Abstract 15324: The Fontan Circulation Shows Decreased Cell Survival and Oxidative Damage

Abstract

Introduction: Single ventricle congenital heart disease such as hypoplastic left heart syndrome (HLHS) with a Fontan circulation accounts for the largest group of children hospitalized with circulation failure, with an in-hospital mortality of 20-50%. We sought to (i) evaluate the mechanisms underlying circulation failure and (ii) identify novel therapeutic targets. Methods: Blood was collected from patients with HLHS s/p Fontan and from controls with normal cardiac anatomy and function (N=5/group). Plasma microvesicles (MV) were isolated and proteomics assessed using data independent acquisition mass spectroscopy. Dysregulated proteins with a fold change >1.5 or < -1.5, p<0.05 were evaluated using Ingenuity pathway analysis. Results: Age of Fontan patients vs. controls was 17.04±2 vs. 15.7±2.5, p=0.4; 20% were male in both groups. 60% of Fontan patients were in NYHA class II/III, 40% in NYHA class IV; 80% had Fontan-associated liver disease. Circulating MVs were released from cardiomyocytes, endothelial cells, and hepatocytes based on cell surface markers. Upregulated proteins (N=27) implicated cell death pathways (Solute carrier family 2, Angiotensinogen, CD14); while downregulated proteins (N=88) implicated impaired cell survival (tyrosine-protein kinase Yes, endothelial growth factors). MVs contained mitochondria and endoplasmic reticulum proteins implicating upregulation in reactive oxygen species signaling (catalase A, S100A8) and downregulation in antioxidant enzymes (GPX1, PRDX 5). Conclusion: Circulating MVs from patients with HLHS s/p Fontan are released from the heart, blood vessels, and liver providing a noninvasive signature of organ remodeling. The MV protein cargo implicates heightened cell death, oxidative damage and impaired cell survival, thereby providing insight into the mechanisms of Fontan associated circulation failure. Figure: Decreased Cell Survival and Oxidative Damage in the Fontan Circulation