Kelly Benjamin, Ravndal Maren, Bach Peter, Telinius Niklas, Bennike Tue Bjerg, Hjortdal Vibeke E
Department of Cardiothoracic Surgery Aarhus University Hospital Aarhus Denmark.
Department of Clinical Medicine Aarhus University Aarhus Denmark.
J Am Heart Assoc. 2025 May 20;14(10):e038648. doi: 10.1161/JAHA.124.038648. Epub 2025 May 15.
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.
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.
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.
尽管接受了多次手术并进行了广泛的随访，但单心室心脏患者一生中仍有显著的残余发病率和死亡率。通过应用血浆蛋白质组的先进表征方法，本研究旨在全面了解Fontan循环患者的蛋白质组学影响。
本研究招募了Fontan循环患者，并以2:1的比例将他们与健康对照进行比较。使用Olink Explorer 3072检测板对2943种血浆蛋白水平进行相对定量。这一前所未有的血浆蛋白数量构成了迄今为止对Fontan蛋白质组最详细的表征。总共纳入了87名个体，其中58名Fontan循环患者年龄为26岁（23 - 38岁），29名健康对照年龄为24岁（20 - 27岁）。经过质量控制后，可对2605种蛋白质进行定量。在对年龄、性别和体重指数进行协变量调整后，其中513种蛋白质在Fontan组中发生了变化（424种增加，89种减少）。从相关生物学功能来看，通路富集分析发现参与血管生成、骨骼和钙稳态、代谢以及炎症和纤维化的蛋白质增加，而参与胆固醇合成以及肌肉结构和功能的蛋白质减少。
本研究是在理解Fontan循环病理生理后果方面迈出的一小步。基于显示出变化的生物学通路和蛋白质，我们推测局部缺氧可能是所报道的多种变化的潜在驱动因素。本研究为未来想要详细研究变化或探索可能治疗靶点的研究提供了基础和方向。
