Liver fibrosis is associated with left ventricular remodeling: insights into the liver-heart axis
Authors: Edin C , Ekstedt M , Karlsson M , Wegmann B , Ebbers T , Swahn E , Ostgren C J , Lundberg P , Carlhall C J 
Published: November 2023

Abstract

Background
Non-alcoholic fatty liver disease (NAFLD), common in type 2 diabetes, has emerged as an important and independent risk factor for adverse cardiac remodeling. Fibrosis in the liver could be a key factor in this relationship. Despite the fact that NAFLD is a long-term progressive disease, imaging studies on this topic are mainly limited to selected patients from tertiary centres.

Purpose
To investigate the relationship between liver fat, liver fibrosis and cardiac remodeling in the general population. We also sought to explore biomarkers of cardiovascular inflammation and fibrosis, for possible mechanistic pathways in these relationships.

Methods
We included 46 participants with type 2 diabetes and 46 age and sex-matched controls (overall 35%/65% F/M, mean age 59.5 ± 4.6), all randomly sampled from the general population. Participants underwent careful clinical phenotyping, including blood sampling, echocardiography, and magnetic resonance imaging (MRI) at 1.5 T. The MRI protocol included sequences for quantification of liver proton density fat fraction (spectroscopy), liver fibrosis (stiffness from elastography at 56 Hz), left ventricular (LV) structure, function, and tissue characteristics (native T1 mapping). We also analyzed ∼290 circulating cardiovascular biomarkers. A Bayesian statistical approach (‘Stochastic Search Variable Selection’) was used to identify the biomarkers most strongly associated with cardiac remodeling.

Results
For liver stiffness, the mean value was 2.1 ± 0.4 kPa and the highest value was 2.9 kPa. The median liver fat value was 5.7% (IQR 9.9%) and 53 participants (58%) displayed hepatic steatosis (liver fat &gt; 5%). LV concentricity increased across quartiles of liver stiffness (P=0.0014 for ANOVA), while LV concentricity and diastolic dysfunction increased across quartiles of liver fat (P=0.0023 and P=0.030 for ANOVA, respectively). Myocardial T1 displayed no relationships to neither liver fat nor liver stiffness. In a multiple linear regression, liver stiffness was positively associated with LV concentricity (Beta=0.26, P=0.0053), independently of diabetes and liver fat. This association was attenuated (Beta=0.17, P=0.077) when adjusting for circulating levels of IL-1 receptor type 2, the biomarker with the strongest association to LV concentricity in the Bayesian statistical analysis.

Conclusion
In our well-characterized subjects from the general population, we found that a majority had hepatic steatosis but overall rather low liver stiffness values. Despite this, liver stiffness was related to increased LV concentricity independently of liver fat and diabetes. This association was attenuated when also adjusting for IL-1 receptor type 2. Our results suggest a link between liver fibrosis and cardiac remodeling also in the early stages of fatty liver disease, possibly involving the IL-1 signaling pathway. Future studies are needed to further establish causality and potential mechanisms.Multiple linear regression analysesLiver magnetic resonance elastogram