# Metabolomic signatures connect and mediate sedentary time-driven mortality risk in patients with cardiovascular disease

## TL;DR

This study identifies specific metabolites that link sedentary behavior to increased mortality risk in cardiovascular disease patients, offering insights for targeted interventions.

## Contribution

The study introduces a novel approach to uncover metabolomic signatures that mediate the relationship between sedentary behavior and mortality in CVD patients.

## Key findings

- 35 metabolites were associated with sedentary behavior and 24 were significantly linked to all-cause mortality.
- Metabolites involved in fatty acid metabolism, branched-chain amino acids, and inflammatory glycoproteins were identified.
- Glycoprotein acetyls and phospholipid ratios mediated up to 36.3% of the mortality risk linked to sedentary behavior.

## Abstract

Increasing evidence highlights the association between sedentary behavior and cardiovascular disease (CVD). However, the molecular mechanisms that link sedentary behavior to adverse cardiovascular outcomes, especially the metabolomics pathways, remain unclear.

Participants with CVD at baseline from 2006 to 2010 in the UK Biobank were involved. The all-cause mortality outcome was obtained through the National Death Registry System. Cox proportional hazards model and the elastic network regression model were employed to identify metabolic signatures related to both sedentary time and the risk of all-cause mortality. Mediation analysis was conducted to examine the mediating effects of selected metabolic signatures to the association of sedentary behavior and mortality. The follow-up data was used for validationt.

This study aims to explore the mediating role of the metabolome in the association between sedentary behavior and all-cause mortality among individuals with CVD, providing metabolic insights for CVD management.

The study included 13,561 baseline CVD participants with concentrations of 249 serum metabolites and sedentary time. Thirty-five metabolites were associated with sedentary behavior. Both sedentary time [hazard ratio (HR), 1.08 (95% CI, 1.04–1.13)] and the integrated metabolic feature which was derived from the 35 identified metabolites were associated with an increased risk of all-cause mortality [HR, 1.16 (95% CI, 1.10–1.21)]. Out of the 35 metabolites selected by elastic net regression, 24 were significantly associated with all-cause mortality. These included metabolites involved in fatty acid metabolism, branched-chain amino acid metabolism and inflammatory-related glycoproteins. The integrated metabolic feature, glycoprotein acetyls, phospholipids to total lipids in very small VLDL percentage, and monounsaturated fatty acids to total fatty acids percentage played 36.3%, 35%, 22%, 20% mediating roles respectively between sedentary behavior and all-cause mortality risk.

Our research has revealed the metabolic effects associated with sedentary behavior and all-cause mortality in patients with CVD, highlighting possible targets for personalized intervention and management.