Aims  Brugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype–phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype–phenotype correlation in BrS. Methods and results Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area. Conclusion  In BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.

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The Brugada syndrome (BrS) is characterized by coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG) and increased risk of sudden cardiac death (SCD). While it is an inheritable disease, determining the true prevalence is a challenge, since patients may report no known family history of the syndrome, present with a normal spontaneous ECG pattern at the time of examination, and test negative for all known BrS-causative genes. In fact, SCD is often the first indication that a person is affected by the syndrome. Men are more likely to be symptomatic than women. Abnormal, low-voltage, fractionated electrograms have been found in the epicardium of the right ventricular outflow tract (RVOT). Ablation of this area abolishes the abnormal electrograms and helps to prevent arrhythmic recurrences. BrS patients are more likely to experience ventricular tachycardia/fibrillation (VT/VF) during fever or during an increase in vagal tone. Isoproterenol helps to reverse the ECG BrS phenotype. In this review, we discuss roles of calcium in various conditions that are relevant to BrS, such as changes in temperature, heart rate, and vagal tone, and the effects of gender and isoproterenol on calcium handling. Studies are warranted to further investigate these mechanisms in models of BrS.

Several lines of evidence support the hypothesis of a toxic role played by wild type SOD1 (WT-SOD1) in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). In this study we investigated both distribution and expression profile of WT-SOD1 in leukocytes from 19 SALS patients and 17 healthy individuals. Immunofluorescence experiments by confocal microscopy showed that SOD1 accumulates in the nuclear compartment in a group of SALS subjects. These results were also confirmed by western blot carried out on soluble nuclear and cytoplasmic fractions, with increased nuclear SOD1 level (p<0.05). In addition, we observed the presence of cytoplasmic SOD1 aggregates in agreement with an increased amount of the protein recovered by the insoluble fraction. A further confirmation of the overall increased level of SOD1 has been obtained from single cells analysis using flow cytometry as cells from SALS patients showed an higher SOD1 protein content (p<0.05). These findings add further evidence to the hypothesis of an altered WT-SOD1 expression profile in peripheral blood mononuclear cells (PBMCs) from patients with ALS suggesting that WT-SOD1 species with different degrees of solubility could be involved in the pathogenesis of the disease.