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Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily targeting the joints. Autoreactive immune cells involved in RA affect other tissues, including skeletal muscle. Patients with RA experience diminished physical function, limited mobility, reduced muscle function, chronic pain, and increased mortality. To explore the impact of RA on skeletal muscle, we engineered electrically responsive, contractile human skeletal muscle constructs (myobundles) using primary skeletal muscle cells isolated from the vastus lateralis muscle of 11 RA patients (aged 57–74) and 10 aged healthy donors (aged 55–76), as well as from the hamstring muscle of 6 young healthy donors (less than 18 years of age) as a benchmark. Since all patients were receiving treatment for the disease, RA disease activity was mild. In 2D culture, RA myoblast purity, growth rate, and senescence were not statistically different than aged controls; however, RA myoblast purity showed greater variance compared to controls. Surprisingly, in 3D culture, contractile force production by RA myobundles was greater compared to aged controls. In support of this finding, assessment of RA myofiber maturation showed increased area of sarcomeric α-actinin expression over time compared to aged controls. Furthermore, a linear regression test indicated a positive correlation between sarcomeric α-actinin protein levels and tetanus force production in RA and controls. Our findings suggest that medications prescribed to RA patients may maintain—or even enhance—muscle function, and this effect is retained and observed in in vitro culture. Future studies regarding the effects of RA therapeutics on RA skeletal muscle, in vivo and in vitro, are warranted.

Background Neighborhood-level socioeconomic status (SES) is associated with health outcomes, including cardiovascular disease and diabetes, but these associations are rarely studied across large, diverse populations. Methods We used Ward’s Hierarchical clustering to define eight neighborhood clusters across North Carolina using 11 census-based indicators of SES, race, housing, and urbanicity and assigned 6992 cardiac catheterization patients at Duke University Hospital from 2001 to 2010 to clusters. We examined associations between clusters and coronary artery disease index > 23 (CAD), history of myocardial infarction, hypertension, and diabetes using logistic regression adjusted for age, race, sex, body mass index, region of North Carolina, distance to Duke University Hospital, and smoking status. Results Four clusters were urban, three rural, and one suburban higher-middle-SES (referent). We observed greater odds of myocardial infarction in all six clusters with lower or middle-SES. Odds of CAD were elevated in the rural cluster that was low-SES and plurality Black (OR 1.16, 95% CI 0.94-1.43) and in the rural cluster that was majority American Indian (OR 1.31, 95% CI 0.91-1.90). Odds of diabetes and hypertension were elevated in two urban and one rural low- and lower-middle SES clusters with large Black populations. Conclusions We observed higher prevalence of cardiovascular disease and diabetes in neighborhoods that were predominantly rural, low-SES, and non-White, highlighting the importance of public health and healthcare system outreach into these communities to promote cardiometabolic health and prevent and manage hypertension, diabetes and coronary artery disease.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, children and families have had to adapt their daily lives. The purpose of this study was to describe changes in the weight-related behaviors of children with obesity after the onset of the COVID-19 pandemic. Methods: Semistructured interviews (n = 51) were conducted from April to June 2020 with parents of children with obesity. Families were participants in a randomized trial testing a clinic-community pediatric obesity treatment model. During interviews, families described their experience during the COVID-19 pandemic, with a particular emphasis on children's diet, physical activity, sleep, and screen time behaviors. Rapid qualitative analysis methods were used to identify themes around changes in children's weight-related behaviors. Results: The mean child age was 9.7 (±2.8) years and the majority of children were Black (46%) or Hispanic (39%) and from low-income families (62%). Most parent participants were mothers (88%). There were differences in the perceived physical activity level of children, with some parents attributing increases in activity or maintenance of activity level to increased outdoor time, whereas others reported a decline due to lack of outdoor time, school, and structured activities. Key dietary changes included increased snacking and more meals prepared and consumed at home. There was a shift in sleep schedules with children going to bed and waking up later and an increase in leisure-based screen time. Parents played a role in promoting activity and managing children's screen time. Conclusions: The COVID-19 pandemic has created unique lifestyle challenges and opportunities for lifestyle modification. Clinical Trials ID: NCT03339440.

Total daily energy expenditure (“total expenditure”, MJ/d) reflects daily energy needs and is a critical variable in human health and physiology, yet it is unclear how daily expenditure changes over the life course. Here, we analyze a large, globally diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 yr. We show that total expenditure is strongly related to fat free mass in a power-law manner and identify four distinct metabolic life stages. Fat free mass-adjusted daily expenditure accelerates rapidly in neonates (0-1yr) to ~46% above adult values at ~1 yr, declines slowly throughout childhood and adolescence (1-20 yr) to adult levels at ~20 yr, remains stable in adulthood (20-60 yr) even during pregnancy, and declines in older adults (60+ yr). These changes in total expenditure shed new light on human development and aging and should help shape nutrition and health strategies across the lifespan.

Cancer survivors are often sedentary. Self-monitoring may promote physical activity through self-activation. We conducted a pilot trial to evaluate whether wearable activity tracker with personalized text message feedback would increase physical activity. We enrolled 30 patients with solid tumor cancers into a non-randomized prospective intervention trial (NCT02627079): 15 had completed treatment in the past year and 15 under active treatment. Each participant received an activity tracker and daily text messages personalized to their activity level. We assessed patient-reported outcomes and 6-min walk (6 MW) at baseline and 3 months. Twenty-six participants completed the study. There was substantial variation in baseline activity. Overall, 39% of participants increased their steps taken by at least 20%, and 23% increased their 6 MW distance by 20% or more. More participants who had completed treatment strongly agreed (73%) that the intervention increased their exercise levels than those receiving active treatment (47%). At 3 months, there was a significant improvement in median Beck Depression Inventory-II and Godin Leisure Index composite scores. At 6 months, 72% still wore their activity tracker at least 4 days per week. We found that the intervention was well-accepted with a high completion rate at 3 months and continued self-use at 6 months. In this pilot study of combined activity tracker and motivational messaging, we found a signal for increased physical activity over a 3-month period. Future research is needed to study this technique for its impact on activity and other physical and psychological measures of well-being. Activity tracker with personalized motivational messaging may be useful in promoting physical activity in cancer survivors.

Supplemental Digital Content is available in the text., Background: Cardiac involvement among hospitalized patients with severe coronavirus disease 2019 (COVID-19) is common and associated with adverse outcomes. This study aimed to determine the prevalence and clinical implications of COVID-19 cardiac involvement in young competitive athletes. Methods: In this prospective, multicenter, observational cohort study with data from 42 colleges and universities, we assessed the prevalence, clinical characteristics, and outcomes of COVID-19 cardiac involvement among collegiate athletes in the United States. Data were collected from September 1, 2020, to December 31, 2020. The primary outcome was the prevalence of definite, probable, or possible COVID-19 cardiac involvement based on imaging definitions adapted from the Updated Lake Louise Imaging Criteria. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for cardiac involvement, and adverse cardiovascular events or hospitalizations. Results: Among 19 378 athletes tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 3018 (mean age, 20 years [SD, 1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least 1 element of cardiac triad testing (12-lead ECG, troponin, transthoracic echocardiography) followed by cardiac magnetic resonance imaging (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21 of 2999 [0.7%]), cardiac troponin (24 of 2719 [0.9%]), and transthoracic echocardiography (24 of 2556 [0.9%]). Definite, probable, or possible SARS-CoV-2 cardiac involvement was identified in 21 of 3018 (0.7%) athletes, including 15 of 2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6 of 198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-CoV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15 of 119 [12.6%]) versus a primary screening CMR (6 of 198 [3.0%]). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (odds ratio, 3.1 [95% CI, 1.2, 7.7]) or at least 1 abnormal triad test result (odds ratio, 37.4 [95% CI, 13.3, 105.3]). Five (0.2%) athletes required hospitalization for noncardiac complications of COVID-19. During clinical surveillance (median follow-up, 113 days [interquartile range=90 146]), there was 1 (0.03%) adverse cardiac event, likely unrelated to SARS-CoV-2 infection. Conclusions: SARS-CoV-2 infection among young competitive athletes is associated with a low prevalence of cardiac involvement and a low risk of clinical events in short-term follow-up.

This study tested the hypothesis that greater mean changes in cardiorespiratory fitness (CRF), in either the absence or presence of reduced interindividual variability, explain larger CRF response rates following higher doses of exercise training. We retrospectively analyzed CRF data from eight randomized controlled trials (RCT; n = 1590 participants) that compared at least two doses of exercise training. CRF response rates were calculated as the proportion of participants with individual confidence intervals (CIs) placed around their observed response that lay above 0.5 metabolic equivalents (MET). CIs were calculated using no-exercise control group-derived typical errors and were placed around each individual’s observed CRF response (post minus pre-training CRF). CRF response rates, mean changes, and interindividual variability were compared across exercise groups within each RCT. Compared with lower doses, higher doses of exercise training yielded larger CRF response rates in eight comparisons. For most of these comparisons (7/8), the higher dose of exercise training had a larger mean change in CRF but similar interindividual variability. Exercise groups with similar CRF response rates also had similar mean changes. Our findings demonstrate that larger CRF response rates following higher doses of exercise training are attributable to larger mean changes rather than reduced interindividual variability. Following a given dose of exercise training, the proportion of individuals expected to improve their CRF beyond 0.5 METs is unrelated to the heterogeneity of individual responses.

We examined the relationship between pain severity and outcomes in patients with heart failure with reduced ejection fraction (HFrEF) in the HF-ACTION randomized controlled trial. Trends of health-related quality of life (HRQoL) measures grouped by patients' self-reported baseline bodily pain severity were compared using correlation tests, and the association between pain severity and clinical outcomes (including a primary composite endpoint of all-cause mortality and all-cause hospitalization) was assessed using multivariable adjusted analyses. Of the 2310 patients, 22.9% reported no pain, 45.8% very mild/mild, 24.9% moderate, and 6.4% severe/very severe. Greater pain severity was associated with worse HRQoL measures (EuroQoL-5D-3L and Kansas City Cardiomyopathy Questionnaire; both p < 0.0001). Compared to those reporting no pain, patients reporting severe/very severe pain had greater risk for the primary endpoint (adjusted hazard ratio 1.42, 95% confidence interval 1.11-1.83, p = 0.01). In patients with HFrEF, greater pain severity was associated with worse HRQoL and clinical outcomes. Trial Registration: NCT00047437.

Background Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures. Methods Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status. Results We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM2.5. Conclusion Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.

Background: Previous studies have demonstrated that aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet can improve neurocognition. However, the mechanisms by which lifestyle improves neurocognition have not been widely studied. We examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants from the Exercise and Nutritional Interventions for Neurocognitive Health Enhancement (ENLIGHTEN) trial. Objective: To examine the association between changes in metabolic function and neurocognition among older adults with cognitive impairment, but without dementia (CIND) participating in a comprehensive lifestyle intervention. Methods: ENLIGHTEN participants were randomized using a 2×2 factorial design to receive AE, DASH, both AE+DASH, or a health education control condition (HE) for six months. Metabolic biomarkers included insulin resistance (homeostatic model assessment [HOMA-IR]), leptin, and insulin-like growth factor (IGF-1); neurotrophic biomarkers included brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF); and inflammatory biomarkers included interleukin-6 (IL-6) and C-Reactive Protein (CRP). Results: Participants included 132 sedentary older adults (mean age = 65 [SD = 7]) with CIND. Results demonstrated that both AE (d = 0.48, p = 0.015) and DASH improved metabolic function (d = 0.37, p = 0.039), without comparable improvements in neurotrophic or inflammatory biomarkers. Greater improvements in metabolic function, including reduced HOMA-IR (B = –2.3 [–4.3, –0.2], p = 0.033) and increased IGF-1 (B = 3.4 [1.2, 5.7], p = 0.004), associated with increases in Executive Function. Conclusion: Changes in neurocognition after lifestyle modification are associated with improved metabolic function.

Disruption of the skeletal muscle circadian clock leads to a preferential shift towards lipid oxidation, while reducing carbohydrate oxidation. These effects are apparent at the whole-body level, including glucose intolerance, increased energy expenditure, and fasting hyperglycemia. We hypothesize that exercise counters these metabolic disturbances by modifying the skeletal muscle clock and reverting substrate metabolism back towards an optimal substrate balance.

Caloric restriction (CR) is a strategy that attenuates aging in multiple nonhuman species. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials are part of a research program aiming to test the effects of CR on aging and longevity biomarkers in humans. Building on CALERIE phase 1, CALERIE phase 2 (CALERIE 2) was the largest study to date to assess sustained CR in healthy humans without obesity. In a 24-month randomized controlled trial comprising 218 participants at baseline, CALERIE 2 showed that moderate CR, 11.9% on average, induced improvements in aging-related biomarkers without adversely affecting psychological or behavioral outcomes. The objectives of this report are to summarize and review the highlights of CALERIE 2 and report previously unpublished results on eating disorder symptoms and cognitive function. This article specifically summarizes the physiological, psychological, aging, behavioral, and safety results of the trial. Also provided are research directions beyond CALERIE 2 that highlight important opportunities to investigate the role of CR in aging, longevity, and health span in humans.

PURPOSE: Calorie restriction (CR) is an effective treatment for obesity-related liver and metabolic disease. However, CR studies in individuals without obesity are needed to see if CR could delay disease onset. Liver biomarkers indicate hepatic health and are linked to cardiometabolic disease. Our aim was to examine the effects of a two-year CR intervention on liver biomarkers in healthy individuals without obesity. METHODS: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study was a two-year randomized controlled trial. Overall, 218 participants (body mass index: 25.1±1.7 kg/m(2)) were enrolled into control group (n=75) that ate ad libitum (AL) or a CR group (n=143) that aimed to decrease energy intake by 25%. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and bilirubin were measured during the trial. RESULTS: At month 24, relative to the AL group, ALP (−7±1 IU/L; P0.99) or AST (2±2 IU/L; P=0.68) were revealed. However, sex-by-treatment-by-time interactions (P

Background The prevalence of child and adolescent obesity and severe obesity continues to increase despite decades of policy and research aimed at prevention. Obesity strongly predicts cardiovascular and metabolic disease risk; both begin in childhood. Children who receive intensive behavioral interventions can reduce body mass index (BMI) and reverse disease risk. However, delivering these interventions with fidelity at scale remains a challenge. Clinic-community partnerships offer a promising strategy to provide high-quality clinical care and deliver behavioral treatment in local park and recreation settings. The Hearts & Parks study has three broad objectives: (1) evaluate the effectiveness of the clinic-community model for the treatment of child obesity, (2) define microbiome and metabolomic signatures of obesity and response to lifestyle change, and (3) inform the implementation of similar models in clinical systems. Methods Methods are designed for a pragmatic randomized, controlled clinical trial (n = 270) to test the effectiveness of an integrated clinic-community child obesity intervention as compared with usual care. We are powered to detect a difference in body mass index (BMI) between groups at 6 months, with follow up to 12 months. Secondary outcomes include changes in biomarkers for cardiovascular disease, psychosocial risk, and quality of life. Through collection of biospecimens (serum and stool), additional exploratory outcomes include microbiome and metabolomics biomarkers of response to lifestyle modification. Discussion We present the study design, enrollment strategy, and intervention details for a randomized clinical trial to measure the effectiveness of a clinic-community child obesity treatment intervention. This study will inform a critical area in child obesity and cardiovascular risk research—defining outcomes, implementation feasibility, and identifying potential molecular mechanisms of treatment response. Clinical trial registration NCT03339440.

Introduction Obesity accounts for a substantial and growing burden of disease globally. Body adiposity is highly heritable, and human genetic studies can lead to biological and therapeutic insights. Rationale Whole-exome sequencing of hundreds of thousands of individuals is complementary to approaches used to date in obesity genetics and has the potential to identify rare protein-coding variants with large phenotypic impact. We sequenced the exomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with body mass index (BMI), a measure of overall adiposity used to define obesity in clinical practice. We complemented exome sequencing with fine-mapping of common alleles, polygenic score analysis, and in vitro and in vivo modeling work. Results We identified 16 genes for which the burden of rare nonsynonymous variants was associated with BMI at exome-wide statistical significance (inverse-variance weighted meta-analysis P < 3.6 × 10−7), including associations at five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). We observed an overrepresentation of genes highly expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance. Protein-truncating variants in GPR75 were found in ~4/10,000 sequenced people and were associated with 1.8 kg/m2 lower BMI, 5.3 kg lower bodyweight, and 54% lower odds of obesity in heterozygous carriers. Knock out of Gpr75 in mice resulted in resistance to weight gain in a high-fat diet model, which was allele-dose dependent (25% and 44% lower weight gain, respectively, for heterozygous Gpr75−/+ mice and knockout Gpr75−/− mice compared with wild type) and accompanied by improved glycemic control and insulin sensitivity. Protein-truncating variants in CALCR were associated with higher BMI and obesity risk, whereas protein-truncating variants in GIPR and two missense alleles [Arg190→Gln (Arg190Gln), Glu288Gly], which we show result in loss of function in vitro, were associated with lower adiposity. Among monogenic obesity genes in the leptin-melanocortin pathway, heterozygous predicted loss-of-function variants in LEP, POMC, PCSK1, and MC4R (but not LEPR) were associated with higher BMI. Rare protein-truncating variants in UBR2, ANO4, and PCSK1 were associated with more than twofold higher odds of obesity in heterozygous carriers, similar to predicted-deleterious nonsynonymous variants in MC4R, which are considered the most common cause of monogenic obesity. Polygenic predisposition due to >2 million common genetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. Conclusion These results suggest that inhibition of GPR75 may be a therapeutic strategy for obesity and illustrate the power of massive-scale exome sequencing for the identification of large-effect coding variant associations and drug targets for complex traits.

Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR., eLife digest Developing a new drug that is both safe and effective is a complex and expensive endeavor. An alternative approach is to ‘repurpose’ existing, safe compounds – that is, to establish if they could treat conditions others than the ones they were initially designed for. To achieve this, methods that can predict the activity of thousands of established drugs are necessary. These approaches are particularly important for conditions for which it is hard to find promising treatment. This includes, for instance, heart failure, dementia and other diseases that are linked to the activity of the hormone insulin becoming modified throughout the body, a defect called insulin resistance. Unfortunately, it is difficult to model the complex actions of insulin using cells in the lab, because they involve intricate networks of proteins, tissues and metabolites. Timmons et al. set out to develop a way to better assess whether a drug could be repurposed to treat insulin resistance. The aim was to build a biological signature of the disease in multiple human tissues, as this would help to make the findings more relevant to the clinic. This involved examining which genes were switched on or off in thousands of tissue samples from patients with different degrees of insulin resistance. Importantly, some of the patients had their condition reversed through lifestyle changes, while others did not respond well to treatment. These ‘non-responders’ provided crucial new clues to screen for active drugs. Carefully piecing the data together revealed the molecules and pathways most related to the severity of insulin resistance. Cross-referencing these results with the way existing drugs act on gene activity, highlighted 138 compounds that directly bind 73 proteins responsible for regulating insulin resistance pathways. Some of the drugs identified are suitable for short-term clinical studies, and it may even be possible to rank similar compounds based on their chemical activity. Beyond giving a glimpse into the complex molecular mechanisms of insulin resistance in humans, Timmons et al. provide a fresh approach to how drugs could be repurposed, which could be adapted to other conditions.

Publisher Copyright: © 2021 The Authors Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures.1–3 This suggestion has profound implications for both the evolution of metabolism and human health. It implies that a long-term increase in activity does not directly translate into an increase in total energy expenditure (TEE) because other components of TEE may decrease in response—energy compensation. We used the largest dataset compiled on adult TEE and basal energy expenditure (BEE) (n = 1,754) of people living normal lives to find that energy compensation by a typical human averages 28% due to reduced BEE; this suggests that only 72% of the extra calories we burn from additional activity translates into extra calories burned that day. Moreover, the degree of energy compensation varied considerably between people of different body compositions. This association between compensation and adiposity could be due to among-individual differences in compensation: people who compensate more may be more likely to accumulate body fat. Alternatively, the process might occur within individuals: as we get fatter, our body might compensate more strongly for the calories burned during activity, making losing fat progressively more difficult. Determining the causality of the relationship between energy compensation and adiposity will be key to improving public health strategies regarding obesity.

Cardiopulmonary exercise testing (CPET) is a dynamic clinical tool for determining the cause for a person's exercise limitation. CPET provides clinicians with fundamental knowledge of the coupling of external to internal respiration (oxygen and carbon dioxide) during exercise. Subtle perturbations in CPET parameters can differentiate exercise responses among individual patients and disease states. However, perhaps due to challenges in interpretation given the amount and complexity of data obtained, CPET is underutilized. In this article, we review fundamental concepts in CPET data interpretation and visualization. We also discuss future directions for how to best utilize CPET results to guide clinical care. Finally, we share a novel three-dimensional (3D) graphical platform for CPET data that simplifies conceptualization of organ system-specific (cardiac, pulmonary, and skeletal muscle) exercise limitations. Our goal is to make CPET testing more accessible to the general medical provider and make the test of greater use in the medical toolbox.

Background: Although lifestyle modifications generally are effective in lowering blood pressure (BP) among patients with unmedicated hypertension and in those treated with 1 or 2 antihypertensive agents, the value of exercise and diet for lowering BP in patients with resistant hypertension is unknown. Methods: One hundred forty patients with resistant hypertension (mean age, 63 years; 48% female; 59% Black; 31% with diabetes; 21% with chronic kidney disease) were randomly assigned to a 4-month program of lifestyle modification (C-LIFE [Center-Based Lifestyle Intervention]) including dietary counseling, behavioral weight management, and exercise, or a single counseling session providing SEPA (Standardized Education and Physician Advice). The primary end point was clinic systolic BP; secondary end points included 24-hour ambulatory BP and select cardiovascular disease biomarkers including baroreflex sensitivity to quantify the influence of the baroreflex on heart rate, high-frequency heart rate variability to assess vagally mediated modulation of heart rate, flow-mediated dilation to evaluate endothelial function, pulse wave velocity to assess arterial stiffness, and left ventricular mass to characterize left ventricular structure. Results: Between-group comparisons revealed that the reduction in clinic systolic BP was greater in C-LIFE (–12.5 [95% CI, –14.9 to –10.2] mm Hg) compared with SEPA(–7.1 [–95% CI, 10.4 to –3.7] mm Hg) ( P =0.005); 24-hour ambulatory systolic BP also was reduced in C-LIFE (–7.0 [95% CI, –8.5 to –4.0] mm Hg), with no change in SEPA (–0.3 [95% CI, –4.0 to 3.4] mm Hg) ( P =0.001). Compared with SEPA, C-LIFE resulted in greater improvements in resting baroreflex sensitivity (2.3 ms/mm Hg [95% CI, 1.3 to 3.3] versus –1.1 ms/mm Hg [95% CI, –2.5 to 0.3]; P 2 [95% CI, 0.2 to 0.6] versus –0.2 ln ms 2 [95% CI, –0.5 to 0.1]; P P =0.022). There were no between-group differences in pulse wave velocity ( P =0.958) or left ventricular mass ( P =0.596). Conclusions: Diet and exercise can lower BP in patients with resistant hypertension. A 4-month structured program of diet and exercise as adjunctive therapy delivered in a cardiac rehabilitation setting results in significant reductions in clinic and ambulatory BP and improvement in selected cardiovascular disease biomarkers. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02342808.

Calorie restriction (CR) slows aging and increases healthy lifespan in model organisms. We tested if CR slowed biological aging in humans using DNA methylation analysis of blood samples from N=197 participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) randomized controlled trial. We quantified CR effects on biological aging by comparing change scores for six epigenetic-clock and Pace-of-Aging measures between n=128 CR-group and n=69 ad-libitum-control-group participants at 12- and 24-month follow-ups. CR effects were strongest for DunedinPACE Pace of Aging (12-month Cohen’s d=0.3; 24-month Cohen’s d=0.2, p0.08). CR effects for other epigenetic clocks were in the opposite direction (all p>0.15). CALERIE intervention slowed Pace of Aging but showed minimal effect on epigenetic clocks hypothesized to reflect longer term accumulation of aging burden.

Objectives The aim of this study was to evaluate the association between age and invasive cardiovascular hemodynamics during upright exercise among healthy adults. Background The marked age-related decline in maximal exercise oxygen uptake (peak VO2) may contribute to the high burden of heart failure among older individuals and their greater severity of exertional symptoms. However, the mechanisms underlying this decline are not well understood. Methods A total of 104 healthy community-dwelling volunteers age 20 to 76 years well screened for cardiovascular disease underwent exhaustive upright exercise with brachial and pulmonary artery catheters; radionuclide ventriculography; and expired gas analysis for the measurement of peak VO2, cardiac output, left ventricular stroke volume, end-diastolic volume, end-systolic volume, ejection fraction, pulmonary capillary wedge pressure, and arteriovenous oxygen difference. Results Over a 5.5-decade age range, there was a 40% decline in peak VO2 due primarily to reduced peak exercise cardiac output; peak arteriovenous oxygen difference was unaffected by age. The lower age-related exercise cardiac output was related to lower peak exercise heart rate and stroke volume. Aging was also associated with lower peak exercise ejection fraction, indicating reduced inotropic reserve. Peak exercise end-diastolic volume was lower with aging despite similar left ventricular filling pressure, suggesting age-related reduced diastolic compliance limiting the use of the Frank-Starling mechanism to compensate for reduced chronotropic and inotropic reserves. These age relationships were unaffected by sex. Conclusions The age-related decline in exercise capacity among healthy persons is due predominantly to cardiac mechanisms, including reduced chronotropic and inotropic reserve and possibly reduced Frank-Starling reserve. Peak exercise left ventricular filling pressure and arteriovenous oxygen difference are unchanged with healthy aging.

We examined whether mechanical stretch affected expression of muscle-specific microRNAs (miRNAs) that regulate proliferation (miR-133a) or differentiation (miR-1, -206). Real-time quantitative RT-PCR was used to assess miRNA regulation in the murine myoblast cell line C2C12 exposed to stretch regimens that promote either proliferation (high stretch: 17%, 1 Hz) or differentiation (moderate stretch: 10%, 0.5 Hz) after adding media that promotes differentiation. Controls consisted of myoblasts cultured under static conditions. While miRNA expression was not affected by high stretch, a significant effect of stretch (P < 0.05) was seen after 4 days with the moderate stretch regimen. All three microRNAs were upregulated by stretch, with the most significant increase for miR-1. Myoblast maturation was enhanced with a moderate stretch regimen, as assessed by a higher percentage of nuclei in straited fibers and an increase in Mef2c gene expression. Correspondingly, HDAC4 protein expression, a direct target of miR-1 and repressor of Mef2, was decreased with the moderate stretch regimen. Over-expression of miR-1 abrogated the effect of stretch on miR-1, miR-133a and miR-206 levels compared to its negative control but did not alter miR-133a or miR-206 levels. Treatment with an antisense mRNA to miR-1 similarly diminished the stretch-mediated response. Results indicate that the differential response of skeletal myoblasts to moderate and high stretch cyclic stretch regimens is due, in part, to muscle specific miRNA expression.

Objectives This study sought to determine whether age modifies the impact of key comorbidities on clinical outcomes for patients with heart failure with reduced ejection fraction (HFrEF). Background Comorbidities impact outcomes in HFrEF. However, the effect of age on the impact of comorbidities on prognosis is not clearly understood. Methods Cox proportional hazards models were used assessed interactions between age and comorbidities on the primary composite endpoint (all-cause mortality or hospitalization) and secondary endpoints in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) multicenter trial of 2,331 patients with HFrEF. Results Age did not significantly modify the effect of any comorbidity on the primary endpoint. However, age significantly modified the effect of body mass index (BMI) on all-cause mortality (interaction p = 0.02). Among patients ≥70 years of age, there was a U-shaped relationship between BMI and 1-year mortality, where BMI of 20 kg/m2 corresponded to 17.6%; a BMI of 30 kg/m2 corresponded to 7.0%; and a BMI of 40 kg/m2 corresponded to 11%. For patients Conclusions In chronic HFrEF, age markedly altered the impact of BMI and depressive symptoms on all-cause mortality, with much higher risk in older patients, but was not as strong a predictor of mortality/hospitalizations as cumulative comorbidity score. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

BACKGROUND: Fasting lactate is elevated in metabolic diseases and could possibly be predictive of the risk of developing the metabolic syndrome. METHODS: Plasma samples were analyzed for fasting lactate to compare lean subjects, non-diabetic subjects with severe obesity, and metabolically impaired subjects. Subjects with severe obesity were studied 1 week before and 1 week to 9 months after gastric bypass surgery. Subjects with components of the metabolic syndrome were studied before and after 6 months exercise intervention. RESULTS: Metabolically impaired subjects had higher fasting lactate concentrations (P

BACKGROUND Greater body weight has been associated impairments in neurocognition and greater dementia risk, although the mechanisms linking weight and neurocognition have yet to be adequately delineated. OBJECTIVE To examine metabolic mechanisms underlying the association between obesity and neurocognition. METHODS We conducted a secondary analysis of weight, neurocognition, and the potentially mediating role of metabolic and inflammatory biomarkers among 160 participants from the ENLIGHTEN trial of vascular cognitive impairment, no dementia (CIND). Neurocognition was assessed using a 45-minute assessment battery assessing Executive Function, Verbal and Visual Memory. We considered three metabolic biomarkers: insulin resistance (homeostatic model assessment [HOMA-IR]), plasma leptin, and insulin-like growth factor (IGF-1). Inflammation was assessed using C-reactive protein. Multiple regression analyses were used. RESULTS Participants included 160 sedentary older adults with CIND. Participants tended to be overweight or obese (mean BMI = 32.5 [SD = 4.8]). Women exhibited higher BMI (p = 0.043), CRP (p

Ranolazine reduces angina frequency and increases exercise capacity. We hypothesized that exercise training with ranolazine would allow subjects to train at greater intensities, resulting in greater improvements in exercise capacity, physical activity, and health-related quality of life (HRQOL). In a pilot study, subjects with chronic stable angina pectoris were randomized to ranolazine (n = 13) or placebo (n = 16). After a 2-week drug titration period, subjects participated in a 12-week exercise program. Peak VO2, physical activity (via accelerometer), and HRQOL were assessed before and after training. After exercise training, peak VO2increased twice as much with ranolazine (2.1 ± 3.4 ml/kg/min) as with placebo (0.9 ± 1.5) (both p

PURPOSE. Conduct a systematic umbrella review to evaluate the relationship of physical activity (PA) with all-cause mortality, cardiovascular mortality, and incident cardiovascular disease; to evaluate the shape of the dose-response relationships; and to evaluate these relationships relative to the 2008 Physical Activity Guidelines Advisory Committee (PAGAC) Report. METHODS. Primary search encompassing 2006 – March, 2018 for existing systematic reviews, meta-analyses, and pooled analyses reporting on these relationships. Graded the strength of evidence using a matrix developed for the PAGAC. RESULTS. The association of self-reported moderate-to-vigorous physical activity (MVPA) on all-cause mortality, cardiovascular disease (CVD) mortality, and atherosclerotic cardiovascular diseases — including incident coronary heart disease, ischemic stroke and heart failure — are very similar. Increasing MVPA to Guidelines amounts in the inactive U.S. population has the potential to have an important and substantial positive impact on these outcomes in the adult population. The following points are clear: the associations of PA with beneficial health outcomes begin when adopting very modest (one-third of Guidelines) amounts; any MVPA is better than none; meeting the 2008 PA guidelines reduces mortality and CVD risk to about 75 percent of the maximal benefit obtained by physical activity alone; PA amounts beyond Guidelines recommendations amount reduces risk even more, but greater amounts of PA are required to obtain smaller health benefits; and there is no evidence of excess risk over the maximal effect observed at about three to five times the amounts associated with current guidelines. When PA is quantified in terms of energy expenditure (MET-hours per week), these relationships hold for walking, running, and biking. CONCLUSIONS. To avoid the risks associated with premature mortality and the development of ischemic heart disease, ischemic stroke, and all-cause heart failure, all adults should strive to reach the 2008 Physical Activity Guidelines for Americans.

PURPOSE. Systematic primary literature review to evaluate the relationship of physical activity —as measured by daily step counts — with all-cause mortality, cardiovascular disease mortality, incident cardiovascular disease, and type 2 diabetes mellitus; to evaluate the shape of dose-response relationships; and to interpret findings in the context of development of the Physical Activity Guidelines for Americans 2(nd) Edition. METHODS. Primary literature search encompassing 2011 – March, 2018 for existing literature reporting on these relationships. RESULTS. Eleven pertinent articles were identified. Seven longitudinal studies examined the relationship between daily step counts and mortality, disease incidence or risk. Two studies examined objectively measured steps per day and all-cause mortality, one was restricted to a relatively small elderly population. One study examined cardiovascular events, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The other four longitudinal studies addressed incident type 2 diabetes. All longitudinal studies reported an inverse relationship between steps per day and outcome risk. In one study, 531 cardiovascular events occurred during more than 45,000 person-years of follow-up. Before intervention, each 2,000 steps per day increment up to 10,000 steps was associated with a 10-percent lower cardiovascular event rate. Also, for every 2,000 steps per day increase over baseline, there was an 8-percent yearly reduction in cardiovascular event rate in individuals with impaired glucose tolerance. CONCLUSIONS. Daily step count is a readily accessible means by which to monitor and set physical activity goals. Recent evidence supports previously limited evidence of an inverse dose-response relationship of daily steps with important health outcomes, including all-cause mortality, cardiovascular events, and type 2 diabetes. However, more independent studies will be required before these observations can be translated into public health guidelines.

PurposeThis systematic umbrella review examines and updates the evidence on the relationship between physical activity (PA) and blood pressure (BP) presented in the 2008 Physical Activity Guidelines Advisory Committee Scientific Report.MethodsWe performed a systematic review to identify syst

Objective To identify temporal trends in the use of exercise treadmill testing (ETT) and cardiorespiratory fitness (CRF) estimated by ETT in metabolic equivalents (METs). Patients and methods We compiled an ETT database of all available treadmill tests—including those with concomitant stress echocardiography and nuclear perfusion imaging studies—performed at Duke University Hospital from January 1, 1970- December 31, 2012. Six different ramp protocols were used in these combined modalities. CRF at maximal exertion was estimated using established metrics. Eligible patients were required to have no missing data on maximal treadmill speed, grade, and protocol. Results The most commonly used ETT protocol was the Bruce (n = 28,877), followed by manual test (n = 7390). Since the 1980’s, the use of ETT for clinical purposes declined substantially; there was a decreased trend in utilization of 9.4% over the decades 1990–1999 and 2000–2009. When standard protocol (Bruce) was assessed in isolation, trends in CRF decreased progressively from 1970 to 2012 (mean METs (standard deviation): 11.7 (4.3) to 10.5 (3.5)). After adjusting for baseline comorbidities, the trend was reduced to a lesser degree. Conclusions The use of ETT at our institution has declined over time, perhaps due to changes in clinical practice. In patients undergoing ETT using the standard Bruce protocol, CRF decreased progressively over the last five decades. Future studies are needed to clarify the etiology of the decrease in use of such a powerful predictor of clinical outcomes in our medical care environment.

IMPORTANCE: Anxiety is common among patients with coronary heart disease (CHD) and is associated with worse health outcomes; however, effective treatment for anxiety in patients with CHD is uncertain. OBJECTIVE: To determine whether exercise and escitalopram are better than placebo in reducing symptoms of anxiety as measured by the Hospital Anxiety and Depression-Anxiety Subscale (HADS-A) and in improving CHD risk biomarkers. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted between January 2016 and May 2020 in a tertiary care teaching hospital in the US and included 128 outpatients with stable CHD and a diagnosed anxiety disorder or a HADS-A score of 8 or higher who were older than 40 years, sedentary, and not currently receiving mental health treatment. INTERVENTIONS: Twelve weeks of aerobic exercise 3 times per week at an intensity of 70% to 85% heart rate reserve, escitalopram (up to 20 mg per day), or placebo pill equivalent. MAIN OUTCOMES AND MEASURES: The primary outcome was HADS-A score. CHD biomarkers included heart rate variability, baroreflex sensitivity, and flow-mediated dilation, along with 24-hour urinary catecholamines. RESULTS: The study included 128 participants. The mean (SD) age was 64.6 (9.6) years, and 37 participants (29%) were women. Participants randomized to the exercise group and escitalopram group reported greater reductions in HADS-A (exercise, −4.0; 95% CI, −4.7 to −3.2; escitalopram, −5.7; 95% CI, −6.4 to −5.0) compared with those randomized to placebo (−3.5; 95% CI, −4.5 to −2.4; P = .03); participants randomized to escitalopram reported less anxiety compared with those randomized to exercise (−1.67; 95% CI, −2.68 to −0.66; P = .002). Significant postintervention group differences in 24-hour urinary catecholamines were found (exercise z score = 0.05; 95% CI, −0.2 to 0.3; escitalopram z score = −0.24; 95% CI, −0.4 to 0; placebo z score = 0.36; 95% CI, 0 to 0.7), with greater reductions in the exercise group and escitalopram group compared with the placebo group (F(1,127) = 4.93; P = .01) and greater reductions in the escitalopram group compared with the exercise group (F(1,127) = 4.37; P = .04). All groups achieved comparable but small changes in CHD biomarkers, with no differences between treatment groups. CONCLUSIONS AND RELEVANCE: Treatment of anxiety with escitalopram was safe and effective for reducing anxiety in patients with CHD. However, the beneficial effects of exercise on anxiety symptoms were less consistent. Exercise and escitalopram did not improve CHD biomarkers of risk, which should prompt further investigation of these interventions on clinical outcomes in patients with anxiety and CHD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02516332

Exercise training beneficially moderates the effects of vascular aging. This study compared the efficacy of Peripheral Remodeling through Intermittent Muscular Exercise (PRIME), a novel training regimen, versus aerobic training on hemodynamic profiles in participants ≥70 years at risk for losing functional independence. Seventy-five participants (52 females, age: 76 ± 5 years) were assessed for hemodynamic and vascular function at baseline, after 4 weeks of either PRIME or aerobic training (Phase 1) and again after a further 8 weeks of aerobic and resistance training (Phase 2). Data were analyzed using 2 × 2 repeated-measures analysis of variance models on the change in each dependent variable. PRIME demonstrated reductions in brachial and aortic mean arterial pressure and diastolic blood pressure (p

Background Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM. Methods Targeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed. Results A total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p = 2 × 10−7, and were differentially associated in participants with and without DM (beta 1.58, p = 8 × 10−8 vs. 0.67, p = 9 × 10−4, respectively; p value for interaction = 0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p = 0.24) than in those without DM (mean ∆ 0.16, p = 0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p = 2.74 × 10−8), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p = 3.21 × 10−9 v. HR 0.90, p = 0.104, p value for interaction = 0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study. Conclusions LCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM. Trial Registration clinicaltrials.gov Identifier: NCT00047437.

Current guidelines published by the American Heart Association and the American College of Cardiology broadly recommend lifestyle approaches to prevent and treat elevated blood pressure and cholesterol. For patients with mildly or moderately elevated blood pressure and blood cholesterol, lifestyle-only approaches are the first line of therapy. The purpose of this scientific statement is to: (1) highlight the mild-moderate–risk patient groups indicated for lifestyle-only treatment for elevated blood pressure or cholesterol; (2) describe recommendations, average effects, and additional considerations when prescribing lifestyle treatment with physical activity; and (3) provide guidance and resources for clinicians to assess, prescribe, counsel, and refer to support increased physical activity in their patients. An estimated 21% and 28% to 37% of US adults, respectively, have mild-moderate–risk blood pressure and cholesterol and should receive lifestyle-only as first-line treatment. Of the recommended lifestyle changes, increasing physical activity has extensive benefits, including improving both blood pressure and blood cholesterol, that are comparable, superior, or complementary to other healthy lifestyle changes. Physical activity assessment and prescription are an excellent lifestyle behavior treatment option for all patients, including for the large population of mild-moderate–risk patients with elevated blood pressure and blood cholesterol.

Night shift work, characterized by behavioral circadian disruption, increases cardiometabolic disease risk. Our long-term goal is to develop a novel methodology to quantify behavioral circadian disruption in field-based settings and to explore relations to four metabolic salivary biomarkers of circadian rhythm. This pilot study enrolled 36 police academy trainees to test the feasibility of using wearable activity trackers to assess changes in behavioral patterns. Using a two-group observational study design, participants completed in-class training during dayshift for six weeks followed by either dayshift or nightshift field-training for six weeks. We developed a novel data-post processing step that improves sleep detection accuracy of sleep episodes that occur during daytime. We next assessed changes to resting heart rate (RHR) and sleep regularity index (SRI) during dayshift versus nightshift field training. Secondarily, we examined changes in field-based assessments of salivary cortisol, uric acid, testosterone, and melatonin during dayshift versus nightshift. Compared to dayshift, nightshift workers experienced larger changes to resting heart rate, sleep regularity index (indicating reduced sleep regularity), and alternations to sleep/wake activity patterns accompanied by blunted salivary cortisol. Salivary uric acid, testosterone, and melatonin did not change. These findings show that nightshift work—a form of behavioral circadian rhythm disruption—was detectable in police trainees using activity trackers alone and in combination with a specialized data analysis methodology.KEY POINTSNight shift work increases cardiometabolic disease risk and this may be a consequence of behavioral circadian misalignment.To advance this hypothesis, methodologies to quantify behavioral irregularities during nightshift in field-based settings are needed.In this pilot study, commercially available activity trackers combined with a novel data processing step were used to assess alterations in sleep/wake patterns in police trainees during dayshift versus nightshift.We also explored relations with four metabolic salivary biomarkers of circadian rhythm during dayshift versus nightshift.Compared to dayshift, nightshift resulted in larger perturbations of resting heart rate, sleep regularity index (indicating reduced regularity), and alterations in sleep and activity patterns; this was accompanied by blunted cortisol.This novel data processing step extends commercially available technology for successful application in real-world shift work settings.

Purpose To explore individual differences in state anxiety following a single, acute bout of aerobic exercise among anxious patients with diagnosed coronary heart disease (CHD). Methods One hundred eighteen CHD patients with elevated symptoms of anxiety enrolled in the UNderstanding the Benefits of Exercise and Escitalopram in Anxious Patients WIth coroNary Heart Disease (UNWIND) clinical trial rated their level of anxiety using a 100-mm visual analog scale before and after a symptom-limited exercise treadmill test. A number of exercise (eg, peak oxygen uptake, exercise duration, maximum heart rate, anaerobic threshold) and psychological variables were examined as potential predictors of exercise response. Changes in anxiety and their association with psychological variables were examined using general linear models. Results Fifty patients (42%) rated a reduction in anxiety relative to their pre-exercise ratings following the exercise treadmill test. While a number of factors were examined, the only factor that distinguished those individuals who reported a reduction in anxiety symptoms compared with those who either remained the same or actually reported an increase in anxiety was a higher pre-exercise visual analog scale anxiety rating. No differences were observed as a function of sex, severity of trait anxiety, the presence of an anxiety disorder, exercise test duration, or age. Conclusions Although many variables were examined, only higher baseline anxiety distinguished those who showed a reduction in their visual analog scale ratings from those whose anxiety remained the same or got worse. The extent to which the response to acute exercise predicts the anxiolytic effects of chronic exercise needs further study.

Background: To provide energy for cardiopulmonary function and maintenance of blood glucose, acute aerobic exercise induces lipolysis, fatty acid oxidation (FAO), glycolysis, and glycogenolysis/gluconeogenesis. These adaptations are mediated by increases in cortisol, growth hormone (GH), and catecholamines and facilitated by a decline in insulin. Branched-chain amino acids (BCAA) also undergo catabolism during intense exercise. Here, we investigated the relationship between BCAA catabolism and metrics of cardiopulmonary function in healthy, well-developed, mature adolescent athletes undergoing an acute bout of maximal aerobic exercise.Hypothesis: We hypothesized: (a) acute maximal exercise in adolescents induces lipolysis, FAO, and BCAA catabolism associated with increases in GH and cortisol and a reduction in insulin; (b) increases in GH are associated with increases in ghrelin; and (c) metrics of cardiopulmonary function (aVO2, rVO2, aVO2/HRmax) following maximal exercise correlate with increases in GH secretion, FAO, and BCAA catabolism.Methods: Blood samples before and after maximal cardiopulmonary exercise in 11 adolescent athletes were analyzed by tandem-mass spectrometry. Paired, two-tailed student's t-tests identified significant changes following exercise. Linear regression determined if pre-exercise metabolite levels, or changes in metabolite levels, were associated with aVO2, rVO2, and aVO2/HRmax. Sex and school of origin were included as covariates in all regression analyses.Results: Following exercise there were increases in GH and cortisol, and decreases in ghrelin, but no changes in glucose or insulin concentrations. Suggesting increased lipolysis and FAO, the levels of glycerol, ketones, β-hydroxybutyrate, and acetylcarnitine concentrations increased. Pyruvate, lactate, alanine, and glutamate concentrations also increased. Plasma concentrations of valine (a BCAA) declined (p = 0.002) while valine degradation byproducts increased in association with decreases in urea cycle amino acids arginine and ornithine. Metrics of cardiopulmonary function were associated with increases in propionylcarnitine (C3, p = 0.013) and Ci4-DC/C4-DC (p < 0.01), byproducts of BCAA catabolism.Conclusions: Induction of lipolysis, FAO, gluconeogenesis, and glycogenolysis provides critical substrates for cardiopulmonary function during exercise. However, none of those pathways were significantly associated with metrics of cardiopulmonary function. The associations between rVO2, and aVO2/HRmax and C3 and Ci4-DC/C4-DC suggest that the cardiopulmonary response to maximal exercise in adolescents is linked to BCAA utilization and catabolism.

ObjectiveCoronary artery disease (CAD) is an age-associated condition that greatly increases the risk of mortality. The purpose of this study was to identify gene variants associated with all-cause mortality among individuals with clinically phenotyped CAD using a genome-wide screening approach.Approach and ResultsWe performed discovery (n = 684), replication (n = 1,088), and meta-analyses (N = 1,503) for association of genomic variants with survival outcome using secondary data from White participants with CAD from two GWAS sub-studies of the Duke Catheterization Genetics Biorepository. We modeled time from catheterization to death or last follow-up (median 7.1 years, max 12 years) using Cox multivariable regression analysis. Target statistical screening thresholds were p × 10–8 for the discovery phase and Bonferroni-calculated p-values for the replication (p < 5.3 × 10–4) and meta-analysis (p < 1.6 × 10–3) phases. Genome-wide analysis of 785,945 autosomal SNPs revealed two SNPs (rs13007553 and rs587936) that had the same direction of effect across all three phases of the analysis, with suggestive p-value association in discovery and replication and significant meta-analysis association in models adjusted for clinical covariates. The rs13007553 SNP variant, LINC01250, which resides between MYTIL and EIPR1, conferred increased risk for all-cause mortality even after controlling for clinical covariates [HR 1.47, 95% CI 1.17–1.86, p(adj) = 1.07 × 10–3 (discovery), p(adj) = 0.03 (replication), p(adj) = 9.53 × 10–5 (meta-analysis)]. MYT1L is involved in neuronal differentiation. TSSC1 is involved in endosomal recycling and is implicated in breast cancer. The rs587936 variant annotated to DAB2IP was associated with increased survival time [HR 0.65, 95% CI 0.51–0.83, p(adj) = 4.79 × 10–4 (discovery), p(adj) = 0.02 (replication), p(adj) = 2.25 × 10–5 (meta-analysis)]. DAB2IP is a ras/GAP tumor suppressor gene which is highly expressed in vascular tissue. DAB2IP has multiple lines of evidence for protection against atherosclerosis.ConclusionReplicated findings identified two candidate genes for further study regarding association with survival in high-risk CAD patients: novel loci LINC01250 (rs13007553) and biologically relevant candidate DAB2IP (rs587936). These candidates did not overlap with validated longevity candidate genes. Future research could further define the role of common variants in survival outcomes for people with CAD and, ultimately, improve longitudinal outcomes for these patients.

Long-term air pollution exposure, notably fine particulate matter, is a global contributor to morbidity and mortality and a known risk factor for coronary artery disease (CAD) and myocardial infarctions (MI). Knowledge of impacts related to source-apportioned PM(2.5) is limited. New modeling methods allow researchers to estimate source-specific long-term impacts on the prevalence of CAD and MI. The Catheterization Genetics (CATHGEN) cohort consists of patients who underwent a cardiac catheterization at Duke University Medical Center between 2002 and 2010. Severity of coronary blockage was determined by coronary angiography and converted into a binary indicator of clinical CAD. History of MI was extracted from medical records. Annual averages of source specific PM(2.5) were estimated using an improved gas-constrained source apportionment model for North Carolina from 2002 to 2010. We tested six sources of PM(2.5) mass for associations with CAD and MI using mixed effects multivariable logistic regression with a random intercept for county and multiple adjustments. PM(2.5) fractions of ammonium bisulfate and ammonium nitrate were associated with increased prevalence of CAD (odds ratio [OR] 1.20; 95% CI = 1.11, 1.22 and OR 1.18; 95% CI = 1.05, 1.32, respectively). PM(2.5) from ammonium bisulfate and ammonium nitrate were also associated with increased prevalence of MI (OR 1.20; 95% CI = 1.10, 1.29 and OR 1.35; 95% CI = 1.20, 1.53, respectively). Greater PM(2.5) concentrations of ammonium bisulfate and ammonium nitrate are associated with greater MI and CAD prevalence. The association with bisulfate suggests aerosol acidity may play a role. Our findings suggest analyses of source specific PM(2.5) mass can reveal novel associations.

Background: The goal was studying the differential effects of aerobic training (AT) vs. resistance training (RT) on cardiac and peripheral arterial capacity on cardiopulmonary (CP) and peripheral vascular (PV) function in sedentary and obese adults.Methods: In a prospective randomized controlled trial, we studied the effects of 6 months of AT vs. RT in 21 subjects. Testing included cardiac and vascular ultrasoundography and serial CP for ventricular-arterial coupling (Ees/Ea), strain-based variables, brachial artery flow-mediated dilation (BAFMD), and peak VO2 (pVO2; mL/kg/min) and peak O2-pulse (O2p; mL/beat).Results: Within the AT group (n = 11), there were significant increases in rVO2 of 4.2 mL/kg/min (SD 0.93) (p = 0.001); O2p of 1.9 mL/beat (SD 1.3) (p = 0.008) and the brachial artery post-hyperemia peak diameter 0.18 mm (SD 0.08) (p = 0.05). Within the RT group (n = 10) there was a significant increase in left ventricular end diastolic volume 7.0 mL (SD 9.8; p = 0.05) and percent flow-mediated dilation (1.8%) (SD 0.47) (p = 0.004). Comparing the AT and RT groups, post exercise, rVO2 2.97, (SD 1.22), (p = 0.03), O2p 0.01 (SD 1.3), (p = 0.01), peak hyperemic blood flow volume (1.77 mL) (SD 140.69) (p = 0.009), were higher in AT, but LVEDP 115 mL (SD 7.0) (p = 0.05) and Ees/Ea 0.68 mmHg/ml (SD 0.60) p = 0.03 were higher in RT.Discussion: The differential effects of AT and RT in this hypothesis generating study have important implications for exercise modality and clinical endpoints.

Background Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT. Methods RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis. Results RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both p < 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways (p < 0.05 for all). Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion (GLDC, BCKDHB, AASS, PYCR, RPL15), (2) increase glycolytic lactate production (AGL, PDK2, LDHB, HIF1A), and (3) reduce oxidative metabolism via altered beta-oxidation (PXMP2, ACSS2), TCA cycle flux (OGDH, SUCLA2, MDH1B), and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT. Conclusion In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid/protein homeostatic pathways. Trial registration ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.

Aims While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. Methods and results We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. Conclusions A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.