Hepatic steatosis associates with leukopoietic activity and atherosclerotic inflammation: mechanistic insights into cardiovascular risk

Abstract

Background

Hepatic steatosis (HS) is associated with an increased risk of major adverse cardiovascular events (MACE). However, the underlying mechanisms linking HS to MACE remain incompletely understood. This study aimed to investigate the role of the leukopoietic-arterial axis in mediating the relationship between imaging markers of HS and MACE.

Methods and materials

This longitudinal retrospective cohort study included 445 individuals without active cancer, liver disease or alcohol abuse, or baseline cardiovascular disease who underwent clinical ¹⁸F-FDG-PET/CT imaging. Hepatic glucose uptake (HGU), uptake in the bone marrow (BM) and spleen (as a marker of leukopoiesis), and activity in the aorta (as a measure of arterial inflammation, ArtI) were evaluated. Hepatic and splenic attenuations were analyzed to assess hepatic attenuation index (HAI) and determine nonalcoholic fatty liver disease (NAFLD) status. Metabolic Dysfunction Associated Steatotic Liver disease (MASLD) was defined based on NAFLD status and other metabolic criteria. MACE was adjudicated.

Results

In fully adjusted models, HGU associated with heightened BM (standardized β [95 % confidence interval]: 0.353 [0.276, 0.430], p < 0.001) and spleen activities (0.548 [0.475, 0.621], p < 0.001) as well as ArtI (0.529 [0.453, 0.605], p < 0.001). Similar associations were observed for HAI and MASLD or NAFLD status. Notably, these associations remained significant after adjusting for other confounders and among individuals without MASLD/NAFLD. A total of 28 individuals developed MACE over 4 years median follow-up. Furthermore, the leukopoietic-arterial activity mediated the link between imaging markers of HS (i.e., HGU, HAI, MASLD) and MACE, (p < 0.05).

Conclusion

Our study suggests an important role for the leukopoietic-arterial axis in HS and MACE. These findings may inform therapeutic avenues for reducing the cardiovascular risk associated with HS.

Structured abstract

This study examines the connection between hepatic steatosis (HS) and major adverse cardiovascular events (MACE) through the leukopoietic-arterial axis. Among 445 patients without history of liver disease or alcohol abuse, imaging markers of hepatic steatosis (i.e., hepatic glucose uptake (HGU)), and metabolic dysfunction associated steatotic liver disease (MASLD), associated with increased activity in bone marrow and spleen, and atherosclerotic plaques. These associations persisted irrespective of MASLD status and after adjusting for relevant confounders. Heightened uptake in leukopoietic tissues and the arteries mediated the relationship between HS markers (i.e., HGU, MASLD) and MACE development. These findings shed light on novel mechanistic pathways and potential targets for interventions to reduce the burden of HS-related CVD.