Brugada Syndrome: Warning of a Systemic Condition?

Abstract

Brugada syndrome (BrS) is a hereditary disorder, characterized by a specific electrocardiogram pattern and highly related to an increased risk of sudden cardiac death. BrS has been associated with other cardiac and non-cardiac pathologies, probably because of protein expression shared by the heart and other tissue types. In fact, the most commonly found mutated gene in BrS, SCN5A, is expressed throughout nearly the entire body. Consistent with this, large meals and alcohol consumption can trigger arrhythmic events in patients with BrS, suggesting a role for organs involved in the digestive and metabolic pathways. Ajmaline, a drug used to diagnose BrS, can have side effects on non-cardiac tissues, such as the liver, further supporting the idea of a role for organs involved in the digestive and metabolic pathways in BrS. The BrS electrocardiogram (ECG) sign has been associated with neural, digestive, and metabolic pathways, and potential biomarkers for BrS have been found in the serum or plasma. Here, we review the known associations between BrS and various organ systems, and demonstrate support for the hypothesis that BrS is not only a cardiac disorder, but rather a systemic one that affects virtually the whole body. Any time that the BrS ECG sign is found, it should be considered not a single disease, but rather the final step in any number of pathways that ultimately threaten the patient's life. A multi-omics approach would be appropriate to study this syndrome, including genetics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics, resulting eventually in a biomarker for BrS and the ability to diagnose this syndrome using a minimally invasive blood test, avoiding the risk associated with ajmaline testing.

Unmasking of Brugada syndrome by lamotrigine in a patient with pre-existing epilepsy: A case report with review of the literature

“…As described previously, the coexistence of epilepsy and BrS has been associated with mutations in genes coding for voltage-gated ion channels, which are coexpressed in cardiac and neural tissue (7). However, it is worth noting that the relationship between genotypes and clinical phenotypes is often not linear; hence mutations in genes co-expressed in cardiac and neuronal tissue may independently induce epilepsy and cardiac arrhythmias.…”

“…The pathophysiological mechanisms underlying BrS and idiopathic epilepsy share a coalescent theme pertaining to the dysregulation of cardiac and neuronal voltage-gated ion channels resulting in the premature excitability of cells, which manifests as cardiac arrhythmias and seizure-like activity, respectively (1,6,7). To identify reports highlighting the coexistence of epilepsy and BrS, we performed a Medline search using the keywords' Brugada syndrome' , "Epilepsy, " and "Seizure."…”

“…Idiopathic epilepsy portrays a similar pathophysiological mechanism to BrS, with mutations in the neuronal voltage-gated sodium channels implicated in the condition's development (6,7). Moreover, some studies have reported the coexistence of idiopathic epilepsy amongst patients with BrS (7).…”

“…Idiopathic epilepsy portrays a similar pathophysiological mechanism to BrS, with mutations in the neuronal voltage-gated sodium channels implicated in the condition's development (6,7). Moreover, some studies have reported the coexistence of idiopathic epilepsy amongst patients with BrS (7). Interestingly, with the conduction of genome-wide association studies amongst patients with idiopathic epilepsy and BrS, some gene mutations coexpressed in both conditions have been identified (8,9).…”

“…Interestingly, with the conduction of genome-wide association studies amongst patients with idiopathic epilepsy and BrS, some gene mutations coexpressed in both conditions have been identified (8,9). A recent emerging hypothesis explaining the coexistence of both conditions suggests that the coexpressed genes code for voltage-gated ion channels expressed within cardiac myocytes and neuronal cells (2,7,10).…”