The importance of variant reinterpretation in inherited cardiovascular diseases: Establishing the optimal timeframe.

Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.

Brugada Syndrome and Pulmonary Atresia with Intact Interventricular Septum: Fortuitous Finding or New Genetic Connection?

Brugada syndrome is a rare arrhythmogenic syndrome associated mainly with pathogenic variants in the SCN5A gene. Right ventricle outflow tract fibrosis has been reported in some cases of patients diagnosed with Brugada syndrome. Pulmonary atresia with an intact ventricular septum is characterized by the lack of a functional pulmonary valve, due to the underdevelopment of the right ventricle outflow tract. We report, for the first time, a 4-year-old boy with pulmonary atresia with an intact ventricular septum who harbored a pathogenic de novo variant in SCN5A, and the ajmaline test unmasked a type-1 Brugada pattern. We suggest that deleterious variants in the SCN5A gene could be implicated in pulmonary atresia with an intact ventricular septum embryogenesis, leading to overlapping phenotypes.

Long-term follow-up of patients with Brugada syndrome: Foremost risk factors associated with overall arrhythmic events.

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 Baskent 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 ±â€…12.2 years (9-71 years), and 52 (76.5%) patients were male. Mean follow-up was 49.6 ±â€…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.

Molecular Autopsy With Banked Cord Blood Reveals Brugada Syndrome in Past Sudden Death Case.

Molecular autopsy has recently been gaining attention as a means of postmortem diagnosis; however, it is usually performed using the victim's blood sample at the time of death. Here, we report the first case of a deceased infant with Brugada syndrome whose diagnosis was made with banked cord blood. A seemingly healthy 1-year-old male infant collapsed while having a fever; this collapse was witnessed by his mother. Despite cardiopulmonary resuscitation, he died of ventricular fibrillation. No abnormalities of cardiac structure were identified on autopsy. Genomic samples were not stored at the time because of a lack of suspicion for familial arrhythmia. Five years later, his sister showed Brugada electrocardiogram pattern while febrile from Kawasaki disease. Their father showed a spontaneous type 1 Brugada electrocardiogram pattern. A heterozygous SCN5A p.R893C variant was found by genetic testing in the proband's father and sister. Furthermore, the proband's genetic testing was performed using his banked cord blood, which identified the same variant. Family history of Brugada syndrome with an SCN5A-R893C variant and clinical evidence led to a postmortem diagnosis of Brugada syndrome in the proband. Identification of this variant in this case later contributed to verifying SCN5A-R893C as a pathogenic variant through data accumulation. Banked cord blood may prove useful for conducting molecular autopsies in previously undiagnosed cases of sudden death in which genomic samples were not stored.

Relationship Between Brugada Syndrome and Ischemic Stroke: A Case Report and Comprehensive Literature Review.

BACKGROUND Brugada syndrome is characterized by specific electrocardiographic changes predisposing individuals to ventricular arrhythmias and sudden cardiac death. Cases of coexisting Brugada syndrome and ischemic stroke are seldom documented, and an underlying pathophysiological link is yet unknown. This article presents a case in which a patient exhibited both Brugada syndrome patterns and an ischemic stroke, prompting a comprehensive literature review to explore the potential association between Brugada syndrome and ischemic stroke. CASE REPORT A 49-year-old man, previously healthy, was admitted to the hospital after being discovered unconscious at his workplace. Physical exam showed low oxygen saturation, fever, and abnormal neurological findings. Head computed tomography revealed a significant posterior circulation ischemic stroke. An electrocardiogram revealed Brugada syndrome type II initially, progressing to type III pattern. Despite efforts, the patient's condition rapidly deteriorated, leading to death within 24 hours. As far as we're aware, Brugada patterns following a posterior circulation ischemic stroke have only been documented in 1 other instance, in which the patient was also diagnosed with atrial fibrillation. CONCLUSIONS Both our literature review and the presented case indicate that Brugada patterns may coexist with and even be associated with ischemic stroke. More extensive research is required to shed light on this potential association. The question of whether Brugada syndrome is a precursor to or a result of ischemic stroke remains unanswered. We propose that patients with ischemic stroke should undergo an evaluation for electrocardiographic signs indicative of Brugada syndrome, particularly if no clear causes, like cardioembolism, are evident.

Predicting and Recognizing Drug-Induced Type I Brugada Pattern Using ECG-Based Deep Learning.

BACKGROUND: Brugada syndrome (BrS) has been associated with sudden cardiac death in otherwise healthy subjects, and drug-induced BrS accounts for 55% to 70% of all patients with BrS. This study aims to develop a deep convolutional neural network and evaluate its performance in recognizing and predicting BrS diagnosis. METHODS AND RESULTS: Consecutive patients who underwent ajmaline testing for BrS following a standardized protocol were included. ECG tracings from baseline and during ajmaline were transformed using wavelet analysis and a deep convolutional neural network was separately trained to (1) recognize and (2) predict BrS type I pattern. The resultant networks are referred to as BrS-Net. A total of 1188 patients were included, of which 361 (30.3%) patients developed BrS type I pattern during ajmaline infusion. When trained and evaluated on ECG tracings during ajmaline, BrS-Net recognized a BrS type I pattern with an AUC-ROC of 0.945 (0.921-0.969) and an AUC-PR of 0.892 (0.815-0.939). When trained and evaluated on ECG tracings at baseline, BrS-Net predicted a BrS type I pattern during ajmaline with an AUC-ROC of 0.805 (0.845-0.736) and an AUC-PR of 0.605 (0.460-0.664). CONCLUSIONS: BrS-Net, a deep convolutional neural network, can identify BrS type I pattern with high performance. BrS-Net can predict from baseline ECG the development of a BrS type I pattern after ajmaline with good performance in an unselected population.

Brugada phenocopy vs. Brugada syndrome: Delineating the differences for optimal diagnosis and management.

Brugada syndrome (BrS) is a genetic disorder known for its characteristic electrocardiogram (ECG) patterns and increased risk of sudden cardiac death. Brugada phenocopy (BrP) presents similar ECG patterns but is distinguished by its reversible nature when the underlying conditions are resolved. This article delineates the intricacies of BrP, emphasizing its etiology, clinical presentation, diagnosis, treatment, and prognosis. The article categorizes BrP based on various underlying causes, including metabolic disturbances, myocardial infarction, and mechanical compression, among others. It also underscores the critical importance of differentiating BrP from BrS to avoid misdiagnosis and inappropriate treatment, such as unnecessary implantation of cardioverter-defibrillators. The reversible aspect of BrP underlines the necessity for an etiology-specific approach to treatment, which not only prevents cardiac death but also highlights the significance of understanding the dynamic nature of ECG patterns. Through an exploration of case studies and current research, this review advocates for increased awareness and further investigation into BrP. It aims to enhance the diagnostic accuracy and management strategies, thereby improving the prognosis for patients presenting with Brugada-like ECG patterns. The review culminates in a call for further research to close existing knowledge gaps and improve patient outcomes.

The role for ambulatory electrocardiogram monitoring in the diagnosis and prognostication of Brugada syndrome: a sub-study of the Rare Arrhythmia Syndrome Evaluation (RASE) Brugada study.

AIMS: Brugada syndrome (BrS) diagnosis and risk stratification rely on the presence of a spontaneous type 1 (spT1) electrocardiogram (ECG) pattern; however, its spontaneous fluctuations may lead to misdiagnosis and risk underestimation. This study aims to assess the role for repeat high precordial lead (HPL) resting and ambulatory ECG monitoring in identifying a spT1, and evaluate its prognostic role. METHODS AND RESULTS: HPL resting and ambulatory monitoring ECGs of BrS subjects were reviewed retrospectively, and the presence of a spT1 associated with ventricular dysrhythmias and sudden cardiac death (SCD). Three-hundred and fifty-eight subjects (77 with spT1 pattern at presentation, Group 1, and 281 without, Group 2) were included. In total, 1651 resting HPL resting and 621 ambulatory monitoring ECGs were available for review, or adequately described. Over a median follow-up of 72 months (interquartile range - IQR - 75), 42/77 (55%) subjects in Group 1 showed a spT1 in at least one ECG. In Group 2, 36/281 subjects (13%) had a newly detected spT1 (1.9 per 100 person-year) and 23 on an HPL ambulatory recording (8%). Seven previously asymptomatic subjects, five of whom had a spT1 (four at presentation and one at follow-up), experienced arrhythmic events; survival analysis indicated that a spT1, either at presentation or during lifetime, was associated with events. Univariate models showed that a spT1 was consistently associated with increased risk [spT1 at presentation: hazard ratio (HR) 6.3, 95% confidence interval (CI) 1.4-28, P = 0.016; spT1 at follow-up: HR 3.1, 95% CI 1.3-7.2, P = 0.008]. CONCLUSION: Repeated ECG evaluation and HPL ambulatory monitoring are vital in identifying transient spT1 Brugada pattern and its associated risk.

Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening.

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.

When to ablate in Brugada and early repolarization syndromes.

INTRODUCTION: Mapping advances have expanded both the feasibility and benefits of ablation as a therapeutic approach, including in the treatment of two heart conditions that contribute to sudden cardiac death in young people: Brugada syndrome (BrS) and early repolarization syndrome (ERS). Although these conditions share a number of similarities, debates persist regarding the underlying pathophysiology and origin of the ventricular arrhythmias associated with them. AREAS COVERED: By synthesizing available data (PubMed), including current recommendations, pathophysiological insights and case reports, patient registries, our aim is to elucidate and establish the nuanced role of radiofrequency ablation (RFA) in therapeutic management. EXPERT OPINION: RFA is a particularly promising approach in BrS, with a proven long-term benefit. Concerning ERS, RFA seems to be interesting at the price of more complex procedures with more nuanced results.

Genetic Testing in Brugada Syndrome: A 30-Year Experience.

BACKGROUND: A pathogenic/likely pathogenic variant can be found in 20% to 25% of patients with Brugada syndrome (BrS) and a pathogenic/likely pathogenic variant in SCN5A is associated with a worse prognosis. The aim of this study is to define the diagnostic yield of a large gene panel with American College of Medical Genetics and Genomics variant classification and to assess prognosis of SCN5A and non-SCN5A variants. METHODS: All patients with BrS, were prospectively enrolled in the Universitair Ziekenhuis Brussel registry between 1992 and 2022. Inclusion criteria for the study were (1) BrS diagnosis; (2) genetic analysis performed with a large gene panel; (3) classification of variants following American College of Medical Genetics and Genomics guidelines. Patients with a pathogenic/likely pathogenic variant in SCN5A were defined as SCN5A+. Patients with a reported variant in a non-SCN5A gene or with no reported variants were defined as patients with SCN5A-. All variants were classified as missense or predicted loss of function. RESULTS: A total of 500 BrS patients were analyzed. A total of 104 patients (20.8%) were SCN5A+ and 396 patients (79.2%) were SCN5A-. A non-SCN5A gene variant was found in 75 patients (15.0%), of whom, 58 patients (77.3%) had a missense variant and 17 patients (22.7%) had a predicted loss of function variant. At a follow-up of 84.0 months, 48 patients (9.6%) experienced a ventricular arrhythmia (VA). Patients without any variant had higher VA-free survival, compared with carriers of a predicted loss of function variant in SCN5A+ or non-SCN5A genes. There was no difference in VA-free survival between patients without any variant and missense variant carriers in SCN5A+ or non-SCN5A genes. At Cox analysis, SCN5A+ or non-SCN5A predicted loss of function variant was an independent predictor of VA. CONCLUSIONS: In a large BrS cohort, the yield for SCN5A+ is 20.8%. A predicted loss of function variant carrier is an independent predictor of VA.

Endocardial repolarization dispersion in BrS: A novel automatic algorithm for mapping activation recovery interval.

INTRODUCTION: Repolarization dispersion in the right ventricular outflow tract (RVOT) contributes to the type-1 electrocardiographic (ECG) phenotype of Brugada syndrome (BrS), while data on the significance and feasibility of mapping repolarization dispersion in BrS patients are scarce. Moreover, the role of endocardial repolarization dispersion in BrS is poorly investigated. We aimed to assess endocardial repolarization patterns through an automated calculation of activation recovery interval (ARI) estimated on unipolar electrograms (UEGs) in spontaneous type-1 BrS patients and controls; we also investigated the relation between ARI and right ventricle activation time (RVAT), and T-wave peak-to-end interval (Tpe) in BrS patients. METHODS: Patients underwent endocardial high-density electroanatomical mapping (HDEAM); BrS showing an overt type-1 ECG were defined as OType1, while those without (latent type-1 ECG and LType1) received ajmaline infusion. BrS patients only underwent programmed ventricular stimulation (PVS). Data were elaborated to obtain ARI corrected with the Bazett formula (ARIc), while RVAT was derived from activation maps. RESULTS: 39 BrS subjects (24 OType1 and 15 LTtype1) and 4 controls were enrolled. OType1 and post-ajmaline LType1 showed longer mean ARIc than controls (306 ± 27.3 ms and 333.3 ± 16.3 ms vs. 281.7 ± 10.3 ms, p = .05 and p < .001, respectively). Ajmaline induced a significant prolongation of ARIc compared to pre-ajmaline LTtype1 (333.3 ± 16.3 vs. 303.4 ± 20.7 ms, p < .001) and OType1 (306 ± 27.3 ms, p < .001). In patients with type-1 ECG (OTtype1 and post-ajmaline LType1) ARIc correlated with RVAT (r = .34, p = .04) and Tpec (r = .60, p < .001), especially in OType1 subjects (r = .55, p = .008 and r = .65 p < .001, respectively). CONCLUSION: ARIc mapping demonstrates increased endocardial repolarization dispersion in RVOT in BrS. Endocardial ARIc positively correlates with RVAT and Tpec, especially in OType1.

Implantable loop recorders in patients with Brugada syndrome: the BruLoop study.

BACKGROUND AND AIMS: Available data on continuous rhythm monitoring by implantable loop recorders (ILRs) in patients with Brugada syndrome (BrS) are scarce. The aim of this multi-centre study was to evaluate the diagnostic yield and clinical implication of a continuous rhythm monitoring strategy by ILRs in a large cohort of BrS patients and to assess the precise arrhythmic cause of syncopal episodes. METHODS: A total of 370 patients with BrS and ILRs (mean age 43.5 ± 15.9, 33.8% female, 74.1% symptomatic) from 18 international centers were included. Patients were followed with continuous rhythm monitoring for a median follow-up of 3 years. RESULTS: During follow-up, an arrhythmic event was recorded in 30.7% of symptomatic patients [18.6% atrial arrhythmias (AAs), 10.2% bradyarrhythmias (BAs), and 7.3% ventricular arrhythmias (VAs)]. In patients with recurrent syncope, the aetiology was arrhythmic in 22.4% (59.3% BAs, 25.0% VAs, and 15.6% AAs). The ILR led to drug therapy initiation in 11.4%, ablation procedure in 10.9%, implantation of a pacemaker in 2.5%, and a cardioverter-defibrillator in 8%. At multivariate analysis, the presence of symptoms [hazard ratio (HR) 2.5, P = .001] and age >50 years (HR 1.7, P = .016) were independent predictors of arrhythmic events, while inducibility of ventricular fibrillation at the electrophysiological study (HR 9.0, P < .001) was a predictor of VAs. CONCLUSIONS: ILR detects arrhythmic events in nearly 30% of symptomatic BrS patients, leading to appropriate therapy in 70% of them. The most commonly detected arrhythmias are AAs and BAs, while VAs are detected only in 7% of cases. Symptom status can be used to guide ILR implantation.

Severe hypothyroidism as a trigger for Brugada-type ECG abnormalities: a case report and literature review.

Brugada syndrome (BrS) is an inherited disorder that can cause ventricular fibrillation and sudden cardiac death in individuals with otherwise structurally normal hearts. Several provoking factors are known to potentially unmask or exacerbate a typical Brugada ECG pattern in predisposed subjects. Hypothyroidism has been suggested as one of these triggers, but the exact mechanisms underlying this relationship remain poorly understood. Moreover, the severity of thyroid dysfunction beyond which a Brugada-type ECG alteration might be triggered is still unclear. We report the case of a 33-year-old male who displayed a Brugada type 1 ECG pattern and was diagnosed with severe hypothyroidism (TSH > 100 mU/L with undetectable levels of fT4 and fT3). Hormonal replacement therapy with levothyroxine was initiated at increasing doses; serial biochemical and ECG controls were performed, initially every 3 weeks up to 15 weeks and afterward every 3 months. The regression of typical Brugada ECG waveforms could be seen at an early stage, when the patient was still taking a low dose of levothyroxine (37.5 µg/day, i.e., one-fourth of his final requirements of 150 µg/day), and laboratory tests still showed a marked alteration of thyroid hormonal parameters. Hypothyroidism may act as a trigger for Brugada-type ECG abnormalities, but a very severe alteration of the hormonal parameters is necessary to prompt these alterations. In our case, the initiation of replacement therapy with levothyroxine rapidly reversed the ECG modifications, even at a low subtherapeutic dose.

[Cardiogenetics in Germany- a view and review]. / Kardiogenetik in Deutschland ­ ein (Rück­)Blick.

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.

Late life-threatening arrhythmia in patients with Brugada syndrome: Results from long-term follow-up in a large Japanese cohort.

INTRODUCTION: Most patients with Brugada syndrome (BrS) are first diagnosed in their 40s, with sudden cardiac death (SCD) often occurring in their 50s. Ventricular fibrillation (VF) may occur in some patients with BrS despite having been asymptomatic for a long period. This study aimed to assess the incidence and risk factors for late life-threatening arrhythmias in patients with BrS. METHODS: Patients with BrS (n = 523; mean age, 51 ± 13 years; male, n = 497) were enrolled. The risk of late life-threatening arrhythmia was investigated in 225 patients who had experienced no cardiac events (CEs: SCD or ventricular tachyarrhythmia) for at least 10 years after study enrollment. The incidence of CEs during the follow-up period was examined. RESULTS: During the follow-up of the 523 patients, 59 (11%) experienced CEs. The annual incidences of CEs were 2.87%, 0.77%, and 0.09% from study enrollment to 3, 3-10, and after 10 years, respectively. Among 225 patients who had experienced no CEs for at least 10 years after enrollment, four patients (1.8%) subsequently experienced CEs. Kaplan-Meier analysis revealed significant differences in the incidence of late CEs between patients with and without a history of symptoms (p = .032). The positive and negative predictive values of late CEs for the programmed electrical stimulation (PES) test were 2.9% and 100%, respectively. CONCLUSION: Our results suggest that patients with BrS who are asymptomatic and have no ventricular tachycardia/VF inducibility by PES are at extremely low risk of experiencing late life-threatening arrhythmias.