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

Ravi V. Shah, Patricia Miller, Laura A. Colangelo, Ariel Chernofsky, Nicholas E. Houstis, Rajeev Malhotra, Raghava S. Velagaleti, David R. Jacobs, Kelley Pettee Gabriel, Jared P. Reis, Donald M. Lloyd-Jones, Clary B. Clish, Martin G. Larson, Ramachandran S. Vasan, Venkatesh L. Murthy, Gregory D. Lewis, Matthew Nayor

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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/m2), we used LASSO (least absolute shrinkage and selection opera-tor) 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.

Original languageEnglish (US)
Article numbere026670
JournalJournal of the American Heart Association
Volume11
Issue number18
DOIs
StatePublished - Sep 20 2022

Bibliographical note

Funding Information:
The FHS is supported by the National Heart, Lung, and Blood Institute contracts N01-HC-25195, HHSN268201500001I, and 75N92019D00031. The CARDIA study is supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). Additional support for this work was provided by the CARDIA Fitness Study (R01-HL078972) and CARDIA Activity and Heart Failure Study (R01-HL149796 to K.P.G.). This work was supported by R01-HL136685 (V.L.M. and R.V.S), R01-HL131029 (R.S.V. and G.D.L.), and American Heart Association grant 15GPSGC24800006 (G.D.L.). R.M. was supported by National Institutes of Health grants R01HL142809 and R01HL159514, grant 18TPA34230025 from the American Heart Association, and the Wild Family Foundation. R.S.V. is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. M.N. was supported by National Institutes of Health grants K23-HL138260 and R01-HL156975 and by a Career Investment Award from the Department of Medicine, Boston University School of Medicine.

Publisher Copyright:
© 2022, American Heart Association Inc.. All rights reserved.

Keywords

  • body mass index
  • cardiorespiratory fitness
  • exercise test
  • linear models
  • longitudinal studies

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