Distress-related metabolites predict future CV events


the study covered in this summary was published on medRxiv.org as a preprint and has not yet been peer reviewed.

Take away key

why it matters

  • It is known that depression and other psychological distress are associated with a higher risk of cardiovascular disease. Identifying metabolites that are elevated with both chronic distress and cardiovascular disease could help clarify their associated underlying mechanisms.

  • A scoring system based on these alterations could be predictive of future cardiovascular disease risk, with a variety of potential uses.

study design

  • A metabolite-based distress score was developed using case-control data from women in the Nurses’ Health Study (NHS).

  • The data was based on biomarker levels in blood samples taken from 2000 to 2002, depression rating questionnaires taken from 1992 to 2004, and anxiety rating questionnaires taken from 1998 and 2004. women were initially free of cancer and cardiovascular disease.

  • Metabolite biomarkers included serotonin, N2, N2-dimethylguanosine, threonine, hippurate, biliverdin, C34:3 PC, glutaminecotinine, creatininearachidonate, 3-methylxanthine, C38:3 PC, tryptophan, GABA, c16:0 ceramide, N4-acetylcytidine, C36:5 PC plasmalogen-B, C18:0 LPE, pseudouridine, thiamin, and DMGV. The Women’s Health Initiative Observational Study (WHI-OS) provided data on 20 of the biomarkers and the Prevención con Dieta Mediterránea (PREDIMED) trial provided data on 17.

  • Distressed participants were matched to control subjects by age, race or ethnicity, menopausal status, fasting status, and date and time of day the blood sample was obtained .

  • Metabolite-based distress scores were compared to incident rates coronary disease (CHD), defined as myocardial infarction or death due to coronary artery disease, in a separate WHI-OS cohort, which included postmenopausal women aged 50 to 79; their data was collected from 1993 to 1998.

  • The scoring system was also applied to data from the PREDIMED trial, a primary prevention study in men and women at high risk of cardiovascular disease.

Principle results

  • In the WHI-OS cohort, a 1 standard deviation increase in distress score showed an odds ratio (OR) of 1.14 (95% CI, 1.03, 1.26) for the incident of coronary artery disease after adjustment for cardiovascular risk factorsout of total and HDL cholesterol. The association was attenuated after further adjustment for total and HDL cholesterol (OR, 1.09; 95% CI, 0.98, 1.21). However, it was significantly associated with an increased risk of cardiovascular disease over 10 years (P = .01).

  • Lower levels of threonine (OR, = 1.22; 95% CI, 1.06 – 1.42) and tryptophan (OR, 1.16, 95% CI, 1.01 – 1.33) were associated with an increased risk of coronary heart disease.

  • Pseudouridine, N2, N2-dimethylguanosine, and ceramide C16:0 also had positive associations with the incidence of coronary artery disease, and biliverdin showed an inverse association.

  • In the PREDIMED cohort, a 1 standard deviation increase in distress score was associated with a fully adjusted OR of 1.17 (95% CI, 1.00, 1.38) for coronary artery disease incident; the results were similar for men and women.

  • Biliverdin and plasmalogen PC C365:5 were inversely and significantly associated with cardiovascular risk in the PREDIMED cohort; Ceramide C16:0 and LPE C18:0 showed positive associations.


  • The metabolite-based distress scoring system was based on cross-sectional data.

  • Systemic variability could have been introduced into the analyzes because the three cohorts studied were distinct populations.

  • The metabolite-based distress score was derived from the Nurses’ Health Study, which included postmenopausal women with limited racial and ethnic diversity.


  • The study was supported by the National Institutes of Health. The WHI metabolomics analysis and the entire WHI program were funded by the National Heart, Lung, and Blood Institute. The authors did not disclose anything.

This is an abstract of a preprint research study, Metabolomic profiles of chronic distress predict future risk of cardiovascular disease, written by Raji Balasubramanian, ScD, of the Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, and colleagues, on MedRxiv powered by Medscape. This study has not yet been peer reviewed. The full text of the study is available at medRxiv.org.


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