Hepatic Steatosis and Fibrosis, Cardiorespiratory Fitness, and Metabolic Mediators in the Community

ABSTRACT Background and Aims Individuals with steatotic liver disease (SLD) are at high cardiovascular disease (CVD) risk, but approaches to characterise and mitigate this risk are limited. By investigating relations, and shared metabolic pathways, of hepatic steatosis/fibrosis and cardiorespiratory fitness (CRF), we sought to identify new avenues for CVD risk reduction in SLD. Methods In Framingham Heart Study (FHS) participants ( N = 2722, age 54 ± 9 years, 53% women), vibration‐controlled transient elastography (VCTE) was performed between 2016–2019 to assess hepatic steatosis (continuous attenuation parameter [CAP]) and fibrosis (liver fibrosis measure [LSM]). Concurrently, participants underwent maximum effort cardiopulmonary exercise testing (CPET), and metabolomic profiling (201 circulating metabolites) was performed in a subsample ( N = 1268). Results Mean BMI was 28.0 ± 5.3, 27% had hepatic steatosis, 7.6% had fibrosis, and peak oxygen uptake (VO 2 ) was 26.2 ± 6.8 mL/kg/min in men and 20.7 ± 6.0 mL/kg/min in women (95% predicted overall). In linear models adjusted for cardiometabolic risk factors, greater CAP and LSM were associated with lower peak VO 2 ( p ≤ 0.002 for all), and the CAP association remained significant after BMI adjustment ( p < 0.0001). We observed shared metabolic architecture of CAP, LSM, and peak VO 2 , with metabolites mediating up to 35% (for CAP) and 74% (for LSM) of the association with peak VO 2 . Metabolite mediators included amino acids and derivatives implicated in cardiometabolic risk and both protective and deleterious lipid species. Conclusions Hepatic steatosis and fibrosis are associated with CRF impairment in the community, and these relations are partly mediated by pathways of altered lipid metabolism and general cardiometabolic risk.