Omega-6/omega-3 oxylipin imbalance and altered 15-LOX and sEH pathways in Fontan physiology

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. The study aims to quantify plasma oxylipins in individuals with Fontan circulation, compared with matched controls, and assess correlations with hemodynamic function and exercise capacity. A total of 20 adult patients with Fontan circulation and 20 matched controls underwent assessment of body composition, frailty, cardiopulmonary exercise testing, and noninvasive hemodynamic evaluation. Absolute plasma oxylipin concentrations were measured using triple quadrupole HPLC-MS/MS. Compared with 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%. In addition, 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 (V̇O_2). 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. ### NEW & NOTEWORTHY Fontan patients exhibit a distinct oxylipin signature characterized by markedly elevated total and ω-6-derived oxylipins, including increased 15-LOX activity and higher sEH product-to-substrate ratios, alongside reduced ω-3 species such as 20-hydroxydocosahexanoic acid (20-HDoHE) and 17,18-dihydroxyeicosatetraenoic acid (DiHETE). Elevated ω-6 oxylipins correlated with poorer exercise capacity, greater frailty, and impaired hemodynamics, whereas ω-3 oxylipins showed the opposite trend. These findings identify oxylipin dysregulation as a central metabolic hallmark and potential therapeutic target in Fontan circulation.