Caligiuri SPB; Department of Health Sciences, Virginia USA
Ravandi A; Aukema HM; Shah AH

American Journal of Physiology – Heart & Circulatory Physiology.
330(5):H1466-H1478, 2026 May 01.

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 omega-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 omega-6 fatty acids were nearly
threefold higher in the Fontan group. Several oxylipins derived from
omega-3 and omega-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). Individuals with Fontan
circulation exhibit marked alterations in circulating oxylipins,
particularly those involving omega-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
omega-6-derived oxylipins, including increased 15-LOX activity and higher
sEH product-to-substrate ratios, alongside reduced omega-3 species such as
20-hydroxydocosahexanoic acid (20-HDoHE) and
17,18-dihydroxyeicosatetraenoic acid (DiHETE). Elevated omega-6 oxylipins
correlated with poorer exercise capacity, greater frailty, and impaired
hemodynamics, whereas omega-3 oxylipins showed the opposite trend. These
findings identify oxylipin dysregulation as a central metabolic hallmark
and potential therapeutic target in Fontan circulation.