The pharmacological provocation test is a pivotal tool in cardiac electrophysiology for the diagnosis of potential causes of sudden cardiac death, sudden cardiac arrest (SCA), arrhythmias, symptoms, or ECG abnormalities. The 2022 European Society of Cardiology Guidelines for the Treatment of Ventricular Arrhythmias and Prevention of Sudden Cardiac Death offered guidance on provocation testing but did not describe the indications and requirements in depth. This clinical consensus statement, led by the European Heart Rhythm Association and approved by major international stakeholders, aims to advise the general cardiologist and the arrhythmia expert who to test and when, where, and how to do it. The statement focuses on current practice for the diagnosis of subclinical arrhythmia syndromes and the causes of SCA, building upon the recommendations of the Guidelines. We address the sodium channel blocker provocation test for patients suspected of Brugada syndrome as well as the use of epinephrine, isoproterenol, adenosine, ergonovine, and acetylcholine.

Brugada syndrome (BrS) continues to pose clinical challenges, despite 3 decades of dedicated research and therapeutic advancements. The pivotal role of implantable cardioverter-defibrillator (ICD) therapy in safeguarding high-risk BrS patients from sudden cardiac death due to ventricular arrhythmias is undeniable. However, the debate on risk stratification and the use of ICDs for primary prevention remains ongoing.

This study aimed to evaluate the clinical features, management, and long-term outcomes of ICD therapy in patients with Brugada syndrome.

BrS-diagnosed patients were prospectively enrolled. Inclusion criteria were: 1) a Brugada type 1 electrocardiogram pattern, either spontaneous or drug induced; 2) ICD implantation; and 3) consistent follow-up. Risk stratification was based on prior arrhythmic events, and the multiparametric Brussel risk score was used from 2017. High-risk patients underwent video-thoracoscopic epicardial ablation starting in 2016. ICD implantation strategies evolved over time, guided by patients' clinical and demographic characteristics.

A total of 306 consecutive Brugada patients (186 male [61%]; mean age 41 ± 17 years; range: 1-82 years) received ICDs at our institution from 1992 to 2022. ICDs were implanted for secondary prevention in 16% of patients. Over the 3 decades, the proportions of secondary prevention implants and asymptomatic patients remained stable, while risk factors fluctuated in the first two decades before stabilizing. During long-term follow-up (median 103 months [63-147 months]), 14% of patients experienced at least 1 sustained ventricular arrhythmia (VA) (1.59 per 100 person-years), 15% had at least 1 inappropriate ICD shock-unaffected by the presence of single or dual leads-and 27% required device revision and/or lead replacement. Patients with secondary prevention ICDs had a higher incidence of both ventricular and supraventricular arrhythmias compared to those with primary prevention ICDs. Loss-of-function mutations and prior nonsustained VAs were associated with sustained VAs. Among high-risk patients, those who underwent epicardial ablation experienced significantly fewer ventricular events. The overall mortality rate was 5.88%, with 22.2% of deaths attributed to cardiac causes.

This 30-year study highlights ICD therapy's critical role in preventing fatal arrhythmias in Brugada syndrome, but also reveals frequent device-related complications, especially in younger patients. Thoracoscopic epicardial ablation significantly reduced VA in high-risk patients, offering a promising adjunctive therapy. These findings emphasize the need for individualized treatment strategies to balance the benefits of ICDs with their risks, and underscore the potential of ablation to improve long-term outcomes.

Brugada syndrome (BrS) is an inherited electrical cardiac disorder that is associated with a higher risk of ventricular fibrillation (VF) and sudden cardiac death (SCD) in patients without structural heart disease. The diagnosis is based on the documentation of the typical pattern in the electrocardiogram (ECG) characterized by a J-point elevation of ≥2 mm, coved-type ST-segment elevation, and negative T wave in one or more right precordial leads, called type 1 Brugada ECG. Risk stratification is particularly difficult in asymptomatic cases. Patients who have experienced documented VF are generally recommended to receive an implantable cardioverter defibrillator to lower the likelihood of sudden death due to recurrent episodes. However, for asymptomatic individuals, the most appropriate course of action remains uncertain. Accurate risk prediction is critical to avoiding premature deaths and unnecessary treatments. Due to the challenges associated with experimental research on human cardiac tissue, alternative techniques such as computational modeling and deep learning-based artificial intelligence (AI) are becoming increasingly important. This study introduces a vision transformer (ViT) model that leverages 12-lead ECG images to predict potentially fatal arrhythmic events in BrS patients. This dataset includes a total of 278 ECGs, belonging to 210 patients which have been diagnosed with Brugada syndrome, and it is split into two classes: event and no event. The event class contains 94 ECGs of patients with documented ventricular tachycardia, ventricular fibrillation, or sudden cardiac death, while the no event class is composed of 184 ECGs used as the control group. At first, the ViT is trained on a balanced dataset, achieving satisfactory results (89% accuracy, 94% specificity, 84% sensitivity, and 89% F1-score). Then, the discarded no event ECGs are attached to additional 30 event ECGs, extracted by a 24 h recording of a singular individual, composing a new test set. Finally, the use of an optimized classification threshold improves the predictions on an unbalanced set of data (74% accuracy, 95% negative predictive value, and 90% sensitivity), suggesting that the ECG signal can reveal key information for the risk stratification of patients with Brugada syndrome.

Exome sequencing has been established as a fundamental tool in genetic diagnostics. It may also provide information about variants in genes unrelated to the primary purpose, so-called secondary findings. Especially, diagnoses of unnoticed inborn cardiac diseases are of high clinical relevance due to therapeutic options in context of prevention of sudden cardiac death.

Exome data of 9962 individuals was analysed for relevant cardiogenetic findings. Genes were selected according to ACMG recommendations for secondary findings (v.3.1). First, a filter for (likely) pathogenic variants, published in the ClinVar database, was used. Second, exome data was screened for loss of function (LoF) variants in genes in which LoF is a known disease pathomechanism. All variants were evaluated by geneticists regarding their pathogenicity.

Pathogenic or likely pathogenic variants were identified in 136 different individuals (136/9962, 1.4%), with the Low-Density Lipoprotein Receptor gene (LDLR, 24/136, 17.6%) and the Titin gene (TTN, 24/136, 17.6%), being the most frequently affected ones. 31.6% (43/136) of the identified variants had been reported beforehand, while 47.1% (64/136) had not been reported. The remaining cases (29/136, 21.3%) were part of research projects with no written reports. In 26.5% (36/136), the finding would have been missed, if only index patients and not their parents had been screened for secondary findings in case of trio ES.

As demonstrated in our study, at least one or two out of one hundred people are likely to carry a pathogenic cardiogenetic variant. Counselling geneticist and clinicians need to be aware of these findings in exome and genome sequencing. Informed consent of the patient regarding the report of secondary findings should absolutely be obtained beforehand.

Sudden cardiac death (SCD) is an abrupt, tragic manifestation of a number of cardiovascular diseases, primarily ion channelopathies and heritable cardiomyopathies. Because these diseases are heritable, genetics play a key role in the diagnosis and management of SCD-predisposing diseases. Historically, genetics have been used to confirm a diagnosis and identify at-risk family members, but a deeper understanding of the genetic causes of SCD could pave the way for individualized therapy, early risk detection, and a transformative shift toward genetically informed therapies. This review focuses on the evolving genetic landscape of SCD-predisposing diseases, the current state of gene therapy and therapeutic development, and the promise of using predictive genetics to identify individuals at risk of SCD.

ECG in Brugada syndrome (BrS) is characterized by a ST-segment elevation in the right precordial leads. Overlap between ST-segment changes in BrS and ischemia may lead to diagnostic challenges. We report a case of a male patient presented with recurrent chest pain episodes and ST elevation in the right precordial leads consistent with Brugada ECG pattern type 1 and was clinically diagnosed with BrS at the age of 30 years. During follow up the patient developed acute myocardial infarction with pronounced ST depression in the right precordial leads, masking the Brugada pattern of the baseline ECG.

Diagnosis of Brugada syndrome (BrS) is based on type 1 morphology (coved type) in electrocardiograms from standard (4th) or higher (2nd or 3rd) intercostal spaces (ICSs). However, the clinical implications of being diagnosed only at higher ICSs remains poorly understood. We aimed to investigate the diagnostic accuracy of higher ICS leads in the Taiwanese Brugada syndrome population and clarify if there is any difference in clinical presentation.

Patients enrolled in the Sudden Arrhythmic Death Syndrome-Taiwan (SADS-TW) registry from 2010/01/01 to 2021/07/30 were retrospectively reviewed. Records were examined for 163 patients whose ECGs in the 2nd, 3rd, and/or 4th ICSs showed a type 1 BrS pattern in at least 1 lead. Baseline characteristics, family history, clinical presentation, SCN5A mutation status, cardiovascular events, and mortality were analyzed.

Using the standard ICS alone, 56.4% patients could be diagnosed with BrS, whereas the remaining 43.6% of patients could only be diagnosed using higher ICSs. The mean age of diagnosis using higher ICSs was 42.2 ± 14.7 years vs. 46.8 ± 14.6 years in patients diagnosed using the standard ICSs (p = 0.048). Hypertension was more prevalent in patients diagnosed by standard ICSs (27.2%) vs. patients diagnosed by higher ICSs (4.2%; p < 0.001). No differences were observed in family history, clinical presentation, SCN5A mutation status, cardiovascular events, or mortality (mean follow-up time = 3.96 ± 3.45 years, p = 0.28).

Using higher intercostal leads could significantly increase the diagnosis rate of BrS in the Taiwanese population, although it would not affect the clinical prognosis.

Little is known about the distribution and clinical course of patients with inherited arrhythmia syndrome (IAS) and concomitant atrial arrhythmias (AAs). The aim of the study is (i) to characterize the distribution of AAs in patients with IAS and (ii) evaluate the long-term clinical course of these patients.

An international multicentre study was performed and involved 28 centres in 16 countries. Inclusion criteria were (i) IAS and (ii) electrocardiographic documentation of AAs. The primary endpoint was a composite of sudden cardiac death, sustained ventricular arrhythmias (VAs), or appropriate implantable cardioverter defibrillator (ICD) interventions. Strokes, inappropriate ICD shocks due to AAs, and the occurrence of sinus node dysfunction were assessed. A total of 522 patients with IAS and AAs were included. Most patients were diagnosed with Brugada syndrome (n = 355, 68%) and long QT syndrome (n = 93, 18%). The remaining patients (n = 71, 14%) presented with short QT syndrome, early repolarization syndrome, catecholaminergic polymorphic ventricular tachycardia, progressive cardiac conduction diseases, or idiopathic ventricular fibrillation. Atrial fibrillation was the most prevalent AA (82%), followed by atrial flutter (9%) and atrial tachycardia (9%). Atrial arrhythmia was the first clinical manifestation of IAS in 52% of patients. More than one type of AA was documented in 23% of patients. Nine patients (3%) experienced VA before the diagnosis of IAS due the use of anti-arrhythmic medications taken for the AA. The incidence of the primary endpoint was 1.4% per year, with a two-fold increase in patients who experienced their first AA before the age of 20 (odds ratio 2.2, P = 0.043). This was consistent across the different forms of IAS. Inappropriate ICD shock due to AAs was reported in 2.8% of patients, strokes in 4.4%, and sinus node dysfunction in 9.6%.

Among patients with IAS and AAs, AA is the first clinical manifestation in about half of the cases, with more than one form of AAs present in one-fourth of the patients. The occurrence of AA earlier in life may be associated with a higher risk of VAs. The occurrence of stroke and sinus node dysfunction is not infrequently in this cohort.

The long-term prognosis of patients with a loss-of-function variant in the cardiac sodium channel gene SCN5A is unknown.

This study aimed to evaluate the long-term arrhythmic risk in patients with an SCN5A loss-of-function variant to identify predictors of arrhythmic events.

Probands and family members with (likely) pathogenic SCN5A loss-of-function variants were retrospectively included. Clinical and electrocardiographic data at baseline and last follow-up were collected. Patients with a history of cardiac arrest, sustained ventricular tachycardia, symptomatic or documented atrial tachy- or bradyarrhythmia, or arrhythmogenic syncope were categorized as symptomatic. Arrhythmic events at follow-up were defined as sudden death, aborted cardiac arrest, documented ventricular fibrillation, and/or sustained ventricular tachycardia.

We included 615 patients (349 men, 242 probands, 157 with a spontaneous type 1 Brugada electrocardiogram, and 111 symptomatic at baseline). During a median follow-up of 9.5 (Q1,Q3 5.0-14.3) years, arrhythmic events occurred in 41 patients (6.7%), equating an overall event rate of 0.7%/y: 2.0%/y in symptomatic and 0.3%/y in asymptomatic patients. In the overall study population, symptoms at baseline, male sex, and QRS prolongation were identified as independent predictors of arrhythmic events. In asymptomatic patients, male sex and QRS prolongation were also identified as predictors. Asymptomatic women with QRS interval < 100 ms did not experience arrhythmic events at follow-up.

Key predictors of arrhythmic risk in patients with an SCN5A loss-of-function variant, regardless of a Brugada syndrome diagnosis, are symptoms at baseline, male sex, and prolonged QRS interval. Our findings may enable more tailored management strategies in patients with an SCN5A loss-of-function variant based on their individual risk profiles.

Atrial tachyarrhythmias (ATAs) are the primary cause of inappropriate implantable cardioverter-defibrillator (ICD) therapy in patients with idiopathic ventricular fibrillation (IVF) and are associated with decreased quality of life and increased mortality. Nonetheless, the incidence of ATAs in IVF cases has not been clarified.

The study sought to determine the incidence and clinical significance of ATAs in patients with IVF compared with those with Brugada syndrome (BrS).

Patients diagnosed with IVF or BrS and receiving ICDs in 6 hospitals were enrolled between February 1997 and July 2020 to compute data regarding the incidence of ATAs, appropriate/inappropriate ICD therapy frequency, and independent predictors of ATAs.

Overall, 137 patients (51 in the IVF group and 86 in the BrS group) were enrolled. ATAs were detected in 22 (43.1%) patients in the IVF group and 17 (19.8%) in the BrS group (P = .006). Inappropriate ICD therapies due to ATAs were more frequently observed in the IVF group than in the BrS group (12 [23.5%] vs 7 [8.1%]; P = .020). Conversely, there was no significant difference in appropriate ICD therapies between the IVF and BrS groups (14 [27.5%] vs 23 [27.1%]; P = 1.000). Cox regression analysis revealed no predictive factors for the development of ATAs in the IVF group.

ATA events were observed more frequently in patients with IVF than in those with BrS, and ATAs led to inappropriate ICD therapy in patients with IVF. Clinicians need to consider the recurrence of not only ventricular arrhythmias, but also the development of atrial arrhythmias for better management of IVF cases.

The characteristics of electrocardiogram (ECG) abnormalities related to cardiac channelopathies potentially linked to sudden cardiac death (SCD) are not widely recognized in Iran. We examined the prevalence of such ECG patterns and their related factors among adult residents of Tehran, Iran.

The clinical characteristics and 12-lead ECGs of Tehran Cohort Study participants were examined. Long QT intervals, short QT intervals, Brugada syndrome (BrS) patterns, and early repolarization (ER) were evaluated using computer-based assessment software validated by cardiologists. Logistic regression models were employed to identify the factors associated with the prevalence of different ECG patterns.

Out of 7678 available ECGs, 7350 were included in this analysis. Long QT interval, ER pattern, BrS patterns, and short QT interval were found in 3.08%, 1.43%, 0.31%, and 0.03% of participants, respectively. The prevalence of long QT interval increased with age, opium consumption, and presence of hypertension. Younger age, lower body mass index (BMI), alcohol use and male sex were independently linked to an elevated prevalence of ER pattern. Most individuals with BrS patterns were men (95%) and had lower BMI, high- and low-density lipoprotein, and total cholesterol compared to those without the BrS pattern. At a mean follow-up of 30.2 ± 5.5 months, all-cause mortality in the group exhibiting abnormal ECG patterns (6.3%) was approximately twice as high as that in the group without such patterns (2.96%).

Abnormal ECG patterns corresponding to channelopathies were relatively rare among adult residents of the Tehran population, and their prevalence was influenced by various factors.

Not applicable.

People with epilepsy are at risk of premature death, of which sudden unexpected death in epilepsy (SUDEP), sudden cardiac death (SCD) and sudden arrhythmic death syndrome (SADS) are the primary, partly overlapping, clinical scenarios. We discuss the epidemiologies, risk factors and pathophysiological mechanisms for these sudden death events. We reviewed the existing evidence on sudden death in epilepsy. Classification of sudden death depends on the presence of autopsy and expertise of the clinician determining aetiology. The definitions of SUDEP, SCD and SADS lead to substantial openings for overlap. Seizure-induced arrhythmias constitute a minority of SUDEP cases. Comorbid cardiovascular conditions are the primary determinants of increased SCD risk in chronic epilepsy. Genetic mutations overlap between the states, yet whether these are causative, associated or incidentally present is often unclear. Risk stratification for sudden death in people with epilepsy requires a multidisciplinary approach, including a review of clinical history, toxicological analysis and complete autopsy with histologic and, preferably, genetic examination. We recommend pursuing genetic testing of relatives of people with epilepsy who died suddenly, mainly if a post-mortem genetic test contained a Class IV/V (pathogenic/likely pathogenic) gene variant. Further research may allow more precise differentiation of SUDEP, SCD and SADS and the development of algorithms for risk stratification and preventative strategies.

Brugada syndrome (BrS) is a rare genetic disorder with specific electrocardiographic (ECG) patterns carrying an increased risk of sudden cardiac death.

The authors present a 36-year-old gentleman who had a travel history to the Central African Republic and came to the hospital with a fever and chest pain. The lab investigation revealed Falciparum Malaria infection and the ECG pattern revealed the type 1 Brugada pattern, which was normalized with anti-malarial medication and symptomatic treatment of fever.

BrS is a disorder with high prevalence in males and people of the Asian continent. Patients can present with symptoms like syncope, seizure, and nocturnal agonal respiration or may be asymptomatic. The ECG pattern of BrS could be seen in the febrile phase and normalized when non-febrile, like in our patient. Prompt treatment of fever and follow-up with cardiologists would be an effective treatment of asymptomatic patients, whereas ICD is a management of choice for symptomatic patients.

For a patient with chest pain, fever, and an ECG pattern of ST elevation, a clinician should think BrS one of the differential diagnoses.

Diagnosis of Brugada syndrome (BrS) may be established by exposing a Type 1 Brugada pattern using a sodium channel blocker. Data on the outcomes of different patient populations with drug-induced Type 1 Brugada pattern are limited. The present study reports on the characteristics and outcome of subjects with ajmaline induced Type 1 Brugada pattern.

A multicenter retrospective study including all consecutive cases of ajmaline-induced Type 1 Brugada pattern from seven centers.

A total of 260 patients (69.9% males, mean age 43.4 ± 13.5) were included. Additional characteristics included history of syncope (n = 56, 21.5%), family history of BrS (n = 58, 22.3%) or sudden cardiac death (n = 47, 18.1%) and ventricular fibrillation (n = 3, 1.2%). Patients were divided into those meeting current diagnostic criteria for drug-induced BrS (DIBrS) and compared to the drug-induced Brugada pattern (DIBrECG). Females were significantly overrepresented in the DIBrS group (n = 50, 40% vs. n = 29, 21.5%, p = .001). A significantly higher prevalence of type 2/3 Brugada ECG at baseline was found in the DIBrECG group (n = 108, 80.8% vs. n = 75, 60% in the DIBrS, p = .026). During a median follow up of three (IQR 1.50-5.32) years, a single event of significant arrhythmia occurred in the DIBrS group.

Less than half of subjects with ajmaline-induced Brugada pattern met current criteria for BrS. These individuals had very low rate of adverse outcomes during a follow up of 3 years, irrespective of the indication for the test or eligibility for the BrS diagnosis.

Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries.

A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart.

The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway.

This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Electrophysiologic testing with programmed ventricular stimulation (PVS) has been utilized to induce ventricular tachycardia (VT), thereby improving risk stratification for patients with ischemic and nonischemic cardiomyopathies and determining the effectiveness of antiarrhythmic therapies, especially catheter ablation. A variety of procedural aspects can be modified during PVS in order to alter the sensitivity and specificity of the test including the addition of multiple baseline pacing cycle lengths, extrastimuli, and pacing locations. The definition of a positive result is also critically important, which has varied from exclusively sustained monomorphic VT (>30 seconds) to any ventricular arrhythmia regardless of morphology. In this review, we discuss the history of PVS and evaluate its role in sudden cardiac death risk stratification in a variety of patient populations. We propose an approach to future investigations that will capitalize on the unique ability to vary the sensitivity and specificity of this test. We then discuss the application of PVS during and following catheter ablation. The strategies that have been utilized to improve the efficacy of intraprocedural PVS are highlighted during a discussion of the limitations of this probabilistic strategy. The role of noninvasive programmed stimulation is also reviewed in predicting recurrent VT and informing management decisions including repeat ablations, modifications in antiarrhythmic drugs, and implantable cardioverter-defibrillator programming. Based on the available evidence and guidelines, we propose an approach to future investigations that will allow clinicians to optimize the use of PVS for risk stratification and assessment of therapeutic efficacy.

The Brugada pattern is associated with a genetic disorder characterized by ST-segment elevation in the right precordial leads on electrocardiogram (EKG) in the absence of structural heart disease. Patients with the Brugada pattern have an increased risk for ventricular tachyarrhythmia and sudden cardiac death. Loss-of-function mutations in the SCN5A gene which encodes the alpha subunit of the cardiac sodium channel have been associated with Brugada syndrome (BrS). We report a case of a patient who was found to have a spontaneous type 1 Brugada pattern on a routine EKG done prior to travel. He underwent electrophysiological testing (EPS) which provoked ventricular tachycardia and underwent implantable cardioverter defibrillator (ICD) placement. His family history revealed a history of sudden cardiac death, abnormal EKG, syncope, dilated cardiomyopathy, and BrS. Genetic testing revealed a variant of uncertain significance (VUS) in the SCN5A gene in the proband and six of his relatives. The SCN5A VUS in this clinical context and segregation with the disease in his family supports its reclassification to pathogenic.

Cardiac tachyarrhythmia presents a significant health care challenge, causing notable morbidity and mortality. Conventional treatments have limitations and potential risks, resulting in an elevated disease burden. Adeno-associated virus (AAV)-mediated gene therapy holds promise as a potential future treatment option. Therefore, we aimed to provide a measured overview of the latest developments in this rapidly growing field. PubMed and Embase databases were searched up to January 2024. Studies that employed AAV as a vector for delivery of therapeutic agents to treat cardiac tachyarrhythmia were included. Of the 26 studies included, 20 published in the last 5 years. There were 22 novel molecular targets identified. More than 80% of the included studies employed small-animal models or used AAV9. In atrial fibrillation preclinical studies, AAV-mediated gene therapy reduced atrial fibrillation inducibility by 81% (odds ratio, 0.19 [0.08-0.45]; P < .01). Similarly, for acquired and inherited ventricular arrhythmia, animal models receiving gene therapy had less inducible ventricular arrhythmia (odds ratio, 0.06 [0.03-0.11]; P < .01). This review highlights the rapid progress of AAV-mediated gene therapy for cardiac tachyarrhythmia. Although these investigations are currently in the early stages of clinical application, they present promising prospects for gene therapy. (PROSPERO registry: CRD42023479448).

Brugada syndrome (BS) is characterized by ST segment elevation in right precordial leads (V1-V3), ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD) in individuals without structural heart disease. The aim of this study is to contribute to the controversial issue of finding the most valuable marker that can predict poor prognosis during follow-up in patients with a diagnosis of BS. A total of 68 patients diagnosed with BS or had Brugada-type ECG change between January 1997 and July 2012 at the Department of Cardiology of Başkent University Faculty of Medicine, Ankara, Turkey, were included in this cohort study. Patients were screened every 6 months for arrhythmia-related syncope, SCD, appropriate and inappropriate defibrillation (shock), AF development and death; collectively defined as "arrhythmic events" and were the primary endpoints. Patients with and without arrhythmic events were compared. The mean age was 34.9 ± 12.2 years (9-71 years), and 52 (76.5%) patients were male. Mean follow-up was 49.6 ± 37.6 months (4-188 months). Univariate analysis showed that male sex (P = .004), type 1 electrocardiographic pattern (P = .008), SCD (P = .036), VT/VF history (P = .046), requirement for electrophysiological studies (P = .034), implantable cardioverter-defibrillator placement (P = .014) were found to demonstrate significant differences in patients with and without arrhythmic events. In multivariable analyzes, spontaneous type 1 ECG presence (HR = 8.54, 95% CI: 0.38-26.37; P = .003) and VT/VF history (HR = 9.21, 95% CI: 0.004-1.88; P = .002) were found to be independently associated with arrhythmic events. We found the presence of spontaneous type 1 ECG and a history of VT/VF to be associated with increased likelihood of overall arrhythmic events in BS. Given the higher risk of poor prognosis, we recommend additional measures in patients with BS who have these features.

Genetic variants of gene SCN5A encoding the alpha-subunit of cardiac voltage-gated sodium channel Nav1.5 are associated with various diseases, including long QT syndrome (LQT3), Brugada syndrome (BrS1), and progressive cardiac conduction disease (PCCD). In the last decades, the great progress in understanding molecular and biophysical mechanisms of these diseases has been achieved. The LQT3 syndrome is associated with gain-of-function of sodium channels Nav1.5 due to impaired inactivation, enhanced activation, accelerated recovery from inactivation or the late current appearance. In contrast, BrS1 and PCCD are associated with the Nav1.5 loss-of-function, which in electrophysiological experiments can be manifested as reduced current density, enhanced fast or slow inactivation, impaired activation, or decelerated recovery from inactivation. Genetic variants associated with congenital arrhythmias can also disturb interactions of the Nav1.5 channel with different proteins or drugs and cause unexpected reactions to drug administration. Furthermore, mutations can affect post-translational modifications of the channels and their sensitivity to pH and temperature. Here we briefly review the current knowledge on biophysical mechanisms of LQT3, BrS1 and PCCD. We focus on limitations of studies that use heterologous expression systems and induced pluripotent stem cells (iPSC) derived cardiac myocytes and summarize our understanding of genotype-phenotype relations of SCN5A mutations.

The development of the cardiogenetics field in Germany has been increasing since the mid-1990s with many national contributions, some of them were really important and groundbreaking. The starting point was and still is the patient and his family, e.g. with a familial form of arrhythmia or cardiomyopathy, the clarification of the genetic cause and the personalized treatment of those being affected. The scientific, always translationally oriented interest in identifying a causative gene and uncovering the underlying pathomechanisms has led to notable contributions for Brugada syndrome, short QT syndrome and cardiac conduction disorders or sinus node dysfunction, but also in DCM or ARVC. What is important, however, is always the way back (bench > bed side): implementation of national and international recommendations for cardiogenetic diagnostics in daily cardiological routine and the personalized care and therapy of those being affected.

Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter IKr-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on IKr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the IKr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.

Pediatric cardiomyopathies (CMs) and electrical diseases constitute a heterogeneous spectrum of disorders distinguished by structural and electrical abnormalities in the heart muscle, attributed to a genetic variant. They rank among the main causes of morbidity and mortality in the pediatric population, with an annual incidence of 1.1-1.5 per 100,000 in children under the age of 18. The most common conditions are dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Despite great enthusiasm for research in this field, studies in this population are still limited, and the management and treatment often follow adult recommendations, which have significantly more data on treatment benefits. Although adult and pediatric cardiac diseases share similar morphological and clinical manifestations, their outcomes significantly differ. This review summarizes the latest evidence on genetics, clinical characteristics, management, and updated outcomes of primary pediatric CMs and electrical diseases, including DCM, HCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), and short QT syndrome (SQTS).

Pilsicainide is a class Ic antiarrhythmic agent that exhibits fully selective sodium channel blockade. In Japan, it is one of the most prescribed medicines for rhythm control in atrial fibrillation. Pilsicainide is mainly excreted by the kidney. Therefore, the plasma concentration of pilsicainide is likely to be increased in patients with renal insufficiency. In this case report, a 90-year-old woman presented with generalized fatigue and loss of appetite. Her ECG showed marked bradycardia and coved-type ST-segment elevation similar to that of the Brugada type 1 pattern. Owing to dehydration, her renal function indices worsened compared with those measured four months prior. The plasma pilsicainide concentration was elevated to 2.67 µg/mL (therapeutic range: 0.20-0.90 µg/mL), indicating pilsicainide toxicity. A transvenous temporary pacemaker was placed; however, the pacing voltage threshold was increased at several sites within the right ventricle. Pilsicainide administration was immediately discontinued. On day 2 of admission, ventricular backup pacing was no longer required, and there was an improvement in renal function and heart failure symptoms, such as pulmonary edema and cardiomegaly. The ECG changes improved alongside the renal function and as the plasma concentration of pilsicainide decreased. In conclusion, elevated plasma concentrations of pilsicainide can induce life-threatening arrhythmias and pacing failure. Therefore, clinicians should prescribe pilsicainide cautiously, particularly in older patients.

Although there is consensus on the management of patients with Brugada Syndrome with high risk for sudden cardiac arrest, asymptomatic or intermediate-risk patients present clinical management challenges. This document explores the management opinions of experts throughout the world for patients with Brugada Syndrome who do not fit guideline recommendations. Four real-world clinical scenarios were presented with commentary from small expert groups for each case. All authors voted on case-specific questions to evaluate the level of consensus among the entire group in nuanced diagnostic and management decisions relevant to each case. Points of agreement, points of controversy, and gaps in knowledge are highlighted.

The aim of this study was to investigate the outcomes of catheter ablation (CA) in preventing arrhythmic events among patients with symptomatic Brugada syndrome (BrS) who declined implantable cardioverter defibrillator (ICD) implantation.

A total of 40 patients with symptomatic BrS were included in the study, of which 18 refused ICD implantation and underwent CA, while 22 patients received ICD implantation. The study employed substrate modification (including endocardial and epicardial approaches) and ventricular fibrillation (VF)-triggering pre-mature ventricular contraction (PVC) ablation strategies. The primary outcomes were a composite endpoint consisting of episodes of VF and sudden cardiac death during the follow-up period. The study population had a mean age of 43.8 ± 9.6 years, with 36 (90.0%) of them being male. All patients exhibited the typical Type 1 BrS electrocardiogram pattern, and 16 (40.0%) were carriers of an SCN5A mutation. The Shanghai risk scores were comparable between the CA and the ICD groups (7.05 ± 0.80 vs. 6.71 ± 0.86, P = 0.351). Ventricular fibrillation-triggering PVCs were ablated in 3 patients (16.7%), while VF substrates were ablated in 15 patients (83.3%). Epicardial ablation was performed in 12 patients (66.7%). During a median follow-up of 46.2 (17.5-73.7) months, the primary outcomes occurred more frequently in the ICD group than in the CA group (5.6 vs. 54.5%, Log-rank P = 0.012).

Catheter ablation is an effective alternative therapy for improving arrhythmic outcomes in patients with symptomatic BrS who decline ICD implantation. Our findings support the consideration of CA as an alternative treatment option in this population.

In Brugada syndrome (BrS), with spontaneous or ajmaline-induced coved ST elevation, epicardial electro-anatomic potential duration maps (epi-PDMs) were detected on a right ventricle (RV) outflow tract (RVOT), an arrhythmogenic substrate area (AS area), abolished by epicardial-radiofrequency ablation (EPI-AS-RFA). Novel CineECG, projecting 12-lead electrocardiogram (ECG) waveforms on a 3D heart model, previously localized depolarization forces in RV/RVOT in BrS patients. We evaluate 12-lead ECG and CineECG depolarization/repolarization changes in spontaneous type-1 BrS patients before/after EPI-AS-RFA, compared with normal controls.

In 30 high-risk BrS patients (93% males, age 37 + 9 years), 12-lead ECGs and epi-PDMs were obtained at baseline, early after EPI-AS-RFA, and late follow-up (FU) (2.7-16.1 months). CineECG estimates temporo-spatial localization during depolarization (Early-QRS and Terminal-QRS) and repolarization (ST-Tpeak, Tpeak-Tend). Differences within BrS patients (baseline vs. early after EPI-AS-RFA vs. late FU) were analysed by Wilcoxon signed-rank test, while differences between BrS patients and 60 age-sex-matched normal controls were analysed by the Mann-Whitney test. In BrS patients, baseline QRS and QTc durations were longer and normalized after EPI-AS-ATC (151 ± 15 vs. 102 ± 13 ms, P < 0.001; 454 ± 40 vs. 421 ± 27 ms, P < 0.000). Baseline QRS amplitude was lower and increased at late FU (0.63 ± 0.26 vs. 0.84 ± 13 ms, P < 0.000), while Terminal-QRS amplitude decreased (0.24 ± 0.07 vs. 0.08 ± 0.03 ms, P < 0.000). At baseline, CineECG depolarization/repolarization wavefront prevalently localized in RV/RVOT (Terminal-QRS, 57%; ST-Tpeak, 100%; and Tpeak-Tend, 61%), congruent with the AS area on epi-PDM. Early after EPI-AS-RFA, RV/RVOT localization during depolarization disappeared, as Terminal-QRS prevalently localized in the left ventricle (LV, 76%), while repolarization still localized on RV/RVOT [ST-Tpeak (44%) and Tpeak-Tend (98%)]. At late FU, depolarization/repolarization forces prevalently localized in the LV (Terminal-QRS, 94%; ST-Tpeak, 63%; Tpeak-Tend, 86%), like normal controls.

CineECG and 12-lead ECG showed a complex temporo-spatial perturbation of both depolarization and repolarization in BrS patients, prevalently localized in RV/RVOT, progressively normalizing after epicardial ablation.

Brugada syndrome (BrS), a genetically inherited ion channelopathy, has been linked to a considerable number of unexplained sudden cardiac deaths in patients without structural heart defects, and Brugada phenocopy (BrP) is a condition where there is an identical electrocardiogram (ECG) pattern to a congenital BrS, but this is due to other reversible etiologies. A 37-year-old male patient with a documented history of hypertension presented with vomiting after taking 43, 10 mg, melatonin pills and binge drinking locally made alcohol 2 days before. ECG showed right ventricular conduction delay with a "saddleback" appearance, with the J point elevated more than 2 mm and the terminal portion of the ST-segment elevated more than 1 mm in leads V1 and/or V2. Which returned to normal after a few hours. The association between the use of melatonin and the finding of the Brugada pattern (BP) in a patient with normal heart structure or abnormal ECGs has been documented in much literature, and although no official melatonin dosage is recommended for adults, melatonin has been reported to cause and protect from arrhythmias through different mechanisms. In our patient, after alcohol intoxication was ruled out as a cause, melatonin was the only significant risk factor related to his ECG findings. The BP can be found in patients with otherwise normal heart structure and ECG records, and an overdose of melatonin, which is used as an over-the-counter sleep medication, was found to be a possible cause of finding this pattern in these patients after excluding other known causes.

Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked recessive neurodegenerative disorder caused by the excessive expansion of cytosine-adenine-guanine repeat sequences in the androgen receptor gene encoded on the Xq11-12 chromosome. SBMA primarily affects adult males and is characterized by weakness and atrophy of the proximal limb muscles, often involving the bulbar muscles. In addition to neuromuscular deficits, nonneuronal symptoms such as hypertension, hyperlipidemia, and liver dysfunction are often observed in patients with SBMA. Previous studies have suggested that SBMA patients have been diagnosed with hypertrophic cardiomyopathy (HCM), while gene detection is lacked. Moreover, according to current reports, SBMA patients can carry Brugada syndrome or HCM respectively, while three kinds of diseases have not been reported to exist in the same patient. Here, we report the first case of a male diagnosed with SBMA combined with HCM and two types of Brugada-pattern electrocardiographic changes, with a heterozygous missense mutation in the TTN gene.

Understanding the circumstances, leading to unmasking of hidden Brugada syndrome is essential for the practicing clinician and the patients so that they are informed adequately to seek prompt medical attention.

Brugada syndrome is a genetic arrhythmia syndrome characterized by a coved type of ST-segment elevation in the ECG. The patients are usually asymptomatic, with unmasking of the disease under certain conditions. We are reporting the case of a patient diagnosed with Brugada syndrome, which was unmasked during an attack of dengue fever.