Although cardiovascular disease (CVD) metrics define risk in individuals aged over 40, CVD’s most initial lesions appear well before this age. Despite the role of metabolism in CVD predecessors, the studies in the biracial, younger populations to define metabolic risk phenotypes remain inadequate. In total, 2330 Black and White young adults (45% Black; mean age, 32 years) in the CARDIA study, in order to identify metabolite profiles associated with an adverse CVD phenome, mechanisms, and outcomes over two decades. Statistical methods and Cox regression generated parsimonious, metabolite-based risk scores validated in less than 1800 individuals in the Framingham Heart Study.

In the CARDIA study, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel CVD pathways. Two multiparametric, metabolite-based scores linked independently to myocardial and vascular health, with metabolites included in each score specifying collagen metabolism, nitric oxide modulation, oxidative stress, hepatic steatosis, and microbial metabolism.  The myocardial scores were lower in Black participants, and the metabolite-based vascular scores were lower in all men. Over a nearly 25-year median follow-up, the myocardial score and the metabolite-based vascular score in the third and fourth decades of life were associated with clinical CVD with a synergistic association with outcome.

In conclusion, myocardial and vascular health’s metabolic signatures in young adulthood specify known/novel metabolic dysfunction pathways relevant to CVD, associated with outcome in 2 independent cohorts. Future efforts to include precision measures of metabolic health in risk hierarchy to negate CVD at its earliest stage are endorsed.