A Fontan procedure is used to manage complex congenital heart defects where only one ventricle is functional. These conditions include tricuspid atresia, hypoplastic left heart syndrome, and double inlet left ventricle. In the Fontan circulation the venous blood is rerouted directly to the pulmonary arteries, allowing blood to bypass the heart and flow directly to the lungs, and the single functional ventricle pump oxygenated blood to the body. While this approach improves survival and quality of life, a univentricular circulation is associated with significant residual morbidity and mortality throughout life.

In the current study, we aimed at providing a comprehensive characterization into the biological impact of living with a Fontan circulation. We obtained blood-plasma samples from 58 adults with a Fontan circulation having undergone the procedure early in life (systemic right ventricle due to any diagnosis, or systemic left ventricle due to tricuspid atresia or double inlet left ventricle), and matched then 2:1 with healthy controls. To characterize the systemic impact of the Fontan circulation, we performed a relative quantification of the levels of 2943 plasma proteins using the Olink® Explorer 3072 platform.

Following quality control and filtering 2605 plasma proteins were quantifiable, of which 513 had significantly changed levels in the Fontan group (424 increased and 89 decreased). Categorizing the significant proteins by their biological function(s) in a pathway enrichment analysis, we found that the changes to biological processes in the Fontan group include angiogenesis, lipoprotein synthesis, metabolism, bone and calcium homeostasis, and muscle structure and function.

The unprecedentedly high number of plasma proteins constitutes the hitherto most detailed characterization of the systemic impact of a Fontan circulation and provides a unique perspective into the Fontan physiology and clinical presentations. This study provides an elaborate and unprecedented insight into the biological impact of living with a Fontan circulation, and we speculate local hypoxia to be a central driver for multiple of the determined changes. This study may provide the foundation and directions for future studies wanting to examine changes in detail and/or explore possible therapeutic targets.