PO37 Genotype- and Phenotype-Specific Serum Lipidomic Profiles Reveal Novel Metabolic Signatures in Type 1 Brugada Syndrome

Background Brugada syndrome (BrS) is an inherited channelopathy linked to sudden cardiac death. Although mutations in the SCN5A gene explain up to 30% of cases, most patients lack identifiable variants, implying additional pathogenic contributors (ref 1,2). Emerging evidence has pointed to disturbances in lipid metabolism in BrS (ref 3-5). Purpose The aim of our study was to define the serum lipidomic profile of patients with type I BrS, also investigating possible relationships with the mutation status of the SCN5A gene. Methods We performed targeted serum lipidomic profiling (HPLC-MS/MS) in 13 patients with spontaneous type 1 BrS, 13 with drug-induced type 1 BrS, and 13 age- and sex-matched healthy controls. We assessed both quantitative and qualitative alterations across lipid classes, including chain length and degree of unsaturation, and examined associations with SCN5A gene status. Results Overall, 131 lipid species across six classes were quantified. Nineteen circulating lipids, mostly triglycerides and phosphatidylcholines, were significantly elevated in spontaneous BrS compared to controls, while no significant differences were observed in the drug-induced group. Fatty acid composition showed longer chain lengths and reduced unsaturation in phosphatidylcholines from spontaneous BrS patients. Pathway enrichment analysis revealed alterations in lipoprotein remodeling and lipid transport. SCN5A-positive patients demonstrated increases in neutral lipids (e.g., triglycerides), whereas SCN5A-negative patients exhibited dysregulation of polar lipids (e.g., phosphatidylcholines and sphingomyelins), indicating genotype-dependent metabolic changes. Conclusions Distinct lipidomic profiles were identified in spontaneous type 1 BrS, which were absent in drug-induced cases compared to controls. Alterations in the levels and composition of phosphatidylcholines and triglycerides, along with alteration in lipid pathways, highlight a metabolic contribution to disease mechanisms. Additionally, lipidomic differences by SCN5A status emphasize genotype-specific pathways in BrS. Taken together, these findings identify serum lipid abnormalities as a potential metabolic hallmark of BrS and support the use of lipidomic profiling as a non-invasive tool to explore disease mechanisms and potentially aid in risk stratification.