Exercise, Endothelium, and Muscle in Fontan: Cause, Effect, or Common Culprit?

Exercise, Endothelium, and Muscle in Fontan: Cause, Effect, or Common Culprit?I read Lui et al.'s 1 article with interest.Their cross-sectional study of 137 paediatric Fontan patients in the Re-Energize Fontan cohort provides a comprehensive assessment of VO 2 , endothelial function (reactive hyperemia index [RHI]), skeletal muscle mass/strength, and biomarkers. 1 The sizable cohort and multidomain evaluation underscore the Fontan circulation's multisystem burden.Peak VO 2 was reduced (approximately 75% predicted) and correlated with a lower RHI (approximately 1.45), reduced leg lean mass (z ≈ -1), weaker strength, and endothelial dysfunction, highlighting interconnected cardiovascular, vascular, and muscular deficits. Endothelial Dysfunction: Cause or Consequence?Endothelial dysfunction is common even in asymptomatic Fontan patients and correlates with lower functional capacity. 2 Chronic shear stress abnormalities, hypoxia, and neurohormonal activation likely contribute.Conversely, impaired endothelial function may worsen Fontan hemodynamics by raising pulmonary/systemic resistance.The precise nature of this relationship is still uncertain.Plasma NOx was used as a marker of NO bioavailability, yet NOx encompasses metabolites derived from all nitric oxide synthase (NOS) isoforms (endothelial nitric oxide synthase [eNOS], inducible nitric oxide synthase [iNOS], and neuronal nitric oxide synthase [nNOS]) and is modulated by inflammatory signaling (via iNOS) and oxidative quenching of NO.Thus, diminished NOx may indicate reduced eNOS output, while preserved NOx levels cannot reliably rule out endothelial dysfunction.