Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease.

Tzoulaki, Ioanna; Castagné, Raphaële; Boulangé, Claire L; Karaman, Ibrahim; Chekmeneva, Elena; Evangelou, Evangelos; Ebbels, Timothy M D; Kaluarachchi, Manuja R; Chadeau-Hyam, Marc; Mosen, David; Dehghan, Abbas; Moayyeri, Alireza; Ferreira, Diana L Santos; Guo, Xiuqing; Rotter, Jerome I; Taylor, Kent D; Kavousi, Maryam; de Vries, Paul S; Lehne, Benjamin; Loh, Marie; ... (2019). Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease. European Heart Journal, 40(34), pp. 2883-2896. Oxford University Press 10.1093/eurheartj/ehz235

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To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD).


We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10-14 to 1.0 × 10-6 (discovery) and P = 5.6 × 10-10 to 1.1 × 10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05).


Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine (ISPM)

UniBE Contributor:

Franco Duran, Oscar Horacio


600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services




Oxford University Press




Beatrice Minder Wyssmann

Date Deposited:

21 May 2019 16:03

Last Modified:

23 Oct 2019 08:22

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Atherosclerosis Coronary artery calcium Epidemiological studies Intima-media thickness Metabolic phenotyping Metabolomics




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