Omega-6/Omega-3 Oxylipin Imbalance and Altered 15-LOX and sEH Pathways in Fontan Physiology.

<b>Background:</b> The Fontan procedure enhances systemic oxygenation and survival in patients with complex congenital heart defects not amenable to biventricular repair. Despite these improvements, individuals with Fontan circulation often develop progressive multisystem dysfunction, the biochemical underpinnings of which remain poorly understood. Oxylipins are bioactive lipid mediators implicated in cardiovascular disease and represent targetable pathways that may contribute to the pathophysiology of the Fontan state. <b>Objectives:</b> To quantify plasma oxylipins in individuals with Fontan circulation, compare to matched controls, and assess correlations with hemodynamic function and exercise capacity. <b>Methods:</b> Twenty adult Fontan patients and twenty matched controls underwent assessment of body composition, frailty, cardiopulmonary exercise testing, and non-invasive hemodynamic evaluation. Absolute plasma oxylipin concentrations were measured using triple quadrupole HPLC-MS/MS. <b>Results:</b> Compared to controls, Fontan participants exhibited significantly increased (34%) total plasma oxylipin concentrations, with a 42% elevation in ω-6 fatty acid-derived oxylipins. Among these, metabolites generated via the 15-lipoxygenase (15-LOX) pathway were elevated by 52%. Additionally, product-to-substrate ratios reflecting putative soluble epoxide hydrolase (sEH) activity for ω-6 fatty acids were nearly threefold higher in the Fontan group. Several oxylipins derived from ω-3 and ω-6 fatty acids, including those generated by 15-LOX and sEH pathways, demonstrated significant correlations with key clinical parameters, including resting and exercise hemodynamics, ventilatory efficiency, and peak oxygen consumption (VO₂). <b>Conclusions:</b> Individuals with Fontan circulation exhibit marked alterations in circulating oxylipins, particularly those involving ω-6 fatty acid metabolism via 15-LOX and sEH. These findings offer mechanistic insights and identify potentially modifiable targets.