Multicohort assessment of plasma metabolomic measurements across the atherosclerosis continuum

Atherosclerosis develops over many years and its underlying mechanisms are still not fully understood. Plasma metabolomics across the different stages of development may help identify biomarkers that clarify disease pathways and improve early risk assessment. We performed untargeted plasma metabolomics using ultra-performance liquid chromatography-mass spectrometry in 8,146 participants without cardiovascular disease from the population-based SCAPIS cohort. Associations of 1,171 circulating metabolites with subclinical coronary atherosclerosis burden, assessed using coronary computed tomography angiography and quantified by segment involvement score, were assessed using multivariable models. Metabolites associated with coronary atherosclerosis were then evaluated in independent cohorts representing later stages of the atherosclerotic disease continuum: imminent myocardial infarction (MIMI, n=2,018), and coronary plaque burden and vulnerability in myocardial infarction survivors (PROSPECT II, n=898). Twelve metabolites, including phosphate, malate, sphingomyelins, amino acids, and one uncharacterized feature, were robustly associated with subclinical coronary atherosclerosis independent of traditional risk factors. Notably, sphingomyelins showed inverse associations with subclinical atherosclerosis, imminent myocardial infarction, and the presence of vulnerable plaques. Malate, N-acetyl-isoputreanine and an uncharacterized molecule (X-25790) were positively associated with subclinical coronary atherosclerosis and with imminent myocardial infarctions. These findings reveal a metabolomic signature across the atherosclerosis continuum, highlighting candidate biomarkers that may enhance understanding of disease mechanisms and aid risk stratification.