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Introduction: Albuminuria, an early marker of kidney damage, is a risk factor for chronic kidney disease (CKD) progression, cardiovascular disease (CVD), and death. Dietary sodium is a risk factor for elevated blood pressure, CVD, and all cause-mortality. It is particularly important in patients with CKD due to increased salt-sensitivity. It is unclear if dietary sodium reduction is associated with reduced albuminuria. Hypothesis: A low sodium diet will reduce albuminuria in patients with CKD. Methods: The Sodium Lowering and Urinary Protein Reduction (SUPER) Trial was a randomized, parallel trial testing the effect of a 24-week dietary sodium reduction intervention compared to usual diet on albuminuria in 151 CKD patients with albuminuria. Participants were eligible if they had an estimated glomerular filtration rate (eGFR) of 30-90 mL/min/1.73 m 2 and an albumin-to-creatinine ratio (ACR) of 30-1,500 mg/g. Intervention group participants received a dietician-led behavioral change intervention targeting sodium intake Results: Study participants were an average of 65.6 years old, 72% African American, and 48% women. Median baseline ACR was 180.3 mg/g in the intervention and 157.4 mg/g in the control group, respectively. Urinary sodium excretion was reduced by 15.5% and 0.0% in the intervention and control groups, respectively. Results for the primary and key secondary outcomes are presented in the Table. Conclusions: The dietician-led dietary sodium reduction intervention succeeded in significantly reducing dietary sodium and BP in patients with CKD and albuminuria. However, no significant differences were observed in ACR, albuminuria, or eGFR between treatment groups.

Introduction: Low-carbohydrate diets lead to weight loss and improvement in hemoglobin A1c and other cardiometabolic outcomes. However, there is limited research on how much of the glycemic effects of low-carbohydrate diets are mediated by weight loss. Hypothesis: The effect of a low-carbohydrate dietary intervention on hemoglobin A1c would be mediated by weight loss. Methods: We conducted a 6-month randomized clinical trial on the effects of a low-carbohydrate diet intervention (target Results: 150 participants (mean [SD] age 59 [8] years; 108 [72%] female; 88 [59%] Black) were randomized to either the low-carbohydrate diet intervention (75 participants) or usual diet (75 participants) arm. Mean (SD) HbA1c was 6.16% (0.30%) at baseline. Six-month data was collected on 142 participants (95%). Compared with the usual diet arm, the low-carbohydrate diet intervention arm had significantly greater 6-month reduction in HbA1c (net difference, -0.23% [95% CI, -0.32 to -0.14%]) and body weight (-5.9 kg [95% CI, -7.4 to -4.4 kg]). In mediation analyses, 59% of the total effect of intervention on 6-month change in hemoglobin A1c was mediated by weight measured at 3 months (Table). Conclusions: In mediation analyses, a substantial proportion (59%) of the total effect of intervention on 6-month change in hemoglobin A1c was mediated through weight measured at 3 months. Future research should further explore contributions of weight loss to reductions in glycemia in other populations.

Introduction: A significant proportion of persons with metabolic syndrome, prediabetes, or type 2 diabetes do not develop atherosclerotic cardiovascular disease (ASCVD). Discordantly normal apolipoprotein B (ApoB) relative to elevated LDL-cholesterol (LDL-C) may help to explain underlying heterogeneity in ASCVD risk among these individuals. Hypothesis: We hypothesized that discordantly normal ApoB (> 100 mg/dL) would be associated with a lower atherosclerosis burden among individuals with metabolic disorders. Methods: There were 331 Bogalusa Heart Study participants with metabolic syndrome (n=107), prediabetes (n=291), or type 2 diabetes (n=34) and LDL-C > 100 who were free of carotid plaque at baseline (2001-02) and underwent carotid ultrasound at follow-up (2013-16). Carotid plaque was defined as a focal wall thickening >1.5 mm. Modified Poisson regression with robust error variance estimated the long-term absence of plaque for normal ApoB after adjusting for established risk factors. Results: Participants were on average 36.3 years old at baseline, 202 (61.0%) were women, and 93 (29.9%) were African American. Overall, LDL-C explained 42.3% of the variability in ApoB as the lipoprotein markers were only modestly correlated (r=0.65). Participants with ApoB > 90 (74.6% versus 57.4%, p=0.001, Figure ). In multivariable modeling, persons with ApoB Conclusions: More than half of persons with metabolic disorders and elevated LDL-C had normal ApoB with a lower burden of carotid atherosclerosis over 13 years follow-up. ApoB better represents the atherogenic lipid burden among persons with metabolic disorders compared to LDL-C and may be especially helpful for persons with the pattern of high triglycerides and low HDL-cholesterol.

BACKGROUND AND AIMS: Women with prior gestational diabetes mellitus (GDM) are at elevated risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors among parous U.S. women ages 20–44 by history of GDM. METHODS AND RESULTS: Using data from the National Health and Nutrition Examination Survey (NHANES) from 2007–2018, 3537 parous women were classified by self-reported GDM history. We compared anthropometric measures, glycemia, blood pressure, lipids, lifestyle factors, cardiovascular health, and cardiometabolic disease prevalence by GDM status. NHANES survey design was taken into account. Women without history of GDM were younger and, after adjusting for age, race/ethnicity, and education, had more favorable cardiometabolic risk factor profiles for measures of anthropometry, glycemia, diabetes, many lipids, physical activity, diet, and overall cardiovascular health than women with history of GDM. Many patterns persisted after further adjustment for lifestyle factors. In analyses stratified by race/ethnicity, many patterns persisted, though there were key differences. Hypertension prevalence differed by GDM history only among Hispanic women. In women of other race/ethnicity, there was no difference in healthy eating or body mass index by GDM history. In non-Hispanic Black women, there was no difference in healthy eating by GDM history. CONCLUSION: Among parous U.S. women ages 20–44, those with history of GDM had less favorable cardiometabolic risk factor profiles than those without history of GDM. This highlights the importance of continued efforts to develop and test multilevel interventions to improve cardiometabolic risk factors among reproductive-age women with a history of GDM.

Background: The increasing prevalence of diabetes mellitus, a major cause of morbidity and mortality worldwide, is a critical public health concern. Though a number of studies have evaluated the associations of metabolites with prediabetes and diabetes, further exploration in this relatively new field may identify novel biomarkers for predicting, detecting, and managing hyperglycemia and diabetes. Objective: We conducted a metabolome-wide association study among 805 white and 426 African-American participants of the Bogalusa Heart Study (BHS) to identify metabolites associated with markers of glycemia and diabetes. Methods: After rigorous quality control, 1,202 metabolites quantified by untargeted, ultra-high performance liquid chromatography tandem-mass spectroscopy were tested for association with fasting glucose, hemoglobin A1c and diabetes. Multiple regression analyses were run in race-stratified and combined samples, adjusting for age, sex, education, blood pressure, body mass index, HDL-cholesterol, smoking, eGFR, fasting glucose (for HbA1c and diabetes), and race (in combined analyses). For fasting glucose and HbA1c, those taking diabetes medications were excluded. Metabolites were considered significant if they were significant (P-5 ; Bonferroni corrected for 1,202 metabolites) in one race group and the entire cohort, with a similar trend observed in the other race group. Results: After Bonferroni corrections, among 72 metabolites significantly associated with at least one glycemic outcome, 27 were novel and in known pathways: 5 from amino acid, 1 from carbohydrate, 18 from lipid, 1 from xenobiotics, and 2 from nucleotide pathways. Metabolites consistently associated with diabetes are shown in the Table . Conclusions: These results identified novel metabolites associated with glycemic outcomes, providing additional evidence on the importance of serum metabolites in hyperglycemia and diabetes.

OBJECTIVE: To identify novel and confirm previously reported metabolites associated with SBP, DBP, and hypertension in a biracial sample of Bogalusa Heart Study (BHS) participants. METHODS: We employed untargeted, ultra-high performance liquid chromatography tandem mass spectroscopy metabolomics profiling among 1249 BHS participants (427 African-Americans and 822 whites) with BP and covariable data collected during the 2013 to 2016 visit cycle. A total of 1202 metabolites were tested for associations with continuous and binary BP phenotypes using multiple linear and logistic regression models, respectively, in overall and race-stratified analyses. RESULTS: A total of 24 novel metabolites robustly associated with BP, achieving Bonferroni-corrected P less than 4.16×10(−5) in the overall analysis and consistent effect sizes across race groups. The identified metabolites included three amino acid and nucleotide metabolites from histidine, pyrimidine, or tryptophan metabolism sub-pathways, seven cofactor and vitamin or xenobiotic metabolites from the ascorbate and aldarate metabolism, bacterial/fungal, chemical, and food component sub-pathways, 10 lipid metabolites from the eicosanoid, phosphatidylcholine, phosphatidylethanolamine, and sphingolipid metabolism sub-pathways, and four still unnamed metabolites. Six previously described metabolites were robustly confirmed by our study (Bonferroni-corrected P < 4.95×10(−4) and consistent effect directions across studies). Furthermore, previously reported metabolites for SBP, DBP, and hypertension demonstrated 5.92-fold, 4.77-fold, and 4.54-fold enrichment for nominally significant signals in the BHS (P=3.08×10(−10), 5.93×10(−8), and 2.30×10(−8), respectively). CONCLUSION: In aggregate, our study provides new information about potential molecular mechanisms underlying BP regulation. We also demonstrate reproducibility of findings across studies despite differences in study populations and metabolite profiling methods.

Background and aims To examine the associations between history of gestational diabetes mellitus (GDM) and breastfeeding with branched-chain amino acids (BCAA) and their metabolites in later life. Methods and results 638 women (mean age 48.0 y) who had participated in the Bogalusa Heart Study and substudies of pregnancy history had untargeted, ultrahigh performance liquid chromatography-tandem mass spectroscopy conducted by Metabolon© on serum samples. Metabolites were identified that were BCAA or associated with BCAA metabolic pathways. History of GDM at any pregnancy (self-reported, confirmed with medical records when possible) as well as breastfeeding were examined as predictors of BCAA using linear models, controlling for age, race, BMI, waist circumference, and menopausal status. None of the BCAA differed statistically by history of either GDM or breastfeeding, although absolute levels of each of the BCAA were higher with GDM and lower with breastfeeding. Of the 27 metabolites on the leucine, isoleucine and valine metabolism subpathway, 1-carboxyethylleucine, 1-carboxyethyvaline, and 3-hydroxy-2-ethylpropionate were higher in women with a history of GDM, but lower in women in women with a history of breastfeeding. Similar results were found for alpha-hydroxyisocaproate, 1-carboxyethylisoleucine, and N-acetylleucine. Conclusions GDM and breastfeeding are associated in opposite directions with several metabolites on the BCAA metabolic pathway.

Objective— The objective of this study is to examine associations between short-term exposure to ambient air pollution and circulating biomarkers of systemic inflammation in participants from the Framingham Offspring and Third Generation cohorts in the greater Boston area. Approach and Results— We included 3996 noncurrent smoking participants (mean age, 53.6 years; 54% women) who lived within 50 km from a central air pollution monitoring site in Boston, MA, and calculated the 1- to 7-day moving averages of fine particulate matter (diameter3 higher 5-day moving average fine particulate matter (diameter Conclusions— Higher short-term exposure to relatively low levels of ambient air pollution was associated with higher levels of C-reactive protein, interleukin-6, and tumor necrosis factor receptor 2 but not fibrinogen or tumor necrosis factor α in individuals residing in the greater Boston area.

Aims The objective of this study was to evaluate the association of chocolate consumption and heart failure (HF) in a large population of Swedish men. Methods We conducted a prospective cohort study of 31,917 men 45-79 years old with no history of myocardial infarction, diabetes, or HF at baseline who were participants in the population-based Cohort of Swedish Men study. Chocolate consumption was assessed through a self-administrated food frequency questionnaire. Participants were followed for HF hospitalization or mortality from January 1, 1998, to December 31, 2011, using record linkage to the Swedish inpatient and cause-of-death registries. Results During 14 years of follow-up, 2,157 men were hospitalized (n=1,901) or died from incident HF (n=256). Compared with subjects who reported no chocolate intake, the multivariable-adjusted rate ratio of HF was 0.88 (95% CI 0.78-0.99) for those consuming 1-3 servings per month, 0.83 (95% CI 0.72-0.94) for those consuming 1-2 servings per week, 0.82 (95% CI 0.68-0.99) for those consuming 3-6 servings per week, and 1.10 (95% CI 0.84-1.45) for those consuming ≥1 serving per day ( P for quadratic trend=.001). Conclusions In this large prospective cohort study, there was a J -shaped relationship between chocolate consumption and HF incidence. Moderate chocolate consumption was associated with a lower rate of HF hospitalization or death, but the protective association was not observed among individuals consuming ≥1 serving per day. Journal Subject Codes: Etiology: Epidemiology, Heart failure: Congestive

Introduction: Exposure to air pollution has been positively associated with systemic inflammation. However, few large scale studies were conducted in regions with low levels of air pollution. We therefore studied the associations of air pollution with systemic inflammation biomarkers among participants in the Framingham Offspring and Third Generation cohorts in Greater Boston area. Methods: We measured C-reactive protein (CRP), fibrinogen, interleukin 6 (IL6), and tumor necrosis factor receptor 2 (TNFR2) in 3943 participants living within 50 km of a central site monitor in Boston. We calculated the 1-, 2-, 3-, 5-, and 7-day moving averages of fine particulate matter (PM 2.5 ), black carbon (BC), sulfate (SO 4 2- ), nitrogen oxides (NO x ), and ozone (O 3 ) prior to the exam visits. We used linear mixed effects models and linear regression models to evaluate repeated measures and cross-sectional associations respectively, adjusting for age, sex, individual and area level measures of socioeconomic position, lifestyle and clinical factors, time trend, and weather. We examined effect modification by age (>/≤ 65 years), sex, and diabetes history. Results: The mean age was 53(±14) years and 54% were women. PM 2.5 , BC, and SO 4 2- were positively associated with CRP across multiple moving averages, and were statistically significant at 5-day moving averages: a 5 μg/m 3 higher PM 2.5 or a 0.5 μg/m 3 higher BC was associated with 3.9% (95% CI: 0.5, 7.3) or 5.3% (95% CI: 0.1, 10.9) higher CRP, respectively. Positive associations were observed for PM 2.5 , BC, and NO x with IL6; and for BC, SO 4 2- , and O 3 with TNFR2. SO 4 2- and O 3 were negatively associated with fibrinogen. Associations of BC and NO x with CRP and of BC with IL6 were of a larger magnitude among participants with diabetes than those without. Conclusions: In a region in compliance with current US-EPA regulation, we find positive associations of short-term exposure to ambient air pollution with CRP, IL6 and TNFR2 but not for fibrinogen.

Background Short‐term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community‐based studies have assessed this association. Methods and Results Two thousand thirty‐five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998–2001) and urinary creatinine‐indexed 8‐epi‐prostaglandin F 2α (8‐epi‐ PGF 2α ) at the seventh and eighth (2005–2008) examinations. We measured fine particulate matter ( PM 2.5 ), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1‐, 2‐, 3‐, 5‐, and 7‐day moving averages of each pollutant. Measured myeloperoxidase and 8‐epi‐ PGF 2α were log e transformed. We used linear regression models and linear mixed‐effects models with random intercepts for myeloperoxidase and indexed 8‐epi‐ PGF 2α , respectively. Models were adjusted for demographic variables, individual‐ and area‐level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM 2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2‐ to 7‐day moving averages of PM 2.5 and sulfate were consistently positively associated with 8‐epi‐ PGF 2α . Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. Conclusions Our community‐based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress.

Background: Exposure to traffic and ambient air pollution is associated with an increased risk of cardiovascular disease, potentially through atherosclerosis promotion. Few studies have assessed associations of these exposures with thoracic aortic calcium (TAC) or abdominal aortic calcium (AAC), which are correlates of atherosclerosis. Objective: We assessed whether living close to a major road and residential exposure to fine particulate matter (PM 2.5 ) were associated with TAC and AAC in a community-based Northeastern U.S. cohort. Methods: TAC was measured from 2002[[Unable to Display Character: –]]2005 and AAC up to two times (2002[[Unable to Display Character: –]]2005; 2008[[Unable to Display Character: –]]2011) among participants from the Framingham Offspring or Third Generation Cohorts. We first assessed associations of residential distance to a major road and PM 2.5 exposure (2003 annual average from a spatiotemporal model) with detectable aortic calcium. We used logistic regression for TAC and generalized estimating equations (logit link) for AAC. As aortic calcium scores were right-skewed, we next used linear regression models and mixed effects models to assess associations with log-transformed TAC and AAC, respectively, among participants with aortic calcium scores > 0 (95% CIs bootstrapped). We also assessed associations with AAC progression. Models were adjusted for demographic variables, individual and area-level markers of socioeconomic position and time. Results: Among 3518 participants with TAC or AAC measured, 52% had AAC measured twice. Mean age was 55.8 years; 50% female. There were no associations of distance to a major road or PM 2.5 with detectable TAC or AAC, though some estimates were in the opposite direction than expected ( Table ). There were no associations with extent of TAC or AAC ( Table ), or with AAC progression. Conclusions: Proximity to a major road and PM 2.5 were not associated with the presence or extent of aortic calcium, or with AAC progression in this cohort from a region with relatively low PM 2.5 levels. Future work should explore these associations in other populations.

Objective— Long-term exposure to traffic and particulate matter air pollution is associated with a higher risk of cardiovascular disease, potentially via atherosclerosis promotion. Prior research on associations of traffic and particulate matter with coronary artery calcium Agatston score (CAC), an atherosclerosis correlate, has yielded inconsistent findings. Given this background, we assessed whether residential proximity to major roadway or fine particulate matter were associated with CAC in a Northeastern US study. Approach and Results— We measured CAC ≤2 times from 2002 to 2005 and 2008 to 2011 among Framingham Offspring or Third-Generation Cohort participants. We assessed associations of residential distance to major roadway and residential fine particulate matter (2003 average; spatiotemporal model) with detectable CAC, using generalized estimating equation regression. We used linear mixed effects models to assess associations with log e (CAC). We also assessed associations with CAC progression. Models were adjusted for demographic variables, socioeconomic position markers, and time. Among 3399 participants, 51% had CAC measured twice. CAC was detectable in 47% of observations. At first scan, mean age was 52.2 years (standard deviation 11.7); 51% male. There were no consistent associations with detectable CAC, continuous CAC, or CAC progression. We observed heterogeneous associations of distance to major roadway with odds of detectable CAC by hypertensive status; interpretation of these findings is questionable. Conclusions— Our findings add to prior work and support evidence against strong associations of traffic or fine particulate matter with the presence, extent, or progression of CAC in a region with relatively low levels of and little variation in fine particulate matter.

Background— Compared with no alcohol consumption, heavy alcohol intake is associated with a higher rate of heart failure (HF) whereas light-to-moderate intake may be associated with a lower rate. However, several prior studies did not exclude former drinkers, who may have changed alcohol consumption in response to diagnosis. This study aimed to investigate the association between alcohol intake and incident HF. Methods and Results— We conducted a prospective cohort study of 33 760 men aged 45 to 79 years with no HF, diabetes mellitus, or myocardial infarction at baseline participating in the Cohort of Swedish Men Study. We excluded former drinkers. At baseline, participants completed a food frequency questionnaire and reported other characteristics. HF was defined as hospitalization for or death from HF, ascertained by Swedish inpatient and cause-of-death records from January 1, 1998, through December 31, 2011. We constructed Cox proportional hazards models to estimate multivariable-adjusted incidence rate ratios. During follow-up, 2916 men were hospitalized for (n=2139) or died (n=777) of incident HF. There was a U-shaped relationship between total alcohol intake and incident HF ( P =0.0004). There was a nadir at light-to-moderate alcohol intake: consuming 7 to Conclusions— In this cohort of Swedish men, there was a U-shaped relationship between alcohol consumption and HF incidence, with a nadir at light-to-moderate intake. Heavy intake did not seem protective.

Background: The relationship between alcohol intake and incident heart failure (HF) is complex. Compared with no alcohol consumption, heavy alcohol intake is associated with higher HF risk whereas light or moderate consumption may be associated with lower risk. Methods: We analyzed 34,581 men 45-79 years old with no history of HF, diabetes mellitus or myocardial infarction (MI) who were participants in the population-based Cohort of Swedish Men study. We excluded former drinkers. At baseline, participants reported how frequently they consumed specific alcoholic beverages in the past year and other characteristics. HF was defined as hospitalization for or death from HF (primary diagnosis), ascertained by Swedish inpatient and cause-of-death records from January 1, 1998 to December 31, 2011. Due to missing values for two covariates, we used Markov chain Monte Carlo multiple imputation to simulate 5 complete datasets. We used Cox proportional hazards models to estimate rate ratios and 95% confidence intervals, adjusting for age, total energy intake, education, body mass index, physical activity, a dietary component score, cigarette smoking, marital status, family history of MI before age 60, history of hypertension and history of high cholesterol. Results: At baseline, mean age was 58.6 years. There were 1592 incident cases of HF over the follow-up period. Compared with never drinkers, the multivariable-adjusted rate of HF was 19% lower among men who drank Conclusions: Light-to-moderate drinking is associated with lower rate of HF compared with never drinking, but the association was not statistically significant.