Distress-Related Metabolite Levels Predicts Future Cardiovascular Events

Why This Matters

  • It is known that depression and other psychologic distress are associated with higher risk for cardiovascular disease. Identification of metabolites that are elevated with both chronic distress and cardiovascular disease might help to clarify their associated underlying mechanisms.

  • A scoring system based on these alterations might be predictive of future risk for cardiovascular disease, 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 were based on biomarker levels in blood samples taken from 2000 to 2002, depression-assessment questionnaires performed from 1992 to 2004, and anxiety-assessment questionnaires performed in 1998 and 2004. The women were initially free of cancer and cardiovascular disease.

  • The metabolite biomarkers included serotonin, N2, N2-dimethylguanosine, threonine, hippurate, biliverdin, C34:3 PC, glutamine, cotinine, creatinine, arachidonate, 3-methylxanthine, C38:3 PC, tryptophan, GABA, c16:0 ceramide, N4-acetylcytidine, C36:5 PC plasmalogen-B, C18:0 LPE, pseudouridine, thiamine, 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.

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

  • Metabolite-based distress scores were compared with rates of incident coronary heart disease (CHD), defined as myocardial infarction or death due to CHD, in a separate cohort from the WHI-OS, which comprised postmenopausal women 50 to 79 years of age; their data were collected from 1993 to 1998.

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


Key Results

  • In the WHI-OS cohort, a 1 standard-deviation increase in the distress score showed an odds ratio (OR) of 1.14 (95% CI, 1.03 - 1.26) for incident CHD after adjustment for known cardiovascular risk factors, excluding 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 increased 10-year risk for cardiovascular disease (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 increased CHD risk.

  • Pseudouridine, N2, N2-dimethlguanosine, and C16:0 ceramide also had positive associations with incident CHD, and biliverdin showed an inverse association.

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

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



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

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

  • The metabolite-based distress score was derived in 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 metabolomic analysis and the overall WHI program was funded by the National Heart, Lung, and Blood Institute. The authors had no disclosures.