Abstract 16138: Hepatic Steatosis, Cardiorespiratory Fitness, and Metabolic Mediators in the Community

Abstract

Background: Cardiorespiratory fitness (CRF) is a powerful predictor of cardiovascular (CV) outcomes and multi-organ reserve capacity. Hypothesis: We hypothesize that hepatic steatosis, an emerging CV risk factor, is associated with lower CRF and that certain metabolites mediate this association. Objective: To determine if hepatic steatosis contributes to impaired CRF in community-dwelling individuals. Methods: Framingham Heart Study participants (n=2722) underwent vibration-controlled transient elastography for assessment of controlled attenuation parameter (CAP; a measure of hepatic steatosis) and maximal cardiopulmonary exercise testing (CPET). In individuals with available metabolomic data (n=1346), we evaluated whether blood metabolites mediate the association of CAP and peak CRF (peak oxygen uptake [VO 2 ]). Results: The study sample (mean age 54±9 years, 53% women) had a peak VO 2 of 95±20% of the predicted value, and 722 participants (26.5%) had hepatic steatosis (defined as CAP≥290 dB/m). In multivariable regression models adjusted for age, sex, alcohol use, smoking, systolic blood pressure, hypertensive medication use, diabetes, and prevalent CV disease, both CAP (continuous) and hepatic steatosis were associated with lower peak VO 2 (in ml/kg/min) and VO 2 at the anaerobic threshold, and unfavorable heart rate and blood pressure responses to exercise (at Bonferroni-adjusted P<0.008 for all; Figure 1). Eighteen out of 201 measured circulating metabolites were associated with both peak VO 2 and CAP in separate multivariable models also adjusted for BMI (at FDR 5%). Of these metabolites, 16 significantly mediated the association between CAP and peak VO 2 , with dimethylguanidino valeric acid and lysophosphatidylcholine 20:1 demonstrating the highest proportion mediated. Conclusions: Hepatic steatosis is associated with impaired CRF in the community and this association is partially mediated by known and novel circulating metabolites.