Metabolomic approaches in prospective cohorts may offer a unique snapshot into
early metabolic perturbations that are associated with a higher risk of
cardiovascular diseases (CVD) in healthy people. We investigated the
association of 105 serum metabolites, including acylcarnitines, amino acids,
phospholipids and hexose, with risk of myocardial infarction (MI) and ischemic
stroke in the European Prospective Investigation into Cancer and Nutrition
(EPIC)-Potsdam (27,548 adults) and Heidelberg (25,540 adults) cohorts. Using
case-cohort designs, we measured metabolites among individuals who were free
of CVD and diabetes at blood draw but developed MI (n = 204 and n = 228) or
stroke (n = 147 and n = 121) during follow-up (mean, 7.8 and 7.3 years) and
among randomly drawn subcohorts (n = 2214 and n = 770). We used Cox regression
analysis and combined results using meta-analysis. Independent of classical
CVD risk factors, ten metabolites were associated with risk of MI in both
cohorts, including sphingomyelins, diacyl-phosphatidylcholines and acyl-alkyl-
phosphatidylcholines with pooled relative risks in the range of 1.21–1.40 per
one standard deviation increase in metabolite concentrations. The metabolites
showed positive correlations with total- and LDL-cholesterol (r ranged from
0.13 to 0.57). When additionally adjusting for total-, LDL- and HDL-
cholesterol, triglycerides and C-reactive protein, acyl-alkyl-
phosphatidylcholine C36:3 and diacyl-phosphatidylcholines C38:3 and C40:4
remained associated with risk of MI. When added to classical CVD risk models
these metabolites further improved CVD prediction (c-statistics increased from
0.8365 to 0.8384 in EPIC-Potsdam and from 0.8344 to 0.8378 in EPIC-
Heidelberg). None of the metabolites was consistently associated with stroke
risk. Alterations in sphingomyelin and phosphatidylcholine metabolism, and
particularly metabolites of the arachidonic acid pathway are independently
associated with risk of MI in healthy adults