Brugada syndrome

Brugada syndrome (BrS) is a condition that is inherited through an autosomal dominant pattern of transmission with variable expression.[1][4][15][9] Mutations of many genes have been implicated in BrS, but only SCN5A gene variants are considered definitely disease-causing.[1][7] However, identifiable SCN5A variants are only found in approximately 20% to 30% of patients with BrS.[1][16][17][18] Mutations of other genes may account for around 2% to 5% of cases.[14][16][17][19]

Features of BrS may be apparent only when induced by certain factors.[1][7] Inducible features of BrS are particularly important to identify in asymptomatic patients (i.e., those who do not have a past history of unexplained cardiac arrest, ventricular arrhythmias, or syncope), but may also be present in symptomatic patients. These include:[1][7]

Febrile illness. This is known to induce type 1 Brugada pattern on ECG and precipitate arrhythmic events.[1][7] In endemic regions, the prevalence of BrS in patients presenting with febrile illness for any reason has been reportedly as high as 4%, around 20-fold greater than a non-febrile control group in one Thai cross-sectional study of 401 patients.[20][21] While in isolation fever is not specific for BrS, in a patient with suspected BrS, it has implications for both diagnosis and management.[1][7]
Medications.[1][7][18] These include sodium-channel blockers (e.g., flecainide, procainamide), psychotropic medications (e.g., tricyclic or tetracyclic antidepressants, lithium), and local anaesthetics. These are known to induce type 1 Brugada ECG changes and may also precipitate arrhythmic events.[1][7][18]
Illicit drugs or alcohol.[1][7] These are known to induce type 1 Brugada ECG changes and may also precipitate arrhythmic events.[1][7][18]

The underlying pathophysiology of Brugada syndrome (BrS) remains unclear.[1] It is likely that there are a number of contributing factors that lead to the typical Brugada pattern on ECG, rather than a single mechanism, because of the range of clinical manifestations and phenocopies.[1]

Around 20% to 30% of people with BrS have identifiable inherited mutations of the SCN5A gene, which causes dysfunctional cardiac voltage gated NaV1.5 sodium channels.[1][7][16][17][18] These defective sodium channels shorten the duration of the cardiac action potential, leading to a reduction of the peak influx of sodium ions and a slowing in the upstroke (phase 0) of the cardiac action potential.[1] Over 300 mutations of the SCN5A gene have been discovered so far.[22] This range of genetic mutations may cause differences in electrophysiological abnormalities, which could explain the different clinical manifestations of BrS.[23][24]

Experimental studies have shown that the function of NaV1.5 sodium channels is also affected by changes in temperature, with additional shortening of the cardiac action potential at higher temperatures.[1]

[Figure caption and citation for the preceding image starts]: Cardiac action potential in Brugada syndrome. Blue line indicates normal ventricular action potential; red line indicates delayed upstroke of action potential in Brugada syndrome. Action potential phases: 0, rapid depolarisation; 1, rapid/early repolarization; 2, plateau; 3, terminal repolarisation; 4, resting potentialKrahn AD et al. JACC Clin Electrophysiol 2022 Mar;8(3):386-405; used with permission [Citation ends]. com.bmj.content.model.Caption@12779fc9

Other genes that have been implicated in BrS (although their significance is disputed; only SCN5A gene variants are considered definitely disease-causing) include SCN10A (which encodes for the a-subunit of the NaV1.8 sodium channel), those that encode for NaV1.5 b-subunits, those involved in NaV1.5 trafficking or expression, and potassium and calcium channel genes.[1][17][19][25][26][27][28][29][30][31]

There is debate about whether BrS is due to a primary repolarisation disorder, a primary depolarisation disorder, or both.[1][32][33] The argument for a primary repolarisation disorder is supported by the fact that patients with BrS have a conduction delay in the right ventricular outflow tract, which is associated with late action potentials.[1] This conduction delay results in heterogeneity of depolarisation around the right ventricular outflow tract, which is thought to predispose the patient to arrhythmias.[1] The argument for a primary depolarisation disorder is supported by evidence that has shown a dispersion of transmural (epicardial-endocardial gradient) action potentials in canine models of pharmacologically induced BrS.[1][33][34] Heterogeneity of repolarisation between the epicardium and endocardium is thought to cause arrhythmias by phase 2 re-entry.[1][34] In addition, both repolarisation and depolarisation abnormalities have been demonstrated in people with BrS, although it is suggested that these repolarisation changes occur secondary to a primary depolarisation disorder.[1]

Some studies have shown that people with BrS have functional changes in the epicardial aspect of the right ventricle.[1][35][36] There have also been histological changes identified in the anterior right ventricular outflow tract that are associated with areas of low voltage and the presence of abnormal fractionated electrograms on electrophysiological studies.[1] These changes include increased collagen and fibrosis, presence of inflammatory infiltrates, and a reduction in connexin-43 (a gap junction protein that provides electrical coupling between myocytes).[1][37][38] Ablation that is targeted to these areas can result in correction of the typical Brugada pattern ECG changes and prevention of ventricular arrhythmias.[1][22][37][38]

ECG classification

Type 1

Coved ST-segment elevation (J-point elevation with a gradual down-sloping ST-segment) ≥2 mm with a negative T-wave in the right precordial leads.[1][4][5][6] Type 1 Brugada pattern may be spontaneous, or induced (e.g., by factors such as fever or sodium-channel blockers).[1][5][7]

Type 2 or 3

Saddleback ST-segment configuration with variable levels of ST-segment elevation.[1][4][6]

[Figure caption and citation for the preceding image starts]: Electrocardiographic patterns in Brugada syndrome showing type 1 (diagnostic) and types 2 and 3 (non-diagnostic) patterns. Type-1 (diagnostic): coved STT morphology in lead V2 with J-point elevation (dark grey line) of ≥0.2 mV (≥2 mm) and a terminal ST-segment elevation (light grey line, J+60 ms) also ≥0.2 mV (≥2 mm). Note the PR interval and wider QRS complex, wide and deep S in lead I, and fractionation in the right precordial ECG leads. Type-2 (non-diagnostic): saddleback STT morphology in lead V2 with J-point elevation (dark grey line) of ≥0.2 mV (≥2 mm) and a terminal ST-segment elevation (light grey line, J+60 ms) ≥0.1 mV (≥1 mm), followed by a positive T wave. Note the less wide and deep S-wave in lead I, less prominent fractionation. Type-3 (non-diagnostic): saddleback STT morphology in lead V2 with J-point elevation (dark grey line) of ≥0.2 mV (≥2 mm) and a terminal ST-segment elevation (light grey line, J+60 ms) <0.1 mV (<1 mm)Marsman EMJ et al. Heart 2022 May;108(9):668-75; used with permission [Citation ends]. com.bmj.content.model.Caption@732d8a51

Pathophysiology

Classification

ECG classification