Abstract / Summary
Aims: Atherosclerosis develops over many years, and its underlying mechanisms are still not fully understood. Studying plasma metabolites at different stages of the disease may help identify biomarkers that clarify how it develops and improve early risk assessment. Methods: We performed untargeted plasma metabolomics with ultra-performance liquid chromatography-mass spectrometry in 8,146 participants without cardiovascular disease from the population-based SCAPIS cohort. We examined how 1,171 circulating metabolites were associated with subclinical coronary atherosclerosis. Atherosclerosis burden was measured using coronary computed tomography angiography and quantified with the segment involvement score, and associations were analyzed using multivariable models. Associated metabolites were then evaluated in independent cohorts with phenotypes representing later stages of the atherosclerotic disease continuum: myocardial infarction within six months (MIMI, n=2,018), and coronary plaque burden and vulnerability in myocardial infarction survivors (PROSPECT II, n=898). Results: Twelve metabolites, including phosphate, malate, sphingomyelins, and amino acids were robustly associated with subclinical coronary atherosclerosis after adjustment for traditional risk factors and additional clinical variables. Notably, malate, N-acetyl-isoputreanine and a nucleoside derivative were positively associated with subclinical coronary atherosclerosis and with myocardial infarctions. Sphingomyelins showed inverse associations with subclinical atherosclerosis, myocardial infarction, and the presence of vulnerable plaques. Conclusions: These findings reveal a metabolomic signature across the atherosclerosis continuum, highlighting candidate biomarkers that may enhance understanding of disease mechanisms and aid risk stratification.