BACKGROUND:Male breast cancer is a rare but increasingly recognized disease with limited data on modifiable risk factors. Specifically, it is not known if the inverse association between cardiorespiratory fitness (CRF) and breast cancer risk reported in women is similar to the association between CRF and breast cancer in men. The study aimed to evaluate the association between CRF and the incidence of male breast cancer in a large, nationally representative cohort of U.S. Veterans. METHODS:We analyzed data from 777,618 male Veterans who completed an exercise treadmill testing (ETT) between 1999 and 2024 within the Veterans Health Administration and had no evidence of breast cancer prior to the ETT. CRF was expressed in peak metabolic equivalents (METs). The cohort was categorized into 4 age-adjusted CRF categories based on the peak METs achieved. The primary outcome was incident male breast cancer, ascertained through the Veterans Affairs Computerized Patient Record System. Cox proportional hazards models were used to estimate hazard ratios (HRs) for breast cancer incidence across CRF categories, adjusted for age, race, body mass index, hypertension, diabetes (T2DM), chronic kidney disease, smoking, and alcohol use. RESULTS:Over a median follow-up of 10.7 years 518 men were diagnosed with breast cancer. After multivariable adjustment, age (HR = 1.24, 95% confidence interval (95%CI): 1.14-1.36) per decade, chronic kidney disease (HR = 2.13; 95%CI: 1.41-3.23), hypertension (HR = 1.57; 95%CI: 1.28-1.92), T2DM (HR = 1.24; 95%CI: 1.02-1.51), and poor CRF (HR = 1.69; 95%CI: 1.24-2.30) were the strongest predictors of breast cancer. Compared to patients in the lowest CRF category, breast cancer risk was 41% lower for individuals in the highest CRF quartile (HR = 0.59; 95%CI: 0.44-0.81). CONCLUSION:Higher CRF was independently associated with a substantially lower risk of breast cancer in men. These findings suggest that CRF may represent a modifiable risk factor in the prevention of male breast cancer, underscoring the broader importance of physical fitness in reducing cancer risk across sexes.

BACKGROUND:Low cardiorespiratory fitness (CRF) and traditional cardiovascular risk factors are associated with mortality, but their relative contributions to mortality and the independent association of CRF remain incompletely understood. METHODS:We analyzed a large Veterans Administration cohort undergoing maximal exercise testing (n=580,290; mean age 65.1±9.7 years) and followed them for 10.2±5.1 years. Relative risks (RRs) for mortality were estimated using Poisson regression with robust (HC3) standard errors across nested models adjusting sequentially for age, sex, BMI, diabetes, smoking, and statin therapy. Population attributable risks (PARs) and exposure impact numbers (EINs) were calculated for low CRF and other major risk factors. RESULTS:Individuals in the highest CRF quintile had approximately 74% lower mortality vs. those in the lowest quintile (<5 METs). Hypertension had the greatest population-level impact (PAR 21.8%; 95% CI 15.2-28.0), followed by low CRF (PAR 14.7%; 95% CI 8.1-21.1). In a fully adjusted sensitivity analysis, low CRF demonstrated the strongest independent association with mortality (RR 1.77; 95% CI 1.75-1.79) compared with hypertension (RR 1.33; 95% CI 1.32-1.35). Absolute EIN was lowest for low CRF (2.36), suggesting that for every 100 individuals whose fitness improved over the observed follow-up period, approximately 24 fewer deaths would be expected. CONCLUSIONS:Low CRF and hypertension were the strongest predictors of mortality and accounted for the greatest proportion of population-level risk. These findings support CRF as a modifiable clinical vital sign and highlight the complementary importance of fitness promotion and blood pressure control for reducing mortality.

Rationale & Objective The obesity paradox, where higher body mass index (BMI) is associated with better survival, has been observed in chronic disease populations. However, the interaction between BMI, cardiorespiratory fitness (CRF), and mortality in CKD remains incompletely understood. We examined the association between BMI, age-adjusted CRF, and all-cause mortality in a large CKD cohort. Study Design Retrospective cohort study. Setting & Participants 13,521 predominantly male US Veterans (97.4% male) with CKD from the Exercise Testing and Health Outcomes Study (ETHOS) within the Veterans Affairs healthcare system. Predictors BMI categories (normal weight <25.0, overweight 25.0-29.9, and obese ≥30.0 kg/m2) and age-adjusted CRF quartiles based on metabolic equivalents (METs) achieved during maximal exercise tolerance testing using Bruce protocol. The index date was the date of exercise testing. Outcome All-cause mortality. Analytical Approach Cox proportional hazards models adjusted for age, sex, diabetes mellitus, hypertension, and cardiovascular disease assessed mortality risk across BMI-fitness combinations, with normal BMI and least fit as reference. Results During a mean follow-up of 7.4 years, 5,144 deaths (38.0%) occurred. Higher BMI was associated with lower mortality risk: overweight (HR 0.82, 95% CI 0.70-0.95) and obese (HR 0.71, 95% CI 0.61-0.82) versus normal BMI. Higher CRF was associated with progressively lower mortality: moderate fit (HR 0.61, 95% CI 0.50-0.74) and most fit (HR 0.49, 95% CI 0.40-0.60) versus least fit. The combination of obese BMI and highest fitness was associated with 64% lower mortality risk (HR 0.36, 95% CI 0.25-0.51). Limitations Predominantly male Veteran population; single baseline BMI and fitness measurements; observational design precludes causal inference. Conclusions In this predominantly male Veteran CKD cohort, higher BMI was associated with lower all-cause mortality across all fitness levels. Age-adjusted CRF demonstrated a strong, graded inverse association with mortality independent of BMI. These observational findings support integrating fitness assessment into CKD management.

Background:Left ventricular hypertrophy (LVH) and type 2 diabetes mellitus (T2DM) are both independent risk factors for mortality. Cardiorespiratory fitness (CRF) is inversely associated with mortality and independently predicts lower mortality risk in T2DM. However, the relationship between CRF, LVH, and mortality risk in T2DM has not been well characterized and was the focus of this study.Methods:A total of 866 individuals with T2DM (mean age 61.6 ± 9.9 years) underwent both a standardized exercise stress test and an echocardiographic evaluation. We then established two fitness categories based on peak CRF (i.e., metabolic equivalents (METs)). Individuals with a peak MET level below the median (<6 METs) were considered Low-Fit, and those with a peak MET level at or above the median (≥6 METs) were classified as fit. Left ventricular mass (LVM) was calculated using a standardized formula and indexed to body size to obtain the LVM index. To assess the interaction between fitness and LVH, we established four groups based on fitness status and the presence or absence of LVH: Low-Fit/No LVH (n = 225); Low-Fit/LVH (n = 236); Fit/No LVH (n = 218); and Fit/LVH (n = 187). The Low-Fit/No LVH group served as the reference category for all survival analyses.Results:Over a total of 24 years of follow-up (median 8.9 years), 346 deaths occurred, corresponding to an annual mortality rate of 4.3% in the entire cohort. In the Cox proportional hazards analysis, models adjusted for age, body mass index (BMI), hypertension, smoking, and medication use, revealed a 20% higher mortality risk in the Low-Fit/LVH group (hazard ratio (HR): 1.20; 95% confidence interval (CI): 0.93–1.56; p = 0.15). In contrast, mortality risk was 41% lower in the Fit/No LVH individuals (HR: 0.59; 95% CI: 0.42–0.82; p = 0.002) and 43% lower in the Fit/LVH individuals (HR: 0.57; 95% CI: 0.40–0.81; p = 0.002).Conclusions:Low-Fit individuals with LVH showed a trend toward higher mortality risk. This risk was significantly mitigated in individuals with moderate fitness regardless of LVH status.

OBJECTIVE:To assess the association between objectively measured cardiorespiratory fitness (CRF) and mortality in patients with chronic kidney disease (CKD). PATIENTS AND METHODS:From a large cohort of US veterans (n=750,302) based on the ETHOS (Exercise Testing and Health Outcomes) study, we identified 45,674 men and women aged 30 to 95 years (mean, 65.1 ± 8.8 years) who completed an exercise treadmill test (ETT) within the Veterans Affairs hospitals across the United States. All were diagnosed with CKD before the ETT by International Classification of Diseases 9th and 10th revision codes. Age- and-sex-specific CRF categories (quintiles) were established based on peak metabolic equivalents (METs) achieved during the ETT. We computed HRs and 95% CIs with Cox regression analyses adjusted for comorbidities and medications. RESULTS:During 15.9 years of follow-up, 24,310 individuals (53.2%) died. The adjusted association between CRF and mortality risk was inverse and graded. For each 1-MET increase in CRF, the adjusted HR for mortality was 12% lower (HR, 0.88; 95% CI, 0.875 to 0.885; P<.001). When risk was assessed across CRF categories using the least-fit CRF category as the referent, the adjusted HRs and CIs were 0.76 (95% CI, 0.73 to 0.78), 0.63 (95% CI, 0.61 to 0.66), 0.49 (95% CI, 0.47 to 0.51), and 0.33 (95% CI, 0.30 to 0.35), for low-fit, moderate-fit, fit, and high-fit individuals, respectively. The pattern of the CRF mortality risk association was similar regardless of age, race, or sex. CONCLUSION:In this large multiethnic study, we found an independent, inverse, and graded association between CRF and mortality in CKD patients. These findings underscore the importance of increasing CRF in CKD patients to lower the risk of mortality.

OBJECTIVE:To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and type 2 diabetes mellitus (T2DM). METHODS:A nationwide cohort of dyslipidemic patients (n=311,269; age 60.8±9.2 years) was treated with statins for 6 months or longer, with no T2DM before statin initiation. All completed a standardized exercise treadmill test between October 1, 1999, and September 3, 2020, with no evidence of ischemia. We formed age- and gender-specific five CRF categories according to peak metabolic equivalents (METs) achieved, four BMI categories, and two statin intensity categories. RESULTS:During a median follow-up of 10.9 years (3,421,650 person-years of observation), 56,994 developed T2DM (incidence rate 16.7 events/1000-person-years). The adjusted risk was 23% higher in patients on high-intensity compared with those on low-intensity statins (HR, 1.23; 95% CI, 1.21 to 1.25). The T2DM risk increased progressively with higher BMI and high-intensity statin regimen to a 4.44-fold increase (HR, 4.44; 95% CI, 4.22 to 4.67) for obese patients. Conversely, the CRF-T2DM association was inverse and graded regardless of BMI or static-intensity regimen and was approximately 30% to 60% lower risk for patients achieving greater than or equal to 8.4±1.2 METs. Compared with least-fit/low-intensity statin-treated patients, T2DM risk was 21% higher for least-fit/high-intensity statin-treated patients (HR, 1.21; 95% CI, 1.18 to 1.25), and 47% lower (HR, 0.53; 95% CI, 0.51 to 0.56) in highly fit/high-intensity statin-treated patients. CONCLUSION:High-intensity statin therapy was associated with an increased risk of T2DM. The risk increased progressively with higher BMI and decreased with higher CRF. Strategies to improve fitness and weight loss in patients on high-intensity statins can potentially lower T2DM risk.

OBJECTIVE:To evaluate the association between cardiorespiratory fitness (CRF), objectively measured by standardized exercise treadmill test (ETT), and colorectal cancer incidence. METHODS:The study involved 643,583 US veterans nationwide (41,968 women) from the Exercise Testing and Health Outcomes Study (ETHOS) cohort. None had cancer diagnosis before ETT or had cancer other than colorectal after ETT. Participants completed an ETT (Bruce) with no evidence of ischemia and were stratified into CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved: least fit (n=119,673; METs: 4.8±1.5), low fit (n=157,059; METs: 7.3±1.4), moderate fit (n=122,194; METs: 8.6±1.4), fit (n=170,324; METs: 10.5±1.0), and high fit (n= 74,333; METs: 13.6±1.8). RESULTS:During a median follow-up period of 10.0 years, totaling 6,632,561 person-years, 8190 participants had colorectal cancer (12.4 events per 10,000 person-years). Cardiorespiratory fitness was inversely associated to colorectal cancer risk, independent of comorbidities, with a 9% risk reduction per 1-MET higher in CRF (hazard ratio [HR], 0.91; 95% CI, 0.90 to 0.92), for men and women and across all races. Compared with least fit, the risk of those in the next CRF category (low fit) was 14% lower (HR, 0.86; 95% CI, 0.81 to 0.91). The risk declined progressively with increased CRF and was 57% lower (HR, 0.43; 95% CI, 0.29 to 0.48) for those in the high-fit group. CONCLUSION:We observed an inverse and graded association between CRF and colorectal cancer incidence, across races and sexes, independent of comorbidities. The lower risk was evident in those with a peak CRF of approximately 8.5 to 10.5 METs, a relatively moderate CRF status attainable by most middle-aged and older individuals.

Objective: The risk of atrial fibrillation (AF) is strongly associated with age, increasing the risk of both cardiovascular events and mortality. Evidence suggests an inverse, independent and graded association between cardiorespiratory fitness (CRF) and AF incidence in younger individuals. However, information on the association between CRF and AF incidence on hypertensive individuals >75 years of age is limited. Design and method: We identified of 57,137 hypertensive individuals ages >75.0 years (mean age 79.4±4.0), with no diagnosis of AF or ischemic cardiac disease prior to or upon completion of a standardized exercise treadmill test (ETT) as a part of clinical evaluation. We established four fitness categories based on age-stratified quartiles of peak METs achieved: Least-fit (3.7±0.8 METs; n=14,518); Low-Fit (5.9±0.9 METs; n=14,518); Moderately-Fit (7.0±0.72 METs; n=11,390); and Highly-Fit (9.8±1.4 METs; n=11,463). Multivariable Cox proportional hazard models were applied after adjusting for age, resting blood pressure, smoking, race, sleep apnea, chronic kidney disease, dyslipidemia, and medications. P-values <0.05 using two sided tests were considered statistically significant. Results: During 482,967.0 person-years of follow-up (median 7.8 years), there were 6,645 new AF cases occurred (11.6%) or 13.8 events per 1000 person-years of follow-up. In multivariable-adjusted analyses, CRF was inversely with the risk of developing AF, independent of all traditional comorbidities. For every 1-MET increase in exercise capacity the AF-risk was 9% lower (HR=0.91; CI: 0.90-0.93; p<0.001). The association across CRF categories was graded. Compared to the Least-Fit category (referent), the risk was 22% lower (HR=0.78; CI: 0.74-0.83; p<0.001) for the Low-Fit; 32% lower (HR=0.68; CI: 0.63-0.73; p<0.001) for the Moderately-Fit, and 40% lower (HR=0.60; CI: 0.56-0.65; p<0.001) for Highly-Fit individuals. Conclusions: Increased CRF reduces the risk of AF in individuals ages >75 years. The association is inverse, independent, and graded. For every 1-MET increase in exercise capacity the AF-risk was 9% lower.

Objective: Chronic hypertension (HTN) is considered a strong risk factor for developing chronic kidney disease (CKD). Increased cardiorespiratory fitness (CRF) is associated with lower CKD risk. However, the CRF-CKD association in patients with HTN has not been assessed. Thus, we examined the the association between CRF and the risk of developing CKD in hypertensive patients. Design and method: Hypertensive individuals (n=471,579; age 63.0+8.8 years) with normal kidney function prior to HTN and no evidence of ischemia indicated by a maximal standardized exercise treadmill test (ETT). The cohort was part of the ETHOS study (n=750,302). We established five CRF categories based on age-and-gender-adjusted peak metabolic equivalents (METs) achieved: Least-Fit (4.5±1.2 METs; n=106,955); Low-Fit Fit (6.9±1.1 METs; n=122,612); Moderate-Fit (8.3±1.2 METs; n=91,995); Fit (10.3±1.2 METs; n=111,472); and High-Fit (13.2±1.6 METs; n=38,545). CKD risk across CRF categories was assessed by multivariable Cox Regression analysis, adjusted for age, blood pressure, body mass index (BMI), alcohol abuse, traditional risk factors, and medications. Results: During 6,146,773.0 person-years of follow-up (median 12.9 years), 58,701 individuals developed CKD (9.6 events/1,000 person-years of observation). The CRF-CKD association was inverse, independent of comorbidities and graded. The risk of developing CKD was 9% lower for each 1-MET increase (Hazard Ratio [HR] 0.91; 95% confidence interval [CI] 0.90-0.93). When CKD risk was assessed across CRF categories using the Least-fit category as the referent, the risk was 20% lower (HR 0.80; CI 0.78-0.81, p<0.001) for those in the Low-fit category (6.9±1.1 METs). The risk declined progressively with increased CRF and was 49% lower for those in the highest CRF category (HR 0.49; CI 0.47-0.51, p<0.001). Similar findings were observed in the subgroup of hypertensive patients with diabetes mellitus (n=192,966). Conclusions: We noted an inverse and dose-response association between CRF and CKD incidence. The risk was attenuated significantly beyond a MET level of 6.9±1.1 METs, suggesting that moderate increases in exercise capacity lowers the risk of developing CKD in hypertensive patients.

BACKGROUND: Hypertension and physical inactivity are risk factors for stroke. The effect of cardiorespiratory fitness (CRF) on stroke risk in patients with hypertension has not been assessed. We evaluated stroke incidence in patients with hypertension according to CRF and changes in CRF. METHODS: We included 483 379 patients with hypertension (mean age±SD; 59.4±9.0 years) and no evidence of unstable cardiovascular disease as indicated by a standardized exercise treadmill test. Patients were assigned to 5 age- and sex-specific CRF categories based on peak metabolic equivalents achieved at the initial exercise treadmill test and in 4 categories based on metabolic equivalent changes over time (n=110 576). Multivariable Cox models, adjusted for age, and comorbidities were used to estimate hazard ratios and 95% CIs for stroke risk. RESULTS: During a median follow-up of 10.6 (interquartile range, 6.6–14.6) years, 15 925 patients developed stroke with an average yearly rate of 3.1 events/1000 person-years. Stroke risk declined progressively with higher CRF and was 55% lower for the High-fit individuals (hazard ratio, 0.45 [95% CI, 0.42–0.48]) compared with the Least-fit. Similar associations were observed across the race, sex, and age spectra. Poor CRF was the strongest predictor of stroke risk of all comorbidities studied (hazard ratio, 2.24 [95% CI, 2.10–2.40]). Changes in CRF reflected inverse and proportional changes in stroke risk. CONCLUSIONS: Poor CRF carried a greater risk than any of the cardiac risk factors in patients with hypertension, regardless of age, race, or sex. The lower stroke risk associated with improved CRF suggests that increasing physical activity, even later in life, may reduce stroke risk.

Abstract Background Comorbidities such as cardiovascular disease, diabetes, obesity and hypertension are associated with more severe COVID-19 outcomes, but the relative impact of cardiorespiratory fitness (CRF) on outcomes in COVID-positive patients is largely unknown. Objective To assess the association between objectively measured CRF and COVID-19-related health outcomes including mortality, hospitalization, and mechanical ventilation in non-COVID vaccinated patients. Design, Setting and Participants. Retrospective analysis of 750,302 subjects (23,140 [mean age 65.8±12.0 years] with a positive COVID-19 test between March 2020 and September 2021) who underwent a maximal exercise test between 1999 and 2020. Main Outcomes and Measures. Association between all-cause mortality, hospitalization due to COVID-19, and need for intubation with risk for severe COVID-19 outcomes after adjustment for 15 covariates. Subjects were stratified into five age-specific CRF categories (Least-fit, Low-fit, Moderate-fit, Fit and High Fit), based on peak metabolic equivalents achieved. Results During a median of follow-up of 100 days, 1,643 (7.1%) patients died, 4,995 (21.6%) were hospitalized, and 927 (4.0%) required intubation for COVID-19 related reasons. When compared to the Least-Fit subjects (referent), the Low-Fit, Moderately-Fit, Fit, and High-Fit subjects had hazard ratios for mortality of 0.82 (95% CI; 0.72-0.93), 0.73 (95% CI; 0.63-0.86), 0.61 (95% CI; 0.53-0.72), and 0.54 (95% CI; 0.45-0.65), respectively (Figure). Subjects who were more fit also had significantly lower need for hospital admissions and intubation. Similar patterns were observed for elderly subjects and subgroups with comorbidities including hypertension, diabetes, cardiovascular disease, and chronic kidney disease; for each of these conditions, those in the High-Fit category had mortality rates that were roughly half those in the Low-Fit category. Conclusion Among subjects positive for COVID-19, higher CRF had a favorable impact on survival, need for hospitalization, and need for intubation regardless of age, BMI, or the presence of comorbidities.

Objective: The recent ESH Guidelines include elevated resting heart rate (RHR) as an independent risk factor among the established and suggested novel risk factors that influence cardiovascular risk in patients with hypertension, indicating sympathetic overdrive. Increased fitness affects both mortality and RHR. However, the association between RHR and mortality risk, adjusted for cardiorespiratory fitness, age, comorbidities and medication has not been fully explored. Design and method: We evaluated the association between RHR and mortality in 422,702 hypertensive patients (mean age 62.5 ± 8.6 years) with no evidence of atrial fibrillation during the entire follow-up. All completed a standardized exercise treadmill test (ETT), with no evidence of overt heart disease prior to and at the time of the ETT. To assess the risk in a wide and clinically relevant spectrum, we established 6 RHR categories per 10 heartbeat intervals ranging from <=60 to >100 beats. We used multivariable Cox regression to assess the RHR-mortality association. We adjusted the models for age, body mass index, cardiac risk factors, exercise capacity, and medications (including b-blockers). Results: During the median follow-up of 10.6 years, providing 4,551,327 person-years, there were 107,863 deaths with an average annual rate of 23.7 events per 1,000 person-years. We noted approximately 7% increase in risk for each 10 heart beats. Mortality risk was significantly elevated at a RHR of >80 beats/min (HR; 1.15, CI; 1.12 - 1.17; p <0.006) and increased progressively to 41% (HR; 1.41, CI; 1.36 - 1.45; p <0.001) for those with a RHR of >100 beats/min. Similar trends were noted for subjects aged <60; 60-69; and >=70 years and those treated with b blockers. In all assessments, mortality risk was consistently overestimated when fitness was not considered. Conclusions: We noted a progressive increase in mortality risk with increased RHR at >80 bpm in hypertensive patients with no AF. The association was independent of comorbidities, and medications.

Abstract Introduction Heart failure (HF) with preserved ejection fraction (HFpEF) is closely associated with traditional cardiac risk factors including hypertension. Strategies to prevent the incidence of HFpEF include lifestyle modifications. However, the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized exercise treadmill test (ETT) and HFpEF incidence in hypertensive patients has not been evaluated. Purpose Evaluated the association between CRF and HFpEF incidence in hypertensive patients. Method We assessed CRF in 390,880 hypertensive patients (mean age 62.7 ± 8.6 years by a standardized exercise treadmill test (ETT) performed across US Veterans Affairs Medical Centers. All had no evidence of HF or myocardial infarction prior to completion of the ETT. We established five age-and-gender-specific CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved during the ETT. Q1 (n=80,569; METs=4.6±1.2); Q2 (n=101,358; METs=7.0±1.1): Q3 (n=77,649; METs=8.4±1.2); Q4 (n=97,624; METs=10.3±0.9); Q5 (n=33,680; METs=13.2±1.5) Results During 5,471,090 person-years of follow-up (median 14.0 years), there were 16,493 HFpEF events with an average annual rate of 2.4 events per 1,000 person-years. The adjusted risk of HFpEF decreased progressively across CRF categories as CRF increased, independent of comorbidities. Compared to Q1 (Referent; 4.6±1.2 METs), the risk was 27% lower (hazard ratio [HR] 0.73, 95% CI 0.69-0.75) for individuals within Q2 (7.0 ±1.1 METs) and 61% lower (HR 0.39, 95% CI 0.36-0.43) for those in Q5. Being unfit carried the highest risk (HR, 2.22; 95% CI, 2.33-2.80) of any other comorbidity. Similar findings were observed for those <65.0 and ≥65 years. Conclusions Higher CRF levels were independently associated with lower HRpEF incidence in a dose-response manner in hypertensive patients. The lower risk was observed at relatively low CRF levels (7.0 METs) achievable by most middle-aged and older individuals by engaging in approximately 25-30 minutes of brisk walk daily.

Objective: To assess the association between cardiorespiratory fitness (CRF) and COVID-19-related health outcomes including mortality, hospitalization, and mechanical ventilation. Patients and Methods: In a retrospective analysis of 750,302 patients included in the Exercise Testing and Health Outcomes Study, we identified 23,140 who had a positive result on COVID-19 testing between March 2020 and September 2021 and underwent a maximal exercise test in the Veterans Affairs Health Care System between October 1, 1999 to September 3, 2020. The association between CRF and risk for severe COVID-19 outcomes, including mortality, hospitalization due to COVID-19, and need for intubation was assessed after adjustment for 15 covariates. Patients were stratified into 5 age-specific CRF categories (Least-Fit, Low-Fit, Moderate-Fit, Fit, and High-Fit), based on peak metabolic equivalents achieved. Results: During a median of follow-up of 100 days, 1643 of the 23,140 patients (7.1%) died, 4995 (21.6%) were hospitalized, and 927 (4.0%) required intubation for COVID-19-related reasons. When compared with the Least-Fit patients (referent), the Low-Fit, Moderate-Fit, Fit, and High-Fit patients had hazard ratios for mortality of 0.82 (95% CI, 0.72 to 0.93), 0.73 (95% CI, 0.63 to 0.86), 0.61 (95% CI, 0.53 to 0.72), and 0.54 (95% CI, 0.45 to 0.65), respectively. Patients who were more fit also had substantially lower need for hospital admissions and intubation. Similar patterns were observed for elderly patients and subgroups with comorbidities including hypertension, diabetes, cardiovascular disease, and chronic kidney disease; for each of these conditions, those in the High-Fit category had mortality rates that were roughly half those in the Low-Fit category. Conclusion: Among patients positive for COVID-19, higher CRF had a favorable impact on survival, need for hospitalization, and need for intubation regardless of age, body mass index, or the presence of comorbidities. (c) 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights are reserved, including those for text and data