Multicohort assessment of plasma metabolomic measurements across the atherosclerosis continuum

Abstract 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. Translational Perspective Coronary atherosclerosis often remains silent until advanced stages, highlighting the need for early detection of individuals at high-risk. Using plasma metabolomics, we identified twelve metabolites associated with subclinical coronary atherosclerosis in participants without prior cardiovascular disease. Several metabolties, including malate, phosphate, specific sphingomyelins, and a nucleoside-like compound, were consistently associated across the atherosclerosis continuum in independent cohorts. These findings underscored potential biomarkers that may advance our understanding of cardiovascular disease and improve cardiovascular risk assessment. However, further studies are needed to determine their clinical utility. Graphic element