Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

BACKGROUND: The association of fitness with cancer risk is not clear. METHODS: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method. RESULTS: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min-1⋅kg-1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min-1⋅kg-1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. DISCUSSION: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

Resting heart rate is a population-level biomarker of cardiorespiratory fitness: The Fenland Study.

INTRODUCTION: Few large studies have evaluated the relationship between resting heart rate (RHR) and cardiorespiratory fitness. Here we examine cross-sectional and longitudinal relationships between RHR and fitness, explore factors that influence these relationships, and demonstrate the utility of RHR for remote population monitoring. METHODS: In cross-sectional analyses (The UK Fenland Study: 5,722 women, 5,143 men, aged 29-65y), we measured RHR (beats per min, bpm) while seated, supine, and during sleep. Fitness was estimated as maximal oxygen consumption (ml⋅min-1⋅kg-1) from an exercise test. Associations between RHR and fitness were evaluated while adjusting for age, sex, adiposity, and physical activity. In longitudinal analyses (6,589 participant subsample), we re-assessed RHR and fitness after a median of 6 years and evaluated the association between within-person change in RHR and fitness. During the coronavirus disease-2019 pandemic, we used a smartphone application to remotely and serially measure RHR (1,914 participant subsample, August 2020 to April 2021) and examined differences in RHR dynamics by pre-pandemic fitness level. RESULTS: Mean RHR while seated, supine, and during sleep was 67, 64, and 57 bpm. Age-adjusted associations (beta coefficients) between RHR and fitness were -0.26, -0.29, and -0.21 ml⋅kg-1⋅beat-1 in women and -0.27, -0.31, and -0.19 ml⋅kg-1⋅beat-1 in men. Adjustment for adiposity and physical activity attenuated the RHR-to-fitness relationship by 10% and 50%, respectively. Longitudinally, a 1-bpm increase in supine RHR was associated with a 0.23 ml⋅min-1⋅kg-1 decrease in fitness. During the pandemic, RHR increased in those with low pre-pandemic fitness but was stable in others. CONCLUSIONS: RHR is a valid population-level biomarker of cardiorespiratory fitness. Physical activity and adiposity attenuate the relationship between RHR and fitness.

Descriptive Epidemiology of Cardiorespiratory Fitness in UK Adults: The Fenland Study.

INTRODUCTION: Cardiorespiratory fitness (CRF) is rarely measured in population studies. Most studies of CRF do not examine differences by population subgroups or seasonal trends. We examined how estimated CRF levels vary by anthropometric, sociodemographic, and behavioral characteristics in a population-based cohort of UK adults (the Fenland Study). METHODS: We used a validated submaximal exercise test to obtain CRF estimates (CRF estimated ) in 5976 women and 5316 men, residing in the East of England. CRF estimated was defined as estimated maximal oxygen consumption per kilogram total body mass (V̇O 2 max tbm ) and fat-free mass (V̇O 2 max ffm ). Descriptive statistics were computed across anthropometric and sociodemographic characteristics, and across the year. Progressive multivariable analyses were performed to examine associations with physical activity energy expenditure (PAEE) and body mass index (BMI). RESULTS: Mean ± SD V̇O 2 max tbm was lower in women (35.2 ± 7.5 mL·min -1 ·kg -1 ) than men (41.7 ± 7.3 mL·min -1 ·kg -1 ) but V̇O 2 max ffm was similar (women: 59.2 ± 11.6 mL·min -1 ·kg -1 ; men: 62.0 ± 10.3 mL·min -1 ·kg -1 ). CRF estimated was inversely associated with age but not after adjustment for PAEE. People in more physically demanding jobs were fitter compared with those in sedentary jobs, but this association was attenuated in women and reversed in men after adjustment for total PAEE. Physical activity energy expenditure and BMI were positively associated with CRF estimated at all levels of adjustment when expressed relative to fat-free mass. CRF estimated was 4% higher in summer than in winter among women, but did not differ by season among men. CONCLUSIONS: CRF estimated was inversely associated with age but less steeply than anticipated, suggesting older generations are comparatively fitter than younger generations. Physical activity energy expenditure and BMI were stronger determinants of the variance in CRF estimated than other characteristic including age. This emphasizes the importance of modifiable physical activity behaviors in public health interventions.

Quantifying the Relationship Between Physical Activity Energy Expenditure and Incident Type 2 Diabetes: A Prospective Cohort Study of Device-Measured Activity in 90,096 Adults.

OBJECTIVE: To investigate the association between accelerometer-derived physical activity energy expenditure (PAEE) and incident type 2 diabetes (T2D) in a cohort of middle-aged adults and within subgroups. RESEARCH DESIGN AND METHODS: Data were from 90,096 UK Biobank participants without prevalent diabetes (mean 62 years of age; 57% women) who wore a wrist accelerometer for 7 days. PAEE was derived from wrist acceleration using a population-specific method validated against doubly labeled water. Logistic regressions were used to assess associations between PAEE, its underlying intensity, and incident T2D, ascertained using hospital episode and mortality data up to November 2020. Models were progressively adjusted for demographic, lifestyle factors, and BMI. RESULTS: The association between PAEE and T2D was approximately linear (n = 2,018 events). We observed 19% (95% CI 17-21) lower odds of T2D per 5 kJ · kg-1 · day-1 in PAEE without adjustment for BMI and 11% (9-13) with BMI adjustment. The association was stronger in men than women and weaker in those with obesity and higher genetic susceptibility to obesity. There was no evidence of effect modification by genetic susceptibility to T2D or insulin resistance. For a given level of PAEE, odds of T2D were lower among those engaging in more moderate-to-vigorous activity. CONCLUSIONS: There was a strong linear relationship between PAEE and incident T2D. A difference in PAEE equivalent to an additional daily 20-min brisk walk was associated with 19% lower odds of T2D. The association was broadly similar across population subgroups, supporting physical activity for diabetes prevention in the whole population.

Longitudinal cardio-respiratory fitness prediction through wearables in free-living environments.

Cardiorespiratory fitness is an established predictor of metabolic disease and mortality. Fitness is directly measured as maximal oxygen consumption (VO2max), or indirectly assessed using heart rate responses to standard exercise tests. However, such testing is costly and burdensome because it requires specialized equipment such as treadmills and oxygen masks, limiting its utility. Modern wearables capture dynamic real-world data which could improve fitness prediction. In this work, we design algorithms and models that convert raw wearable sensor data into cardiorespiratory fitness estimates. We validate these estimates' ability to capture fitness profiles in free-living conditions using the Fenland Study (N=11,059), along with its longitudinal cohort (N = 2675), and a third external cohort using the UK Biobank Validation Study (N = 181) who underwent maximal VO2max testing, the gold standard measurement of fitness. Our results show that the combination of wearables and other biomarkers as inputs to neural networks yields a strong correlation to ground truth in a holdout sample (r = 0.82, 95CI 0.80-0.83), outperforming other approaches and models and detects fitness change over time (e.g., after 7 years). We also show how the model's latent space can be used for fitness-aware patient subtyping paving the way to scalable interventions and personalized trial recruitment. These results demonstrate the value of wearables for fitness estimation that today can be measured only with laboratory tests.

Cardiorespiratory fitness assessment using risk-stratified exercise testing and dose-response relationships with disease outcomes.

Cardiorespiratory fitness (CRF) is associated with mortality and cardiovascular disease, but assessing CRF in the population is challenging. Here we develop and validate a novel framework to estimate CRF (as maximal oxygen consumption, VO2max) from heart rate response to low-risk personalised exercise tests. We apply the method to examine associations between CRF and health outcomes in the UK Biobank study, one of the world's largest and most inclusive studies of CRF, showing that risk of all-cause mortality is 8% lower (95%CI 5-11%, 2670 deaths among 79,981 participants) and cardiovascular mortality is 9% lower (95%CI 4-14%, 854 deaths) per 1-metabolic equivalent difference in CRF. Associations obtained with the novel validated CRF estimation method are stronger than those obtained using previous methodology, suggesting previous methods may have underestimated the importance of fitness for human health.

Validation of Submaximal Step Tests and the 6-Min Walk Test for Predicting Maximal Oxygen Consumption in Young and Healthy Participants.

Background: This study aimed to test the validity of three different submaximal tests (i.e., 3-min step test with 20.3-cm step box height (3MST20), 3-min step test with 30-cm step box height (3MST30), and 6-min walk test (6MWT)) in estimating maximal oxygen consumption (VO2max) in young and healthy individuals. Methods: The 3MST20, 3MST30, 6MWT, as well as the cardiopulmonary exercise test (CPET) were performed in 73 participants (37 men and 36 women; mean age: 30.8 ± 9.3 years). All participants visited the clinic three times in a random order for anthropometric measurements, three submaximal tests, and the VO2max test. Multiple linear regression analyses were conducted to construct the VO2max prediction equations for each submaximal test. Results: The prediction equations developed based on multiple regression analyses for each submaximal tests were as follows: 3MST20: VO2max = 86.0 - 10.9 × sex (male = 1, female = 2) - 0.4 × age - 0.1 × weight - 0.1 × heart rate recovery at 30 s (HRR30s); 3MST30: VO2max = 84.5 - 10.2 × sex (male = 1, female = 2) - 0.4 × age - 0.1 × weight - 0.1 × HRR30s; and 6MWT: VO2max = 61.1 - 11.1 × sex (male = 1, female = 2) - 0.4 × age - 0.2 × weight - 0.2 × (distance walked·10-1). The estimated VO2max values based on formulated equations were 37.0 ± 7.9, 37.3 ± 7.6, and 36.9 ± 7.9 mL∙kg-1∙min-1 derived from the 3MST20, 3MST30, and 6MWT, respectively. These estimated VO2max values were not significantly different from the measured VO2max value, 37.3 mL∙kg-1∙min-1. The estimated VO2max based on the 3MST20, 3MST30, and 6MWT results explained 73.4%, 72.2%, and 74.4% of the variances in the measured VO2max (p < 0.001), respectively. Conclusions: The 3MST20, 3MST30, and 6MWT were valid in estimating VO2max in relatively young and healthy Asian individuals.

Association Between Muscle Strength and Modeling Estimates of Muscle Tissue Heterogeneity in Young and Old Adults.

OBJECTIVES: Assessing aging muscle through estimates of muscle heterogeneity may overcome some of the limitations of grayscale analyses. The objectives of this study included determining statistical model parameters that characterize muscle echogenicity and are associated with strength in younger and older participants. METHODS: Thirty-three community-dwelling participants were assigned to younger and older groups. Quantitative B-mode ultrasound scanning of the rectus femoris and isometric grip strength testing were completed. Shape or dispersion parameters from negative binomial distribution, Nakagami, gamma, and gamma mixture models were fitted to the grayscale histograms. RESULTS: The mean ages ± SDs of the younger and older groups were 24.0 ± 2.3 and 65.1 ± 6.5 years, respectively. Statistical model shape and dispersion parameters for the grayscale histograms significantly differed between the younger and older participants (P = .002-.006). Among all of the statistical models considered, the gamma mixture model showed the best fit with the grayscale histograms (χ2 goodness of fit = 62), whereas the Nakagami distribution displayed the poorest fit (χ2 goodness of fit = 2595). Grayscale values were significantly associated with peak grip strength force in younger adult participants (R2 = 0.36; P < .008). However, the negative binomial dispersion parameter k (adjusted R2 = 0.70; P < .001) and gamma shape parameter α (adjusted R2 = 0.68; P < .01) showed the highest associations with peak grip strength force in older adult participants. CONCLUSIONS: The negative binomial dispersion parameter k and the gamma shape parameter α have clinical relevance for the assessment of age-related muscle changes. Statistical models of muscle heterogeneity may characterize the association between muscle tissue composition estimates and strength better than grayscale measures in samples of community-dwelling older adults.

Eccentric Exercise Program Design: A Periodization Model for Rehabilitation Applications.

The applied use of eccentric muscle actions for physical rehabilitation may utilize the framework of periodization. This approach may facilitate the safe introduction of eccentric exercise and appropriate management of the workload progression. The purpose of this data-driven Hypothesis and Theory paper is to present a periodization model for isokinetic eccentric strengthening of older adults in an outpatient rehabilitation setting. Exemplar and group data are used to describe the initial eccentric exercise prescription, structured familiarization procedures, workload progression algorithm, and feasibility of the exercise regimen. Twenty-four men (61.8 ± 6.3 years of age) completed a 12-week isokinetic eccentric strengthening regimen involving the knee extensors. Feasibility and safety of the regimen was evaluated using serial visual analog scale (VAS, 0-10) values for self-reported pain, and examining changes in the magnitude of mean eccentric power as a function of movement velocity. Motor learning associated with the familiarization sessions was characterized through torque-time curve analysis. Total work was analyzed to identify relative training plateaus or diminished exercise capacity during the progressive phase of the macrocycle. Variability in the mean repetition interval decreased from 68 to 12% during the familiarization phase of the macrocycle. The mean VAS values were 2.9 ± 2.7 at the start of the regimen and 2.6 ± 2.9 following 12 weeks of eccentric strength training. During the progressive phase of the macrocycle, exercise workload increased from 70% of the estimated eccentric peak torque to 141% and total work increased by 185% during this training phase. The slope of the total work performed across the progressive phase of the macrocycle ranged from -5.5 to 29.6, with the lowest slope values occurring during microcycles 8 and 11. Also, mean power generation increased by 25% when eccentric isokinetic velocity increased from 60 to 90° s-1 while maintaining the same workload target. The periodization model used in this study for eccentric exercise familiarization and workload progression was feasible and safe to implement within an outpatient rehabilitation setting. Cyclic implementation of higher eccentric movement velocities, and the addition of active recovery periods, are featured in the proposed theoretical periodization model for isokinetic eccentric strengthening.

Short-Term Adaptation of Joint Position Sense Occurs during and after Sustained Vibration of Antagonistic Muscle Pairs.

Proprioception is critical for the control of many goal-directed activities of daily living. While contributions from skin and joint receptors exist, the muscle spindle is thought to play an important role in allowing accurate judgments of limb position and movement to occur. The discharges elicited from muscle spindles can be degraded by simultaneous agonist-antagonist tendon vibration, causing proprioception to be distorted. Despite this, changes in limb perception that may result from sensory adaptation to this stimulus remain misunderstood. The purpose of this study was, therefore, to investigate short-term proprioceptive adaptation resulting from vibration of antagonistic muscle pairs. We measured elbow joint position sense in 21 healthy young adults while 80 Hz vibration was applied simultaneously to the distal tendons of the elbow flexor and extensor muscles. Matching errors were then analyzed during early and late adaptation phases to assess short-term adaptation to the vibration stimuli. Participants committed significant undershoot errors during the early adaptation phase, but were comparable to baseline measurements during the late adaptation phase. When we removed the vibration stimuli and conducted a second joint position matching task, matching variability increased significantly, and participants committed overshoot errors. These results bring into question the efficacy of simultaneous agonist-antagonist tendon vibration to degrade proprioceptive acuity.