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Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable., (© 2024. The Author(s).)

Regular exercise leads to widespread salutary effects, and there is increasing recognition that exercise-stimulated circulating proteins can impart health benefits. Despite this, limited data exist regarding the plasma proteomic changes that occur in response to regular exercise. Here, we perform large-scale plasma proteomic profiling in 654 healthy human study participants before and after a supervised, 20-week endurance exercise training intervention. We identify hundreds of circulating proteins that are modulated, many of which are known to be secreted. We highlight proteins involved in angiogenesis, iron homeostasis, and the extracellular matrix, many of which are novel, including training-induced increases in fibroblast activation protein (FAP), a membrane-bound and circulating protein relevant in body-composition homeostasis. We relate protein changes to training-induced maximal oxygen uptake adaptations and validate our top findings in an external exercise cohort. Furthermore, we show that FAP is positively associated with survival in 3 separate, population-based cohorts.

The aim of the HERITAGE Family Study was to investigate individual differences in response to a standardized endurance exercise program, the role of familial aggregation, and the genetics of response levels of cardiorespiratory fitness and cardiovascular disease and diabetes risk factors. Here we summarize the findings and their potential implications for cardiometabolic health and cardiorespiratory fitness. It begins with overviews of background and planning, recruitment, testing and exercise program protocol, quality control measures, and other relevant organizational issues. A summary of findings is then provided on cardiorespiratory fitness, exercise hemodynamics, insulin and glucose metabolism, lipid and lipoprotein profiles, adiposity and abdominal visceral fat, blood levels of steroids and other hormones, markers of oxidative stress, skeletal muscle morphology and metabolic indicators, and resting metabolic rate. These summaries document the extent of the individual differences in response to a standardized and fully monitored endurance exercise program and document the importance of familial aggregation and heritability level for exercise response traits. Findings from genomic markers, muscle gene expression studies, and proteomic and metabolomics explorations are reviewed, along with lessons learned from a bioinformatics-driven analysis pipeline. The new opportunities being pursued in integrative -omics and physiology have extended considerably the expected life of HERITAGE and are being discussed in relation to the original conceptual model of the study., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Maximal oxygen uptake (VO 2 max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO 2 max, and of increases of VO 2 max in response to exercise training (ΔVO 2 max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO 2 max and ΔVO 2 max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's ΔVO 2 max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans.

Importance: Obesity is a major determinant of disease burden worldwide. Polygenic risk scores (PRSs) have been posited as key predictors of obesity. How a PRS can be translated to the clinical encounter (especially in the context of fitness, activity, and parental history of overweight) remains unclear., Objective: To quantify the relative importance of a PRS, fitness, activity, parental history of overweight, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in young adulthood on BMI trends over 25 years., Design, Setting, and Participants: This population-based prospective cohort study at 4 US centers included white individuals and black individuals with assessments of polygenic risk of obesity, fitness, activity, and BMI in young adulthood (in their 20s) and up to 25 years of follow-up. Data collected between March 1985 and August 2011 were analyzed from April 25, 2019, to September 29, 2019., Main Outcomes and Measures: Body mass index at the initial visit and 25 years later., Results: This study evaluated an obesity PRS from a recently reported study of 1608 white individuals (848 women [52.7%]) and 909 black individuals (548 women [60.3%]) across the United States. At baseline (year 0), mean (SD) overall BMI was 24.2 (4.5), which increased to 29.6 (6.9) at year 25. Among white individuals, the PRS (combined with age, sex, self-reported parental history of overweight, and principal components of ancestry) explained 11.9% (at year 0) and 13.6% (at year 25) of variation in BMI. Although the addition of fitness increased the explanatory capability of the model (24.0% variance at baseline and up to 18.1% variance in BMI at year 25), baseline BMI in young adulthood was the strongest factor, explaining 52.3% of BMI in midlife in combination with age, sex, and self-reported parental history of overweight. Accordingly, models that included baseline BMI (especially BMI surveillance over time) were better in predicting BMI at year 25 compared with the PRS. In fully adjusted models, the effect sizes for fitness and the PRS on BMI were comparable in opposing directions. The added explanatory capacity of the PRS among black individuals was lower than among white individuals. Among white individuals, addition of baseline BMI and surveillance of BMI over time was associated with improved precision of predicted BMI at year 25 (mean error in predicted BMI 0 kg/m2 [95% CI, -11.4 to 11.4] to 0 kg/m2 [95% CI, -8.5 to 8.5] for baseline BMI and mean error 0 kg/m2 [95% CI, -5.3 to 5.3] for BMI surveillance)., Conclusions and Relevance: Cardiorespiratory fitness in young adulthood and a PRS are modestly associated with midlife BMI, although future BMI is associated with BMI in young adulthood. Fitness has a comparable association with future BMI as does the PRS. Caution should be exercised in the widespread use of polygenic risk for obesity prevention in adults, and close clinical surveillance and fitness may have prime roles in limiting the adverse consequences of elevated BMI on health.

Background: This study examined the cross-sectional and longitudinal associations of cardiorespiratory fitness (CRF) and ideal cardiovascular health (CVH)., Methods: CRF and the 7 CVH components were measured in 11,590 (8865 males; 2725 females) adults at baseline and in 2532 (2160 males; 372 females) adults with at least one follow-up examination from the Aerobics Center Longitudinal Study. Ideal CVH score was calculated as a composite of 7 measures, each scored 0 to 2. CVH groups were based on participant point score: ≤7 (poor), 8 to 11 (intermediate), and 12 to 14 (ideal). Analyses included general linear, logistic regression, and linear mixed models., Results: At baseline, participants in the high CRF category had 21% and 45% higher mean CVH scores than those in the moderate and poor CRF categories (P < .001). The adjusted odds (95% confidence interval) of being in the poor CVH group at baseline were 4.9 (4.4-5.4) and 16.9 (14.3-19.9) times greater for individuals with moderate and low CRF, respectively, compared with those with high CRF (P < .001). Longitudinal analysis found that for every 1-minute increase in treadmill time, CVH score increased by 0.23 units (P < .001) independent of age, sex, exam number, and exam year., Conclusions: Higher CRF is associated with better CVH profiles, and improving CRF over time is independently associated with greater improvements in CVH.

There is evidence from human twin and family studies as well as mouse and rat selection experiments that there are considerable interindividual differences in the response of cardiorespiratory fitness (CRF) and other cardiometabolic traits to a given exercise programme dose. We developed this consensus statement on exercise response variability following a symposium dedicated to this topic. There is strong evidence from both animal and human studies that exercise training doses lead to variable responses. A genetic component contributes to exercise training response variability.In this consensus statement, we (1) briefly review the literature on exercise response variability and the various sources of variations in CRF response to an exercise programme, (2) introduce the key research designs and corresponding statistical models with an emphasis on randomised controlled designs with or without multiple pretests and post-tests, crossover designs and repeated measures designs, (3) discuss advantages and disadvantages of multiple methods of categorising exercise response levels-a topic that is of particular interest for personalised exercise medicine and (4) outline approaches that may identify determinants and modifiers of CRF exercise response. We also summarise gaps in knowledge and recommend future research to better understand exercise response variability., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Intrinsic cardiorespiratory fitness (CRF) is defined as the level of CRF in the sedentary state. There are large individual differences in intrinsic CRF among sedentary adults. The physiology of variability in CRF has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored in the present study by interrogating intrinsic CRF-associated DNA sequence variation and skeletal muscle gene expression data from the HERITAGE Family Study through an integrative bioinformatics guided approach. A combined analytic strategy involving genetic association, pathway enrichment, tissue-specific network structure, cis-regulatory genome effects, and expression quantitative trait loci was used to select and rank genes through a variation-adjusted weighted ranking scheme. Prioritized genes were further interrogated for corroborative evidence from knockout mouse phenotypes and relevant physiological traits from the HERITAGE cohort. The mean intrinsic V̇o 2max was 33.1 ml O 2 ·kg -1 ·min -1 (SD = 8.8) for the sample of 493 sedentary adults. Suggestive evidence was found for gene loci related to cardiovascular physiology ( ATE1 , CASQ2 , NOTO , and SGCG ), hematopoiesis ( PICALM , SSB , CA9 , and CASQ2 ), skeletal muscle phenotypes ( SGCG , DMRT2 , ADARB1 , and CASQ2 ), and metabolism ( ATE1 , PICALM , RAB11FIP5 , GBA2 , SGCG , PRADC1 , ARL6IP5 , and CASQ2 ). Supportive evidence for a role of several of these loci was uncovered via association between DNA variants and muscle gene expression levels with exercise cardiovascular and muscle physiological traits. This initial effort to define the underlying molecular substrates of intrinsic CRF warrants further studies based on appropriate cohorts and study designs, complemented by functional investigations. NEW & NOTEWORTHY Intrinsic cardiorespiratory fitness (CRF) is measured in the sedentary state and is highly variable among sedentary adults. The physiology of variability in intrinsic cardiorespiratory fitness has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored computationally in the present study, with further corroborative evidence obtained from analysis of phenotype data from knockout mouse models and human cardiovascular and skeletal muscle measurements.

Background: Most of the existing literature has linked a baseline cardiorespiratory fitness or change between baseline and one follow-up measurement of cardiorespiratory fitness to hypertension. The purpose of the study is to assess the association between longitudinal patterns of cardiorespiratory fitness changes with time and incident hypertension in adult men and women., Methods: Participants were aged 20 to 82 years, were free of hypertension during the first 3 examinations, and received at least 4 preventive medical examinations at the Cooper Clinic in Dallas, Texas, from 1971 to 2006. They were classified into 1 of 5 groups based on all of the measured cardiorespiratory fitness values (in metabolic equivalents) during maximal treadmill tests. Logistic regression was used to compute odds ratios and 95% confidence intervals., Results: Among 4932 participants (13% women), 1954 developed hypertension. After controlling for baseline potential confounders, follow-up duration, and number of follow-up visits, odds ratios (95% confidence intervals) for hypertension were 1.00 for the decreasing group (referent), 0.64 (0.52-0.80) for the increasing group, 0.89 (0.70-1.12) for the bell-shape group, 0.78 (0.62-0.98) for the U-shape group, and 0.83 (0.69-1.00) for the inconsistent group. The general pattern of the association was consistent regardless of participants' baseline cardiorespiratory fitness or body mass index levels., Conclusions: An increasing pattern of cardiorespiratory fitness provides the lowest risk of hypertension in this middle-aged relatively healthy population. Identifying specific pattern(s) of cardiorespiratory fitness change may be important for determining associations with comorbidity, such as hypertension., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Low cardiorespiratory fitness has been established as a risk factor for cardiovascular-related morbidity. However, research about the impact of fitness on lipid abnormalities, including atherogenic dyslipidemia, has produced mixed results. The purpose of this investigation is to examine the influence of baseline fitness and changes in fitness on the development of atherogenic dyslipidemia., Methods: All participants completed at least 3 comprehensive medical examinations performed by a physician that included a maximal treadmill test between 1976 and 2006 at the Cooper Clinic in Dallas, Texas. Atherogenic dyslipidemia was defined as a triad of lipid abnormalities: low high-density-lipoprotein cholesterol ([HDL-C] <40 mg/dL), high triglycerides ([TGs] ≥200 mg/dL), and high low-density-lipoprotein cholesterol ([LDL-C] ≥160 mg/dL)., Results: A total of 193 participants developed atherogenic dyslipidemia during an average of 8.85 years of follow-up. High baseline fitness was protective against the development of atherogenic dyslipidemia in comparison with those with low fitness (odds ratio [OR] 0.57; 95% confidence interval [CI], 0.37-0.89); however, this relationship became nonsignificant after controlling for baseline HDL-C, LDL-C, and TG levels. Participants who maintained fitness over time had lower odds of developing atherogenic dyslipidemia than those with a reduction in fitness (OR 0.56; 95% CI, 0.34-0.91) after adjusting for baseline confounders and changes in known risk factors., Conclusions: High fitness at baseline and maintenance of fitness over time are protective against the development of atherogenic dyslipidemia., Competing Interests: DISCLOSURES None, (Copyright © 2016 Elsevier Inc. All rights reserved.)

Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity. NEW & NOTEWORTHY Multi-omics and in silico explorations of the genes and underlying biology of submaximal exercise capacity and its response to 20 wk of endurance training were undertaken. Prioritized genes were identified: 13 genes for variation in submaximal exercise capacity in the sedentary state and 5 genes for the response level to endurance training, with no overlap between them. Genes and pathways associated with submaximal exercise capacity in the sedentary state are different from those underlying trainability. [ABSTRACT FROM AUTHOR]

Background: Whether higher cardiorespiratory fitness (CRF) confers protection against cardiovascular disease (CVD) in individuals with manifest hypercholesterolemia is poorly understood. Methods: Participants were 8920 men aged 20–82 years with hypercholesterolemia but no history of CVD and/or cancer and who received a preventive examination at the Cooper Clinic in Dallas, TX, USA, during 1974–2001. CRF was quantified as maximal treadmill test duration and was grouped for analysis as low, moderate, or high based on the traditional Aerobics Center Longitudinal Study cutpoints. Using Cox regression analyses, we computed hazard ratios and 95% confidence intervals for risk of mortality based on CRF. Results: During an average of 17 years of follow-up, 329 CVD and 290 cancer deaths occurred. After control for baseline age, examination year, body mass index, total cholesterol, smoking, alcohol intake, physical activity, hypertension, diabetes, and parental history of CVD, hazard ratios (95% confidence interval) for CVD deaths across moderate and high categories of CRF (with low fit as referent) were: 0.66 (0.50–0.87) and 0.55 (0.39–0.79), respectively. There was an inverse association between CRF and CVD death among normal-weight (trend p < 0.0001), younger (<60 y, trend p = 0.01), and inactive men (trend p = 0.002). However, no significant association was found between CRF and cancer mortality. Conclusions: Among men with hypercholesterolemia, higher CRF was associated with a lower risk of dying from CVD independent of other clinical risk factors. Our findings underscored the importance of promoting CRF in the primary prevention of CVD in patients with hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Over the last fifty years, cardiorespiratory fitness (CRF) has been firmly established as an important risk factor for cardiovascular disease (CVD) and all-cause mortality. Mounting evidence supports a strong and inverse association between baseline CRF and the risk of developing hypertension (HTN) and dyslipidemia. Accumulating evidence also suggests that improving or maintaining a certain level of CRF over time leads to lower incidence of HTN and dyslipidemia and improves survival. These findings are promising, with significant public health importance, and warrant further evaluation to elucidate the role of longitudinal changes in CRF during the lifespan on CVD morbidity and mortality, as well as all-cause survival. [ABSTRACT FROM AUTHOR]

Over the last fifty years, cardiorespiratory fitness (CRF) has been firmly established as an important risk factor for cardiovascular disease (CVD) and all-cause mortality. Mounting evidence supports a strong and inverse association between baseline CRF and the risk of developing hypertension (HTN) and dyslipidemia. Accumulating evidence also suggests that improving or maintaining a certain level of CRF over time leads to lower incidence of HTN and dyslipidemia and improves survival. These findings are promising, with significant public health importance, and warrant further evaluation to elucidate the role of longitudinal changes in CRF during the lifespan on CVD morbidity and mortality, as well as all-cause survival. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) prevalence in the United States is significantly higher in African Americans vs Whites. Yet, the physiological mechanisms contributing to this health disparity have been poorly described. To design effective strategies to reduce this disparity, there is a need to determine whether racial differences in diabetes prevalence are attributable to modifiable or non-modifiable factors. This review synthesizes and critically evaluates the potential physiological and genetic mechanisms that may contribute to the higher susceptibility of African Americans to T2D. These mechanisms include: 1) obesity and fat distribution; 2) metabolic flexibility; 3) muscle physiology; 4) energy expenditure and fitness; and 5) genetics. We focus on the clinical significance of findings and limitations of the recent literature. [ABSTRACT FROM AUTHOR]

Purpose: To examine the cross-sectional association between cardiorespiratory fitness (CRF) and ideal cardiovascular health (CVH) in middle-aged adults. Methods: The association between CRF and ideal CVH score was examined in 11,590 adults (8,865 men, 2,725 women) from the Aerobics Center Longitudinal Study. CRF was measured as duration in minutes from a maximal treadmill test. The AHA's ideal CVH score was calculated on a 14 point scale using data on smoking status, BMI, physical activity (MET-min/wk), healthy diet, total cholesterol, blood pressure, and fasting plasma glucose recorded between 1987 and 1999. Participants were grouped into categories of inadequate (0-4), average (5-9), and optimum (10-14) based on their CVH score. Three CRF groups were created from age- and sex-specific quintiles based on the previously established cutpoints of treadmill time: low, moderate, and high CRF. We used general linear and logistic regression models adjusted for age, sex, and year of examination to evaluate the association of CRF with ideal CVH score. Results: The mean CVH score for men was 8.4 ± 2.2 and 9.7 ± 2.0 for women. Approximately 33% of men and 57% of women had optimum CVH, while only a small proportion of participants had inadequate CVH (5.1% M, 1.4% F). Treadmill time was moderately correlated (p<0.0001) with CVH score in both men (r=0.56) and women (r=0.50). CRF explained 16% and sex 18% of the variance in CVH score (both p<0.0001). Our adjusted model found that participants in the optimum CVH category had 20% and 43% higher CRF levels than those in the average and inadequate CVH groups (p<0.0001), respectively (Figure 1). The adjusted odds (95% CI) of having optimum CVH were 14.0 (11.0-17.8) and 3.1 (2.4-4.0) times greater for high CRF and moderate CRF, respectively, compared to low CRF (p<0.0001). Discussion: Higher levels of cardiorespiratory fitness are associated with better cardiovascular health profiles in both men and women. Thus, improving fitness represents a strategy to improve cardiovascular and public health. [ABSTRACT FROM AUTHOR]