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Extracellular Vesicle Transcriptomic Signatures Of Protein-losing Enteropathy Vulnerability Following Single-ventricle Palliation
Rohit Ganduboina, MBBS1, Michele Dell'Aquilla, MD1, Xander Jacquemyn, MD2, Marcus Haw, MD3, Osama El Tayeb, MD3, Sandeep Sainathan, MD3.
1Northwell Health Cardiovascular Institute, New Hyde Park, NY, USA, 2University of Pittsburgh, Pittsburgh, PA, USA, 3Corewell Health, Helen Devos Children's Hospital/ Michigan State University, Grand Rapids, MI, USA.
Objective(s):Protein-losing enteropathy (PLE) is among the most severe complications following single-ventricle palliation (SVP), yet early molecular vulnerability signals remain poorly defined.
Methods:Publicly available transcriptomic datasets GSE269879 and GSE130647 were analyzed. A PLE-associated miRNA signature related to lymphatic/endothelial remodeling, immune regulation, intestinal barrier dysfunction, leukocyte migration, and protein-loss biology was derived and validated by comparing Fontan patients with established PLE versus non-PLE Fontan patients in GSE130647. The validated signature was then projected onto paired perioperative extracellular vesicle (EV) transcriptomic samples from patients undergoing Glenn or Fontan palliation in GSE269879 (n=17) using single-sample gene set enrichment analysis to generate composite PLE-EVS scores.
Results:The derived PLE miRNA signature significantly distinguished Fontan patients with PLE from non-PLE patients in the validation cohort (Wilcoxon P=5.16×10⁻⁶; Figure1A). When applied to perioperative EV transcriptomes, PLE-EVS demonstrated heterogeneous patient-level trajectories following palliation (Figure 1B). Most patients demonstrated postoperative reduction in composite PLE-EVS scores (Figure 1C). However, a subset demonstrated persistent or relatively elevated postoperative PLE-EVS, suggesting a potential molecular vulnerability phenotype (Figure 1D).
Conclusions:PLE-EVS are detectable within perioperative transcriptomes following SVP and demonstrate inter-patient heterogeneity despite similar procedures. While most patients showed postoperative reduction in PLE-EVS scores, a subset demonstrated persistent/ relatively elevated PLE-EVS, potentially reflecting patient-specific biologic differences. These exploratory findings support the potential role of EV transcriptomic profiling for future molecular risk stratification, although further validation remains necessary.
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