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Background The study aimed to show the relationship between a large number of circulating metabolites and subsequent cardiovascular disease (CVD) and subclinical markers of CVD in the general population.

Methods and Results In 2278 individuals free from CVD in the EpiHealth study (aged 45-75 years, mean age 61 years, 50% women), 790 annotated nonxenobiotic metabolites were measured by mass spectroscopy (Metabolon). The same metabolites were measured in the PIVUS (Prospective Investigation of Vasculature in Uppsala Seniors) study (n=603, all aged 80 years, 50% women), in which cardiac and carotid artery pathologies were evaluated by ultrasound. During a median follow-up of 8.6 years, 107 individuals experienced a CVD (fatal or nonfatal myocardial infarction, stroke, or heart failure) in EpiHealth. Using a false discovery rate of 0.05 for age- and sex-adjusted analyses and P<0.05 for adjustment for traditional CVD risk factors, 37 metabolites were significantly related to incident CVD. These metabolites belonged to multiple biochemical classes, such as amino acids, lipids, and nucleotides. Top findings were dimethylglycine and N-acetylmethionine. A lasso selection of 5 metabolites improved discrimination when added on top of traditional CVD risk factors (+4.0%, P=0.0054). Thirty-five of the 37 metabolites were related to subclinical markers of CVD evaluated in the PIVUS study. The metabolite 1-carboxyethyltyrosine was associated with left atrial diameter as well as inversely related to both ejection fraction and the echogenicity of the carotid artery.

Conclusions Several metabolites were discovered to be associated with future CVD, as well as with subclinical markers of CVD. A selection of metabolites improved discrimination when added on top of CVD risk factors.