Abstract 4145489: Serum Proteomics Approach to Identify the ‘Hepatic Factor’ Causing Pulmonary Arteriovenous Malformations Post-Glenn Shunt

Introduction: Pulmonary Arteriovenous Malformations (PAVMs) are a main surgical complication of second-stage palliative Glenn shunt for single ventricle. PAVMs lead to early mortality. Currently there is no available treatment as its physiopathology remains unknown. Hypothesis: This study hypothesizes that hepatic-derived factor causing PAVMs could be proteome-derived. Goals: To discern differences in proteomic profiles of patient-paired serum from superior vena cava (SVC) and hepatic vein (HV) as a preliminary approach to identify PAVM-related hepatic vein blood-enriched factors. Methods: Paired full blood samples were collected from SVC and HV origin during routine cardiac catheterization of patients with diverse cardiac congenital malformations from 0 to 1 years of age (n=3). Serum was extracted and high abundant proteins were depleted. Single-pot solid-phase-enhanced sample preparation method and trypsinization digestion coupled with label-free data-dependent acquisition liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was performed. Subgroup differential expression analysis by abundance ratio (SVC/HV) (Adj. P-Value<0,05) was used to identify differentially upregulated proteins uniquely expressed in HV. Proteins with only one unique peptide identifier were discarded. Gene ontology biological analysis and functional pathways analysis were performed using PANTHER. Results: Differential proteomic profiles were evidenced according to serum origin. 4706 peptides coding for 605 common proteins, 68 unique proteins to SVC and 110 unique for HV were identified. From 50 protein coding genes found upregulated in HV sample (P<0,05), 16 had >1 unique peptide identifier and 5 were found to be uniquely expressed in HV. Overrepresentation of integrin signaling pathway was identified (fold enrichment 21.56, FDR P=0,0265) related to these 16 HV upregulated expression genes. Conclusion: Serum proteomic profile per sample origin analysis is promising for understanding PAVM physiopathology. Functional gene ontology pathway associating integrin signaling pathway enhancement in HV proteome, known to play a role in vascular anomalies, may serve as a first milestone for the “hepatic-factor” identification. Further validation experiments are required. In vitro induced pluripotent stem cell PAVM proof-of-concept model is under development.