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Published on: January 28, 2020
Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population: Results From the
Ersin Cavus1,2, Mahir Karakas1,2, Francisco M Ojeda1
1Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
Insights
Metabolomic profiling identified five phosphatidylcholines (PCs) associated with increased coronary heart disease (CHD) risk. Lower levels of these PCs indicate higher CHD risk, offering insights into disease mechanisms.
Area of Science:
- Cardiovascular Disease Epidemiology
- Metabolomics
- Biomarker Discovery
Background:
- Coronary heart disease (CHD) risk stratification is complex due to intricate causative mechanisms.
- Metabolomic profiling presents an opportunity to identify novel biomarkers for enhanced CHD risk assessment.
Purpose of the Study:
- To investigate the association between circulating metabolites and the incidence of CHD within a large-scale European cohort.
- To evaluate the predictive value of specific metabolites for incident CHD events.
Main Methods:
- A case-cohort study design was employed using the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) cohort, including 10,741 individuals across six European countries.
- Targeted metabolomic profiling was performed on serum samples to quantify 141 metabolites.
- Weighted Cox proportional hazard models and C-indices were used to assess associations between metabolites and CHD onset.
Main Results:
- Over a median follow-up of 9.2 years, 2,166 incident CHD events occurred.
- Twenty-four metabolites were significantly associated with incident CHD (nominal P < .05), including phosphatidylcholines (PCs), lysoPCs, amino acids, and sphingolipids.
- Five specific PCs (acyl-alkyl-PC C40:6, diacyl-PC C40:6, acyl-alkyl-PC C38:6, diacyl-PC C38:6, and diacyl-PC C38:5) remained significant after multiple testing correction, with lower levels correlating to increased CHD risk.
Conclusions:
- Five phosphatidylcholines are significantly associated with an increased risk of incident coronary heart disease.
- These metabolites demonstrate a comparable discriminatory ability to traditional risk factors but do not improve risk assessment when added to existing models.
- The findings contribute to a better understanding of the underlying pathophysiology of CHD.
Importance:
Risk stratification for coronary heart disease (CHD) remains challenging because of the complex causative mechanism of the disease. Metabolomic profiling offers the potential to detect new biomarkers and improve CHD risk assessment.
Objective:
To evaluate the association between circulating metabolites and incident CHD in a large European cohort.
Design, Setting, And Participants:
This population-based study used the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) case-cohort to measure circulating metabolites using a targeted approach in serum samples from 10 741 individuals without prevalent CHD. The cohort consisted of a weighted, random subcohort of the original cohort of more than 70 000 individuals. The case-cohort design was applied to 6 European cohorts: FINRISK97 (Finland), Monitoring of Trends and Determinants in Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA; Germany), MONICA-Brianza and Moli-sani (Italy), DanMONICA (Denmark), and the Scottish Heart Health Extended Cohort (United Kingdom).
Main Outcomes And Measures:
Associations with time to CHD onset were assessed individually by applying weighted and adjusted Cox proportional hazard models. The association of metabolites with CHD onset was examined by C indices.
Results:
In 10 741 individuals (4157 women [38.7%]; median [interquartile range] age, 56.5 [49.2-62.2] years), 2166 incident CHD events (20.2%) occurred over a median (interquartile range) follow-up time of 9.2 (4.5-15.0) years. Among the 141 metabolites analyzed, 24 were significantly associated with incident CHD at a nominal P value of .05, including phosphatidylcholines (PCs), lysoPCs, amino acids, and sphingolipids. Five PCs remained significant after correction for multiple testing: acyl-alkyl-PC C40:6 (hazard ratio [HR], 1.13 [95% CI, 1.07-1.18]), diacyl-PC C40:6 (HR, 1.10 [95% CI, 1.04-1.15]), acyl-alkyl-PC C38:6 (HR, 1.11 [95% CI, 1.05-1.16]), diacyl-PC C38:6 (HR, 1.09 [95% CI, 1.04-1.14]) and diacyl-PC C38:5 (HR, 1.10 [95% CI, 1.05-1.16]). Lower levels of these metabolites were associated with increased risk of incident CHD. The strength of the associations competes with those of classic risk factors (C statistics: acyl-alkyl-PC C40:6, 0.756 [95% CI, 0.738-0.774], diacyl-PC C40:6, 0.754 [95% CI, 0.736-0.772], acyl-alkyl-PC C38:6, 0.755 [95% CI, 0.736-0.773], diacyl-PC C38:6, 0.754 [95% CI, 0.736-0.772]), diacyl-PC C38:5, 0.754 [95% CI, 0.736-0.772]). Adding metabolites to a base risk model including classic risk factors high-sensitivity C-reactive protein and high-sensitivity troponin I did not improve discrimination by C statistics.
Conclusions And Relevance:
Five PCs were significantly associated with increased risk of incident CHD and showed comparable discrimination with individual classic risk factors. Although these metabolites do not improve CHD risk assessment beyond that of classic risk factors, these findings hold promise for an improved understanding of the pathophysiology of CHD.
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