Liver fibrosis in heart failure patients is associated with adverse outcomes, signs of congestion, and αv integrin-related processes: insights from BIOSTAT-CHF
M Z K Tow, W Ouwerkerk, M L Win, M S Hussain, A P M Lang, I R Mordi, A M Choy, J F Dillon, A A Voors, P N Brennan, C C LangAbstract
Introduction
Liver disease is common in heart failure (HF) and is associated with worse outcomes, although the pathophysiological mechanisms remain poorly understood. Previous studies suggest that liver fibrosis without steatosis carries a poorer prognosis in HF patients.
Purpose
We report the outcomes and clinical characteristics of HF patients with liver fibrosis measured by non-invasive tests (NITs), and use high-throughput proteomics to identify pathophysiological processes and potential therapeutic targets.
Methods
We analysed 3,017 HF patients from the index and validation cohorts of BIOSTAT-CHF with FIB-4 scores available, of whom 1,531 had variables required for the novel LiverRisk score (LRS). Fibrosis was defined by FIB-4 ≥2.67 or LRS ≥10 and ruled out by FIB-4 ≤1.3 or LRS ≤6. Steatosis was defined using the hepatic steatosis index (HSI) with a rule-in and rule-out of ≥36 and <30 respectively. Cox proportional hazards models were sequentially adjusted for NT-proBNP, age, sex and alcohol consumption. The primary outcome was mortality or HF hospitalisation. 359 blood biomarkers were quantified using proximity extension assays at baseline. Pathway analysis was performed on these biomarkers using principal component and over-representation analyses.
Results
Liver fibrosis prevalence was 20.5% in the index cohort and 16.5% in the validation cohort. Patients with liver fibrosis had greater signs of systemic congestion (peripheral oedema, hepatomegaly, jugular venous distension) and elevated right heart pressures. On univariate analysis, liver fibrosis significantly predicted the primary outcome [FIB-4 ≥2.67: HR 2.04 (1.61-2.57), p<0.001 | LRS ≥10: HR 1.97 (1.28-3.01), p<0.001]. After adjustment for NT-proBNP, age, sex and alcohol consumption, liver fibrosis remained significantly associated with the primary outcome [FIB-4 ≥2.67: HR 1.26 (1.06-1.51), p<0.01 | LRS ≥10: HR 1.68 (1.23-2.29), p=0.001]. Patients with fibrosis and low steatotic burden had the highest risk of outcomes [LRS ≥10 and HSI <30: HR 7.86 (4.03-15.1), p<0.001]. Pathway analysis showed fibrosis was associated with ECM remodelling, negative regulation of angiogenesis, MAPK/EGFR/PI3K signalling and inflammation, centrally mediated by TGFβ receptor II and integrin αv. (Figures 1and 2)
Conclusion
In patients with new-onset or worsening HF, liver fibrosis is associated with mortality or HF hospitalisation, systemic congestion, and elevated right heart pressures. Proteomic analysis identified αv integrin signalling as a central mediator of liver fibrosis in HF patients, representing a potential therapeutic target, which can be modified by αv integrin inhibitors such as bexotegrast.Figure 1.Central IllustrationFigure 2.Log FC of central biomarkers