Background: The underlying biological mechanisms linking blood pressure (BP) and cardiovascular diseases (CVD) are only partly understood. We aimed to identify metabolic signatures associated with systolic (SBP) and diastolic (DBP) and investigate their subsequent association with risk of CVD.
Methods: The study included 201,742 UK Biobank participants with measurements on 249 metabolic biomarkers. A multi-step adaptive elastic net penalized regression with 10-fold cross-validation was employed to identify metabolic signatures for SBP and DBP. External validation was conducted on 848 participants from the Epirus Health Study (EHS). We further assessed the associations between BP metabolic signatures and incident composite CVD (N = 6,742), myocardial infarction (MI) (N = 4,192), and stroke (N = 2,757) in the UK Biobank, using multivariable Cox regression models.
Results: The metabolic signatures comprised 31 and 25 metabolites, robustly correlated with SBP and DBP, respectively, in both UK Biobank and EHS. Following adjustments (including BP), the metabolic signature for SBP was positively associated with incident MI (HR=1·11, 95% CI 1·07-1·15) and CVD (HR=1·07, 95% CI 1·04-1·10). Similarly, the metabolic signature for DBP was associated with an increased risk of MI (HR=1·16, 95% CI, 1·12-1·20) and CVD (HR=1·09, 95% CI, 1·05-1·12). The associations between the signatures and stroke were not significant. The metabolic signatures partly mediated the total effect of the BP traits on the risk of MI and CVD.
Conclusions: Our findings may enhance our understanding of the biological mechanisms through which BP affects CVD.