Background Cardiorespiratory fitness (fitness) is associated with cardiovascular disease (CVD) mortality. However, the extent to which fitness improves risk classification when added to traditional risk factors is unclear. Methods and Results Fitness was measured by the Balke protocol in 66 371 subjects without prior CVD enrolled in the Cooper Center Longitudinal Study between 1970 and 2006; follow-up was extended through 2006. Cox proportional hazards models were used to estimate the risk of CVD mortality with a traditional risk factor model (age, sex, systolic blood pressure, diabetes mellitus, total cholesterol, and smoking) with and without the addition of fitness. The net reclassification improvement and integrated discrimination improvement were calculated at 10 and 25 years. Ten-year risk estimates for CVD mortality were categorized as <1%, 1% to <5%, and ≥5%, and 25-year risk estimates were categorized as <8%, 8% to 30%, and ≥30%. During a median follow-up period of 16 years, there were 1621 CVD deaths. The addition of fitness to the traditional risk factor model resulted in reclassification of 10.7% of the men, with significant net reclassification improvement at both 10 years (net reclassification improvement=0.121) and 25 years (net reclassification improvement=0.041) (P<0.001 for both). The integrated discrimination improvement was 0.010 at 10 years (P<0.001), and the relative integrated discrimination improvement was 29%. Similar findings were observed for women at 25 years. Conclusions A single measurement of fitness significantly improves classification of both short-term (10-year) and long-term (25-year) risk for CVD mortality when added to traditional risk factors.

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Importance Cardiorespiratory fitness (CRF) as assessed by formalized incremental exercise testing is a strong independent predictor of numerous chronic diseases but has received little attention as a predictor of incident cancer or survival following a diagnosis of cancer. Objective To assess the association between midlife CRF and incident cancer and survival following a cancer diagnosis. Design Prospective, observational cohort study. Setting Preventive medicine clinic Participants and Exposures The prospective, observational cohort study included 13,949 community-dwelling men who had a baseline fitness examination. All men completed a comprehensive medical examination, a cardiovascular risk factor assessment, and incremental treadmill exercise test to evaluate CRF. We utilized age-sex specific distribution of treadmill duration from the overall CCLS population to define fitness groups as low (lowest 20%), moderate (middle 40%), and high (upper 40%) fit groups. The adjusted multivariable model included: age, exam year, body mass index, smoking, total cholesterol, systolic blood pressure, diabetes, fasting glucose. Main Outcome Measures (1) Incident prostate, lung, and colorectal cancer, and (2) all-cause mortality and cause-specific mortality among men who developed cancer are Medicare age (on or after age 65 years). Results Compared to low CRF, the adjusted hazard ratio (HR) for incident lung, colorectal, and prostate cancer among men with high CRF was 0.45 (95% CI: 0.29-0.68), 0.56 (95% CI: 0.36-0.87), 1.22 (95% CI: 1.02-1.46), respectively. Among those diagnosed with cancer at Medicare age (65 years), high CRF in mid-life was associated with an adjusted 36% (HR 0.64, 95% CI: 0.45-0.93) risk reduction in all cancer related deaths and a 69% reduction in cardiovascular disease mortality following a cancer diagnosis (HR 0.31, 95% CI: 0.15-0.62) compared to low fit men in mid-life. Conclusions and Relevance There is a strong inverse relationship between midlife CRF and incident lung and colorectal cancer but not prostate cancer. High mid-life CRF is also protective against the risk of cause-specific mortality in those diagnosed with cancer at Medicare age.