Cardiac Channelopathies in the Pediatric Patient: Brugada Syndrome.

Sodium channelopathy with an overlap of Brugada syndrome, paroxysmal atrial fibrillation, and progressive cardiac conduction system dysfunction

Funding Acknowledgements Type of funding sources: None. Background/introduction A pathogenic/likely pathogenic (P/LP) variant can be found in 20-25% of patients with Brugada syndrome (BrS) and a P/LP variant in SCN5A is associated with a worse prognosis. However, the diagnostic yield and the prognosis of gene testing in pediatric BrS syndrome is unclear. Purpose The aim of this study is to define the diagnostic yield of SCN5A gene testing with ACMG standardized variant classification in a large cohort of pediatric BrS. Furthermore, a correlation between the clinical outcomes and the genetic background of children with BrS in comparison with adult BrS is aimed. Methods All consecutive patients diagnosed with BrS, between 1992 and 2022 were enrolled in a prospective monocentric registry. Inclusion criteria were: 1) BrS diagnosis; 2) Genetic analysis for SCN5A gene and 3) classification of gene variants following current ACMG guidelines. Pediatric patients were defined if ≤ 12 years of age. The primary endpoint was ventricular arrhythmias (VA) occurrence, defined as documented SCD, aborted SCD, ventricular tachycardia or ventricular fibrillation or appropriate ICD intervention. Results A total of 500 BrS patients were included, 41 pediatric patients and 459 adult patients. Among children with BrS, 19 patients (46.3%) had a P/LP variant (P+) in SCN5A gene. No P/LP variants could be identified in 22 (53.7%) pediatric patients (P-). After a mean follow-up of 140.2 months, 3 children (7.3%) experienced a VA, treated with appropriate ICD shock. Inappropriate shocks occurred in 3 pediatric patients (7.3%). At survival analysis, P- pediatric patients had higher VA free survival during the follow-up, compared with P+ pediatric patients (Log-Rank p=0.021), Figure 1. There was no difference in VA free survival between pediatric and adult BrS patients both without (P-), (Log-Rank p=0.19) and with (P+) a P/LP variant (Log-Rank p=0.91), Figure 2. Conclusion In a large BrS cohort, the diagnostic yield for SCN5A P/LP variants in the pediatric population is 46.3%. P+ children with BrS have a worse arrhythmic prognosis.

AimsA pathogenic/likely pathogenic (P/LP) variant in SCN5A is found in 20–25% of patients with Brugada syndrome (BrS). However, the diagnostic yield and prognosis of gene panel testing in paediatric BrS is unclear. The aim of this study is to define the diagnostic yield and outcomes of SCN5A gene testing with ACMG variant classification in paediatric BrS patients compared with adults.Methods and resultsAll consecutive patients diagnosed with BrS, between 1992 and 2022, were prospectively enrolled in the UZ Brussel BrS registry. Inclusion criteria were: (i) BrS diagnosis; (ii) genetic analysis performed with a large gene panel; and (iii) classification of gene variants following ACMG guidelines. Paediatric patients were defined as ≤16 years of age. The primary endpoint was ventricular arrhythmias (VAs). A total of 500 BrS patients were included, with 63 paediatric patients and 437 adult patients. Among children with BrS, 29 patients (46%) had a P/LP variant (P+) in SCN5A and no variants were found in 34 (54%) patients (P−). After a mean follow-up of 125.9 months, 8 children (12.7%) experienced a VA, treated with implanted cardioverter defibrillator shock. At survival analysis, P− paediatric patients had higher VA-free survival during the follow-up, compared with P+ paediatric patients. P+ status was an independent predictor of VA. There was no difference in VA-free survival between paediatric and adult BrS patients for both P− and P+.ConclusionIn a large BrS cohort, the diagnostic yield for P/LP variants in the paediatric population is 46%. P+ children with BrS have a worse arrhythmic prognosis.

COVID-19 Infection Unmasking Brugada Syndrome

Quinidine effective for the management of ventricular and atrial arrhythmias associated with Brugada syndrome

Asyndrome characterized by ST-segment elevation in right precordial leads (V1 to V3) that is unrelated to ischemia, electrolyte disturbances, or obvious structural heart disease was reported as early as 1953,1 but was first described as a distinct clinical entity associated with a high risk of sudden cardiac death in 1992.2–4⇓⇓ The Brugada syndrome is a familial disease that displays an autosomal dominant mode of transmission, with incomplete penetrance and an incidence ranging between 5 and 66 per 10 000. In regions of Southeast Asia where it is endemic, the clinical presentation of Brugada syndrome is distinguished by a male predominance (8:1 ratio of male:female) and the appearance of arrhythmic events at an average age of 40 years (range: 1 to 77 years).2,5⇓ Although a number of candidate genes are considered plausible, thus far the syndrome has been linked only to mutations in SCN5A , the gene encoding for the α subunit of the sodium channel.6 A number of ambiguities exist concerning the diagnosis of Brugada syndrome. The electrocardiographic signature of the syndrome is dynamic and often concealed, but can be unmasked by potent sodium channel blockers such as flecainide, ajmaline, and procainamide,7 although the specificity of this effect for uncovering patients at risk for sudden death has been an issue of concern. A recent report by Remme et al8 has shown that the number of idiopathic ventricular fibrillation patients diagnosed as having Brugada syndrome is a sensitive function of the diagnostic criteria applied. What are the proper diagnostic criteria for identifying Brugada syndrome? A definitive answer to this question has been out of reach and is the reason for the establishment of a special Arrhythmia Working Group of the European Society of Cardiology that met from August 31 to …

Electrical storm in a febrile patient with Brugada syndrome and COVID-19 infection

Sleep is generally considered to be a protected period, when the cardiovascular system benefits from the restorative influences of the sleeping brain. However, the dynamics of cardiovascular control during sleep can tax the capacity of the diseased coronary circulation and myocardium with surges in sleep-state–related autonomic activity and disruptions in airway function and central nervous system regulation. In this regard, sleep may constitute an autonomic stress test for the heart. The scope of sleep-related risk for atrial and ventricular arrhythmias is substantial. The major subgroups susceptible to adverse influences of surges in autonomic activity during sleep are those with ischemic heart disease, heart failure, and channelopathies (Table).1 It is significant that 20% of myocardial infarctions and 15% of sudden deaths occur at night in the United States.2 Most atrial arrhythmias in patients younger than 61 years of age have nocturnal onset.3 The young are not immune to risk, as sudden infant death syndrome (SIDS) claims 2500 lives in the United States annually.4 Cardiovascular risk is compounded by comorbid factors, most notably apnea, which affects an estimated 4% to 9% of the general population5 and is considerably more prevalent among obese individuals.6 The more common form is obstructive sleep apnea (OSA), with partial or complete collapse of the pharynx. Half of heart failure patients experience either OSA or central sleep apnea (CSA) with central nervous system–mediated periodic breathing, commonly referred to as Cheyne-Stokes respiration. Such cardiorespiratory disturbances profoundly alter autonomic nervous system activity and increase risk of arrhythmia, hypertension, and myocardial infarction. View this table: Table. Patient Groups at Potentially Increased Risk for Nocturnal Cardiac Events It is surprising, as recently underscored by Malhotra and Loscalzo,7 that the significance of cardiovascular risk during sleep may not be duly recognized within the cardiology community. The reasons are …

Brugada syndrome (BrS) is a rare inherited arrhythmia syndrome. Affected children may experience life-threatening symptoms, mainly during fever. The percentage of SCN5A variant carriers in children is higher than in adults. Current diagnostic and follow-up policies for children with (a family history of) BrS vary between centres. Here, we present a consensus statement based on the current literature and expert opinions to standardise the approach for all children with BrS and those from BrS families in the Netherlands. In summary, BrS is diagnosed in patients with a spontaneous type 1 electrocardiogram (ECG) pattern or with a Shanghai score ≥ 3.5 including ≥ 1 ECG finding. A sodium channel-blocking drug challenge test should only be performed after puberty with a few exceptions. A fever ECG is indicated in children with suspected BrS, in children with a first-degree family member with definite or possible BrS according to the Shanghai criteria with a SCN5A variant and in paediatric SCN5A variant carriers. In-hospital rhythm monitoring during fever is indicated in patients with an existing type 1 ECG pattern and in those who develop such a pattern. Genetic testing should be restricted to SCN5A. Children with BrS and children who carry an SCN5A variant should avoid medication listed at www.brugadadrugs.org and fever should be suppressed. Ventricular arrhythmias or electrical storms should be treated with isoproterenol infusion.Supplementary InformationThe online version of this article (10.1007/s12471-022-01723-6) contains supplementary material, which is available to authorized users.

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