arrhythmogenic effect of COVID-19 can be expected, potentially contributing to disease outcome. This may be of importance for patients with an increased risk of cardiac arrhythmias, either secondary to acquired conditions or comorbidities or consequent to inherited syndromes. Management of patients with inherited arrhythmia syndromes such as long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia in the setting of the COVID-19 pandemic may prove particularly challenging. Depending on the inherited defect involved, these patients may be susceptible to proarrhythmic effects of COVID-19–related issues such as fever, stress, electrolyte disturbances, and use of antiviral drugs. Here, we describe the potential COVID-19–associated risks and therapeutic considerations for patients with distinct inherited arrhythmia syndromes and provide recommendations, pending local possibilities, for their monitoring and management during this pandemic.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing., Amsterdam Cardiovascular Sciences fellowship; Dutch Heart Foundation (CVON Predict-2/Concor-genes); Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [VICI 016.150.610]; Fondation LeducqLeducq Foundation, R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict-2/Concor-genes), Netherlands Organization for Scientific Research (VICI 016.150.610), and Fondation Leducq. See Supplement for all Acknowledgements.

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P P Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Background Early prehospital recognition of critical conditions such as ST‐segment–elevation myocardial infarction (STEMI) has prognostic relevance. Current international electrocardiographic STEMI thresholds are predominantly based on individuals of Western European descent. However, because of ethnic electrocardiographic variability both in health and disease, there is a need to reevaluate diagnostic ST‐segment elevation thresholds for different populations. We hypothesized that fulfillment of ST‐segment elevation thresholds of STEMI criteria (STE‐ECGs) in apparently healthy individuals is ethnicity dependent. Methods and Results HELIUS (Healthy Life in an Urban Setting) is a multiethnic cohort study including 10 783 apparently healthy subjects of 6 different ethnicities (African Surinamese, Dutch, Ghanaian, Moroccan, South Asian Surinamese, and Turkish). Prevalence of STE‐ECGs across ethnicities, sexes, and age groups was assessed with respect to the 2 international STEMI thresholds: sex and age specific versus sex specific. Mean prevalence of STE‐ECGs was 2.8% to 3.4% (age/sex‐specific and sex‐specific thresholds, respectively), although with large ethnicity‐dependent variability. Prevalences in Western European Dutch were 2.3% to 3.0%, but excessively higher in young (45% STE‐ECGs. Conclusions The accuracy of diagnostic tests partly relies on background prevalence in healthy individuals. In apparently healthy subjects, there is a highly variable ethnicity‐dependent prevalence of ECGs with ST‐segment elevations exceeding STEMI thresholds. This has potential consequences for STEMI evaluations in individuals who are not of Western European descent, putatively resulting in adverse outcomes with both over‐ and underdiagnosis of STEMI.

Background In the prehospital triage of patients presenting with symptoms suggestive of acute myocardial ischemia, reliable myocardial ischemia detection in the electrocardiogram (ECG) is pivotal. Due to large interindividual variability and overlap between ischemic and nonischemic ECG‐patterns, incorporation of a previous elective (reference) ECG may improve accuracy. The aim of the current study was to explore the potential value of serial ECG analysis using subtraction electrocardiography. Methods SUBTRACT is a multicenter retrospective observational study, including patients who were prehospitally evaluated for acute myocardial ischemia. For each patient, an elective previously recorded reference ECG was subtracted from the ambulance ECG. Patients were classified as myocardial ischemia cases or controls, based on the in‐hospital diagnosis. The diagnostic performance of subtraction electrocardiography was tested using logistic regression of 28 variables describing the differences between the reference and ambulance ECGs. The Uni‐G ECG Analysis Program was used for state‐of‐the‐art single‐ECG interpretation of the ambulance ECG. Results In 1,229 patients, the mean area‐under‐the‐curve of subtraction electrocardiography was 0.80 (95%CI: 0.77–0.82). The performance of our new method was comparable to single‐ECG analysis using the Uni‐G algorithm: sensitivities were 66% versus 67% (p‐value > .05), respectively; specificities were 80% versus 81% (p‐value > .05), respectively. Conclusions In our initial exploration, the diagnostic performance of subtraction electrocardiography for the detection of acute myocardial ischemia proved equal to that of state‐of‐the‐art automated single‐ECG analysis by the Uni‐G algorithm. Possibly, refinement of both algorithms, or even integration of the two, could surpass current electrocardiographic myocardial ischemia detection.

BACKGROUND: The literature on fever-related arrhythmic events (AEs) in Brugada syndrome (BrS) is currently limited to few case reports and small series. OBJECTIVE: The present study aimed to describe the characteristics of fever-related AE in a large cohort of patients with BrS. METHODS: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter study on 678 patients with BrS with first AE documented at the time of aborted cardiac arrest (n = 426) or after prophylactic implantable cardioverter-defibrillator implantation (n = 252). RESULTS: In 35 of 588 patients (6%) with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%), and proband (70%). The mean age at the time of AE was 29 ± 24 years (range 0.3-76 years). Most patients (80%) presented with aborted cardiac arrest and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope, and spontaneous type 1 Brugada electrocardiogram were noted in 17%, 40%, and 71% of patients, respectively. Ventricular fibrillation was induced at electrophysiology study in 9 of 19 patients (47%). An SCN5A mutation was found in 14 of 28 patients (50%). The highest proportion of fever-related AE was observed in the pediatric population (age

ObjectiveTo determine the accuracy of QT measurement in a smartphone-operated, single-lead ECG (1L-ECG) device (AliveCor KardiaMobile 1L).DesignCross-sectional, within-patient diagnostic validation study.Setting/participantsPatients underwent a 12-lead ECG (12L-ECG) for any non-acute indication in primary care, April 2017–July 2018.InterventionSimultaneous recording of 1L-ECGs and 12L-ECGs with blinded manual QT assessment.Outcomes of interest(1) Difference in QT interval in milliseconds (ms) between the devices; (2) measurement agreement between the devices (excellent agreement Results250 ECGs of 125 patients were included. The mean QTc interval, using Bazett’s formula (QTcB), was 393±25 ms (mean±SD) in 1L-ECGs and 392±27 ms in lead I of 12L-ECGs, a mean difference of 1±21 ms, which was not statistically different (paired t-test (p=0.51) and Bland Altman method (p=0.23)). In terms of agreement between 1L-ECGs and lead I, QTcB had excellent agreement in 66.9% and clinically acceptable agreement in 93.4% of observations. The sensitivity and specificity of detecting extreme QTc were 0% and 99.2%, respectively. The comparison of 1L-ECG QTcB with lead II of 12L-ECGs showed a significant difference (p=ConclusionSmartphone-operated 1L-ECGs can be used to accurately measure the QTc interval compared with simultaneously obtained 12L-ECGs in a primary care population. This may provide an opportunity for monitoring the effects of potential QTc-prolonging medications.

Objectives This study evaluated the yield of ajmaline testing and assessed the occurrence of confounding responses in a large cohort of families with unexplained cardiac arrest (UCA) or sudden unexplained death (SUD). Background Ajmaline testing to diagnose Brugada syndrome (BrS) is routinely used in the evaluation of SUD and UCA, but its yield, limitations, and appropriate dosing have not been studied in a large cohort. Methods We assessed ajmaline test response and genetic testing results in 637 individuals from 482 families who underwent ajmaline testing for SUD or UCA. Results Overall, 89 individuals (14%) from 88 families (18%) had a positive ajmaline test result. SCN5A mutations were identified in 9 of 86 ajmaline-positive cases (10%). SCN5A mutation carriers had positive test results at significantly lower ajmaline doses than noncarriers (0.75 [0.64 to 0.98] mg/kg vs. 1.03 [0.95 to 1.14] mg/kg, respectively; p 1mg/kg than in those obtained at ≤1mg/kg (7 of 48 vs. 0 of 41 individuals; Fisher’s exact test: p = 0.014). Conclusions In line with previous, smaller studies, a positive ajmaline response was observed in a large proportion of UCA/SUD families. Importantly, our data emphasize the potential for confounding possibly false-positive ajmaline responses in this population, particularly at high doses, which could possibly lead to a misdiagnosis. Clinicians should consider all alternative causes in UCA/SUD and avoid ajmaline doses >1 mg/kg.

Aims Long QT syndrome (LQTS) is associated with malignant arrhythmias and sudden death from birth to advanced age. Prolongation of the QT-interval, may however be concealed on standard electrocardiograms (ECG). The brisk-standing-test (BST) was developed to guide LQTS-diagnosis and treatment in adults. We hypothesized that the BST may be used in prepubertal children to identify LQTS subjects. Accordingly, reference values for the BST should be available to prevent incorrect diagnosis and treatment of LQTS. In this study, we aim to present reference values for prepubertal children. Methods and results Healthy, prepubertal children, aged 7-13 years underwent a standard supine resting ECG and during continuous ECG recording performed a BST. The QT-interval and heart rate corrected QTc were measured during the different BST stages. Fifty-seven children, 29 boys (10.2 +/- 1.1 years) and 28 girls (9.9 +/- 1.1 years) were included. Baseline characteristics and response to standing were not statistically different for boys and girls: mean supine pre-standing heart rate 74 +/- 9 vs. 77 +/- 9 bpm, supine pre-standing QTc 406 +/- 27 vs. 407 +/- 17 ms, maximal heart rate upon standing 109 +/- 11 vs. 112 +/- 11 bpm, and QTc at maximal heart rate 484 +/- 29 vs. 487 +/- 35 ms. The QT interval corrected for heart rate-prolongation at maximal tachycardia after standing was 79 +/- 26 (19-144) ms, which is significantly longer than previously published values in adults (50 +/- 30 ms). Conclusions The QT interval corrected for heart rate prolongation after brisk standing in healthy prepubertal children is more pronounced than in healthy adults. This finding advocates distinct prepubertal cut-off values because using adult values for prepubertal children would yield false positive results with the risk of incorrect LQTS-diagnosis and overtreatment.

AimsIdiopathic ventricular fibrillation (IVF) is a rare cause of sudden cardiac arrest. Implantable cardioverter-defibrillator (ICD) implantation is currently the only treatment option. Limited data are available on the prevalence and complications of ICD therapy in these patients. We sought to investigate ICD therapy and its complications in patients with IVF.Methods and resultsPatients were selected from a national registry of IVF patients. Patients in whom no underlying diagnosis was found during follow-up were eligible for inclusion. Recurrence of ventricular arrhythmia (VA) was derived from medical and ICD records, electrogram records of ICD therapies were used to differentiate between appropriate or inappropriate interventions. Independent predictors for appropriate ICD shock were calculated using cox regression. In 217 IVF patients, recurrence of sustained VAs occurred in 66 patients (30%) during a median follow-up period of 6.1 years. Ten patients died (4.6%). Thirty-eight patients (17.5%) experienced inappropriate ICD therapy, and 32 patients (14.7%) had device-related complications. Symptoms before cardiac arrest [hazard ratio (HR): 2.51, 95% confidence interval (CI): 1.48–4.24], signs of conduction disease (HR: 2.27, 95% CI: 1.15–4.47), and carrier of the DPP6 risk haplotype (HR: 3.24, 1.70–6.17) were identified as independent predictors of appropriate shock occurrence.ConclusionImplantable cardioverter-defibrillator therapy is an effective treatment in IVF, treating recurrences of potentially lethal VAs in approximately one-third of patients during long-term follow-up. However, device-related complications and inappropriate shocks were also frequent. We found significant predictors for appropriate ICD therapy. This may imply that these patients require additional management to prevent recurrent events.

Age, sex and race have an influence on the cardiac repolarization and therefore the QTc-interval. Racial differences are probably the result of the presence of considerable heterogeneity among race/ethnicity for multiple genetic loci that influence the QT-interval. Age- and sex-related differences in QTc-interval are most likely the result of changes in sex-specific hormones. Although the exact mechanisms and pathophysiology of the effect of sex hormones on the QTc-interval and arrhythmogenesis are not known, testosterone appears to shorten the QTc-interval in males. In females, however, there is a more complex interaction between progesterone and oestrogen. In addition, the autonomic nervous system and gonadotropins may play an important part in this complex interaction.

Objectives To assess the effect of chronic total occlusion percutaneous coronary intervention (CTO PCI) on ventricular ectopy (VE) and symptomatology during exercise testing. Background During exercise, the hypoxic myocardium in the CTO-territory can act as a substrate for VE and could lead to anginal complaints. Methods In the EXPLORE-trial, 302 ST-segment elevation myocardial infarction (STEMI)-patients were randomized to CTO PCI or no-CTO PCI. For this sub-study, we analyzed all available exercise electrocardiograms (X-ECGs) at 4 months follow-up on symptoms and electrocardiographic parameters. Results A total of 155 X-ECGs were available, 80 in the CTO PCI group (51.6%) and 75 in the no-CTO PCI group (48.4%). There were no differences regarding exercised time, achieved endurance, ST-deviation nor maximum heart-rate. The percentage of patients experiencing chest-pain during exercise was lower in the CTO PCI group (0% vs. 8.5%, p = .03). Also, there was a trend towards a higher maximum systolic blood pressure (SBP, 185 mmHg vs. 175, p = .09). No difference in VE was found between randomization groups, but patients with successful CTO PCI had a higher frequency of VE, compared to failed and no-CTO PCI (26% vs. 8%, p = .02). This did not result in higher frequencies of sustained ventricular arrhythmias or mortality. Conclusion In conclusion, in STEMI-patients, CTO PCI is associated with a small reduction of chest-pain during exercise and tended to be associated with an increase of maximum SBP. The observation that successful CTO PCI was associated with more VE during exercise, compared with failed/no-CTO PCI needs further exploration.

Aims Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG). Methods and results In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose–response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P Conclusion We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.

Background: Long QT syndrome (LQTS) is associated with potentially fatal arrhythmias. Treatment is very effective, but its diagnosis may be challenging. Importantly, different methods are used to assess the QT interval, which makes its recognition difficult. QT experts advocate manual measurements with the tangent or threshold method. However, differences between these methods and their performance in LQTS diagnosis have not been established. We aimed to assess similarities and differences between these 2 methods for QT interval analysis to aid in accurate QT assessment for LQTS. Methods: Patients with a confirmed pathogenic variant in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) genes and their family members were included. Genotype-positive patients were identified as LQTS cases and genotype-negative family members as controls. ECGs were analyzed with both methods, providing inter- and intrareader validity and diagnostic accuracy. Cutoff values based on control population’s 95th and 99th percentiles, and LQTS-patients’ 1st and 5th percentiles were established based on the method to correct for heart rate, age, and sex. Results: We included 1484 individuals from 265 families, aged 33±21 years and 55% females. In the total cohort, QT Tangent was 10.4 ms shorter compared with QT Threshold (95% limits of agreement±20.5 ms, P Tangent was shorter than QT Threshold ( P 0.96), and a high diagnostic accuracy (area under the curve >0.84). Using the current guideline cutoff (QTc interval 480 ms), both methods had similar specificity but yielded a different sensitivity. QTc interval cutoff values of QT Tangent were lower compared with QT Threshold and different depending on the correction for heart rate, age, and sex. Conclusion: The QT interval varies depending on the method used for its assessment, yet both methods have a high validity and can both be used in diagnosing LQTS. However, for diagnostic purposes current guideline cutoff values yield different results for these 2 methods and could result in inappropriate reassurance or treatment. Adjusted cutoff values are therefore specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for LQTS ( www.QTcalculator.org ) has been made available as an aid in the interpretation of the QT interval.

BACKGROUND Familial idiopathic ventricular fibrillation (IVF) is a severe disease entity and is notoriously difficult to manage because there are no clinical risk indicators for premature cardiac arrest. Previously, we identified a link between familial IVF and a risk haplotype on chromosome 7q36 (involving the arrhythmia gene DPP6). OBJECTIVE The purpose of this study was to expand our knowledge of familial IVF and to discuss its (extended) clinical characteristics. METHODS We studied 601 family members and probands: 286 DPP6 risk-haplotype positive (haplotype-positive) and 315 DPP6 risk-haplotype negative (haplotype-negative) individuals. Clinical parameters, a combination of all-cause mortality and (aborted) cardiac arrest and differences between haplotype-positives and haplotype-negatives, were evaluated. RESULTS There were no differences in electrocardiographic indices between haplotype-positives and haplotype-negatives, or between haplotype-positives with or without events. Cardiac magnetic resonance documented slightly larger ventricular volumes in haplotype-positives compared to controls (P

Background Implantable cardioverter-defibrillators (ICDs) are implanted with the intention to prolong life in selected patients with inherited arrhythmia syndromes, but ICD implantation is also associated with inappropriate shocks and complications. Objective We aimed to quantify the rate of inappropriate shocks and other ICD-related complications to be able to weigh benefit and harm in these patients. Methods We performed a systematic review and meta-analysis of inappropriate shock and/or other ICD-related complication rates, including ICD-related mortality, in patients with inherited arrhythmia syndromes, that is, arrhythmogenic right ventricular cardiomyopathy/dysplasia, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, dilated cardiomyopathy due to a mutation in the lamin A/C gene, long QT syndrome, and short QT syndrome. We searched MEDLINE and EMBASE from inception to May 30, 2014. Results Of 2471 unique citations, 63 studies comprising 4916 patients with inherited arrhythmia syndromes (mean age of 39 ± 15 years) were included. Inappropriate shocks occurred in 20% of patients (crude annual rate of 4.7% per year), with a significantly higher rate in studies published before 2008 (6.1% per year vs 4.1% per year). Moreover, 22% experienced ICD-related complications (4.4% per year) and there was a 0.5% ICD-related mortality (0.08% per year). Conclusion ICD implantation carries a significant risk of inappropriate shocks and inhospital and postdischarge complications in relatively young patients with inherited arrhythmia syndromes. These data can be used to better inform patients and physicians about the expected risk of adverse ICD events and thereby facilitate shared decision making.

It has been nearly 25 years since Pedro and Josep Brugada described a disease entity harming young patients with no obvious structural heart disease and peculiar right precordial electrocardiogram (ECG) characteristics. This disease entity is now known as the type-1 or coved-type Brugada ECG and the

Aims: Management of patients with inherited cardiac ion channelopathy is hindered by variability in disease severity and sudden cardiac death (SCD) risk. Here, we investigated the modulatory role of hypertrophy on arrhythmia and SCD risk in sodium channelopathy.Methods and results: Follow-up data was collected from 164 individuals positive for the SCN5A-1795insD founder mutation and 247 mutation-negative relatives. A total of 38 (obligate) mutation-positive patients died suddenly or suffered life-threatening ventricular arrhythmia. Of these, 18 were aged >40 years, a high proportion of which had a clinical diagnosis of hypertension and/or cardiac hypertrophy. While pacemaker implantation was highly protective in preventing bradycardia-related SCD in young mutation-positive patients, seven of them aged >40 experienced life-threatening arrhythmic events despite pacemaker treatment. Of these, six had a diagnosis of hypertension/hypertrophy, pointing to a modulatory role of this co-morbidity. Induction of hypertrophy in adult mice carrying the homologous mutation (Scn5a1798insD/+) caused SCD and excessive conduction disturbances, confirming a modulatory effect of hypertrophy in the setting of the mutation. The deleterious effects of the interaction between hypertrophy and the mutation were prevented by genetically impairing the pro-hypertrophic response and by pharmacological inhibition of the enhanced late sodium current associated with the mutation.Conclusion: This study provides the first evidence for a modulatory effect of co-existing cardiac hypertrophy on arrhythmia risk and treatment efficacy in inherited sodium channelopathy. Our findings emphasize the need for continued assessment and rigorous treatment of this co-morbidity in SCN5A mutation-positive individuals.

Background: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs). Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between males and females in patients with BrS with their first AE. Methods: The multicenter Survey on Arrhythmic Events in BRUgada Syndrome collected data on the first AE in 678 patients with BrS including 619 males (91.3%) and 59 females (8.7%) aged 0.27–84 years (mean age 42.5 ± 14.1 years) at the time of AE occurrence. Results: After excluding pediatric patients, it was found that females were older than males (49.5 ± 14.4 years vs 43 ± 12.7 years, respectively; P =.001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, the male to female ratio for AEs was ≈9-fold higher than that in White. Spontaneous type 1 BrS ECG was associated with an earlier onset of AEs in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS ECG was present in males and females above the age of 60 years. Females less frequently showed spontaneous type 1 BrS ECG (41% vs 69%; P, SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction Chronic total coronary occlusions (CTOs) have been associated with a higher prevalence of ventricular arrhythmias compared to patients without a CTO. We evaluated the effect of CTO revascularization on electrocardiographic (ECG) variables. Methods We studied a selection of ST-elevation myocardial infarction patients with a concomitant CTO enrolled in the EXPLORE trial. ECG variables and cardiac function were analysed at baseline and at 4 months follow-up. Results Patients were randomized to percutaneous coronary intervention (PCI) of their CTO (n = 77) or to no-CTO PCI (n = 81). At follow-up, median QT dispersion was significantly lower in the CTO PCI group compared to the no-CTO PCI group (46 ms [33–58] vs. 54 ms [37–68], P = 0.043). No independent association was observed between ECG variables and cardiac function. Conclusion Revascularization of a CTO after STEMI significantly shortened QT dispersion at 4 months follow-up. These findings support the hypothesis that CTO revascularization reduces the pro-arrhythmic substrate in CTO patients.

Aims Diagnosing long QT syndrome (LQTS) is challenging due to a considerable overlap of the QTc-interval between LQTS patients and healthy controls. The aim of this study was to investigate the added value of T-wave morphology markers obtained from 12-lead electrocardiograms (ECGs) in diagnosing LQTS in a large cohort of genepositive LQTS patients and gene-negative family members using a support vector machine.Methods and results A retrospective study was performed including 688 digital 12-lead ECGs recorded from genotype-positive LQTS patients and genotype-negative relatives at their first visit. Two models were trained and tested equally: a baseline model with age, gender, RR-interval, QT-interval, and QTc-intervals as inputs and an extended model including morphology features as well. The best performing baseline model showed an area under the receiver-operating characteristic curve (AUC) of 0.821, whereas the extended model showed an AUC of 0.901. Sensitivity and specificity at the maximal Youden's indexes changed from 0.694 and 0.829 with the baseline model to 0.820 and 0.861 with the extended model. Compared with clinically used QTc-interval cut-off values (> 480 ms), the extended model showed a major drop in false negative classifications of LQTS patients.Conclusion The support vector machine-based extended model with T-wave morphology markers resulted in a major rise in sensitivity and specificity at the maximal Youden's index. From this, it can be concluded that T-wave morphology assessment has an added value in the diagnosis of LQTS.

The cardiac rhythm disorder Brugada syndrome (BrS) is characterized by a signature electrocardiogram (ECG) characterized by coved-type right precordial ST-segment elevation, has a presumed prevalence of 1:2,000, and is associated with a relatively high incidence of ventricular fibrillation (VF)–

BACKGROUND: Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their first arrhythmic event (AE) after prophylactic implantation of an implantable cardioverter-defibrillator (ICD) is limited. OBJECTIVES: The objectives of this study were (1) to compare clinical, electrocardiographic, electrophysiologic, and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (group A) with profiles of those in whom the AE was documented after prophylactic ICD implantation (group B) and (2) to characterize group B patients' profile using the class II indications for ICD implantation established by HRS/EHRA/APHRS expert consensus statement in 2013. METHODS: A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 patients with BrS who exhibited their AE (group A, n = 426; group B, n = 252). RESULTS: The first AE occurred in group B patients 6.7 years later than in group A (mean age 46.1 ± 13.3 years vs 39.4 ± 15.1 years; P < .001). Group B patients had a higher incidence of family history of sudden cardiac death and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not. CONCLUSION: Patients with BrS with the first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of sudden cardiac death and SCN5A mutations as compared with those presenting with aborted cardiac arrest. Only 75% of patients who exhibited an AE after receiving a prophylactic ICD complied with the 2013 class II indications, suggesting that efforts are still required for improving risk stratification.