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Proteomics has been leveraged to study type 2 diabetes (T2D), but the majority of available data are from White participants. Here, we extend prior work by analyzing a large cohort of self-identified African Americans (AAs) in the Jackson Heart Study (JHS, n=1,313). We found 325 proteins associated with incident diabetes after adjusting for age, sex, and batch (FDR-q

Physical activity and its sustained and purposeful performance – exercise – promote a broad and diverse set of metabolic and cardiovascular health benefits. Regular exercise is the most effective way to improve cardiorespiratory fitness, a measure of one’s global cardiovascular, pulmonary and metabolic health and one of the strongest predictors of future health risk. Here, we describe how exercise affects individual organ systems related to cardiometabolic health, including the promotion of insulin and glucose homeostasis through improved efficiency in skeletal muscle glucose utilization and enhanced insulin sensitivity; beneficial changes in body composition and adiposity; and improved cardiac mechanics and vascular health. We subsequently identify knowledge gaps that remain in exercise science, including heterogeneity in exercise responsiveness. While the application of molecular profiling technologies in exercise science has begun to illuminate the biochemical pathways that govern exercise-induced health promotion, much of this work has focused on individual organ systems and applied single platforms. New insights into exercise-induced secreted small molecules and proteins that impart their effects in distant organs (“exerkines”) highlight the need for an integrated approach towards the study of exercise and its global effects; efforts that are ongoing.

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including β-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. Article Highlights Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual’s ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans. Plasma proteomic profiles from 650 adult humans are measured before and after a 20-week exercise regimen to determine proteins associated with baseline cardiorespiratory fitness and improvements in response to exercise.

High-throughput proteomic profiling using antibody or aptamer-based affinity reagents is used increasingly in human studies. However, direct analyses to address the relative strengths and weaknesses of these platforms are lacking. We assessed findings from the SomaScan1.3K ( N = 1301 reagents), the SomaScan5K platform ( N = 4979 reagents), and the Olink Explore ( N = 1472 reagents) profiling techniques in 568 adults from the Jackson Heart Study and 219 participants in the HERITAGE Family Study across four performance domains: precision, accuracy, analytic breadth, and phenotypic associations leveraging detailed clinical phenotyping and genetic data. Across these studies, we show evidence supporting more reliable protein target specificity and a higher number of phenotypic associations for the Olink platform, while the Soma platforms benefit from greater measurement precision and analytic breadth across the proteome.

ObjectivesWe investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits.MethodsA total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%–75% of participants’ maximal oxygen uptake (VO2max)) with VO2max, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses.ResultsOnly one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits.ConclusionsInterindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve.

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

Introduction: C-reactive protein (CRP) and GlycA are established biomarkers of inflammation. Regular exercise tends to decrease CRP and GlycA levels. However, the molecules underlying CRP and GlycA and their responses to exercise training are less known. Hypothesis: We hypothesized that distinct protein signatures exist for both baseline levels and exercise responsiveness of CRP and GlycA, however with some overlap of proteins across signatures. Methods: Measures were performed before and after 20 weeks of exercise training in 652 Black and White adults from the HERITAGE Family Study. 4,979 circulating proteins were measured using SomaScan. High-sensitivity CRP was measured using automated assays. GlycA was quantified by NMR spectroscopy (LabCorp). Linear mixed models were used to test: 1) Association of baseline proteins with baseline hsCRP and GlycA and 2) Association of change in protein with changes in hsCRP and GlycA. Models were adjusted for age, sex, race, BMI, with family membership as a random variable, with change models also adjusting for baseline trait value. Significance was determined as FDR Results: Baseline levels (r=0.51, p-40 < p < 1.2x10 -08 ), with serum amyloid A-2 and A-1 (SAA2, SAA) among the top 6 hits for 3 of 4 models (Table 1). Conclusions: More unique proteins were associated with GlycA levels at both timepoints, with most hsCRP proteins overlapping with GlycA proteins. Overall, a substantial number of proteins are associated with CRP and GlycA levels regardless of when they are measured, which has potential implications for using proteins as signatures of these inflammatory biomarkers.

Introduction: Elevated plasma triglycerides (TG) are associated with risk of cardiovascular disease and are modifiable through lifestyle interventions such as regular exercise. However, TG responses to regular exercise are characterized by significant inter-individual differences. Hypothesis: We hypothesized that baseline levels of circulating proteins and metabolites are associated with TG response to exercise and can predict exercise-induced changes in plasma TG traits. Methods: We measured circulating proteins (n=4979 proteins) and metabolites (n=300) in 650 Black and White adults of the HERITAGE Family Study who completed 20 weeks of exercise training and had complete data on TG traits. We investigated two TG-related traits that significantly improved with training: fasting TG and large TG-rich lipoprotein particle concentration (LTRLP). The association between baseline analyte values and exercise-induced changes in TG traits were examined using linear mixed models adjusted for age, sex, race, BMI, baseline trait value, and the random effect of family membership. Significance was determined as FDR Results: Regular exercise significantly reduced plasma TG (-1.03±1.3 mmol/L, p=0.01) and LTRLP (-0.24±2.2 nmol/L, p= 0.007), with their training-induced changes moderately correlated (r=0.4, pTable 1 ). Similarly, elastic net regression yielded distinct models of 99 analytes for TG and 315 analytes for LTRLP responses to exercise with accuracy of RMSE=1.28 mmol/L for TG and 2.16 nmol/L for the LTRLP model. Conclusions: We identified panels of proteins and metabolites associated with exercise-induced changes in TG traits and demonstrate, within our data, circulating analytes hold promise for predicting the exercise responsiveness of plasma TG-related traits.

Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes associated metabolites, we leveraged a method that measures 305 targeted or “known” and 2,342 nontargeted or “unknown” compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)—a community cohort of self-identified African Americans (AAs), who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate (FDR)

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions. Sin financiación 5.05º JCR (2021) Q2, 47/146 Endocrinology & Metabolism 8.561 SJR (2021) Q1, 2/128 Endocrinology No data IDR 2021 UEM

Physical activity (PA) and exercise are widely recognized as essential components of primary and secondary cardiovascular disease (CVD) prevention efforts and are emphasized in the health promotion guidelines of numerous professional societies and committees. The protean benefits of PA and exercise extend across the spectrum of CVD, and include the improvement and reduction of risk factors and events for atherosclerotic CVD (ASCVD), cardiometabolic disease, heart failure, and atrial fibrillation, respectively. Here, we highlight recent insights into the salutary effects of PA and exercise on the primary and secondary prevention of ASCVD, including their beneficial effects on both traditional and non-traditional risk mediators; exercise "prescriptions" for ASCVD; the role of PA regular exercise in the prevention and treatment of heart failure; and the relationships between, PA, exercise and atrial fibrillation. While our understanding of the relationship between exercise and CVD has evolved considerably, several key questions remain including the association between extreme volumes of exercise and subclinical ASCVD and its risk; high-intensity exercise and resistance (strength) training as complementary modalities to continuous aerobic exercise; and dose- and intensity-dependent associations between exercise and atrial fibrillation. Recent advances in molecular profiling technologies (i.e., genomics, transcriptomics, proteomics, and metabolomics) have begun to shed light on inter-individual variation in cardiometabolic responses to PA and exercise and may provide new opportunities for clinical prediction in addition to mechanistic insights.

Objective: Our primary objective was to examine the associations of the Mediterranean (MED), the Dietary Approaches to Stop Hypertension (DASH), and the Alternate Healthy Eating Index (AHEI) diet with total mortality. Our secondary objective was to examine the association of these three dietary patterns with cardiovascular disease (CVD) and cancer mortality. Research: Design and Methods: We prospectively studied 15,768 men from the Physicians’ Health Study who completed a semi-quantitative food-frequency questionnaire. Scores from each dietary pattern were divided into quintiles. Multivariable Cox regression models were used to estimate hazard ratio’s (95% confidence intervals) of mortality. Results: At baseline, average age was 65.9 ± 8.9 years. There were 1763 deaths, including 488 CVD deaths and 589 cancer deaths. All diet scores were inversely associated with risk for all-cause mortality: Hazard ratios (95% CI) of all-cause mortality from lowest to highest quintile for MED diet were 1.0 (reference), 0.85 (0.73–0.98), 0.80 (0.69–0.93), 0.77 (0.66–0.90), and 0.68 (0.58–0.79), corresponding values were 1.0 (reference), 0.96 (0.82–1.12), 0.95 (0.82–1.11), 0.88 (0.75–1.04), and 0.83 (0.71–0.99) for DASH diet and 1.0 (reference), 0.88 (0.77–1.02), 0.82 (0.71–0.95), 0.69 (0.59, 0.81), and 0.56 (0.47–0.67) for AHEI diet, after adjusting for age, energy, smoking, exercise, BMI, hypertension, coronary heart disease, congestive heart failure, diabetes, and atrial fibrillation. For cause-specific mortality, MED and AHEI scores were inversely associated with lower risk for CVD mortality, whereas AHEI and MED scores were inversely associated with lower risk for cancer mortality. Conclusion: Within this cohort of male physicians, AHEI, MED, and DASH scores were each inversely associated with mortality from all causes.

Introduction: Regular exercise beneficially increases plasma HDL-C levels at the group level. However, variation in individual HDL-C responses to exercise highlight a need for predictive biomarkers of exercise response. Hypothesis: We hypothesized that baseline abundance of circulating proteins is predictive of HDL-C response to exercise and that identified proteins are part of a complex biological network of exercise response. Methods: We measured over 5,000 circulating proteins using an aptamer-affinity based platform (SomaScan) in 667 black and white adults from the HERITAGE Family Study. Fasting plasma HDL-C was measured at baseline and following 20 weeks of supervised endurance exercise training. To predict exercise induced changes in HDL-C using baseline abundance of circulating proteins, models were created using LASSO regression and a 70/30 training test data split with 10-fold cross validation. Biological pathways, networks, and functions involving proteins identified in predictive modeling were investigated by ingenuity pathway analysis (IPA) and integrated molecular pathway level analysis (IMPaLA). Results: Regular exercise significantly increased HDL-C in the sample by 1.5 ± 4.6 mg/dL (p Conclusions: Circulating proteins may allow for prediction of exercise induced changes in HDL-C. Additionally, proteins predictive of HDL-C response to exercise are associated with important biological pathways and may provide insights into the molecular mechanisms of the benefits of regular exercise.

Background: Heart failure (HF) is a heterogeneous disease characterized by significant metabolic disturbances; however, the breadth of metabolic dysfunction before the onset of overt disease is not well understood. The purpose of this study was to determine the association of circulating metabolites with incident HF to uncover novel metabolic pathways to disease. Methods: We performed targeted plasma metabolomic profiling in a deeply phenotyped group of Black adults from the JHS (Jackson Heart Study; n=2199). We related metabolites associated with incident HF to established etiological mechanisms, including increased left ventricular mass index and incident coronary heart disease. Furthermore, we evaluated differential associations of metabolites with HF with preserved ejection fraction versus HF with reduced ejection fraction. Results: Metabolites associated with incident HF included products of posttranscriptional modifications of RNA, as well as polyamine and nitric oxide metabolism. A subset of metabolite-HF associations was independent of well-established HF pathways such as increased left ventricular mass index and incident coronary heart disease and included homoarginine (per 1 SD increase in metabolite level, hazard ratio, 0.77; P =1.2×10 −3 ), diacetylspermine (hazard ratio, 1.34; P =3.4×10 −3 ), and uridine (hazard ratio, 0.79; P , 3×10 −4 ). Furthermore, metabolites involved in pyrimidine metabolism (orotic acid) and collagen turnover ( N -methylproline) among others were part of a distinct metabolic signature that differentiated individuals with HF with preserved ejection fraction versus HF with reduced ejection fraction. Conclusions: The integration of clinical phenotyping with plasma metabolomic profiling uncovered novel metabolic processes in nontraditional disease pathways underlying the heterogeneity of HF development in Black adults.

Background: Increased left ventricular (LV) mass is associated with future adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect black individuals. To understand the mechanisms that drive disease, particularly in black individuals, we undertook a proteomic screen in a black cohort and compared it to a white cohort. Methods: We measured 1305 plasma proteins using an aptamer-based proteomic platform (SOMAscan™) in 1772 black participants in the Jackson Heart Study (JHS) with available baseline LV mass as assessed by 2D echocardiography, as well as 1600 free of HF with follow-up assessment of incident cases. Mean follow-up time was 11 years; 152 cases of incident HF hospitalization were identified. Models were adjusted for age, sex, body mass index, estimated glomerular filtration rate (as calculated by CKD-EPI equation), systolic blood pressure, hypertension treatment, presence of diabetes, total/HDL cholesterol, prevalent coronary disease, and current smoking status. Incident HF models were also adjusted for incident coronary heart disease. We then compared protein associations in JHS to those observed in whites from the Framingham Heart Study (FHS) to examine significant differences. Results: In JHS, there were 112 proteins associated with LV mass and 10 proteins associated with incident HF hospitalization with FDR -8 , HR = 1.46 [1.20, 1.79], p = 0.0002). The strongest association with LV mass was more novel: leukotriene A4 hydrolase (LKHA4) (β = 0.05 [0.04, 0.06], p = 2.6 x 10 -15 ). Conversely, Fractalkine/CX3CL1 showed a novel association with incident HF (HR = 1.32 [1.14, 1.54], p = 0.0003). While proteins like Cystatin C and N-terminal pro-BNP showed consistent effects in FHS, LKHA4 and Fractalkine were significantly different. Conclusions: We identify several novel biological pathways specific to black individuals hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and Fractalkine. Further studies are needed to validate these results and elucidate the detailed underlying mechanisms.

Brief SummaryCOVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear.1,2Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: theABOlocus and the 3p21.31 locus.3To understand how these loci might confer risk and whether this differs by race, we utilized proteomic profiling and genetic information from three cohorts including black and white participants to identify proteins influenced by these loci. We observed that variants in theABOlocus are associated with levels of CD209/DC-SIGN, a known binding protein for SARS-CoV and other viruses,4as well as multiple inflammatory and thrombotic proteins, while the 3p21.31 locus is associated with levels of CXCL16, a known inflammatory chemokine.5Thus, integration of genetic information and proteomic profiling in biracial cohorts highlights putative mechanisms for genetic risk in COVID-19 disease.

IMPORTANCE: African American individuals have disproportionate rates of coronary heart disease (CHD) but lower levels of coronary artery calcium (CAC), a marker of subclinical CHD, than non-Hispanic White individuals. African American individuals may have distinct metabolite profiles associated with incident CHD risk compared with non-Hispanic White individuals, and examination of these differences could highlight important processes that differ between them. OBJECTIVES: To identify novel biomarkers of incident CHD and CAC among African American individuals and to replicate incident CHD findings in a multiethnic cohort. DESIGN, SETTING, AND PARTICIPANTS: This analysis targeted plasma metabolomic profiling of 2346 participants in the Jackson Heart Study (JHS), a prospective population-based cohort study that included 5306 African American participants who were examined at baseline (2000-2004) and 2 follow-up visits. Replication of CHD-associated metabolites was sought among 1588 multiethnic participants from the Women’s Health Initiative (WHI), a prospective population-based multiethnic cohort study of 161 808 postmenopausal women who were examined at baseline (1991-1995) and ongoing follow-up visits. Regression analyses were performed for each metabolite to examine the associations with incident CHD and CAC scores. Data were collected from the WHI between 1994 and 2009 and from the JHS between 2000 and 2015. All data were analyzed from November 2020 to August 2021. EXPOSURES: Plasma metabolites. MAIN OUTCOMES AND MEASURES: Incident CHD was defined as definite or probable myocardial infarction or definite fatal CHD in both the JHS and WHI cohorts. In the JHS cohort, silent myocardial infarction between examinations (as determined by electrocardiography) and coronary revascularization were included in the incident CHD analysis. Coronary artery calcium was measured using a 16-channel computed tomographic system and reported as an Agatston score. RESULTS: Among 2346 African American individuals in the JHS cohort, the mean (SD) age was 56 (13) years, and 1468 individuals (62.6%) were female. Among 1588 postmenopausal women in the WHI cohort, the mean (SD) age was 67 (7) years; 217 individuals (13.7%) self-identified as African American, 1219 (76.8%) as non-Hispanic White, and 152 (9.6%) as other races or ethnicities. In the fully adjusted model including 1876 individuals, 46 of 303 targeted metabolites were associated with incident CHD (false discovery rate q

IMPORTANCE: Metabolic responses to exercise training are variable. Metabolite profiling may aid in the clinical assessment of an individual’s responsiveness to exercise interventions. OBJECTIVE: To investigate the association between a novel circulating biomarker of hepatic fat, dimethylguanidino valeric acid (DMGV), and metabolic health traits before and after 20 weeks of endurance exercise training. DESIGN, SETTING, AND PARTICIPANTS: This study involved cross-sectional and longitudinal analyses of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, a 20-week, single-arm endurance exercise clinical trial performed in multiple centers between 1993 and 1997. White participants with sedentary lifestyles who were free of cardiometabolic disease were included. Metabolomic tests were performed using a liquid chromatography, tandem mass spectrometry method on plasma samples collected before and after exercise training in the HERITAGE study. Metabolomics and data analysis were performed from August 2017 to May 2018. EXPOSURES: Plasma DMGV levels. MAIN OUTCOME AND MEASURES: The association between DMGV levels and measures of body composition, plasma lipids, insulin, and glucose homeostasis before and after exercise training. RESULTS: Among the 439 participants included in analyses from HERITAGE, the mean (SD) age was 36 (15) years, 228 (51.9%) were female, and the median (interquartile range) body mass index was 25 (22-28). Baseline levels of DMGV were positively associated with body fat percentage, abdominal visceral fat, very low-density lipoprotein cholesterol, and triglycerides, and inversely associated with insulin sensitivity, low-density lipoprotein cholesterol, high-density lipoprotein size, and high-density lipoprotein cholesterol (range of β coefficients, 0.17-0.46 [SEs, 0.026-0.050]; all P

Introduction Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent disease which is strongly associated with cardiometabolic disease (CMD). Type 2 diabetes (DM2) is associated with worse outcomes in this patient population; however, it is not clear if the addition of other cardiometabolic risk factors further increases this risk. Hypothesis We expect that an increasing number of CMDs will correlate with worse outcomes in this population. Methods We analyzed 1767 subjects from the Americas subgroup of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) database and stratified patients into 4 groups based on number of CMDs (hypertension, DM2, hyperlipidemia, and obesity). The association of these groups (0-1, 2, 3, and 4 CMDs) with the primary outcome in TOPCAT (composite of cardiovascular death, HF hospitalization, and aborted cardiovascular death) were compared using Cox proportional hazards modeling. Results Of the 1767 subjects, 347 had 0-1 CMDs, 579 had 2 CMDs, 503 had 3 CMDs, and 338 had 4 CMDs. After adjusting for covariates*, there was a significant increase in the primary outcome in groups with 3 (HR: 1.26, p = 0.03) or 4 CMDs (HR: 1.59, p = 0.0003) when compared to patients with 0-2 CMDs (Fig 1A). Notably, groups with 3-4 CMDs had more patients with DM2 (greater than 70%) than those with 0-2 CMDs (less than 15%). Among subjects with DM2, additional CMDs did not increase the risk of the primary outcome (Fig 1B). Conclusions Increasing burden of CMDs is associated with poor outcomes in patients with HFpEF, driven by the presence of DM2 in higher CMD groups. The addition of CMDs to DM2 did not confer increased risk in these patients.

High-throughput profiling of metabolic status (metabolomics) allows for the assessment of small-molecule metabolites that may participate in exercise-induced biochemical pathways and corresponding cardiometabolic risk modification. We sought to describe the changes in a diverse set of plasma metabolite profiles in patients undergoing chronic exercise training and assess the relationship between metabolites and cardiometabolic response to exercise.A secondary analysis was performed in 216 middle-age abdominally obese men and women (mean ± SD, 52.4 ± 8.0 yr) randomized into one of four groups varying in exercise amount and intensity for 6-month duration: high amount high intensity, high amount low intensity, low amount low intensity, and control. One hundred forty-seven metabolites were profiled by liquid chromatography-tandem mass spectrometry.No significant differences in metabolite changes between specific exercise groups were observed; therefore, subsequent analyses were collapsed across exercise groups. There were no significant differences in metabolite changes between the exercise and control groups after 24 wk at a Bonferroni-adjusted statistical significance (P3.0 × 10). Seven metabolites changed in the exercise group compared with the control group at P0.05. Changes in several metabolites from distinct metabolic pathways were associated with change in cardiometabolic risk traits, and three baseline metabolite levels predicted changes in cardiometabolic risk traits.Metabolomic profiling revealed no significant plasma metabolite changes between exercise and control after 24 wk at Bonferroni significance. However, we identified circulating biomarkers that were predictive or reflective of improvements in cardiometabolic traits in the exercise group.

Low-output heart failure represents a high-acuity, heterogeneous physiologic state marked by end-organ hypoperfusion and substantial morbidity and mortality. The clinical symptoms and exam findings vary widely, and it may manifest subtly with non-specific features of fatigue or sinus tachycardia, or present dramatically with altered sensorium, marked hypotension, and multi-organ failure. The diverse presentation of low-output heart failure highlights the importance of its prompt recognition and subsequent risk stratification. Treatment goals are focused on initial stabilization of systemic blood pressure and improved tissue and end-organ perfusion, and may be achieved through a combination of veno- and vasodilators, inotropic agents, and in severe cases, mechanical circulatory support. The following case presentation illustrates the complex findings seen in low-output heart failure, and offers a systematic approach to its evaluation and management.

Background— African Americans develop chronic kidney disease and pulmonary hypertension (PH) at disproportionately high rates. Little is known whether PH heightens the risk of heart failure (HF) admission or mortality among chronic kidney disease patients, including patients with non–end-stage renal disease. Methods and Results— We analyzed African Americans participants with chronic kidney disease (estimated glomerular filtration rate 2 or urine albumin/creatinine >30 mg/g) and available echocardiogram-derived pulmonary artery systolic pressure (PASP) from the Jackson Heart Study (N=408). We used Cox models to assess whether PH (PASP>35 mm Hg) was associated with higher rates of HF hospitalization and mortality. In a secondary, cross-sectional analysis, we examined the relationship between cystatin C (a marker of renal function) and PASP and potential mediators, including BNP (B-type natriuretic peptide) and endothelin-1. In our cohort, the mean age was 63±13 years, 70% were female, 78% had hypertension, and 22% had PH. Eighty-five percent of the participants had an estimated glomerular filtration rate >30 mL/min per 1.73 m 2 . During follow-up, 13% were hospitalized for HF and 27% died. After adjusting for potential confounders, including BNP, PH was found to be associated with HF hospitalization (hazard ratio, 2.37; 95% confidence interval, 1.15–4.86) and the combined outcome of HF hospitalization or mortality (hazard ratio, 1.84; confidence interval, 1.09–3.10). Log cystatin C was directly associated with PASP (adjusted β =2.5 [95% confidence interval, 0.8–4.1] per standard deviation change in cystatin C). Mediation analysis showed that BNP and endothelin-1 explained 56% and 40%, respectively, of the indirect effects between cystatin C and PASP. Conclusions— Among African Americans with chronic kidney disease, PH, which is likely pulmonary venous hypertension, was associated with a higher risk of HF admission and mortality.

Summary Background and aims Eggs are a ubiquitous and important source of dietary cholesterol and nutrients, yet their relationship to coronary heart disease (CHD) remains unclear. While some data have suggested a positive association between egg consumption and CHD, especially among diabetic subjects, limited data exist on the influence of egg consumption on subclinical disease. Thus, we sought to examine whether egg consumption is associated with calcified atherosclerotic plaques in the coronary arteries. Methods In a cross-sectional design, we studied 1848 participants of the NHLBI Family Heart Study without known CHD. Egg consumption was assessed by a semi-quantitative food frequency questionnaire and coronary-artery calcium (CAC) was measured by cardiac CT. We defined prevalent CAC using an Agatston score of at least 100 and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Results Mean age was 56.5 years and 41% were male. Median consumption of eggs was 1/week. There was no association between frequency of egg consumption and prevalent CAC. Odds ratios (95% CI) for CAC were 1.0 (reference), 0.95 (0.66–1.38), 0.94 (0.63–1.40), and 0.90 (0.57–1.42) for egg consumption of almost never, 1–3 times per month, once per week, and 2+ times per week, respectively ( p for trend 0.66), adjusting for age, sex, BMI, smoking, alcohol, physical activity, income, field center, total calories, and bacon. Additional control for hypertension and diabetes mellitus, or restricting the analysis to subjects with diabetes mellitus or fasting glucose >126 mg/dL did not alter the findings. Conclusions These data do not provide evidence for an association between egg consumption and prevalent CAC in adult men and women.

Summary Background Experimental studies have demonstrated the role of vitamin D in key pathways related to cardiovascular health. While several studies have investigated the impact of vitamin D therapy on outcomes in subjects with prevalent heart failure, limited research exists on the relationship of dietary vitamin D consumption with the risk of heart failure. Thus, we sought to investigate whether dietary vitamin D consumption was associated with a lower risk of incident heart failure in a large prospective cohort of male physicians. Methods and results We prospectively studied 19,635 males from the Physicians' Health Study. Dietary vitamin D information was obtained from a baseline food frequency questionnaire, and heart failure information was obtained by questionnaire and validated in a subsample. Mean age was 66.4 years. Median dietary vitamin D consumption was 200.4 IU and only 2.3% of the subjects used vitamin D supplements. After an average follow-up of 9.3 years, there were 858 new cases of heart failure identified. Higher intake of dietary vitamin D was not associated with incident heart failure in a multivariable adjusted model: hazard ratios (95% CI) of incident heart failure were 1.0 (reference), 1.29 (1.04–1.60), 1.17 (0.94–1.46), 1.22 (0.98–1.53), and 1.16 (0.92–1.46) from lowest to highest age- and energy-adjusted vitamin D quintile, respectively, after adjusting for age, BMI, race, exercise, alcohol use, smoking, calories, and prevalent atrial fibrillation ( p for linear trend = 0.64). Conclusions These data are consistent with a lack of an association between dietary vitamin D and incident heart failure in this population of professionally-employed middle-aged males.

Congestive heart failure (HF) remains one of the leading causes of morbidity and mortality in the USA, and its prevalence continues to rise with an aging population. Few nutritional guidelines exist for the prevention of HF, but recent evidence demonstrating beneficial effects of dietary interventions in the prevention and treatment of cardiovascular disease (CVD) offers promise for their role in HF. The current review summarizes pertinent data from both clinical trials and observational studies focused on the potential contribution of individual food items, supplements, and dietary patterns to the primary and secondary prevention of HF. We further highlight gaps in our understanding of the role of diet in HF and future directions to help bridge important areas of need.

Background The American Heart Association (AHA) established recommendations based on 7 ideal health behaviors and factors with the goal of improving cardiovascular health (CVH) and reducing both morbidity and mortality from cardiovascular disease by 20% by 2020. Few studies have investigated their association with subclinical coronary heart disease. We sought to examine whether the 7 AHA CVH metrics were associated with calcified atherosclerotic plaque in the coronary arteries. Methods In a cross-sectional design, we studied 1,731 predominantly white men and women from the National Heart, Lung, and Blood Institute Family Heart Study without prevalent coronary heart disease. Diet was assessed by a semiquantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC using an Agatston score of 100+ and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Results Mean age was 56.8 years, and 41% were male. The median number of ideal CVH metrics was 3, and no participant met all 7. There was a strong inverse relationship between number of ideal CVH metrics and prevalent CAC. Odds ratios (95% CI) for CAC of 100+ were 1.0 (reference), 0.37 (0.29-0.45), 0.35 (0.26-0.44), and 0.27 (0.20-0.36) among subjects with 0 to 1, 2, 3, and 4+ ideal CVH metrics, respectively ( P = .0001), adjusting for sex, age, field center, alcohol, income, education, and energy consumption. Conclusions These data demonstrate a strong and graded inverse relationship between AHA ideal CVH metrics and prevalent CAC in adult men and women.

Background: African Americans (AA) develop chronic kidney disease (CKD) and pulmonary hypertension (PH) at disproportionately high rates. It is unknown whether PH heightens the risk of heart failure (HF) admission or mortality among CKD patients, including non-end stage disease. Methods: We

Heart failure (HF) with preserved ejection fraction (HFpEF) is difficult to curate in a large database of electronic medical records since it requires verification of HF diagnosis and left ventricular ejection fraction (LVEF) values to be consistently ≥ 50%. We used national Veterans Affairs