G004 Transcriptional Profiling of Ion Channel Genes in Right-Ventricular Myocardial Diseases: Particular Signature for Brugada Syndrome

Brugada syndrome is an inherited arrhythmia syndrome associated with sudden cardiac death. Na+-current dysfunction is central in Brugada syndrome, but mutations in the cardiac Na+-channel gene SCN5A are present in only ∼ 20 % of probands. Since only a minority of Brugada patients has detectable mutations, we considered alternative disease mechanisms involving a consistent pattern of variations in cardiac electrogenenic processes. We specifically hypothesized that a common pattern of cardiac ion channel and transporter gene-expression might contribute to the pathophysiology of Brugada syndrome by producing a phenotypic background that facilitates expression of characteristic ECG abnormalities and arrhythmogenesis in the context of appropriate genotypic and/or environmental factors. To test this notion, we applied high-throughput real-time PCR, which permits accurate quantification of up to hundreds of transcripts in minute biological samples, to obtained full profiling of ion-channel expression in right-ventricular septal endomyocardial biopsies from 10 patients with Brugada syndrome in comparison with biopsies from 11 non-diseased organ donors, 7 heart transplant recipients, 10 patients with arrhythmogenic right-ventricular cardiomyopathy and 9 with idiopathic right-ventricular outflow-tract tachycardia. Brugada patients showed distinct and reproducible clustering differences versus the two control and two ventricular tachyarrhythmia groups, including 14 of 77 genes encoding important ion-channel/ion-transporter subunits. Nav1.5, Kv4.3 and Kir3.4 were more weakly-expressed, while Nav2.1 and TWIK1 were more strongly-expressed, in Brugada syndrome. Important differences were also seen in transcripts involved in Ca2+-homeostasis, including stronger expression of RYR2 and NCX1. The molecular profile of five Brugada patients with SCN5A mutations did not differ from Brugada patients without SCN5A mutations. Brugada patients exhibit a common ion-channel molecular expression signature, irrespective of the culprit gene. This finding has potentially important implications for our understanding of the pathophysiology of Brugada syndrome, with possible therapeutic and diagnostic implications.