Network Analyses Links Epicardial Fat Metabolism to Human Coronary Heart Disease

The generation of tissue-specific integrated networks (INs) through the merging of transcriptional regulatory, protein-protein interaction and genome-scale metabolic networks allows for a rigorous investigation of the biological processes that are altered in cardiovascular disease (CVD) subjects. We developed INs for left ventricle (LV) and visceral adipose tissue (omentum) of healthy subjects and compared these with LV and epicardial fat INs for CVD subjects. We investigated changes in co-regulation for enzymes in pathways that are known to be associated with the development and progression of CVD for each tissue type. Global gene expression changes between healthy and CVD subjects were determined for both tissue types and reporter metabolite analyses were performed. The application and combination of these different network approaches enabled us to associate low levels of Coenzyme Q10 with cardiac remodelling in the LV. We also found increasing homocysteine levels with dysregulation of the adipocytokine pathway in the epicardial fat of CVD subjects and validated our predictions by detecting increased plasma metabolite levels associated with homocysteine in CVD subjects.