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[Preprint]. 2023 Jun 7:2023.06.05.23290997.
doi: 10.1101/2023.06.05.23290997.

Intrahepatic transcriptomics differentiate advanced fibrosis and clinical outcomes in adults with the Fontan circulation

Katia Bravo-Jaimes  1   2 , Xiuju Wu  3 , Leigh C Reardon  2   4 , Gentian Lluri  2   3 , Jeannette P Lin  2   3 , Jeremy P Moore  2   4 , Glen Van Arsdell  2   3 , Reshma Biniwale  1   2   3   4   5   6   7   8   9 , Ming-Sing Si  1   2   3   4   5   6   7   8   9 , Bita V Naini  5 , Robert Venick  6 , Sammy Saab  6 , Christopher L Wray  7 , Reid Ponder  2 , Carl Rosenthal  8 , Alexandra Klomhaus  9 , Kristina I Böstrom  3 , Jamil A Aboulhosn  2   3 , Fady M Kaldas  8
Affiliations

Intrahepatic transcriptomics differentiate advanced fibrosis and clinical outcomes in adults with the Fontan circulation

Katia Bravo-Jaimes et al. medRxiv. .

Update in

Abstract

Background: The molecular mechanisms underlying Fontan associated liver disease (FALD) remain largely unknown. We aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes.

Methods: This retrospective cohort study included adults with the Fontan circulation at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Clinical, laboratory, imaging and hemodynamic data prior to the liver biopsy were extracted from medical records. Patients were classified into early (F1-F2) or advanced fibrosis (F3-F4). RNA was isolated from formalin-fixed paraffin embedded liver biopsy samples; RNA libraries were constructed using rRNA depletion method and sequencing was performed on Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were carried out using DESeq2 and Metascape. Medical records were comprehensively reviewed for a composite clinical outcome which included decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, protein-losing enteropathy, chronic kidney disease stage 4 or higher, or death.

Results: Patients with advanced fibrosis had higher serum BNP levels and Fontan, mean pulmonary artery and capillary wedge pressures. The composite clinical outcome was present in 23 patients (22%) and was predicted by age at Fontan, right ventricular morphology and presence of aortopulmonary collaterals on multivariable analysis. Samples with advanced fibrosis had 228 up-regulated genes compared to early fibrosis. Samples with the composite clinical outcome had 894 up-regulated genes compared to those without it. A total of 136 up-regulated genes were identified in both comparisons and these genes were enriched in cellular response to cytokine stimulus, response to oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-beta signaling pathway, and vasculature development.

Conclusions: Patients with FALD and advanced liver fibrosis or the composite clinical outcome exhibit up-regulated genes including pathways related to inflammation, congestion, and angiogenesis. This adds further insight into FALD pathophysiology.

Keywords: Fontan outcomes; Fontan-associated liver disease; liver fibrosis; single ventricle; transcriptomics.

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Conflict of interest statement

Disclosures: The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Unadjusted cumulative incidence function comparing time to the clinical composite outcome, relative to date of Fontan, between patients with early vs advanced fibrosis.
Figure 2.
Figure 2.
A. Volcano plot showing 231 DEGs (228 up-regulated) in patients with FALD and advanced fibrosis vs early fibrosis. B. Volcano plot showing 906 DEGs (894 up-regulated) in patients with FALD and the clinical composite outcomes vs those without it.
Figure 3.
Figure 3.
A. Gene ontology and pathway enrichment analysis among patients with advanced liver fibrosis. B. Gene disease association enrichment analysis using 136 DEGs and the DisGeNet platform.
Figure 4.
Figure 4.
Violin plot demonstrating the gene count distribution in specific overlapping genes among patients with FALD according to the degree of liver fibrosis.
Figure 5.
Figure 5.
Violin plot demonstrating the gene count distribution in specific overlapping genes among patients with FALD according to the presence of the composite outcome.
See this image and copyright information in PMC

References

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