Circulating Biomarkers in Failing Fontan Circulation: Current Evidence and Future Directions

Patients with Fontan circulation are at lifelong risk for a range of complications involving multiple organ systems. As survival into adulthood increases, there is an urgent need to refine strategies for long-term follow-up and the early detection of Fontan-related sequelae. This narrative review aims to provide a comprehensive summary of the current evidence regarding the use of circulating blood biomarkers as non-invasive tools for assessing and monitoring Fontan physiology. We critically analyzed available studies investigating serum biomarkers related to key pathological mechanisms associated with Fontan failure, encompassing not only cardiac dysfunction but also systemic inflammation, endothelial dysfunction, hepatic and renal impairment, and altered bone metabolism. Several biomarkers have shown promise in reflecting global systemic impairments as well as end-organ involvement in Fontan patients. However, current data are insufficient to support evidence-based clinical recommendations for standardized specific biomarkers, mainly due to the small sample sizes, heterogeneous patient populations, and limited longitudinal data in the available studies. Only a large-scale, prospective, multi-center, and multidisciplinary research will permit us to identify a panel of specific biomarkers of clinical utility in this population. Artificial intelligence (AI) and machine learning (ML) approaches could be applied to integrate all these heterogeneous datasets. Furthermore, "omics"-based studies, including proteomics, metabolomics, lipidomics, and microRNA profiling, hold great potential for uncovering novel biomarkers and pathophysiological pathways, ultimately paving the way for precision medicine in the management of Fontan patients.