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Concept: Brugada syndrome

156

The Brugada syndrome (BrS) is a malignant, genetically-determined, arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals with structurally normal hearts. The diagnosis of the BrS is mainly based on the presence of a spontaneous or Na + channel blocker induced characteristic, electrocardiographic (ECG) pattern (type 1 or coved Brugada ECG pattern) typically seen in leads V1 and V2 recorded from the 4th to 2nd intercostal (i.c.) spaces. This pattern needs to be distinguished from similar ECG changes due to other causes (Brugada ECG phenocopies). This review focuses mainly on the ECG-based methods for diagnosis and arrhythmia risk assessment in the BrS. Presently, the main unresolved clinical problem is the identification of those patients at high risk of SCD who need implantable cardioverter-defibrillator (ICD), which is the only therapy with proven efficacy. Current guidelines recommend ICD implantation only in patients with spontaneous type 1 ECG pattern, and either history of aborted cardiac arrest or documented sustained VT (class I), or syncope of arrhythmic origin (class IIa) because they are at high risk of recurrent arrhythmic events (up to 10% or more annually for those with aborted cardiac arrest). The majority of BrS patients are asymptomatic when diagnosed and considered to have low risk (around 0.5% annually) and therefore not indicated for ICD. The majority of SCD victims in the BrS, however, had no symptoms prior to the fatal event and therefore were not protected with an ICD. While some ECG markers such as QRS fragmentation, infero-lateral early repolarisation, and abnormal late potentials on signal-averaged ECG are known to be linked to increased arrhythmic risk, they are not sufficiently sensitive or specific. Potential novel ECG-based strategies for risk stratification are discussed based on computerised methods for depolarisation and repolarisation analysis, a composite approach targeting several major components of ventricular arrhythmogenesis, and the collection of large digital ECG databases in genotyped BrS patients and their relatives.

Concepts: Cardiology, Implantable cardioverter-defibrillator, Cardiac arrest, Cardiac electrophysiology, Ventricular fibrillation, Sudden cardiac death, Brugada syndrome, Cardiac dysrhythmia

27

SCN5A encodes the α subunit of the major cardiac sodium channel NaV1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5AE558X/+ pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5AE558X/+ hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5AE558X/+ pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.

Concepts: Mutation, Heart, Medical emergencies, Cardiac arrest, Cardiac electrophysiology, Sodium channel, Sudden cardiac death, Brugada syndrome

26

Brugada syndrome is a genetically determined familial disease with autosomal dominant transmission and variable penetrance, conferring a predisposition to sudden cardiac death due to ventricular arrhythmias. The syndrome is characterized by a typical electrocardiographic pattern in the right precordial leads. This article will focus on the new electrocardiographic features recently agreed on by expert consensus helping to identify this infequent electrocardiographic pattern.

Concepts: Genetics, Disease, Cardiac arrest, Cardiac electrophysiology, Ventricular fibrillation, Sudden cardiac death, Brugada syndrome, Catecholaminergic polymorphic ventricular tachycardia

13

Guidelines recommend the use of implanted cardioverter-defibrillators in patients with Brugada syndrome and induced ventricular tachyarrhythmias, but there is no evidence supporting it.

Concepts: Implantable cardioverter-defibrillator, Cardiac electrophysiology, Syndromes, Brugada syndrome

8

The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial.

Concepts: Cardiac electrophysiology, Syndromes, Hypertrophic cardiomyopathy, Right-wing politics, Brugada syndrome

3

Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.

Concepts: DNA, Gene, Genetics, Gene expression, Sodium, Sodium channel, Ion channels, Brugada syndrome

3

Distinguishing genetic variants that cause disease from variants that are rare but benign is one of the principal challenges in contemporary clinical genetics, particularly as variants are identified at a pace exceeding the capacity of researchers to characterise them functionally.

Concepts: Genetics, Cardiology, Ventricular tachycardia, Tachycardia, Brugada syndrome

2

Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome; SADS) may identify relatives at risk of fatal arrhythmias.

Concepts: Death, Cardiac arrest, Cardiac electrophysiology, Syndromes, Brugada syndrome, Cardiac dysrhythmia

2

Risk stratification in asymptomatic patients remains by far the most important yet unresolved clinical problem in the Brugada syndrome (BrS).

Concepts: Cardiac electrophysiology, Syndromes, Asymptomatic, Brugada syndrome

2

Brugada Syndrome (BrS) is an autosomal dominant channelopathy with variable penetrance affecting the sodium channel. It reduces the transport of sodium ions essential for proper generation of the cardiac action potential. The resulting inhomogeneous repolarisation in areas of the RV epicardium causes malignant ventricular arrhythmias. BrS is diagnosed by typical cove shaped ST elevation of > 2mm in ≥1 RV precordial lead V1, V2 occurring spontaneously or after provocative drug test with IV administration of Class 1 antiarrhythmic drug such as flecainide or ajmaline. The incidence of BrS is variable being higher in South East Asians and is generally quoted as 1:2000. It is responsible for up to 20% of sudden arrhythmic deaths in those without structural heart disease. Typical presentation is syncope or resuscitated sudden death and symptoms usually occur at night or at rest especially after a large meal. Fever is a common trigger, particularly in children. Genetic testing for BrS is a Class 2A indication and the yield has increased recently to nearly 40%. Genetic testing assists with family screening.

Concepts: Genetics, Cancer, Action potential, Cardiac electrophysiology, Sodium, Sodium channel, Channelopathy, Brugada syndrome