Targeted Metabolomic Profiling Reveals Inflammation – Associated longitudinalchanges in Plasma Metabolites Following on-pump Coronary Bypass Surgery

Aims. Cardiac surgery leads to major post-operative changes in metabolism, but their exact nature and the underlying risk factors are incompletely understood. We aimed to characterize changes in plasma metabolites after coronary artery bypass grafting (CABG) to identify intra- and post-operative risk factors for global and specific alterations in plasma metabolites post-operatively.Methods. We performed a targeted metabolomic screen on plasma samples from patients undergoing on-pump CABG for coronary artery disease (CAD) (n=24), collected 1 day before surgery and on post-op days 1, 3, and 7. We assessed correlations with parameters of intra-operative course (cardiopulmonary bypass time and aortic cross-clamping time), intensive care unit (ICU) care (length of ICU stay, duration of mechanical ventilation, duration of epinephrine/dobutamine or norepinephrine therapy), and systemic inflammation (C-reactive protein, blood leukocyte count).Results. Of the potentially detectable 1019 analytes, 970 passed the quality screen and were included in the analysis. With respect to d0, the greatest degree of change in metabolite populations occurred by d1, but substantial changes persisted through d7. Metabolites could be classified into those which were predominantly downregulated (e.g., triglycerides, bile acids, cholesterol esters, lysophosphatidylcholines, indoles and derivatives), up- or downregulated (e.g., phosphatidylinositol, phosphatidylethanolamines, phosphatidic acids, ceramides), or upregulated (free fatty acids, monoglycerides). Concentrations of food- and/or microbiota-derived metabolites (indole derivatives, trimethylamine N-oxide, trigonelline) were markedly reduced particularly on d1 and d3. Changes in metabolite concentrations correlated most strongly with plasma C-reactive protein concentration (r = -0.67 to 0.59) and blood leukocyte count (-0.63 to 0.32) and less with intra-operative (-0.62 to 0.5) and ICU care (-0.52 to 0.38) parameters. Of note, neither CRP nor leukocyte count correlated significantly with an intra-operative or ICU parameter.Conclusions. These results reveal pronounced changes in plasma metabolite populations after CABG, which likely result from the combined effects of surgical and post-operative stress, systemic inflammation, reduced dietary intake, and changes in gut microflora.Clinical perspective. Identifying metabolic signatures of surgery related acute inflammatory responses helps understanding the pathomechanism of post-surgical stress. In this targeted metabolomic analysis of plasma samples from CAD patients undergoing on-pump CABG, we demonstrate significant metabolite alterations persisting up to seven days post-surgery. Notably, these changes appear to correlate primarily with surgical trauma rather than the use of cardiopulmonary bypass (CPB), highlighting the safety of CPB in cardiac surgery. By identifying individual up- and downregulated metabolite classes, this study ultimately provides potential metabolite targets to address postoperative inflammatory and stress responses through either targeted prophylactic or therapeutic interventions.