Blood‐Based Fingerprint of Cardiorespiratory Fitness and Long‐Term Health Outcomes in Young Adulthood

BACKGROUND: Cardiorespiratory fitness is a powerful predictor of health outcomes that is currently underused in primary prevention, especially in young adults. We sought to develop a blood‐based biomarker of cardiorespiratory fitness that is easily translatable across populations. METHODS AND RESULTS: Maximal effort cardiopulmonary exercise testing for quantification of cardiorespiratory fitness (by peak oxygen uptake) and profiling of >200 metabolites at rest were performed in the FHS (Framingham Heart Study; 2016–2019). A metabolomic fitness score was derived/validated in the FHS and was associated with long‐term outcomes in the younger CARDIA (Coronary Artery Risk Development in Young Adults) study. In the FHS (derivation, N=451; validation, N=914; age 54±8 years, 53% women, body mass index 27.7±5.3 kg/m(2)), we used LASSO (least absolute shrinkage and selection operator) regression to develop a multimetabolite score to predict peak oxygen uptake (correlation with peak oxygen uptake r=0.77 in derivation, 0.61 in validation; both P<0.0001). In a linear model including clinical risk factors, a ≈1‐SD higher metabolomic fitness score had equivalent magnitude of association with peak oxygen uptake as a 9.2‐year age increment. In the CARDIA study (N=2300, median follow‐up 26.9 years, age 32±4 years, 44% women, 44% Black individuals), a 1‐SD higher metabolomic fitness score was associated with a 44% lower risk for mortality (hazard ratio [HR], 0.56 [95% CI, 0.47–0.68]; P<0.0001) and 32% lower risk for cardiovascular disease (HR, 0.68 [95% CI, 0.55–0.84]; P=0.0003) in models adjusted for age, sex, and race, which remained robust with adjustment for clinical risk factors. CONCLUSIONS: A blood‐based biomarker of cardiorespiratory fitness largely independent of traditional risk factors is associated with long‐term risk of cardiovascular disease and mortality in young adults.