부산대학교 도서관

Introduction: Ceramides biosynthesis is dysregulated in obesity, yet their role as mediators of obesity-induced myocardial dysfunction is unclear.Objective: We investigate the causal role of AT-derived ceramides in regulating the myocardial redox state and explore their prognostic value in patients with CVD.Methods: In 880 cardiac surgery patients, 20 sphingolipids were measured in plasma, subcutaneous-, thoracic- and epicardial-AT biopsies and their secretomes. Myocardial redox state was measured and the contribution of NOXs, uncoupled eNOS and mitochondrial oxidases to O2 production quantified. Median follow-up was 8.3 years. Genetic variants were identified to predict CVD outcomes using cis-Mendelian Randomisation. The underlying mechanisms were explored using differentiated H9c2 cardiomyocytes in vitro and human myocardial tissue ex vivo.Results: C16:0-ceramide (CerC16) was the most abundant ceramide secreted from AT (p<0.0001). Patients with high plasma CerC16 and C16:0-glucosylceramide (GlcC16) had significantly increased myocardial O2 production (vs low/int.) (A). Patients with rs112572487(B), an intronic SNP in UGCG, had significantly increased plasma GlcC16 (C) and myocardial NOX-derived O2 (D) vs those without. Exogenous CerC16 (20nM) induced O2 production in H9c2 cardiomyocytes and human myocardial tissue (E), an effect prevented by the UGCG inhibitor D-PDMP. Importantly, high plasma GlcC16 led to a higher risk of cardiac death and/or heart failure (HR=2.128 [1.101, 4.115], p=0.025) vs low/int. levels, a relationship also seen with rs112572487 (F). rs112572487 also led to an increased risk of new, post-operative atrial fibrillation in hospital (HR=1.805 [1.188, 2.742], p=0.006).Conclusions: We demonstrate for the first time, that AT-derived ceramides are causally related with dysregulated myocardial redox signalling and adverse cardiovascular disease outcomes in patients with advanced atherosclerosis.