• Jari A Laukkanen, Setor K Kunutsor, Thomas Yates, Peter Willeit, Urho M Kujala, Hassan Khan, and Francesco Zaccardi.
• Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland. Electronic address: jari.a.laukkanen@jyu.fi.
• Mayo Clin. Proc. 2020 May 1; 95 (5): 867-878.

ObjectiveTo investigate whether the inverse associations of cardiorespiratory fitness (CRF) with all-cause and cardiovascular mortality in the general population vary among individuals who are at different levels of pretest risk.Patients And MethodsCardiorespiratory fitness was assessed through submaximal bicycle tests in 58,892 participants aged 40 to 69 years who completed baseline questionnaires between January 1, 2006, and December 31, 2010, in the UK Biobank Prospective Study. Participants were categorized into risk categories, which determined allocation to an individualized bicycle protocol. The groups at minimal risk (category 1), small risk (category 2), and medium risk (category 3) were tested at 50%, 35% of the predicted maximal workload, and constant level, respectively. We investigated associations of CRF with mortality across different levels of pretest risk and determined whether CRF improves risk prediction.ResultsDuring a median follow-up of 5.8 years, 936 deaths occurred. Cardiorespiratory fitness was linearly associated with mortality risk. Comparing extreme fifths of CRF, the multivariable-adjusted hazard ratios (95% CIs) for mortality were 0.63 (0.52-0.77), 0.54 (0.36-0.82), 0.81 (0.46-1.43), and 0.58 (0.48-0.69) in categories 1, 2, and 3 and overall population, respectively. The addition of CRF to a 5-year mortality risk score containing established risk factors was associated with a C-index change (0.0012; P=.49), integrated discrimination improvement (0.0005; P<.001), net reclassification improvement (+0.0361; P=.005), and improved goodness of fit (likelihood ratio test, P<.001). Differences in 5-year survival were more pronounced across levels of age, smoking status, and sex.ConclusionCardiorespiratory fitness, assessed by submaximal exercise testing, improves mortality risk prediction beyond conventional risk factors and its prognostic relevance varies across cardiovascular risk levels.Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

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