The Proteomic Profile of Adults With a Fontan Circulation

BACKGROUND: The Fontan circulation is associated with unique physiology resulting from surgical and hemodynamic alterations. Limited data exist on the circulating proteome in adults with a Fontan circulation. OBJECTIVES: We aimed to understand how the Fontan circulation impacts the circulating plasma proteome, potentially identifying molecular targets to prevent or treat Fontan-associated complications. METHODS: We enrolled 162 adults with a Fontan circulation and 36 age/sex-matched control participants without known cardiovascular disease: 192 participants (161 = Fontan, 31 = Control) had 975 proteins measured via Olink proteomics platform (proximity extension assay) and 85 participants (72 = Fontan, 13 = Control) had 1,265 proteins measured by SomaLogic proteomics platform (single-stranded DNA aptamers). RESULTS: Overall, 331 (33.9%) and 501 (39.6%) proteins measured via Olink proteomics platform and SomaLogic proteomics platform, respectively, were differentially expressed with an age- and sex-adjusted P < 0.05 between the Fontan and control groups. Among the 491 proteins measured by both platforms, 5 proteins were consistently among the 30 most differentially expressed proteins between Fontan and control for both: angiopoietin-2, contactin-5, insulin-like growth factor-binding protein 7, thrombospondin-2, and tartrate-resistant acid phosphatase type 5. Proteomic signatures in the Fontan circulation were associated with cardiac and renal perturbations, even before clinical evidence of end-organ failure. CONCLUSIONS: The plasma proteome in adults with a Fontan circulation is markedly different from the proteome of biventricular controls, with widespread perturbations across metabolic, inflammatory, and organ-specific pathways. This hypothesis-generating, foundational work suggests that broad-based proteomics may help identify mechanisms of compensation and deterioration in this poorly understood population.