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Published on: January 31, 2025
Systemic Changes in Adults With a Fontan Circulation: Insights From the Plasma Proteome
Benjamin Kelly1,2, Maren Ravndal3, Peter Bach2
1Department of Cardiothoracic Surgery Aarhus University Hospital Aarhus Denmark.
Insights
Individuals with a Fontan circulation show altered plasma proteomes, with changes in proteins related to angiogenesis, metabolism, and inflammation. Local hypoxia may drive these proteomic shifts, offering future therapeutic targets.
Area of Science:
- Cardiovascular Research
- Proteomics
- Human Physiology
Background:
- Individuals with a univentricular heart and Fontan circulation experience significant long-term health issues.
- Understanding the plasma proteome in Fontan circulation is crucial for managing residual morbidity and mortality.
Purpose of the Study:
- To comprehensively characterize the plasma proteome in individuals with Fontan circulation.
- To identify proteomic differences compared to healthy controls.
Main Methods:
- Plasma protein levels were quantified in 58 individuals with Fontan circulation and 29 healthy controls using Olink Explorer panels.
- Relative quantification of 2605 plasma proteins was performed after quality control.
Main Results:
- A total of 513 proteins were significantly altered in the Fontan circulation group compared to controls.
- Increased proteins were associated with angiogenesis, bone/calcium homeostasis, metabolism, inflammation, and fibrosis.
- Decreased proteins were linked to cholesterol synthesis and muscle structure/function.
Conclusions:
- This study provides the most detailed characterization of the Fontan proteome to date.
- Local hypoxia is a potential driver of observed proteomic changes.
- Findings lay the groundwork for future research into therapeutic targets for Fontan circulation complications.
Background:
Despite multiple surgeries and extensive follow-up, individuals with a univentricular heart have significant residual morbidity and mortality throughout life. By applying a state-of-the-art characterization of the plasma proteome, this study aimed at providing a comprehensive insight into the proteomic impact of living with a Fontan circulation.
Methods And Results:
This study enrolled individuals with a Fontan circulation and compared them 2:1 with healthy controls. Relative quantification of the levels of 2943 plasma proteins was performed using Olink Explorer 3072 panels. The unprecedented number of plasma proteins constitutes the most detailed characterization of the Fontan proteome to date. A total of 87 individuals, 58 with a Fontan circulation age 26 (23-38) and 29 healthy controls age 24 years (20-27) were included. Following quality control 2605 proteins were quantifiable. Of these, 513 were changed in the group with Fontan (424 increased and 89 decreased) after covariate adjustment for age, sex, and body mass index. Looking at the related biological function(s), a pathway enrichment analysis found that proteins involved in angiogenesis, bone and calcium homeostasis, metabolism, and inflammation and fibrosis increased, whereas proteins involved in cholesterol synthesis and muscle structure and function were decreased.
Conclusions:
This study represents a small step in understanding the pathophysiological consequences of the Fontan circulation. Based on biological pathways and proteins displaying changes, we speculate local hypoxia to be a potential driver for multiple of the reported changes. This study provides the foundation and direction for future studies wanting to examine changes in detail or explore possible therapeutic targets.
