Integrating novel biomarkers and physiology in monitoring Fontan patients: FGF23, HAOX1 and arterial wave reflection

Patients with Fontan circulation face evolving risk for cardiovascular morbidity and mortality, yet the interplay between cardiac function, vascular properties, and circulating proteins is incompletely defined. We hypothesized that biochemical biomarkers and multimodal cardiovascular profile differ significantly between Fontan patients and controls, and that selected markers may serve as predictors of reduced single ventricle function. We conducted a prospective observational study at a tertiary pediatric heart center including 31 individuals with Fontan circulation and 52 matched controls. Cardiac function was assessed by echocardiography; vascular phenotyping included carotid intima-media thickness, central and peripheral blood pressure, augmentation index corrected for heart rate, carotid-femoral pulse wave velocity, aging index, and reactive hyperemia index. Compared to controls, the Fontan group had increased pulse wave reflection and central systolic pressure as well as decreased echocardiographic markers of systolic and diastolic function, while pulse wave velocity and other vascular parameters were not significantly different between the groups. Levels of 92 circulating cardiovascular biomarkers were quantified in a subset of 25 of the Fontan cohort and 81 controls using a proximity extension assay. Twenty-two biomarkers differed significantly in the Fontan group compared to controls, including FGF23, REN, HAOX1, and IL17D. Levels of several of these biomarkers correlated with patient age. Most importantly, HAOX1 (a peroxisomal oxidase linked to redox metabolism) and FGF23 (a bone-derived hormone regulating phosphate and vitamin D homeostasis) correlated negatively with ejection fraction within the Fontan group. By contrast, BNP was not associated with cardiac function in the Fontan group. None of the biomarkers correlated with central arterial parameters. In summary, central arterial hemodynamics and biomarkers such as FGF23 and HOAX1 may improve monitoring of cardiovascular function in single ventricle patients with Fontan circulation.