Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation

Katia Bravo-Jaimes; Xiuju Wu; Leigh C Reardon; Gentian Lluri; Jeannette P Lin; Jeremy P Moore; Glen van Arsdell; Reshma Biniwale; Ming-Sing Si; Bita V Naini; Robert Venick; Sammy Saab; Christopher L Wray; Reid Ponder; Carl Rosenthal; Alexandra Klomhaus; Kristina I Böstrom; Jamil A Aboulhosn; Fady M Kaldas

doi:10.1016/j.jacc.2023.12.005

Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation

J Am Coll Cardiol. 2024 Feb 20;83(7):726-738. doi: 10.1016/j.jacc.2023.12.005.

Authors

Katia Bravo-Jaimes¹, Xiuju Wu², Leigh C Reardon³, Gentian Lluri⁴, Jeannette P Lin⁴, Jeremy P Moore³, Glen van Arsdell⁵, Reshma Biniwale⁵, Ming-Sing Si⁵, Bita V Naini⁶, Robert Venick⁷, Sammy Saab⁸, Christopher L Wray⁹, Reid Ponder¹⁰, Carl Rosenthal¹¹, Alexandra Klomhaus¹², Kristina I Böstrom², Jamil A Aboulhosn⁴, Fady M Kaldas¹³

Affiliations

¹ Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida, USA; Ahmanson/UCLA Adult Congenital Heart Disease Center, University of California, Los Angeles, California, USA.
² Division of Cardiology, Department of Medicine, University of California, Los Angeles, California, USA.
³ Ahmanson/UCLA Adult Congenital Heart Disease Center, University of California, Los Angeles, California, USA; Department of Pediatric Cardiology, University of California, Los Angeles Mattel Children's Hospital, Los Angeles, California, USA.
⁴ Ahmanson/UCLA Adult Congenital Heart Disease Center, University of California, Los Angeles, California, USA; Division of Cardiology, Department of Medicine, University of California, Los Angeles, California, USA.
⁵ Ahmanson/UCLA Adult Congenital Heart Disease Center, University of California, Los Angeles, California, USA; Division of Congenital Cardiovascular Surgery, University of California, Los Angeles Mattel Children's Hospital, Los Angeles, California USA; Department of Surgery, University of California-Los Angeles, Los Angeles, California, USA.
⁶ Department of Pathology and Lab Services, University of California, Los Angeles, California, USA.
⁷ Department of Gastroenterology, Hepatology, and Nutrition, University of California, Los Angeles Mattel Children's Hospital, Los Angeles, California, USA.
⁸ Pfleger Liver Institute, University of California, Los Angeles, California, USA.
⁹ Department of Anesthesiology, University of California, Los Angeles, California, USA.
¹⁰ Ahmanson/UCLA Adult Congenital Heart Disease Center, University of California, Los Angeles, California, USA.
¹¹ Dumont-UCLA Liver Transplant Center, Department of Surgery, University of California, Los Angeles, California, USA.
¹² Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
¹³ Dumont-UCLA Liver Transplant Center, Department of Surgery, University of California, Los Angeles, California, USA. Electronic address: FKaldas@mednet.ucla.edu.

PMID: 38355242
DOI: 10.1016/j.jacc.2023.12.005

Abstract

Background: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown.

Objectives: This study 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. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape.

Results: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-β signaling pathway, and vasculature development.

Conclusions: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.

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

MeSH terms

Adult
Female
Fibrosis
Fontan Procedure*
Gene Expression Profiling
Heart Defects, Congenital* / genetics
Heart Defects, Congenital* / surgery
Humans
Liver Cirrhosis / genetics
Liver Cirrhosis / pathology
Liver Diseases* / genetics
Liver Diseases* / surgery
Male
RNA
Retrospective Studies

Substances

RNA

Grants and funding

R01 HL158053/HL/NHLBI NIH HHS/United States