The Association between Cardiorespiratory Fitness and the Risk of Breast Cancer in Women.

INTRODUCTION: Studies have shown an inverse association between the risk of breast cancer in women and physical activity. However, information on the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized test and the risk of developing breast cancer is limited. PURPOSE: To examine the CRF-breast cancer risk association in healthy females. METHODS: This retrospective study was derived from the Exercise Testing and Health Outcomes Study cohort ( n = 750,302). Female participants ( n = 44,463; mean age ± SD; 55.1 ± 8.9 yr) who completed an exercise treadmill test evaluation (Bruce protocol) at the Veterans Affairs Medical Centers nationwide from 1999 to 2020 were studied. The cohort was stratified into four age-specific CRF categories (Least-fit, Low-fit, Moderate-fit, and Fit), based on the peak METs achieved during the exercise treadmill test. RESULTS: During 438,613 person-years of observation, 994 women developed breast cancer. After controlling for covariates, the risk of breast cancer was inversely related to exercise capacity. For each 1-MET increase in CRF, the risk of cancer was 7% lower (HR, 0.93; 95% CI, 0.90-0.95; P < 0.001). When risk was assessed across CRF categories with the Least-fit group as the referent, the risk was 18% lower for Low-fit women (HR, 0.82; 95% CI, 0.70-0.96; P = 0.013), 31% for Moderate-fit (HR, 0.69; 95% CI, 0.58-0.82; P < 0.001), and 40% for Fit (HR, 0.60; 95% CI, 0.47-0.75; P < 0.001). CONCLUSIONS: We observed an inverse and graded association between CRF and breast cancer risk in women. Thus, encouraging women to improve CRF may help attenuate the risk of developing breast cancer.

Progression to Insulin Therapy in Patients With Type 2 Diabetes According to Cardiorespiratory Fitness, Body Mass Index, and Statin Therapy.

OBJECTIVE: To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and progression to insulin therapy in type 2 diabetes mellitus (T2DM). METHODS: Participants were patients with T2DM (mean age, 62.7±8.4 years; men, 178,992; women, 8360) not treated with insulin, with no evidence of uncontrolled cardiovascular disease, who completed an exercise treadmill test between October 1, 1999, and September 3, 2020. Of these, 158,578 were treated with statins and 28,774 were not. We established 5 age-specific CRF categories according to peak metabolic equivalents of task achieved during an exercise treadmill test. RESULTS: During a median follow-up period of 9.0 years, 51,182 patients progressed to insulin therapy with an average annual incidence rate of 28.4 events/1000 person-years. The adjusted progression rate was 27% higher in statin-treated patients (hazard ratio [HR], 1.27; 95% CI, 1.24 to 1.31), related directly to BMI and inversely related to CRF. A progressively higher rate was noted in statin-treated vs non-statin-treated patients within all BMI categories, ranging from 23% for normal weight to 90% for those with BMI of 35 kg/m2 and higher. The statin-CRF interaction revealed 43% higher rate in the least-fit statin-treated patients (HR, 1.43; 95% CI, 1.35 to 1.51) and a progressive decline with increased CRF to 30% lower risk in highly fit statin-treated patients (HR, 0.70; 95% CI, 0.66 to 0.75). CONCLUSION: In patients with T2DM, the statin-related progression to insulin therapy was associated with relatively low CRF and high BMI levels. The progression rate was mitigated by increased CRF regardless of BMI. Clinicians should foster regular exercise for patients with T2DM to enhance CRF and to lessen the rate of progression to insulin therapy.

Cardiorespiratory fitness and risk of heart failure with preserved ejection fraction.

AIMS: Preventive strategies for heart failure with preserved ejection fraction (HFpEF) include pharmacotherapies and lifestyle modifications. However, the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized exercise treadmill test (ETT) and the risk of HFpEF has not been evaluated. Thus, we evaluated the association between CRF and HFpEF incidence. METHODS AND RESULTS: We assessed CRF in US Veterans (624 551 men; mean age 61.2 ± 9.7 years and 43 179 women; mean age 55.0 ± 8.9 years) by a standardized ETT performed between 1999 and 2020 across US Veterans Affairs Medical Centers. All had no evidence of heart failure or myocardial infarction prior to completion of the ETT. We assigned participants to one of five age- and gender-specific CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved during the ETT and four categories based on CRF changes in those with two ETT evaluations (n = 139 434) ≥1.0 year apart. During a median follow-up of 10.1 years (interquartile range 6.0-14.3 years), providing 6 879 229 person-years, there were 16 493 HFpEF events with an average annual rate of 2.4 events per 1000 person-years. The adjusted risk of HFpEF decreased across CRF categories as CRF increased, independent of comorbidities. For fit individuals (≥10.5 METs) the hazard ratio (HR) was 0.48 (95% confidence interval [CI] 0.46-0.51) compared with least fit (≤4.9 METs; referent). Being unfit carried the highest risk (HR 2.88, 95% CI 2.67-3.11) of any other comorbidity. The risk of unfit individuals who became fit was 37% lower (HR 0.63, 95% CI 0.57-0.71), compared to those who remained unfit. CONCLUSIONS: Higher CRF levels are independently associated with lower HFpEF in a dose-response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF.

Changes in Cardiorespiratory Fitness and Survival in Patients With or Without Cardiovascular Disease.

BACKGROUND: The association between cardiorespiratory fitness (CRF) and mortality risk is based mostly on 1 CRF assessment. The impact of CRF change on mortality risk is not well-defined. OBJECTIVES: This study sought to evaluate changes in CRF and all-cause mortality. METHODS: We assessed 93,060 participants aged 30-95 years (mean 61.3 ± 9.8 years). All completed 2 symptom-limited exercise treadmill tests, 1 or more years apart (mean 5.8 ± 3.7 years) with no evidence of overt cardiovascular disease. Participants were assigned to age-specific fitness quartiles based on peak METS achieved on the baseline exercise treadmill test. Additionally, each CRF quartile was stratified based on CRF changes (increase, decrease, no change) observed on the final exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for all-cause mortality. RESULTS: During a median follow-up of 6.3 years (IQR: 3.7-9.9 years), 18,302 participants died with an average yearly mortality rate of 27.6 events per 1,000 person-years. In general, changes in CRF ≥1.0 MET were associated with inverse and proportionate changes in mortality risk regardless of baseline CRF status. For example, a decline in CRF of >2.0 METS was associated with a 74% increase in risk (HR: 1.74; 95% CI: 1.59-1.91) for low-fit individuals with CVD, and 69% increase (HR: 1.69; 95% CI: 1.45-1.96) for those without CVD. CONCLUSIONS: Changes in CRF reflected inverse and proportional changes in mortality risk for those with and without CVD. The impact of relatively small CRF changes on mortality risk has considerable clinical and public health significance.

Cardiorespiratory Fitness and Mortality Risk Across the Spectra of Age, Race, and Sex.

BACKGROUND: Cardiorespiratory fitness (CRF) is inversely associated with all-cause mortality. However, the association of CRF and mortality risk for different races, women, and elderly individuals has not been fully assessed. OBJECTIVES: The aim of this study was to evaluate the association of CRF and mortality risk across the spectra of age, race, and sex. METHODS: A total of 750,302 U.S. veterans aged 30 to 95 years (mean age 61.3 ± 9.8 years) were studied, including septuagenarians (n = 110,637), octogenarians (n = 26,989), African Americans (n = 142,798), Hispanics (n = 35,197), Native Americans (n = 16,050), and women (n = 45,232). Age- and sex-specific CRF categories (quintiles and 98th percentile) were established objectively on the basis of peak METs achieved during a standardized exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for mortality across the CRF categories. RESULTS: During follow-up (median 10.2 years, 7,803,861 person-years of observation), 174,807 subjects died, averaging 22.4 events per 1,000 person-years. The adjusted association of CRF and mortality risk was inverse and graded across the age spectrum, sex, and race. The lowest mortality risk was observed at approximately 14.0 METs for men (HR: 0.24; 95% CI: 0.23-0.25) and women (HR: 0.23; 95% CI: 0.17-0.29), with no evidence of an increase in risk with extremely high CRF. The risk for least fit individuals (20th percentile) was 4-fold higher (HR: 4.09; 95% CI: 3.90-4.20) compared with extremely fit individuals. CONCLUSIONS: The association of CRF and mortality risk across the age spectrum (including septuagenarians and octogenarians), men, women, and all races was inverse, independent, and graded. No increased risk was observed with extreme fitness. Being unfit carried a greater risk than any of the cardiac risk factors examined.

The Microstructure of Attentional Control in the Dorsal Attention Network.

The top-down control of attention involves command signals arising chiefly in the dorsal attention network (DAN) in frontal and parietal cortex and propagating to sensory cortex to enable the selective processing of incoming stimuli based on their behavioral relevance. Consistent with this view, the DAN is active during preparatory (anticipatory) attention for relevant events and objects, which, in vision, may be defined by different stimulus attributes including their spatial location, color, motion, or form. How this network is organized to support different forms of preparatory attention to different stimulus attributes remains unclear. We propose that, within the DAN, there exist functional microstructures (patterns of activity) specific for controlling attention based on the specific information to be attended. To test this, we contrasted preparatory attention to stimulus location (spatial attention) and to stimulus color (feature attention), and used multivoxel pattern analysis to characterize the corresponding patterns of activity within the DAN. We observed different multivoxel patterns of BOLD activation within the DAN for the control of spatial attention (attending left vs. right) and feature attention (attending red vs. green). These patterns of activity for spatial and feature attentional control showed limited overlap with each other within the DAN. Our findings thus support a model in which the DAN has different functional microstructures for distinctive forms of top-down control of visual attention.

Exercise blood pressure, cardiorespiratory fitness and mortality risk.

OBJECTIVE: To assess the cardiorespiratory fitness (CRF) impact on the association between exercise blood pressure (BP) and mortality risk. PATIENTS AND METHODS: We assessed CRF in 15,004 US Veterans (mean age 57.5 ± 11.2 years) who completed a standardized treadmill test between January 1, 1988 and July 28, 2017 and had no evidence of ischemia. They were classified as Unfit or Fit according to the age-specific metabolic equivalents (METs) achieved <50% (6.2 ± 1.6 METs; n = 8440) or ≥ 50% (10.5 ± 2.4 METs; n = 6264). To account for the impact of resting systolic BP (SBP) on outcomes, we calculated the difference (Peak SBP-Resting SBP) and termed it SBP-Reserve. We noted a significant increase in mortality associated with SBP-Reserve ≤52 mmHg and stratified the cohort accordingly (SBP-Reserve ≤52 mmHg and > 52 mmHg). We applied multivariable Cox models to estimate hazard ratios (HR) and 95% confidence interval (CIs) for outcomes. RESULTS: Mortality risk was significantly elevated only in Unfit individuals with SBP-Reserve ≤52 mmHg compared to those with SBP-Reserve >52 mmHg (HR = 1.35; CI: 1.24-1.46; P < 0.001). We then assessed the CRF and SBP-Reserve interaction on mortality risk with Fit individuals with SBP-Reserve >52 mmHg serving as the referent. Mortality risk was 92% higher (HR = 1.92%; 95% CI: 1.77-2.09; P < 0.001) in Unfit individuals with SBP-Reserve ≤52 mmHg and 47% higher (HR = 1.47; 95% CI: 1.33-1.62; P < 0.001) in those with SBP-Reserve >52 mmHg. CONCLUSION: Low CRF was associated with increased mortality risk regardless of peak exercise SBP. The risk was substantially higher in individuals unable to augment their exercise SBP >52 mmHg beyond resting levels.

Working Memory Capacity Is Negatively Associated with Memory Load Modulation of Alpha Oscillations in Retention of Verbal Working Memory.

Working memory capacity (WMC) measures the amount of information that can be maintained online in the face of distraction. Past work has shown that the efficiency with which the frontostriatal circuit filters out task-irrelevant distracting information is positively correlated with WMC. Recent work has demonstrated a role of posterior alpha oscillations (8-13 Hz) in providing a sensory gating mechanism. We investigated the relationship between memory load modulation of alpha power and WMC in two verbal working memory experiments. In both experiments, we found that posterior alpha power increased with memory load during memory, in agreement with previous reports. Across individuals, the degree of alpha power modulation by memory load was negatively associated with WMC, namely, the higher the WMC, the less alpha power was modulated by memory load. After the administration of topiramate, a drug known to affect alpha oscillations and have a negative impact on working memory function, the negative correlation between memory load modulation of alpha power and WMC was no longer statistically significant but still somewhat detectable. These results suggest that (1) individuals with low WMC demonstrate stronger alpha power modulation by memory load, reflecting possibly an increased reliance on sensory gating to suppress task-irrelevant information in these individuals, in contrast to their high WMC counterparts who rely more on frontal areas to perform this function and (2) this negative association between memory load modulation of alpha oscillations and WMC is vulnerable to drug-related cognitive disruption.

Compensatory Neural Activity in Response to Cognitive Fatigue.

Prolonged continuous performance of a cognitively demanding task induces cognitive fatigue and is associated with a time-related deterioration of objective performance, the degree of which is referred to cognitive fatigability. Although the neural underpinnings of cognitive fatigue are poorly understood, prior studies report changes in neural activity consistent with deterioration of task-related networks over time. While compensatory brain activity is reported to maintain motor task performance in the face of motor fatigue and cognitive performance in the face of other stressors (e.g., aging) and structural changes, there are no studies to date demonstrating compensatory activity for cognitive fatigue. High-density electroencephalography was recorded from human subjects during a 160 min continuous performance of a cognitive control task. While most time-varying neural activity showed a linear decline over time, we identified an evoked potential over the anterior frontal region which demonstrated an inverted U-shaped time-on-task profile. This evoked brain activity peaked between 60 and 100 min into the task and was positively associated with better behavioral performance only during this interval. Following the peak and during subsequent decline of this anterior frontal activity, the rate of performance decline also accelerated. These findings demonstrate that this anterior frontal brain activity, which is not part of the primary task-related activity at baseline, is recruited to compensate for fatigue-induced impairments in the primary task-related network, and that this compensation terminates as cognitive fatigue further progresses. These findings may be relevant to understanding individual differences in cognitive fatigability and developing interventions for clinical conditions afflicted by fatigue. SIGNIFICANCE STATEMENT: Fatigue refers to changes in objective performance and subjective effort induced by continuous task performance. We examined the neural underpinnings of cognitive fatigue in humans using a prolonged continuous performance task and high-density electroencephalography with the goal of determining whether compensatory processes exist to maintain performance in the face of fatigue. We identified brain activity demonstrating an inverted U-shaped time-on-task profile. This brain activity showed features consistent with a compensatory role including: peaking between 60 and 100 min into the task, a positive association with behavioral performance only during this interval, and accelerated performance decline following its peak. These findings may be relevant to understanding individual differences in cognitive fatigue and developing interventions for clinical conditions afflicted by fatigue.