Publications by authors named "William E Kraus"

391 Publications

Genome-Wide Variants Associated With Longitudinal Survival Outcomes Among Individuals With Coronary Artery Disease.

Front Genet 2021 1;12:661497. Epub 2021 Jun 1.

School of Medicine, Duke Molecular Physiology Institute, Duke University, Durham, NC, United States.

Objective: Coronary 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 Results: We performed discovery ( = 1,099), replication ( = 404), and meta-analyses ( = 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 × 10 for the discovery phase and Bonferroni-calculated -values for the replication ( < 5.3 × 10) and meta-analysis ( < 1.6 × 10) 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 -value association in discovery and replication and significant meta-analysis association in models adjusted for clinical covariates. The rs13007553 SNP variant, , which resides between and , conferred increased risk for all-cause mortality even after controlling for clinical covariates [HR 1.47, 95% CI 1.17-1.86, = 1.07 × 10 (discovery), = 0.03 (replication), = 9.53 × 10 (meta-analysis)]. is involved in neuronal differentiation. is involved in endosomal recycling and is implicated in breast cancer. The rs587936 variant annotated to was associated with increased survival time [HR , 95% CI -0.83, = 4.79 × 10 (discovery), = 0.02 (replication), = 2.25 × 10 (meta-analysis)]. is a ras/GAP tumor suppressor gene which is highly expressed in vascular tissue. has multiple lines of evidence for protection against atherosclerosis.

Conclusion: Replicated findings identified two candidate genes for further study regarding association with survival in high-risk CAD patients: novel loci (rs13007553) and biologically relevant candidate (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.
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http://dx.doi.org/10.3389/fgene.2021.661497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204081PMC
June 2021

Evaluation of PM air pollution sources and cardiovascular health.

Environ Epidemiol 2021 Jun 20;5(3):e157. Epub 2021 May 20.

United States Environmental Protection Agency, RTP, Durham, North Carolina.

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 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 were estimated using an improved gas-constrained source apportionment model for North Carolina from 2002 to 2010. We tested six sources of PM mass for associations with CAD and MI using mixed effects multivariable logistic regression with a random intercept for county and multiple adjustments. PM 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 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 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 mass can reveal novel associations.
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http://dx.doi.org/10.1097/EE9.0000000000000157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196100PMC
June 2021

Physical Activity as a Critical Component of First-Line Treatment for Elevated Blood Pressure or Cholesterol: Who, What, and How?: A Scientific Statement From the American Heart Association.

Hypertension 2021 Jun 2:HYP0000000000000196. Epub 2021 Jun 2.

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.
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http://dx.doi.org/10.1161/HYP.0000000000000196DOI Listing
June 2021

Increasing physical activity in Cancer Survivors through a Text-messaging Exercise motivation Program (ICanSTEP).

Support Care Cancer 2021 May 28. Epub 2021 May 28.

Department of Population Health Sciences, Duke School of Medicine, Durham, NC, 27710, USA.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Implication For Cancer Survivors: Activity tracker with personalized motivational messaging may be useful in promoting physical activity in cancer survivors.
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http://dx.doi.org/10.1007/s00520-021-06281-yDOI Listing
May 2021

Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions.

PLoS One 2021 27;16(5):e0240764. Epub 2021 May 27.

Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.

Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic biomarkers that are associated with beneficial metabolic changes to weight loss and which distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N = 443), STRRIDE-PD (exercise intervention, N = 163), and CBD (surgical cohort, N = 125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p = 2.3e-5) and diacylglycerols (DAGs; p = 1.6e-4), with higher baseline TAG and DAG levels associated with a greater improvement in insulin resistance with weight loss. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240764PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158886PMC
May 2021

Early Identification of Patients at Risk for Incident Heart Failure With Preserved Ejection Fraction: Novel Approach to Echocardiographic Trends.

J Card Fail 2021 May 7. Epub 2021 May 7.

Division of Cardiology, Duke University School of Medicine, Durham, North Carolina; Division of Cardiology, Duke Molecular Physiology Institute, Durham, North Carolina.

Background: Heart failure with preserved ejection fraction (HFpEF) continues to increase in prevalence with a 50% mortality rate within 3 years of diagnosis, but lacking effective evidence-based therapies. Specific echocardiographic markers are not typically used to trigger alarm before acute HFpEF decompensation. The goal of this study was to retrospectively track changes in echocardiographic markers leading to the time of incident HFpEF hospitalization.

Methods And Results: In a single-center, retrospective analysis, patients with HFpEF admitted between 2007 and 2014 were identified using the International Classification of Diseases, 9th Revision with search refined using the European Society of Cardiology HFpEF guidelines. Using linear mixed effects models, changes in echocardiographic markers preceding acute HF decompensation owing to incident HFpEF were analyzed. We report on an incident HFpEF cohort of 242 patients, extending 18 years retrospectively, and including 675 echocardiograms analyzed from the overall sample at 14 distinct time intervals before acute decompensation. The regression models demonstrated 3 echocardiographic markers with statistically significant increases across multiple time intervals including, arterial elastance (P = .006), right atrial pressure estimate (P < .001), and right ventricular systolic pressure (P = .006). Other echocardiographic markers had individual time intervals with significant increases before acute decompensation, including (a) left atrial diameter, 8 to 10 years before HFpEF diagnosis, (b) left ventricular filling pressure 2 to 6 years before HFpEF diagnosis, (c) ventricular elastance 3 to 6 months before HFpEF diagnosis, and (d) ventricular elastance/arterial elastance as early as 10 to 20 years and as late as 3 to 6 months before HFpEF diagnosis. Furthermore, African Americans presented with incident HFpEF at an average younger age than White patients (65.6 ± 15.2 years vs. 76.7 years ± 11.7, P < .001).

Conclusions: Noninvasive echocardiographic markers associated with incident HFpEF diagnosis showed long, mid, and acute range, significant changes as far back as 10 to 20 years and as close as 3 to 6 months before acute HFpEF decompensation. Including a diverse study cohort is critical to understanding the phenotypic differences of HFpEF. This hypothesis-generating study identified a novel approach to identifying trends in echocardiographic markers that may be used as a signal of impending incident HFpEF.
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http://dx.doi.org/10.1016/j.cardfail.2021.03.013DOI Listing
May 2021

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

Genome Med 2021 Apr 30;13(1):74. Epub 2021 Apr 30.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

Methods: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.

Results: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.

Conclusions: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
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http://dx.doi.org/10.1186/s13073-021-00877-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088054PMC
April 2021

Cardiopulmonary Exercise Testing in the Coronavirus Disease - 2019 Era: Safety and Protocol Considerations.

Curr Sports Med Rep 2021 May;20(5):259-265

Duke Molecular Physiology Institute.

Abstract: Cardiopulmonary exercise testing (CPX) is a valuable tool in both clinical practice and research settings. Therefore, it is advantageous for human performance laboratories to continue operating during the coronavirus disease 2019 (COVID-19) pandemic. All institutions should adhere to general COVID-19 guidelines provided by the Centers for Disease Control. Because of the testing environment, CPX laboratories must consider additional precautionary safety measures. This article provides recommendations for modifying the CPX protocol to ensure safety for all stakeholders during the pandemic. These modifications are universal across all populations, types of institutions and testing modalities. Preliminary measures include careful review of federal, local, and institutional mandates. The description outlines how to evaluate a testing environment and alter workflow. Guidelines are provided on what specific personal protective equipment should be acquired; as well as necessary actions before, during, and after the CPX test. These precautions will limit the possibility of both clients and staff from contracting or spreading the disease while maintaining testing volume in the laboratory.
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http://dx.doi.org/10.1249/JSR.0000000000000843DOI Listing
May 2021

Weight-Related Behaviors of Children with Obesity during the COVID-19 Pandemic.

Child Obes 2021 Apr 26. Epub 2021 Apr 26.

Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA.

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. Semistructured interviews ( = 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. 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. The COVID-19 pandemic has created unique lifestyle challenges and opportunities for lifestyle modification. Clinical Trials ID: NCT03339440.
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http://dx.doi.org/10.1089/chi.2021.0038DOI Listing
April 2021

Aerobic Versus Resistance Training Effects on Ventricular-Arterial Coupling and Vascular Function in the STRRIDE-AT/RT Trial.

Front Cardiovasc Med 2021 1;8:638929. Epub 2021 Apr 1.

Division of Cardiology, Duke University School of Medicine, Durham, NC, United States.

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. 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 VO (pVO mL/kg/min) and peak O-pulse (Op; mL/beat). Within the AT group ( = 11), there were significant increases in rVO of 4.2 mL/kg/min (SD 0.93) ( = 0.001); Op of 1.9 mL/beat (SD 1.3) ( = 0.008) and the brachial artery post-hyperemia peak diameter 0.18 mm (SD 0.08) ( = 0.05). Within the RT group ( = 10) there was a significant increase in left ventricular end diastolic volume 7.0 mL (SD 9.8; = 0.05) and percent flow-mediated dilation (1.8%) (SD 0.47) ( = 0.004). Comparing the AT and RT groups, post exercise, rVO 2.97, (SD 1.22), ( = 0.03), Op 0.01 (SD 1.3), ( = 0.01), peak hyperemic blood flow volume (1.77 mL) (SD 140.69) ( = 0.009), were higher in AT, but LVEDP 115 mL (SD 7.0) ( = 0.05) and Ees/Ea 0.68 mmHg/ml (SD 0.60) = 0.03 were higher in RT. The differential effects of AT and RT in this hypothesis generating study have important implications for exercise modality and clinical endpoints.
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http://dx.doi.org/10.3389/fcvm.2021.638929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049562PMC
April 2021

Exploring Differences in Cardiorespiratory Fitness Response Rates Across Varying Doses of Exercise Training: A Retrospective Analysis of Eight Randomized Controlled Trials.

Sports Med 2021 Mar 11. Epub 2021 Mar 11.

School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s40279-021-01442-9DOI Listing
March 2021

A standard calculation methodology for human doubly labeled water studies.

Cell Rep Med 2021 Feb 16;2(2):100203. Epub 2021 Feb 16.

Maastricht University, Maastricht, the Netherlands.

The doubly labeled water (DLW) method measures total energy expenditure (TEE) in free-living subjects. Several equations are used to convert isotopic data into TEE. Using the International Atomic Energy Agency (IAEA) DLW database (5,756 measurements of adults and children), we show considerable variability is introduced by different equations. The estimated rCO is sensitive to the dilution space ratio (DSR) of the two isotopes. Based on performance in validation studies, we propose a new equation based on a new estimate of the mean DSR. The DSR is lower at low body masses (<10 kg). Using data for 1,021 babies and infants, we show that the DSR varies non-linearly with body mass between 0 and 10 kg. Using this relationship to predict DSR from weight provides an equation for rCO over this size range that agrees well with indirect calorimetry (average difference 0.64%; SD = 12.2%). We propose adoption of these equations in future studies.
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http://dx.doi.org/10.1016/j.xcrm.2021.100203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897799PMC
February 2021

Aerobic, Resistance, and Combination Training on Health-Related Quality of Life: The STRRIDE-AT/RT Randomized Trial.

Front Sports Act Living 2020 11;2:620300. Epub 2021 Feb 11.

Duke University Medical Center, Duke Molecular Physiology Institute, Durham, NC, United States.

The main purpose of this study was to determine the differential effects of aerobic training (AT), resistance training (RT), and a combination of aerobic and resistance training (AT/RT) on changes in self-rated HrQoL measures, including the Short-Form 36 (SF-36) survey and Satisfaction with Physical Function and Appearance survey. We also sought to determine if combination training (AT/RT) has a more or less additive effect compared to AT or RT alone on self-rated HrQoL measures. Participants ( = 137) completed one of three 8-month exercise interventions: (1) AT: 14 kcal exercise expenditure per kg of body weight per week (KKW; equivalent to roughly 12 miles/week) at 65-80% of peak oxygen consumption; (2) RT: 3 days per week, 8 exercises, 3 sets per exercise, 8-12 repetitions per set; (3) AT/RT: full combination of the AT and RT interventions. The SF-36 survey, Satisfaction with Physical Function and Appearance survey, physical fitness, and anthropometrics were assessed at baseline and post-intervention. Paired -tests determined significant pre- vs. post-intervention scores within groups ( < 0.05). Analyses of covariance determined differences in change scores among groups ( < 0.05). On average, participants were 49.0 ± 10.6 years old, obese (BMI: 30.6 ± 3.2 kg/m), female (57.7%), and Caucasian (84.7%). Following the 8-month intervention, exercise groups improved peak VO (all groups), strength (RT and AT/RT), and anthropometric measures (AT and AT/RT). For the SF-36, RT ( = 0.03) and AT/RT ( < 0.001) significantly improved their physical component score; only AT/RT ( < 0.001) significantly improved their mental component score. Notably, all groups significantly improved both their satisfaction with physical function and appearance scores (All Groups: < 0.001 for both outcomes). We found that aerobic, resistance, or combination exercise training improves several components of self-rated HrQoL, including physical function, appearance, and mental well-being. : No. NCT00275145.
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http://dx.doi.org/10.3389/fspor.2020.620300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905223PMC
February 2021

Effects of Amount, Intensity, and Mode of Exercise Training on Insulin Resistance and Type 2 Diabetes Risk in the STRRIDE Randomized Trials.

Front Physiol 2021 4;12:626142. Epub 2021 Feb 4.

Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States.

Background: Lipoprotein Insulin Resistance Index (LP-IR) and Diabetes Risk Index are novel spectroscopic multimarkers of insulin resistance and type 2 diabetes risk. As the Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) randomized trials have previously demonstrated the ability of exercise training to improve traditional markers of insulin action, the aim of this study was to examine the effects of exercise amount, intensity, and mode on LP-IR and the Diabetes Risk Index.

Methods: A total of 503 adults with dyslipidemia [STRRIDE I ( = 194), STRRIDE AT/RT ( = 139)] or prediabetes [STRRIDE-PD ( = 170)] were randomized to control or one of 10 exercise interventions, ranging from doses of 8-23 kcal/kg/week; intensities of 50-75% V̇O; and durations of 6-8 months. Two groups included resistance training and one included dietary intervention (7% weight loss goal). Fasting plasma samples were obtained at baseline and 16-24 h after the final exercise bout. LP-IR, the Diabetes Risk Index, and concentrations of the branched chain amino acids valine and leucine were determined using nuclear magnetic resonance spectroscopy. LP-IR and the Diabetes Risk Index scores range from 0-100 and 1-100, respectively (greater scores indicate greater risk). Paired t-tests determined significance within groups ( < 0.05).

Results: After training, six exercise groups significantly improved LP-IR (ranging from -4.4 ± 8.2 to -12.4 ± 14.1), and four exercise groups significantly improved the Diabetes Risk Index (ranging from -2.8 ± 8.2 to -8.3 ± 10.4). The most beneficial interventions for both LP-IR and the Diabetes Risk Index were low amount/moderate intensity aerobic, aerobic plus resistance, and aerobic plus diet.

Summary: Multiple exercise interventions improved LP-IR and the Diabetes Risk Index. In those with dyslipidemia, adding resistance to aerobic training elicited a synergistic effect on insulin resistance and type 2 diabetes risk. In individuals with prediabetes, combining a dietary intervention and weight loss with aerobic training resulted in the most robust type 2 diabetes risk improvement.
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http://dx.doi.org/10.3389/fphys.2021.626142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892901PMC
February 2021

Association between short-term exposure to ambient fine particulate matter and myocardial injury in the CATHGEN cohort.

Environ Pollut 2021 Apr 5;275:116663. Epub 2021 Feb 5.

Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

Exposure to fine particulate matter (PM) has been associated with a higher risk for coronary events. Elevated circulating cardiac troponins (cTn) are suggestive of myocardial injury in both ischemic and non-ischemic conditions. However, little is known about the association between PM and cTn. In this study, we investigated short-term PM effects on cardiac troponin T (cTnT), as well as N-terminal-pro brain natriuretic peptide (NT-pro BNP) and inflammatory biomarkers among cardiac catheterized participants. We analyzed 7444 plasma cTnT measurements in 2732 participants who presented to Duke University Hospital with myocardial infarction symptoms between 2001 and 2012, partly along with measurements of NT-pro BNP and inflammatory biomarkers. Daily PM concentrations were predicted by a neural network-based hybrid model and were assigned to participants' residential addresses. We applied generalized estimating equations to assess associations of PM with biomarker levels and the risk of a positive cTnT test (cTnT > 0.1 ng/mL). The median plasma cTnT concentration at presentation was 0.05 ng/mL and the prevalence of a positive cTnT test was 35.4%. For an interquartile range (7.6 μg/m) increase in PM on the previous day, cTnT concentrations increased by 7.7% (95% CI: 3.4-12.3) and the odds ratio of a positive cTnT test was 1.08 (1.01-1.16). Participants under 60 years (effect estimate: 15.2%; 95% CI: 7.4-23.5) or living in rural areas (12.3%; 95% CI: 4.8-20.3) were more susceptible. There was evidence for increases in fibrinogen and NT-pro BNP associated with elevated PM on the concurrent and previous two days. Our study suggests that acute PM exposure may elevate indicators of myocardial tissue damage. This finding substantiates the association of air pollution exposure with adverse cardiovascular events.
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http://dx.doi.org/10.1016/j.envpol.2021.116663DOI Listing
April 2021

Greater Pain Severity Is Associated with Worse Outcomes in Patients with Heart Failure.

J Cardiovasc Transl Res 2021 Feb 9. Epub 2021 Feb 9.

Duke Clinical Research Institute, Durham, NC, USA.

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.
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http://dx.doi.org/10.1007/s12265-021-10104-0DOI Listing
February 2021

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

Eur Heart J 2021 03;42(9):919-933

Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands.

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.
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http://dx.doi.org/10.1093/eurheartj/ehaa1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936531PMC
March 2021

Exercise protects against cardiac and skeletal muscle dysfunction in a mouse model of inflammatory arthritis.

J Appl Physiol (1985) 2021 Mar 7;130(3):853-864. Epub 2021 Jan 7.

Department of Medicine, Duke University School of Medicine, Durham, North Carolina.

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis impacting primarily joints and cardiac and skeletal muscle. RA's distinct impact on cardiac and skeletal muscle tissue is suggested by studies showing that new RA pharmacologic agents strongly improve joint inflammation, but have little impact on RA-associated mortality, cardiovascular disease, and sarcopenia. Thus, the objective is to understand the distinct effects of RA on cardiac and skeletal muscle, and to therapeutically target these tissues through endurance-based exercise as a way to improve RA mortality and morbidity. We utilize the well-characterized RA mouse model, the K/BxN mouse, to investigate cardiac and skeletal muscle pathologies, including the use of wheel-running exercise to mitigate these pathologies. Strikingly, we found that K/BxN mice, like patients with RA, also exhibit both cardiac and skeletal muscle myopathies that were correlated with circulating IL-6 levels. Three months of wheel-running exercise significantly improved K/BxN joint swelling and reduced systemic IL-6 concentrations. Importantly, there were morphological, gene expression, and functional improvements in both the skeletal muscle and cardiac myopathies with exercise. The K/BxN mouse model of RA recapitulated important RA clinical comorbidities, including altered joint, cardiac and skeletal muscle function. These morphological, molecular, and functional alterations were mitigated with regular exercise, thus suggesting exercise as a potential therapeutic intervention to lessen disease activity in the joint and the peripheral tissues, including the heart and skeletal muscle. RA, even when controlled, is associated with skeletal muscle weakness and greater risk of cardiovascular disease (CVD). Using exercise as a therapeutic against, the progression of RA is often avoided due to fear of worsening RA pathology. We introduce the K/BxN mouse as an RA model to study both myocardial and skeletal muscle dysfunction. We show that endurance exercise can improve joint, cardiac, and skeletal muscle function in K/BxN mice, suggesting exercise may be beneficial for patients with RA.
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http://dx.doi.org/10.1152/japplphysiol.00576.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988790PMC
March 2021

Accelerated epigenetic age as a biomarker of cardiovascular sensitivity to traffic-related air pollution.

Aging (Albany NY) 2020 12 7;12(23):24141-24155. Epub 2020 Dec 7.

Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.

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 PM.

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.
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http://dx.doi.org/10.18632/aging.202341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762491PMC
December 2020

Novel plasma biomarkers improve discrimination of metabolic health independent of weight.

Sci Rep 2020 12 7;10(1):21365. Epub 2020 Dec 7.

Duke Molecular Physiology Institute, Duke University School of Medicine, 300 North Duke St, Durham, NC, 27701, USA.

We sought to determine if novel plasma biomarkers improve traditionally defined metabolic health (MH) in predicting risk of cardiovascular disease (CVD) events irrespective of weight. Poor MH was defined in CATHGEN biorepository participants (n > 9300), a follow-up cohort (> 5600 days) comprising participants undergoing evaluation for possible ischemic heart disease. Lipoprotein subparticles, lipoprotein-insulin resistance (LP-IR), and GlycA were measured using NMR spectroscopy (n = 8385), while acylcarnitines and amino acids were measured using flow-injection, tandem mass spectrometry (n = 3592). Multivariable Cox proportional hazards models determined association of poor MH and plasma biomarkers with time-to-all-cause mortality or incident myocardial infarction. Low-density lipoprotein particle size and high-density lipoprotein, small and medium particle size (HMSP), GlycA, LP-IR, short-chain dicarboxylacylcarnitines (SCDA), and branched-chain amino acid plasma biomarkers were independently associated with CVD events after adjustment for traditionally defined MH in the overall cohort (p = 3.3 × 10-3.6 × 10), as well as within most of the individual BMI categories (p = 8.1 × 10-1.4 × 10). LP-IR, GlycA, HMSP, and SCDA improved metrics of model fit analyses beyond that of traditionally defined MH. We found that LP-IR, GlycA, HMSP, and SCDA improve traditionally defined MH models in prediction of adverse CVD events irrespective of BMI.
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http://dx.doi.org/10.1038/s41598-020-78478-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721699PMC
December 2020

Beta-blocker and ACE-inhibitor dosing as a function of body surface area: From the HF-ACTION trial.

Am Heart J 2021 03 24;233:1-4. Epub 2020 Nov 24.

Duke Clinical Research Institute, Durham, NC; Division of Cardiology, Duke University School of Medicine, Durham, NC.

Recognizing that body surface area (BSA) is a commonly used metric to inform medication dosing across fields of medicine, it is possible that patients with heart failure with reduced ejection fraction (HFrEF) with higher BSA may be more likely to tolerate higher doses of GDMT. Using the HF-ACTION trial, we examined (1) the relationship between BSA and achievement of target dosing of evidence-based beta-blocker and angiotensin-converting enzyme inhibitor (ACEI) therapy, and (2) the associations and interactions between target dosing, clinical outcomes, and BSA.
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http://dx.doi.org/10.1016/j.ahj.2020.11.003DOI Listing
March 2021

Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.

Cell Rep 2020 11;33(6):108375

Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA; Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA; Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA. Electronic address:

Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. Metabolites and genes related to BCAA metabolism and nitrogen handling were strongly associated with glycine in correlation analyses. Stable isotope labeling in Zucker fatty rats (ZFRs) shows that glycine acts as a carbon donor for the pyruvate-alanine cycle in a BCAA-regulated manner. Inhibition of the BCAA transaminase (BCAT) enzymes depletes plasma pools of alanine and raises glycine levels. In high-fat-fed ZFRs, dietary glycine supplementation raises urinary acyl-glycine content and lowers circulating triglycerides but also results in accumulation of long-chain acyl-coenzyme As (acyl-CoAs), lower 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in muscle, and no improvement in glucose tolerance. Collectively, these studies frame a mechanism for explaining obesity-related glycine depletion and also provide insight into the impact of glycine supplementation on systemic glucose, lipid, and amino acid metabolism.
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http://dx.doi.org/10.1016/j.celrep.2020.108375DOI Listing
November 2020

Evaluating the precision of EBF1 SNP x stress interaction association: sex, race, and age differences in a big harmonized data set of 28,026 participants.

Transl Psychiatry 2020 10 20;10(1):351. Epub 2020 Oct 20.

Behavioral Medicine Research Center, Duke University School of Medicine, Durham, NC, USA.

In prior work, we identified a novel gene-by-stress association of EBF1's common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to "racism/discrimination" (P = 0.036) and "not meeting basic needs" (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e-03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.
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http://dx.doi.org/10.1038/s41398-020-01028-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572375PMC
October 2020

A Role for Exercise to Counter Skeletal Muscle Clock Disruption.

Exerc Sport Sci Rev 2021 Jan;49(1):35-41

Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA.

Disruption of the skeletal muscle circadian clock leads to a preferential shift toward 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 toward an optimal substrate balance.
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http://dx.doi.org/10.1249/JES.0000000000000235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773215PMC
January 2021

Polygenic Score for β-Blocker Survival Benefit in European Ancestry Patients With Reduced Ejection Fraction Heart Failure.

Circ Heart Fail 2020 12 4;13(12):e007012. Epub 2020 Oct 4.

Department of Internal Medicine, Center for Individualized and Genomic Medicine Research (D.E.L., J.A.L., R.S., H.G., N.Z., J.L., L.K.W.), Henry Ford Hospital, Detroit, MI.

Background: β-Blockers (BBs) are mainstay therapy for heart failure with reduced ejection fraction. However, individual patient responses to BB vary, which may be partially due to genetic variation. The goal of this study was to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in heart failure with reduced ejection fraction patients.

Methods: Derivation and validation analyses were performed in n=1436 total HF patients of European descent and with ejection fraction <50%. The PRP was derived in a random subset of the Henry Ford Heart Failure Pharmacogenomic Registry (n=248) and then validated in a meta-analysis of the remaining patients from Henry Ford Heart Failure Pharmacogenomic Registry (n=247), the TIME-CHF (Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure; n=431), and HF-ACTION trial (Heart Failure: a Controlled Trial Investigating Outcomes of Exercise Training; n=510). The PRP was constructed from a genome-wide analysis of BB×genotype interaction predicting time to all-cause mortality, adjusted for Meta-Analysis Global Group in Chronic Heart Failure score, genotype, level of BB exposure, and BB propensity score.

Results: Five-fold cross-validation summaries out to 1000 single-nucleotide polymorphisms identified optimal prediction with a 44 single-nucleotide polymorphism score and cutoff at the 30th percentile. In validation testing (n=1188), greater BB exposure was associated with reduced all-cause mortality in patients with low PRP score (n=251; hazard ratio, 0.19 [95% CI, 0.04-0.51]; =0.0075) but not high PRP score (n=937; hazard ratio, 0.84 [95% CI, 0.53-1.3]; =0.448)-a difference that was statistically significant ( interaction, 0.0235). Results were consistent regardless of atrial fibrillation, ejection fraction (≤40% versus 41%-50%), or when examining cardiovascular death.

Conclusions: Among patients of European ancestry with heart failure with reduced ejection fraction, a PRP distinguished patients who derived substantial survival benefit from BB exposure from a larger group that did not. Additional work is needed to prospectively test clinical utility and to develop PRPs for other population groups and other medications.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.007012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738407PMC
December 2020

Effects of caloric restriction on human physiological, psychological, and behavioral outcomes: highlights from CALERIE phase 2.

Nutr Rev 2021 01;79(1):98-113

Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.

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.
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http://dx.doi.org/10.1093/nutrit/nuaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727025PMC
January 2021

Metabolic and Neurocognitive Changes Following Lifestyle Modification: Examination of Biomarkers from the ENLIGHTEN Randomized Clinical Trial.

J Alzheimers Dis 2020 ;77(4):1793-1803

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.

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.
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http://dx.doi.org/10.3233/JAD-200374DOI Listing
January 2020

Skeletal muscle capillary density is related to anaerobic threshold and claudication in peripheral artery disease.

Vasc Med 2020 10 25;25(5):411-418. Epub 2020 Aug 25.

Department of Medicine, Medical College of Georgia, Augusta, GA, USA.

Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, causing claudication and exercise intolerance. Exercise intolerance may result from reduced skeletal muscle capillary density and impaired muscle oxygen delivery. This cross-sectional study tested the hypothesis that capillary density is related to claudication times and anaerobic threshold (AT) in patients with PAD. A total of 37 patients with PAD and 29 control subjects performed cardiopulmonary exercise testing on a treadmill for AT and gastrocnemius muscle biopsies. Skeletal muscle capillary density was measured using immunofluorescence staining. PAD had decreased capillary density (278 ± 87 vs 331 ± 86 endothelial cells/mm, = 0.05), peak VO (15.7 ± 3.9 vs 24.3 ± 5.2 mL/kg/min, ⩽ 0.001), and VO at AT (11.5 ± 2.6 vs 16.1 ± 2.8 mL/kg/min, ⩽ 0.001) compared to control subjects. In patients with PAD, but not control subjects, capillary density was related to VO at AT ( = 0.343; = 0.038), time to AT ( = 0.381; = 0.020), and time after AT to test termination ( = 0.610; ⩽ 0.001). Capillary density was also related to time to claudication ( = 0.332; = 0.038) and time after claudication to test termination ( = 0.584; ⩽ 0.001). In conclusion, relationships between capillary density, AT, and claudication symptoms indicate that, in PAD, exercise limitations are likely partially dependent on limited skeletal muscle capillary density and oxidative metabolism.
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http://dx.doi.org/10.1177/1358863X20945794DOI Listing
October 2020

Effect of 2 years of calorie restriction on liver biomarkers: results from the CALERIE phase 2 randomized controlled trial.

Eur J Nutr 2021 Apr 14;60(3):1633-1643. Epub 2020 Aug 14.

Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA, 70808, USA.

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 2-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 2-year randomized controlled trial. Overall, 218 participants (body mass index: 25.1 ± 1.7 kg/m) were enrolled into a 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; P < 0.01) and GGT (- 0.11 ± 0.04 log IU/L; P = 0.02) decreased and bilirubin increased (0.21 ± 0.06 log mg/dL; P < 0.01) in the CR group; no between-group differences in ALT (- 1 ± 1 IU/L; P > 0.99) or AST (2 ± 2 IU/L; P = 0.68) were revealed. However, sex-by-treatment-by-time interactions (P < 0.01) were observed, with CR (vs. control) inducing reduced ALT and GGT and increased AST in men only (P ≤ 0.02).

Conclusions: In metabolically healthy individuals without obesity, 2 years of CR improves several liver biomarkers, with potentially greater improvements in men. These data suggest that sustained CR may improve long-term liver and metabolic disease risk in healthy adults.

Trial Registration: Clinicaltrials.gov (NCT00427193). Registered January 2007.
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http://dx.doi.org/10.1007/s00394-020-02361-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882001PMC
April 2021