Background: Despite restoration of systemic and pulmonary circulation and normalized oxygen saturation, patients with Fontan circulation experience frailty, exercise intolerance, and impaired exercise hemodynamics. Altered cytokine-chemokine profiles have been reported, but their relationship with Fontan pathophysiology remains poorly defined.

Methods: Adult Fontan patients and matched controls were assessed for frailty, cardiopulmonary exercise capacity, and resting/exercise-augmented hemodynamics. Plasma cytokine-chemokine concentrations were measured using multiplex ELISA.

Results: Twenty Fontan patients (mean age 28.8 ± 9.8 years; 35% female) and 20 controls (29.7 ± 6.0 years; 30% female) were studied. Fontan patients had slower 5× sit-to-stand times (9.6 ± 3.1 vs. 5.7 ± 1.3 sec; p<0.0001), lower VO₂max (% predicted), and reduced stroke index, cardiac index, and cardiac power index. TNF-α, IL-1β, IL-6, IFN-γ, IL-8, IP-10, MCP-1, and SDF-1α were elevated in Fontan patients, while IL-10 and MIP-1α were not different. SDF-1α and IP-10 correlated with frailty, impaired oxygen uptake, and hemodynamic parameters.

Conclusion: Elevated SDF-1α and IP-10 are associated with frailty and impaired exercise hemodynamics in Fontan patients. These novel findings suggest a role for inflammation in Fontan-associated dysfunction and warrant further investigation.