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

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-ß signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.

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

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.

Fontan operation at less than 3 years of age is not a risk factor for long-term failure.

OBJECTIVES: The age at which the Fontan operation is performed varies globally. Over the last decade, the median age of patients having the Fontan in Australia and New Zealand has been 4.6 years, including 6% of patients younger than 3 years. Long-term outcomes of an early Fontan operation are unclear and are described in this study. METHODS: Patients from the Australian and New Zealand Fontan Registry were grouped by age at Fontan. A Fontan before 3 years (early Fontan) was compared to the combined second and third quartiles by age at surgery in the Registry (3.6-6.1 years; control). Outcomes included Fontan failure (death, transplant, New York Heart Association functional group III/IV heart failure, Fontan takedown or conversion, protein losing enteropathy and plastic bronchitis), arrhythmias, thromboembolism and reinterventions. RESULTS: A total of 191 patients who had early Fontan operations were compared to 781 controls. Profound or progressive cyanosis was noted more frequently in the early than in the control group (63% vs 23%; P < 0.001). The early group was followed up for a median 22.1 years. The incidence of long-term failure was similar between the 2 groups (early, 1.08 failures per 100 patient-years of follow-up vs control, 0.99; log-rank P = 0.79). Adjusted for risk factors, early age at Fontan was not a risk factor for long-term failure [hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.77-1.76; P = 0.48], new-onset arrhythmia (HR 0.93, 95% CI 0.63-1.39; P = 0.73), thromboembolism (HR 0.50, 95% CI 0.28-0.91; P = 0.024) or reintervention (HR 1.08, 95% CI 0.80-1.45; P = 0.62). CONCLUSIONS: Having the Fontan operation at an early age was not a risk factor for short- or long-term adverse outcomes in our cohort.

Impact of adiposity on clinical outcomes in people living with a Fontan circulation.

BACKGROUND: To assess the association between body composition and the risk of adverse outcomes in Fontan patients. METHODS: Participants from the Australian and New Zealand Fontan Registry with dual-energy X-ray absorptiometry scans were included. Appendicular lean mass (ALM), appendicular lean mass index (ALM divided by height squared; ALMI) and total body fat mass percentage (%BF) were calculated. ALMI and %BF z-scores were derived using age- and sex-matched reference ranges. The primary outcome was Fontan failure (death, transplantation, New York Heart Association functional class III/IV, protein-losing enteropathy, and plastic bronchitis) or moderate-or-severe ventricular dysfunction. RESULTS: 144 patients were included. Mean %BF was 29% (SD 10) with 50% having increased adiposity. Mean ALMI z-score was -1.4 (SD 1.1); one third of patients had skeletal muscle deficiency (ALMI z-score < -1 and -2) and another third had Fontan-associated myopaenia (ALMI z-score < -2). Age and %BF were associated with the risk of the endpoint in univariable regression (age: HR 1.09 per year, 95% CI 1.02-1.17, p = 0.01; %BF: HR 1.08, 95% CI 1.01-1.17, p = 0.03). On multivariable regression, every 1% increase in %BF was associated with a 10% increased risk of reaching the clinical endpoint (HR 1.10, 95% CI 1.01-1.19; p = 0.03). ALM was not associated with the endpoint (HR 1.02 per kg, 95% CI 0.88-1.20, p = 0.77). CONCLUSIONS: Increased adiposity is associated with higher risk for adverse outcomes. Prospective studies to assess lifestyle interventions to optimise body composition should be prioritised.