Metabolomic analysis of 92 pulmonary embolism patients from a nested case–control study identifies metabolites associated with adverse clinical outcomes

Essentials Risk‐stratification often fails to predict clinical deterioration in pulmonary embolism ( PE ). First‐ever high‐throughput metabolomics analysis of risk‐stratified PE patients. Changes in circulating metabolites reflect a compromised energy metabolism in PE . Metabolites play a key role in the pathophysiology and risk stratification of PE .Summary Background Patients with acute pulmonary embolism ( PE ) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low‐risk and high‐risk PE is limited, so current risk‐stratification efforts often fail to predict clinical deterioration and are insufficient to guide management. Objectives To improve our understanding of the physiology differentiating low‐risk from high‐risk PE , we conducted the first‐ever high‐throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case–control study. Patients/methods We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 h of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk‐strata. Results When we compared 46 low‐risk with 46 intermediate/high‐risk PE s, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: tricarboxylic acid ( TCA ) cycle, fatty acid metabolism (acyl carnitine) and purine metabolism, (hypo)xanthine/inosine containing. Additionally, energy, nucleotide and amino acid pathways were downregulated in intermediate/high‐risk PE patients. When we compared 28 intermediate‐risk with 18 high‐risk PE patients, 41 metabolites differed at a nominal P ‐value level. These metabolites were enriched in fatty acid metabolism (acyl cholines), and hemoglobin and porphyrin metabolism. Conclusion Our results suggest that high‐throughput metabolomics can provide insight into the pathophysiology of PE . Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high‐risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE .