Cellular Mechanisms of the BrS

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Summary

Cellular Mechanisms of the BrS

BrS is considered a heritable autosomal dominant disease⁹ and more than 390 mutations have been identified in the SCN5A gene encoding the α-subunit of the cardiac INa-channel.¹⁰ However, presently SCN5A mutations are found only in 11–37 % of the genotyped patients.^7,11 Recent data has suggested that heritability may be related to common genetic variation instead of being strictly monogenic.¹² Many patients with the BrS have no family history presumably due to under-diagnosis in the other family members, low penetrance or sporadic disease.¹³

The cellular basis of the BrS is still not fully understood.¹⁴ According to the “repolarisation theory”, reduction of the inward Na+ current leads to unopposed transient outward (Ito) current in some epicardial regions of the right ventricular outflow tract (RVOT), which causes either delayed expression of the action potential (AP) dome and epicardial AP prolongation or loss of the dome and AP shortening. The net effect is a potentially arrhythmogenic magnification of repolarisation dispersion between the RVOT endo- and epicardium, and between different RVOT epicardial regions. The repolarisation theory was initially promoted on the basis of experimental studies^15,16,17 and was later supported by clinical data such as “spike and dome” configuration with deep notching of monophasic action potentials (MAP) from the RVOT epicardium but not endocardium,¹⁸ paradoxical shortening of the RVOT epicardial activation-recovery intervals (ARI) during augmentation of Brugada-type ST segment elevation,¹⁹ steep AP duration restitution (slope >1) in the RVOT^20,21,22 (both clinically and experimentally), longer ARI in the RVOT epicardium recorded from the conus branch of the right coronary artery than in the endocardium of patients with BrS and type 1 ECG pattern but not in controls²³ and others.

There is also mounting evidence from experimental,²² histopathological,24 computational,²⁵ clinical electrophysiological^23,25 and imaging²⁶ studies for the presence of conduction abnormalities in the RVOT and their importance for the genesis of ventricular arrhythmias in BrS^22,23 (“depolarisation theory”). Delay of the RVOT activation relative to the rest of the RV has also been proposed as a mechanism of the Brugada type ECG changes on the surface ECG.²⁷ The presence of late potentials and prolonged filtered QRS duration on signal-averaged ECG (SAECG) as well as increased notching and fragmentation of the QRS on the standard ECG are linked to increased arrhythmic risk in BrS.^28,29,30,31 The reported cases of patients presenting with both arrhythmogenic right ventricular cardiomyopathy (ARVC) and BrS with SCN5A mutations,³² further attest to the likely role of conduction abnormalities in the BrS. A third hypothesis unifying the above two explains the BrS with abnormal expression of the neural crest cells during the embryological development of the RVOT. This defect in the embryogenesis of the RVOT leads to both abnormally augmented electrical gradients during repolarisation as well as to delayed activation of the RVOT.³³

From electrocardiographic point of view, the characteristic elevation of the J point and ST segment of the type 1 Brugada ECG pattern (see below) results from early relative (intracellular) positivity of the unaffected zone (RVOT endocardium according to the “repolarisation theory” or normally activated myocardium outside the RVOT according to the “depolarisation theory”), whereas the negative T wave is an expression of late epicardial relative (intracellular) positivity in the affected RVOT zone due to either prolongation of the epicardial APs or its delayed activation.

Clinical Manifestations of the BrS

The symptoms associated with the BrS are due to re-entry ventricular arrhythmias typically arising in the affected zone of the RV. If they last briefly (seconds) and terminate spontaneously they can be asymptomatic or cause palpitations; longer arrhythmias lead to syncope or nocturnal agonal respiration, or can degenerate into VF and cardiac arrest. The duration of the arrhythmia is unpredictable with currently available methods and every arrhythmic episode can be fatal. Therefore, the assessment of the degree of arrhythmic risk and the need for prophylactic treatment is by far the most important aspect of the management of these patients.