Advances and Challenges in the Management of Brugada Syndrome: A Comprehensive Review.

Brugada syndrome (BrS) is an inherited arrhythmogenic disorder marked by distinctive ST-segment elevations on electrocardiograms (ECG) and an increased risk of sudden cardiac death. Characterized by mutations primarily in the SCN5A gene, BrS disrupts cardiac ion channel function, leading to abnormal electrical activity and arrhythmias. Although BrS primarily affects young, healthy males, it poses significant diagnostic challenges due to its often concealed or intermittent ECG manifestations and clinical presentation that can mimic other cardiac disorders. Current management strategies focus on symptom control and prevention of sudden death, with implantable cardioverter-defibrillators (ICD) serving as the primary intervention for high-risk patients. However, the complications associated with ICDs and the lack of effective pharmacological options necessitate a cautious and personalized approach. Recent advancements in catheter ablation have shown promise, particularly for managing ventricular fibrillation (VF) storms and reducing ICD shocks. Additionally, pharmacological treatments such as quinidine have been effective in specific cases, though their use is limited by availability and side effects. This review highlights significant gaps in the BrS literature, particularly in terms of long-term management and novel therapeutic approaches. The importance of genetic screening and tailored treatment strategies to better identify and manage at-risk individuals is emphasized. The review aims to enhance the understanding of BrS and improve patient outcomes, advocating for a multidisciplinary approach to this complex syndrome.

Novel SCN5A gene mutation in a patient affected by multifocal ectopic premature Purkinje-related contractions syndrome.

We report the case of a 36-year-old woman who presented to the emergency department complaining of palpitations and asthenia. Investigations showed frequent ventricular ectopy and severe left ventricular ejection fraction impairment. She was diagnosed with a peculiar condition defined multifocal ectopic premature Purkinje-related contractions syndrome, which in some cases can be associated with a dilated cardiomyopathy phenotype. Genetic testing showed a novel mutation in the SCN5A gene (c.673C > G). In the context of acute left ventricular dysfunction in a young patient, we discuss the clinical presentation of this rare condition and its clinical management, as well as its genetic substrate.

Brugada syndrome in Iran: Insights from a 12-year longitudinal study.

BACKGROUND: Brugada syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads, which is not explained by ischemia, electrolyte disturbances, or obvious structural heart disease. AIM: In present study, we aim to evaluate presentation, long-term outcome, genetic findings, and therapeutic interventions in patients with BrS. METHODS: Between September 2001 and June 2022, all consecutive patients with diagnosis of BrS were enrolled in the present study. All patients gave written informed consent for the procedure, and the local ethical committee approved the study. RESULTS: Of the 76 cases, 79% were proband and 21% were detected during screening after diagnosis of BrS in a family member. Thirty-three (43%) patients had a typical spontaneous electrocardiogram (ECG) pattern. Thirty percent of the patients were symptomatic; symptomatic patients were more likely to have spontaneous type 1 Brugada ECG pattern in their ECGs (p = .01), longer PR interval (p = .03), and SCN5A mutation (p = .01) than asymptomatic patients. The mean PR interval was considerably longer in men than women (p = .034). SCN5A mutation was found in 9 out of 50 (18%) studied patients. Fifteen percent received appropriate implantable cardioverter-defibrillator (ICD) therapy and inappropriate ICD interventions were observed in 17%. Presentation with aborted SCD or arrhythmic syncope was the only predictor of adverse outcome in follow-up (odds ratio: 3.1, 95% confidence interval: 0.7-19.6, p = .001). CONCLUSIONS: Symptomatic patients with BrS are more likely to present with spontaneous type 1 Brugada ECG pattern, longer PR interval, and pathogenic mutation in SCN5A gene. Appropriate ICD interventions are more likely in symptomatic patients and those with SCN5A mutation.

Case Report: SCN5A mutations in three young patients with sick sinus syndrome.

Background: Sick Sinus Syndrome (SSS) is generally regarded as a degenerative disease with aging; however, genetic mutations have been confirmed to be associated with SSS. Among them, mutations in SCN5A are common in patients with SSS. We report three young SSS patients with SCN5A mutations at different sites that have not been previously reported in Asian patients. Case presentation: The three patients were all young females who presented with symptoms of severe bradycardia and paroxysmal atrial flutter, for which two patients received ablation therapy. However, after ablation, Holter monitoring indicated a significant long cardiac arrest; therefore, the patients received pacemaker implantation. The three patients had familial SSS, and genetic testing was performed. Mutations were found in SCN5A at different sites in the three families. All three patients received pacemaker implantation, resulting in the symptoms of severe bradycardia disappearing. Conclusion: SCN5A heterozygous mutations are common among patients clinically affected by SSS. Their causative role is confirmed by our data and by the co-occurrence of genetic arrhythmias among our patients. Genetic testing for SSS cannot be performed as a single gene panel because of feasible literature results, but in presence of familial and personal history of SSS in association with arrhythmias can provide clinically useful information.

Bioinformatics Insights on the Physicochemical Properties of SCN5A Mutant Proteins Associated with the Brugada Syndrome.

BACKGROUND: The Brugada syndrome (BrS) is a heart rhythm condition that is commonly associated with a strong predisposition for sudden cardiac death. Malignant ventricular arrhythmias could occur secondary to the dysfunction of the cardiac sodium voltage-gated Na(v)1.5 channel (SCN5A). OBJECTIVE: This study aimed to perform a multiparametric computational analysis of the physicochemical properties of SCN5A mutants associated with BrS using a set of bioinformatics tools. METHODS: In-house algorithms were calibrated to calculate, in a double-blind test, the Polarity Index Method (PIM) profile and protein intrinsic disorder predisposition (PIDP) profile of each sequence, and computer programs specialized in the genomic analysis were used. RESULTS: Specific regularities in the charge/polarity and PIDP profile of the SCN5A mutant proteins enabled the re-creation of the taxonomy, allowing us to propose a bioinformatics method that takes advantage of the PIM profile to identify this group of proteins from their sequence. CONCLUSION: Bioinformatics programs could reproduce characteristic PIM and PIDP profiles of the BrS-related SCN5A mutant proteins. This information can contribute to a better understanding of these altered proteins.

SCN5A overlap syndromes: An open-minded approach.

SCN5A overlap syndromes are clinical entities that express a phenotype combining aspects of different canonical SCN5A-related arrhythmia syndromes or a variable arrhythmic phenotype among individuals carrying the same SCN5A mutation. Here we review the literature addressing SCN5A overlap syndromes as well as the principal mechanisms currently proposed. Among others, a multifactorial determination encompassing an interaction between SCN5A variant(s), other genetic polymorphisms, and possibly environmental factors seems the most plausible hypothesis.

Reentry in cardiac ventricular epicardial tissue due to SCN5A L812Q gene mutation: a computational study.

Cardiovascular diseases are the major cause of sudden death. Brugada syndrome is an inherited rare disease, that leads to death due to ventricular fibrillation (VF). Brugada Syndrome is related to mutations in the genes that encode SCN5A, a subunit of sodium ion channel (NaV). This computational study investigates the mechanism of loss of function gene mutation (SCN5A L812Q) in sodium ion channel that leads to spiral wave and further develops into VF in an epicardial tissue with homozygous condition. Study was made on wild type, L812Q heterozygous mutated and homozygous mutated ventricular tissues. Ten Tusscher human ventricular cell model (TP06) was used for the simulation study. VF is developed when a spiral wave that causes ventricular arrhythmia breaks. This leads to the formation of multiple spiral waves that are activated on different regions of the ventricles called wave break. This is observed in the epicardial tissue with homozygous condition as the effect of SCN5A L812Q gene mutation. This indicates that VF occurs in the SCN5A L812Q gene mutated homozygous ventricular epicardial tissue that may further lead to Brugada syndrome.