Data availability
There are restrictions to the availability of some of the clinical data generated in the present study (Figs. 1 and 2), because we do not have permission in our informed consent from research subjects to share data outside our institution without their authorization. Where permissible, the datasets generated and/or analyzed during the present studies are available from the corresponding author Stanley L. Hazen (hazens@ccf.org) on request. An answer can be expected within 14 d.
Code availability
Custom R codes used in this manuscript are available at ‘https://doi.org/10.5281/zenodo.6780497’. The BinBase database is accessible using the following link ‘https://bitbucket.org/fiehnlab/binbase/src/master/?’.
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Acknowledgements
This work is supported by grants from the NIH and Office of Dietary Supplements P01 HL147823, R01 HL103866 (S.L.H.), the Leducq Foundation 17CVD01 (S.L.H. and U.L.) and the Deutsche Forschungsgemeinschaft WI 5229/1-1 (M.W.). A.H. is a participant in the BIH-Charité Advanced Clinician Scientist Program funded by the Charité—Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio Study was partially funded by the Sanofi-Aventis Deutschland GmbH (I.D. and U.L.). P.P.S. was supported in part by an AHA postdoctoral grant 20POST35210937. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank G. Deshpande (Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic) for technical support during whole blood in vitro thrombosis studies. We also thank M. Ferrell for assistance in data analysis and T. Weeks (both at the Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic) for editing the manuscript.
Ethics declarations
Competing interests
Hazen reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, being a paid consultant formerly for Procter and Gamble and currently with Zehna Therapeutics. He also reports having received research funds from Procter and Gamble, Zehna Therapeutics and Roche Diagnostics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, a wholly owned subsidiary of Quest Diagnostics, Procter and Gamble and Zehna therapeutics. Tang reports being a consultant for Sequana Medical A.G., Owkin Inc., Relypsa Inc. and PreCardiac Inc., having received an honorarium from Springer Nature for authorship/editorship and American Board of Internal Medicine for exam writing committee participation—all unrelated to the subject and contents of this paper. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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Peer review information
Nature Medicine thanks Andrew Gray, Steffen Massberg and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ming Yang, in collaboration with the Nature Medicine team.
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Extended data
Extended Data Fig. 1 Polyol metabolites and major adverse cardiovascular events (MACE) in untargeted metabolomics analyses of the discovery cohort.
Shown are boxplots with relative levels for the indicated polyol (defined as compounds with two or more hydroxyl groups) area in both patients with (red) and without (blue) incident (3 yr) MACE ranked by Mann Whitney P values. Compound relative areas are shown as log of fold change (no MACE vs. MACE) to facilitate comparison. Boxes represent interquartile ranges (IQR) with the notch indicating the median. Lower whiskers represent smallest observation (≥25% quantile -1.5×IQR) and upper whiskers largest observation (≤75% quantile +1.5×IQR). Two-sided P values were calculated by Mann–Whitney U-test. N for no MACE = 1041, n for MACE = 116. False discovery rate corrected two-sided P values (Benjamini-Hochberg method) are indicated as follows: ****P<0.0001, ***P < 0.001, **P < 0.01, *P < 0.05.
Extended Data Fig. 2 Chromatographic separation of erythritol from its structural isomer threitol.
After exhaustive acetylation with acetic acid anhydride, the polyols erythritol and its structural isomer, threitol, were baseline resolved by the HPLC method developed. Shown are the chromatograms generated by multiple reaction monitoring transitions (MRM) for the derivatized plasma analytes (m/z 308; [M+NH4]+) and synthetic isotopically labeled erythritol internal standard (D6-Erythritol; m/z 314; [M+NH4]+). With the column matrix and mobile phase /gradient employed, coupled with the characteristic parent [M+NH4+] —> daughter ion transition used (for both erythritol and threitol), baseline chromatographic resolution of the two structural isomers was achieved.
Extended Data Fig. 3 Plasma levels of erythritol are elevated in patients with major adverse cardiovascular events (MACE) and coronary artery disease (CAD) in both US and European validation cohorts.
Erythritol levels in patients stratified by presence of (3 year) MACE or CAD. Data are shown as log of plasma Erythritol. Plotted are individual values as dots. Boxes represent interquartile ranges (IQR) with the notch indicating the median. Lower whiskers represent smallest observation (≥25% quantile – 1.5×IQR) and upper whiskers largest observation (≤75% quantile + 1.5×IQR). Two-sided P values were calculated by Mann–Whitney U-test. Numbers of subjects within each group are indicated.
Extended Data Fig. 4 Erythritol increases platelet aggregation responses to submaximal concentrations of agonists.
ADP-stimulated and Thrombin receptor-activating peptide(TRAP)6-stimulated platelet aggregometry responses of human
