Brugada Syndrome: More than a Monogenic Channelopathy

Abstract

Brugada syndrome (BrS) is an inherited cardiac channelopathy first diagnosed in 1992 but still considered a challenging disease in terms of diagnosis, arrhythmia risk prediction, pathophysiology and management. Despite about 20% of individuals carrying pathogenic variants in the SCN5A gene, the identification of a polygenic origin for BrS and the potential role of common genetic variants provide the basis for applying polygenic risk scores for individual risk prediction. The pathophysiological mechanisms are still unclear, and the initial thinking of this syndrome as a primary electrical disease is evolving towards a partly structural disease. This review focuses on the main scientific advancements in the identification of biomarkers for diagnosis, risk stratification, pathophysiology and therapy of BrS. A comprehensive model that integrates clinical and genetic factors, comorbidities, age and gender, and perhaps environmental influences may provide the opportunity to enhance patients’ quality of life and improve the therapeutic approach.

Brugada syndrome: from genetics, diagnosis to clinical therapy

“…Patients with BrS usually exhibit a type I ECG pattern of an ST-segment elevation >2 mm coupled with a descending negative T wave in more than one right precordial lead. Such type I ECG pattern may be observed spontaneously or after provocative drug testing with sodium channel blockers such as ajmaline, flecainide, pilsicainide, or procainamide [7] . Moreover, polygenic risk scores (PRS) are also indicated with good predictive accuracy, which could enable the application of PRS in the diagnosis of BrS, particularly for population studies [8] .…”

“…Under normal physiological conditions, activation and inactivation of Nav1.5 are controlled by voltage to guarantee regular cardiac electrical function. SCN5A encodes the alpha subunit of Nav1.5 sodium channel, the LOF of which would result in aberrant transmitting of electrical signals, resulting in various arrhythmic pathologies [1,7] .…”

“…Evidence to date suggests that propofol can be safely applied for anesthesia in patients with BrS, although benzodiazepines may be even safer. Lidocaine appears to be optimal, even when used in combination with epinephrine, and should be preferred to other local anesthetics with a longer half-life [7,9,13,28] .…”

“…These variants mainly result in gain-of-function (GOF) of the potassium channel and increased I to currents. Changes in both ion channels in cardiomyocytes significantly affect electrical conduction of intracardiac signals and induce arrhythmic events [7] . In addition to Na + and K + ions, Ca 2+ is another key ion in arrhythmogenesis.…”

“…For example, genes that regulate expression of ion channel genes at the transcriptional level ( ZFHX3 and TBX5 ) and genes encoding proteins that affect ion channels ( RANGRF ) are indicated in the etiology of BrS. For a full spectrum of genes involved, please refer to a recent review [7] for details. Recent research has mainly focused on the regulatory and transcriptional function of noncoding messenger RNA (mRNA), which is believed to govern gene expression in particular those encoding ion channels, resulting in defective ion channels and resultant clinical symptoms [17] .…”