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

Ioanna Tzoulaki; Raphaële Castagné; Claire L Boulangé; Ibrahim Karaman; Elena Chekmeneva; Evangelos Evangelou; Timothy M D Ebbels; Manuja R Kaluarachchi; Marc Chadeau-Hyam; David Mosen; Abbas Dehghan; Alireza Moayyeri; Diana L Santos Ferreira; Xiuqing Guo; Jerome I Rotter; Kent D Taylor; Maryam Kavousi; Paul S de Vries; Benjamin Lehne; Marie Loh; Albert Hofman; Jeremy K Nicholson; John Chambers; Christian Gieger; Elaine Holmes; Russell Tracy; Jaspal Kooner; Philip Greenland; Oscar H Franco; David Herrington; John C Lindon; Paul Elliott

doi:10.1093/eurheartj/ehz235

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

Eur Heart J. 2019 Sep 7;40(34):2883-2896. doi: 10.1093/eurheartj/ehz235.

Authors

Ioanna Tzoulaki^{1

2

3

4}, Raphaële Castagné^{1

5}, Claire L Boulangé^{6

7}, Ibrahim Karaman^{1

2

4}, Elena Chekmeneva⁷, Evangelos Evangelou^{1

2

3}, Timothy M D Ebbels⁷, Manuja R Kaluarachchi^{6

7}, Marc Chadeau-Hyam^{1

2}, David Mosen^{1

2}, Abbas Dehghan^{1

2

4}, Alireza Moayyeri⁸, Diana L Santos Ferreira⁹, Xiuqing Guo^{10

11}, Jerome I Rotter^{10

11}, Kent D Taylor^{10

11}, Maryam Kavousi¹², Paul S de Vries^{12

13}, Benjamin Lehne¹, Marie Loh¹, Albert Hofman^{12

14}, Jeremy K Nicholson^{6

7}, John Chambers^{1

15}, Christian Gieger¹⁶, Elaine Holmes^{6

7}, Russell Tracy¹⁷, Jaspal Kooner^{14

18}, Philip Greenland¹⁹, Oscar H Franco^{11

20}, David Herrington²¹, John C Lindon^{6

7}, Paul Elliott^{1

2

4}

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, UK.
² MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, UK.
³ Department of Hygiene and Epidemiology, University of Ioannina Medical School, University Campus Road 455 00, Ioannina, Greece.
⁴ Dementia Research Institute, Imperial College London, Norfolk Place, London, UK.
⁵ LEASP, UMR 1027, Inserm-Université Toulousse III Paul Sabatier, Toulousse, France.
⁶ Metabometrix Ltd, Imperial Incubator, Bessemer Building, Prince Consort Road, London, UK.
⁷ Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, South Kensington Campus, London, UK.
⁸ Farr Institute of Health Informatics Research, University College London Institute of Health Informatics, 222 Euston Road, London, UK.
⁹ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfiled Grove, Bristol, UK.
¹⁰ Department of Pediatrics, Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA, USA.
¹¹ Department of Medicine, Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA, USA.
¹² Department of Epidemiology, Erasmus University Medical Center, University Medical Center Rotterdam, CA Rotterdam, the Netherlands.
¹³ Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston, TX, USA.
¹⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, USA.
¹⁵ London North West Healthcare NHS Trust, Northwick Park Hospital, Watford Rd, Harrow, UK.
¹⁶ German Research Centre for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstraße 1, D Neuherberg, Germany.
¹⁷ M.D. College of Medicine University of Vermont, The Robert Larner, Given Medical Bldg, E-126, 89 Beaumont Ave, Burlington, VT, USA.
¹⁸ National Heart & Lung Institute, Faculty of Medicine, Imperial College London, Guy Scadding Building, Dovehouse St, Chelsea, London, UK.
¹⁹ Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, 680 North Lake Shore Drive, Suite, 1400, Chicago, IL, USA.
²⁰ Institute of Social and Preventive Medicine (ISPM), University of Bern, Mittelstrasse 43, Bern, Switzerland.
²¹ Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.

Abstract

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

Methods and results: 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).

Conclusion: 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.

Keywords: Atherosclerosis; Coronary artery calcium; Epidemiological studies; Intima-media thickness; Metabolic phenotyping; Metabolomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Cardiovascular Diseases / blood
Cardiovascular Diseases / etiology*
Carotid Artery Diseases / blood
Carotid Artery Diseases / complications*
Carotid Artery Diseases / metabolism*
Coronary Artery Disease / blood
Coronary Artery Disease / complications*
Coronary Artery Disease / metabolism*
Female
Humans
Male
Middle Aged
Prospective Studies
Proton Magnetic Resonance Spectroscopy

Abstract

Publication types

MeSH terms

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