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Background and aim Plasma citric acid cycle (CAC) metabolites might be likely related to cardiovascular disease (CVD). However, studies assessing the longitudinal associations between circulating CAC-related metabolites and CVD risk are lacking. The aim of this study was to evaluate the association of baseline and 1-year levels of plasma CAC-related metabolites with CVD incidence (a composite of myocardial infarction, stroke or cardiovascular death), and their interaction with Mediterranean diet interventions. Methods and results Case-cohort study from the PREDIMED trial involving participants aged 55–80 years at high cardiovascular risk, allocated to MedDiets or control diet. A subcohort of 791 participants was selected at baseline, and a total of 231 cases were identified after a median follow-up of 4.8 years. Nine plasma CAC-related metabolites (pyruvate, lactate, citrate, aconitate, isocitrate, 2-hydroxyglutarate, fumarate, malate and succinate) were measured using liquid chromatography-tandem mass spectrometry. Weighted Cox multiple regression was used to calculate hazard ratios (HRs). Baseline fasting plasma levels of 3 metabolites were associated with higher CVD risk, with HRs (for each standard deviation, 1-SD) of 1.46 (95%CI:1.20–1.78) for 2-hydroxyglutarate, 1.33 (95%CI:1.12–1.58) for fumarate and 1.47 (95%CI:1.21–1.78) for malate (p of linear trend

BACKGROUND: Arginine-derived metabolites are involved in oxidative and inflammatory processes related to endothelial functions and cardiovascular risks. OBJECTIVES: We prospectively examined the associations of arginine catabolism metabolites with the risks of atrial fibrillation (AF) or heart failure (HF), and evaluated the potential modifications of these associations through Mediterranean diet (MedDiet) interventions in a large, primary-prevention trial. METHODS: Two nested, matched, case-control studies were designed within the Prevención con Dieta Mediterránea (PREDIMED) trial. We selected 509 incident cases and 547 matched controls for the AF case-control study and 326 cases and 402 matched controls for the HF case-control study using incidence density sampling. Fasting blood samples were collected at baseline and arginine catabolism metabolites were measured using LC-tandem MS. Multivariable conditional logistic regression models were applied to test the associations between the metabolites and incident AF or HF. Interactions between metabolites and intervention groups (MedDiet groups compared with control group) were analyzed with the likelihood ratio test. RESULTS: Inverse association with incident AF was observed for arginine (OR per 1 SD, 0.83; 95% CI: 0.73–0.94), whereas a positive association was found for N1-acetylspermidine (OR for Q4 compared with Q1 1.58; 95% CI: 1.13–2.25). For HF, inverse associations were found for arginine (OR per 1 SD, 0.82; 95% CI: 0.69–0.97) and homoarginine (OR per 1 SD, 0.81; 95% CI: 0.68–0.96), and positive associations were found for the asymmetric dimethylarginine (ADMA) and symmetric dimethlyarginine (SDMA) ratio (OR per 1 SD, 1.19; 95% CI: 1.02–1.41), N1-acetylspermidine (OR per 1 SD, 1.34; 95% CI: 1.12–1.60), and diacetylspermine (OR per 1 SD, 1.20; 95% CI: 1.02–1.41). In the stratified analysis according to the dietary intervention, the lower HF risk associated with arginine was restricted to participants in the MedDiet groups (P-interaction = 0.044). CONCLUSIONS: Our results suggest that arginine catabolism metabolites could be involved in AF and HF. Interventions with the MedDiet may contribute to strengthen the inverse association between arginine and the risk of HF. This trial was registered at controlled-trials.com as ISRCTN35739639.

BackgroundThe extent to which physical activity attenuates the detrimental effects of sugar (SSBs)- or artificially-sweetened beverages (ASBs) on the risk of cardiovascular disease is unknown.MethodsWe used Cox proportional-hazards models to calculate hazard ratios and 95% confidence interval [HR (CI)] between SSB or ASB intake and physical activity with cardiovascular disease risk among 65,730 women in the Nurses’ Health Study (1980-2016) and 39,418 men in the Health Professional’s Follow-up Study (1986-2016), who were free from chronic diseases at baseline. SSBs and ASBs were assessed every 4-years and physical activity biannually.ResultsA total of 13,269 cardiovascular events were ascertained during 3,001,213 person-years of follow-up. Compared with those that never/rarely consumed SSBs or ASBs, HR and 95% CI for cardiovascular disease for participants consuming ≥2 servings/day were 1.21 (95% CI,1.12 to 1.32;P-trendP-trend=0.06), respectively. In the joint analyses, for participants meeting and not meeting physical activity guidelines (ConclusionsOur findings suggest that among physically active participants, higher SSB intake, but not ASBs, is associated with a higher cardiovascular risk. Our results support current recommendations to limit the intake of SSB and maintain adequate physical activity levels.Clinical PerspectiveWhat is new?Consumption of sugar- or artificially-sweetened beverages and physical activity are independently associated with cardiovascular disease; nevertheless, the role that physical activity plays in the associations between sugar- and artificially-sweetened beverages consumption and cardiovascular disease warrants further analysis since physical activity could offset the health risk that would have been induced by their consumption.In two US cohorts, not meeting physical activity guidelines jointly with a greater intake of sugar- or artificially-sweetened beverages was associated with a higher risk of cardiovascular disease; however, even when individuals were physically active, higher consumption of sugar-sweetened beverages was associated with a higher cardiovascular risk.What are the clinical implications?Our results provide further evidence of the intake of sugar-sweetened beverages and low physical activity as factors negatively impacting cardiovascular health.Our results support public health recommendations and policies to limit the intake of sugar-sweetened beverages and meet and maintain adequate physical activity levels.

Background: Recent advances in metabolomic studies have shown promise in elucidating the biological pathways underpinning aging processes and mortality in animal models, but data in humans are lacking. We aimed to evaluate the associations between metabolite profiles, all-cause and cause-specific mortality, and longevity. Methods: Within three prospective cohorts (Nurses’ Health Study [NHS], NHSII, and Health Professional’s Follow-up Study), we measured plasma metabolites from 11,523 participants (mean age 54 years, 86% female) using high-throughput liquid chromatography-mass spectrometry. Participants were free of cardiovascular disease and cancer at blood collection. Metabolome-wide association analyses were conducted for all-cause, cardiovascular, and cancer mortality using Cox proportional hazards regression and longevity (attaining 85 years of age) using logistic regression. Both pre-defined and data-driven metabolite groups were also evaluated. We further developed a multi-metabolite profile score for all-cause mortality using an elastic-net regularized Cox model and assessed its associations with mortality and longevity. Results for all-cause mortality were replicated among 1878 participants (mean age 67 years, 58% female) from the PREDIMED trial. Results: We documented 4252 deaths (including 864 cardiovascular deaths and 1070 cancer deaths) and 3048 achieving longevity over a median follow-up of 22.6 years in the NHS/NHSII/HPFS, and 126 deaths during a follow-up of 4.7 years in the PREDIMED. Higher levels of three nucleosides (N2,N2-dimethylguanosine, pseudouridine, and N4-acetylcytidine), 4-acetamidobutanoic acid, triacylglycerols with ≤56 carbons and ≤3 double bonds, and several other lipids were associated with increased risk of all-cause mortality and corresponding decreased likelihood of longevity; whereas L-serine, L-glutamine, and TAGs with >56 carbons or >3 double bonds were associated with lower mortality risk and higher odds of achieving longevity. A multi-metabolite profile score comprising 73 metabolites was positively associated with all-cause (HR per 1-SD increment=1.25 [95% CI: 1.21, 1.30] in NHS/NHSII/HPFS and 1.47 [95% CI: 1.22, 1.78] in PREDIMED), cardiovascular (HR=1.34 [95% CI:1.24, 1.45]), and cancer mortality (HR=1.15 [95% CI:1.08, 1.24]) and inversely associated with longevity (OR=0.79 [95% CI: 0.74, 0.86]). Conclusions: We identified multiple metabolites associated with mortality and longevity. Our findings provide insights into the biological pathways that lead to death and open up new avenues to incorporate these metabolomic markers in clinical and research settings.

Dried fruits contain many bioactive compounds broadly classified as phytochemicals includingphenolics, flavonoids, carotenoids, proanthocyanidins, stilbenes, chalcones/dihydrochalcones,and phytoestrogens. These compounds have antioxidant effects that may benefit health. Dried fruitsare also a diverse group of foods with varying fibre contents. The evaluation of the biological activityof these bioactive compounds, including their bioaccessibility and bioavailability, may contributeto the understanding of the health effects of dried fruits. Limited evidence suggests that driedfruits (raisins, cranberries, dates, and prunes) affect human gut microbiota composition in a potentiallybeneficial manner (in terms of effects on Bifidobacteria, Faecalibacterium prausnitzii, Lactobacillus,Ruminococcaceae, Klebsiella spp., and Prevotella spp.). There is little epidemiological evidence about theassociation of dried fruit consumption with cardiovascular disease incidence and mortality, as well asthe risk of type 2 diabetes or obesity. Clinical trial evidence for the effects of dried fruit consumptionon cardiovascular risk factors, including glycaemic control, is mixed. Clinical trial evidence suggestsprunes might preserve bone mineral density in postmenopausal women. Consumption of driedfruits is associated with higher-quality diets. Studies are needed to increase our understanding of thehealth effects of dried fruits and the underlying biological mechanisms. Dried fruits contain many bioactive compounds broadly classified as phytochemicals including phenolics, flavonoids, carotenoids, proanthocyanidins, stilbenes, chalcones/dihydrochalcones, and phytoestrogens. These compounds have antioxidant effects that may benefit health. Dried fruits are also a diverse group of foods with varying fibre contents. The evaluation of the biological activity of these bioactive compounds, including their bioaccessibility and bioavailability, may contribute to the understanding of the health effects of dried fruits. Limited evidence suggests that dried fruits (raisins, cranberries, dates, and prunes) affect human gut microbiota composition in a potentially beneficial manner (in terms of effects on Bifidobacteria, Faecalibacterium prausnitzii, Lactobacillus, Ruminococcaceae, Klebsiella spp., and Prevotella spp.). There is little epidemiological evidence about the association of dried fruit consumption with cardiovascular disease incidence and mortality, as well as the risk of type 2 diabetes or obesity. Clinical trial evidence for the effects of dried fruit consumption on cardiovascular risk factors, including glycaemic control, is mixed. Clinical trial evidence suggests prunes might preserve bone mineral density in postmenopausal women. Consumption of dried fruits is associated with higher-quality diets. Studies are needed to increase our understanding of the health effects of dried fruits and the underlying biological mechanisms.

Background and ObjectivesWomen have higher lifetime risk of stroke than men, and metabolic factors seem more strongly associated with stroke for women than men. However, few studies in either men or women have evaluated metabolomic profiles and incident stroke.MethodsWe applied liquid chromatography–tandem mass spectrometry to measure 519 plasma metabolites in a discovery set of women in the Nurses' Health Study (NHS; 454 incident ischemic stroke cases, 454 controls) with validation in 2 independent, prospective cohorts: Prevención con Dieta Mediterránea (PREDIMED; 118 stroke cases, 791 controls) and Nurses' Health Study 2 (NHS2; 49 ischemic stroke cases, 49 controls). We applied logistic regression models with stroke as the outcome to adjust for multiple risk factors; the false discovery rate was controlled through the q value method.ResultsTwenty-three metabolites were significantly associated with incident stroke in NHS after adjustment for traditional risk factors (q < 0.05). Of these, 14 metabolites were available in PREDIMED and 3 were significantly associated with incident stroke: methionine sulfoxide, N6-acetyllysine, and sucrose (q < 0.05). In NHS2, one of the 23 metabolites (glucuronate) was significantly associated with incident stroke (q < 0.05). For all 4 metabolites, higher levels were associated with increased risk. These 4 metabolites were used to create a stroke metabolite score (SMS) in the NHS and tested in PREDIMED. Per unit of standard deviation of SMS, the odds ratio for incident stroke was 4.12 (95% confidence interval [CI] 2.26–7.51) in PREDIMED, after adjustment for risk factors. In PREDIMED, the area under the receiver operating characteristic curve (AUC) for the model including SMS and traditional risk factors was 0.70 (95% CI 0.75–0.79) vs the AUC for the model including the traditional risk factors only of 0.65 (95% CI 0.70–0.75), corresponding to a 5% improvement in risk prediction with SMS (p < 0.005).DiscussionMetabolites associated with stroke included 2 amino acids, a carboxylic acid, and sucrose. A composite SMS including these metabolites was associated with ischemic stroke and showed improvement in risk prediction beyond traditional risk factors.Classification of EvidenceThis study provides Class II evidence that a SMS accurately predicts incident ischemic stroke risk.

Scope: Consumption of meat has been associated with a higher risk of type 2 diabetes (T2D), but if plasma metabolite profiles associated with these foods reflect this relationship is unknown. The objective is to identify a metabolite signature of consumption of total meat (TM), red meat (RM), processed red meat (PRM), and fish and examine if they are associated with T2D risk. Methods and results: The discovery population includes 1833 participants from the PREDIMED trial. The internal validation sample includes 1522 participants with available 1-year follow-up metabolomic data. Associations between metabolites and TM, RM, PRM, and fish are evaluated with elastic net regression. Associations between the profiles and incident T2D are estimated using Cox regressions. The profiles included 72 metabolites for TM, 69 for RM, 74 for PRM, and 66 for fish. After adjusting for T2D risk factors, only profiles of TM (Hazard Ratio (HR): 1.25, 95% CI: 1.06-1.49), RM (HR: 1.27, 95% CI: 1.07-1.52), and PRM (HR: 1.27, 95% CI: 1.07-1.51) are associated with T2D. Conclusions: The consumption of TM, its subtypes, and fish is associated with different metabolites, some of which have been previously associated with T2D. Scores based on the identified metabolites for TM, RM, and PRM show a significant association with T2D risk. The PREDIMED study was funded by NIH grants R01 HL118264 and R01 DK102896 and by the Spanish Ministry of Health (Instituto de Salud Carlos III, The PREDIMED Network grant RD 06/0045, 2006–2013, coordinated by MAM-G; and a previous network grant RTIC-G03/140, 2003–2005, coordinated R. Estruch). Additional grants were received from the Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional (Projects CNIC-06/2007, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2009-12304, and AGL2010-22319-C03-03) and the Generalitat Valenciana (ACOMP2010-181, AP-111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159, ACOMP/213/165, and PROMETEO17/2017). M.G.-F. is supported by R21AG070375-01A1. J.S.-S. gratefully acknowledges the financial support by ICREA under the ICREA Academia program. I.P.-G. receives a grant from the Ministerio de Ciencia, Innovación y Universidades (MICINN) (FPU 17/01925). S.K.N. gratefully acknowledges support from a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR, MFE-171207).

Shangzhi Gao,1 Corbin Quick,2 Marta Guasch-Ferre,3 Zhu Zhuo,2 John M Hutchinson,2 Li Su,1 Frank Hu,3 Xihong Lin,2 David Christiani1,4 1Environmental Health, Harvard University T H Chan School of Public Health, Boston, MA, USA; 2Biostatistics, Harvard University T H Chan School of Public Health, Boston, MA, USA; 3Nutrition, Harvard University T H Chan School of Public Health, Boston, MA, USA; 4Pulmonary and Critical Care Division, Department of Medicine, MA General Hospital, Boston, Massachusetts, USACorrespondence: David ChristianiEnvironmental Health, Harvard University T H Chan School of Public Health, Boston, MA, 02115, USAEmail dchris@hsph.harvard.eduIntroduction: Human metabolism and inflammation are closely related modulators of homeostasis and immunity. Metabolic profiling is a useful tool to understand the association between metabolism and inflammation at a systemic level.Objective: To investigate the longitudinal associations between the concentration of plasma metabolites and biomarkers related to inflammation and oxidative stress.Methods: We conducted a repeated cross-sectional analysis consisting of 8 short-term panels that included 88 healthy adult male welders in Massachusetts, USA. In each panel, we collected 1– 6 repeated measurements of blood and urine. We used a human vascular injury panel assay and custom cytokine/chemokine assay to quantify inflammatory biomarker plasma levels, liquid chromatography-mass spectrometry to quantify the concentrations of 665 plasma metabolites, and a competitive enzyme-linked immunoassay to quantify urinary 8-OHdG and 8-isoprostane levels. We used linear mixed effects models to estimate the longitudinal association between each inflammatory and oxidative stress biomarker and each metabolite.Results: At a 5% FDR threshold, we detected ≥ 1metabolite association for 8 unique inflammatory and oxidative stress biomarkers: urinary 8-isoprostane, plasma C-reactive protein (CRP), serum amyloid A (SAA), intercellular adhesion molecule 1, circulating vascular cell adhesion molecule-1, interleukin 8 (IL-8), interleukin 10 (IL-10) and vascular endothelial growth factor. Specifically, 3 metabolites in the androgenic steroids pathway were negatively associated with SAA; 3 dihydrosphingomyelins metabolites were positively associated with 1 or more of CRP, SAA, IL-8 and IL-10; 4 metabolites in acyl choline metabolism pathways were negatively associated with IL-8; 7 lysophospholipid metabolites were negatively associated with 1 or more of CRP, SAA and IL-8; 4 sphingomyelins were positively associated with CRP and/or SAA; and 10 metabolites in the xanthine pathway were positively associated with urinary 8-isoprostane.Conclusion: We found that metabolites in phospholipid groups had strong associations with multiple inflammatory biomarkers, especially CRP, SAA and IL-8. The mechanism of these associations warrants further investigation.Keywords: metabolism, inflammation, phospholipids, metals, particulates, metabolomics, occupational health

BACKGROUND: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities. OBJECTIVES: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia. METHODS: Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate

BACKGROUND: Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also associated with lower risk of cardiometabolic diseases. OBJECTIVES: The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD. METHODS: The discovery population included 1833 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m(2)): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training–validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models. RESULTS: A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P

AIMS/HYPOTHESIS: Plant-based diets, especially when rich in healthy plant foods, have been associated with a lower risk of type 2 diabetes. However, whether plasma metabolite profiles related to plant-based diets reflect this association was unknown. The aim of this study was to identify the plasma metabolite profiles related to plant-based diets, and to evaluate the associations between the identified metabolite profiles and the risk of type 2 diabetes. METHODS: Within three prospective cohorts (Nurses’ Health Study, Nurses’ Health Study II and Health Professionals Follow-up Study), we measured plasma metabolites from 10,684 participants using high-throughput LC MS. Adherence to plant-based diets was assessed by three indices derived from the food frequency questionnaire: an overall Plant-based Diet Index (PDI), a Healthful Plant-based Diet Index (hPDI), and an Unhealthy Plant-based Diet Index (uPDI). Multi-metabolite profiles related to plant-based diet were identified using elastic net regression with a training/testing approach. The prospective associations between metabolite profiles and incident type 2 diabetes were evaluated using multivariable Cox proportional hazards regression. Metabolites potentially mediating the association between plant-based diets and type 2 diabetes risk were further identified. RESULTS: We identified multi-metabolite profiles comprising 55 metabolites for PDI, 93 metabolites for hPDI and 75 metabolites for uPDI. Metabolite profile scores based on the identified metabolite profiles were correlated with the corresponding diet index (Pearson r = 0.33–0.35 for PDI, 0.41–0.45 for hPDI, and 0.37–0.38 for uPDI, all p < 0.001). Metabolite profile scores of PDI (HR per 1 SD higher = 0.81 [95% CI 0.75, 0.88]) and hPDI (HR per 1 SD higher = 0.77 [95% CI 0.71, 0.84]) showed an inverse association with incident type 2 diabetes, whereas the metabolite profile score for uPDI was not associated with the risk. Mutual adjustment for metabolites selected in the metabolite profiles, including trigonelline, hippurate, isoleucine and a subset of triacylglycerols, attenuated the associations of diet indices PDI and hPDI with lower type 2 diabetes risk. The explainable proportion of PDI/hPDI-related diabetes risk by these metabolites ranged between 8.5% and 37.2% (all p < 0.05). CONCLUSIONS/INTERPRETATION: Plasma metabolite profiles related to plant-based diets, especially a healthy plant-based diet, were associated with a lower risk of type 2 diabetes among a generally healthy population. Our findings support the beneficial role of healthy plant-based diets in diabetes prevention and provide new insights for future investigation.

BACKGROUND Due to the rapidly increasing availability of metabolomics data in prospective studies, an update of the meta evidence on metabolomics and type 2 diabetes risk is warranted. PURPOSE To conduct an updated systematic review and meta-analysis of plasma, serum, and urine metabolite markers and incident type 2 diabetes. DATA SOURCES We searched PubMed and Embase until 6 March 2021. STUDY SELECTION We selected prospective observational studies where investigators used high-throughput techniques to investigate the relationship between plasma, serum, or urine metabolites and incident type 2 diabetes. DATA EXTRACTION Baseline metabolites per-SD risk estimates and 95% CIs for incident type 2 diabetes were extracted from all eligible studies. DATA SYNTHESIS A total of 61 reports with 71,196 participants and 11,771 type 2 diabetes cases/events were included in the updated review. Meta-analysis was performed for 412 metabolites, of which 123 were statistically significantly associated (false discovery rate–corrected P < 0.05) with type 2 diabetes risk. Higher plasma and serum levels of certain amino acids (branched-chain, aromatic, alanine, glutamate, lysine, and methionine), carbohydrates and energy-related metabolites (mannose, trehalose, and pyruvate), acylcarnitines (C4-DC, C4-OH, C5, C5-OH, and C8:1), the majority of glycerolipids (di- and triacylglycerols), (lyso)phosphatidylethanolamines, and ceramides included in meta-analysis were associated with higher risk of type 2 diabetes (hazard ratio 1.07–2.58). Higher levels of glycine, glutamine, betaine, indolepropionate, and (lyso)phosphatidylcholines were associated with lower type 2 diabetes risk (hazard ratio 0.69–0.90). LIMITATIONS Substantial heterogeneity (I2 > 50%, τ2 > 0.1) was observed for some of the metabolites. CONCLUSIONS Several plasma and serum metabolites, including amino acids, lipids, and carbohydrates, are associated with type 2 diabetes risk.

BACKGROUND: Current evidence on associations between intakes of linoleic acid (LA), the predominant n–6 (ω-6) fatty acid, and mortality is inconsistent and has not been summarized by a systematic review and meta-analysis. OBJECTIVE: The aim was to perform a systematic review and meta-analysis of prospective cohort studies to examine associations between LA intake and mortality. METHODS: We conducted a comprehensive search of MEDLINE and EMBASE databases through 31 July 2019 for prospective cohort studies reporting associations of LA (assessed by dietary surveys and/or LA concentrations in adipose tissue or blood compartments) with mortality from all causes, cardiovascular disease (CVD), and cancer. Multivariable-adjusted RRs were pooled using random-effects meta-analysis. RESULTS: Thirty-eight studies reporting 44 prospective cohorts were identified; these included 811,069 participants with dietary intake assessment (170,076 all-cause, 50,786 CVD, and 59,684 cancer deaths) and 65,411 participants with biomarker measurements (9758 all-cause, 6492 CVD, and 1719 cancer deaths). Pooled RRs comparing extreme categories of dietary LA intake (high vs low) were 0.87 (95% CI: 0.81, 0.94; I(2) = 67.9%) for total mortality, 0.87 (95% CI: 0.82, 0.92; I(2) = 3.7%) for CVD mortality, and 0.89 (95% CI: 0.85, 0.93; I(2) = 0%) for cancer mortality. Pooled RRs for each SD increment in LA concentrations in adipose tissue/blood compartments were 0.91 (95% CI: 0.87, 0.95; I(2) = 64.1%) for total mortality, 0.89 (95% CI: 0.85, 0.94; I(2) = 28.9%) for CVD mortality, and 0.91 (95% CI: 0.84, 0.98; I(2) = 26.3%) for cancer mortality. Meta-regressions suggested baseline age and dietary assessment methods as potential sources of heterogeneity for the association between LA and total mortality. CONCLUSIONS: In prospective cohort studies, higher LA intake, assessed by dietary surveys or biomarkers, was associated with a modestly lower risk of mortality from all causes, CVD, and cancer. These data support the potential long-term benefits of PUFA intake in lowering the risk of CVD and premature death.

Objective The objective of this study was to evaluate the effect of skipping breakfast on body composition and cardiometabolic risk factors. Methods This study conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating breakfast skipping compared with breakfast consumption. Inclusion criteria included age ≥ 18, intervention duration ≥ 4 weeks, ≥ 7 participants per group, and ≥ 1 body composition measure. Random-effects meta-analyses of the effect of breakfast skipping on body composition and cardiometabolic risk factors were performed. Results Seven RCTs (n = 425 participants) with an average duration of 8.6 weeks were included. Compared with breakfast consumption, breakfast skipping significantly reduced body weight (weighted mean difference [WMD] = -0.54 kg [95% CI: -1.05 to -0.03], P = 0.04, I2 = 21.4%). Percent body fat was reported in 5 studies and was not significantly different between breakfast skippers and consumers. Three studies reported on low-density lipoprotein cholesterol (LDL), which was increased in breakfast skippers as compared with breakfast consumers (WMD = 9.24 mg/dL [95% CI: 2.18 to 16.30], P = 0.01). Breakfast skipping did not lead to significant differences in blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, C-reactive protein, insulin, fasting glucose, leptin, homeostatic model assessment of insulin resistance, or ghrelin. Conclusions Breakfast skipping may have a modest impact on weight loss and may increase LDL in the short term. Further studies are needed to provide additional insight into the effects of breakfast skipping.

Background Olive oil intake has been associated with lower risk of cardiovascular disease (CVD) in Mediterranean populations, but little is known about these associations in the U.S population. Objectives This study sought to examine whether olive oil intake is associated with total CVD, coronary heart disease (CHD), and stroke risk. Methods This study included 61,181 women from the Nurses’ Health Study (1990 to 2014) and 31,797 men from the Health Professionals Follow-up Study (1990 to 2014) who were free of cancer, heart disease, and stroke at baseline. Diet was assessed using food frequency questionnaires at baseline and then every 4 years. Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results During 24 years of follow-up, this study documented 9,797 incident cases of CVD, including 6,034 CHD cases and 3,802 stroke cases. After adjusting for major diet and lifestyle factors, compared with nonconsumers, those with higher olive oil intake (>0.5 tablespoon/day or >7 g/day) had 14% lower risk of CVD (pooled HR: 0.86; 95% CI: 0.79 to 0.94) and 18% lower risk of CHD (pooled HR: 0.82; 95% CI: 0.73 to 0.91). No significant associations were observed for total or ischemic stroke. Replacing 5 g/day of margarine, butter, mayonnaise, or dairy fat with the equivalent amount of olive oil was associated with 5% to 7% lower risk of total CVD and CHD. No significant associations were observed when olive oil was compared with other plant oils combined. In a subset of participants, higher olive oil intake was associated with lower levels of circulating inflammatory biomarkers and a better lipid profile. Conclusions Higher olive oil intake was associated with lower risk of CHD and total CVD in 2 large prospective cohorts of U.S. men and women. The substitution of margarine, butter, mayonnaise, and dairy fat with olive oil could lead to lower risk of CHD and CVD.

Background Tricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF. Methods We used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d / l -2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use. Results Comparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d / l -2-hydroxyglutarate were associated with a higher risk of AF [ORQ4 vs. Q1 (95% CI): 1.80 (1.21–2.67), 2.13 (1.45–3.13), 1.87 (1.25–2.81) and 1.95 (1.31–2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01–1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d / l -2-hydroxyglutarate were 2.15 (1.29–3.56), 2.16 (1.25–3.72), 2.63 (1.56–4.44) and 1.82 (1.10–3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF. Conclusion These findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes.

Background Previous studies suggest that different foods rich in saturated fatty acids (SFA), particularly meat and dairy, have diverging directions of association with risks of total cardiovascular disease (CVD) and CVD subtypes.(1,2) Purpose To investigate the associations between SFA from different dietary sources and risks of total CVD, ischaemic heart disease (IHD), and stroke. Methods We analysed data on 114,285 UK Biobank participants who had completed ≥2 24-h dietary assessments and were free of CVD at the date of the latest 24-h dietary assessment. Risks of incident (non-fatal and fatal) total CVD, IHD and stroke by intakes of SFA from different sources were estimated using multivariable Cox regressions. Additional models assessed the role of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C) as potential mediators. We also estimated the associations between modelled isoenergetic substitution of 5% energy from SFA from meat with SFA from dairy, polyunsaturated fatty acids, monounsaturated fatty acids, carbohydrates from whole grains and carbohydrates from fruit and vegetables, and risk of CVD outcomes. A false discovery rate controlling procedure was used to account for multiple testing. Results Over a median 8.5 years of follow-up, there were 4,365, 3,394, and 1,041 cases of total CVD, IHD and stroke, respectively. There were no significant associations between total SFA intake and CVD outcomes. SFA from meat was positively associated with total CVD (hazard ratio for each 5% of energy, 1.19; 95% CI, 1.05–1.35) and IHD (1.21; 1.05–1.39) risk independently of lifestyle and cardiovascular risk factors. However, the estimates were attenuated and non-significant for both total CVD (1.11; 0.98–1.26) and IHD (1.12; 0.97–1.29) after adjustment for BMI. SFA from dairy was inversely associated with IHD risk (0.89; 0.82–0.96) in the multivariable model, however this finding was also attenuated after adjustment for BMI and did not pass correction for multiple testing (0.91; 0.84 to 0.98). Modelled replacement of 5% of energy from SFA from meat with carbohydrates from whole grains or carbohydrates from fruit and vegetables were associated with lower risk of stroke in the multivariable model (0.86; 0.78–0.94 & 0.86; 0.78–0.95, respectively) and the model adjusted for BMI and LDL-C (0.87; 0.79–0.96 & 0.86; 0.78–0.95, respectively). Conclusion(s) SFA from meat was associated with a higher risk of total CVD and IHD, while SFA from dairy was associated with lower risk of IHD, although BMI seemed to account for a large proportion of these associations. It is possible that diverging associations of SFA from different sources with CVD risk may explain the overall null association with total SFA observed in this study and some previous observational studies. Randomised controlled trials are needed to confirm whether replacing SFA from meat by carbohydrate from wholegrains or fruit and vegetables may be beneficial in reducing stroke risk. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Clarendon Fund and Jesus College Clarendon Old Members' AwardJesus College Graduate Scholarship

Although insufficient or prolonged sleep duration is associated with cardiovascular disease, sleep duration is not included in most lifestyle scores. This study evaluates the relationship between a lifestyle score, including sleep duration and cardiovascular disease risk.A prospective analysis among 67,250 women in the Nurses' Health Study and 29,114 men in Health Professionals Follow-up Study (1986-2016) was conducted in 2021. Lifestyle factors were updated every 2-4 years using self-reported questionnaires. The traditional lifestyle score was defined as not smoking, having a normal BMI, being physically active (≥30 minutes/day of moderate physical activity), eating a healthy diet, and drinking alcohol in moderation. Low-risk sleep duration, defined as sleeping ≥6 to8 hours/day, was included as an additional component in the updated lifestyle score. Cox proportional hazard regression models were used to estimate cardiovascular disease risk. The likelihood-ratio test and C-statistics were used to compare both scores.A total of 11,710 incident cardiovascular disease cases during follow-up were documented. The multivariable-adjusted hazard ratios comparing 6 with 0 low-risk factors in the healthy lifestyle score including sleep duration were 0.17 (95% CI=0.12, 0.23) for cardiovascular disease, 0.14 (95% CI=0.10, 0.21) for coronary heart disease, and 0.20 (95% CI=0.12, 0.33) for stroke. Approximately 66% (95% CI=56%, 75%) of cardiovascular disease, 67% (95% CI=54%, 77%) of coronary heart disease, and 62% (95% CI=42%, 76%) of stroke cases were attributable to poor adherence to a healthy lifestyle including sleep. Adding sleep duration to the score slightly increased the C-statistics from 0.64 (95% CI=0.63, 0.64) to 0.65 (95% CI=0.64, 0.65) (p0.001).Adopting a healthy lifestyle including sleep recommendations could substantially reduce the risk of cardiovascular disease in U.S. adults.

OBJECTIVES: Sugar-sweetened beverage (SSB) consumption is associated with a higher risk of type 2 diabetes (T2D), but the metabolic changes linking SSB consumption to T2D are not fully understood. Thus, we aimed to identify a plasma metabolomic signature of SSB consumption and evaluate its association with incident T2D. METHODS: We used liquid chromatography–mass spectrometry to measure plasma metabolites (>200) among 3,434 participants from three US cohorts: Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS). SSB consumption (servings/day; sodas, fruit punches, and other sugary drinks) was estimated from food frequency questionnaires. We used elastic net regression with 10-fold-cross-validation to identify metabolites associated with higher SSB consumption among a training set of participants (n = 2068) and replicated the association in a testing set (n = 1366). A metabolomic signature score was calculated as the weighted sum of SSB-associated metabolites. Pearson correlation (r) coefficients and 95% confidence intervals (CI) between the metabolomic signature and self-reported SSB consumption were calculated. We used multivariable Cox regression models to estimate hazard ratios (HR) and CI of the identified metabolomic signature with incident T2D among all participants. RESULTS: We identified an SSB plasma metabolomic signature of 71 metabolites, primarily lipids and amino acids. Pearson correlation (r) coefficients between self-reported SSBs and the plasma metabolomic signature were 0.18 (95% CI: 0.14, 0.22; P

Fatty acid metabolic dysregulation in mitochondria is a common mechanism involved in the development of heart failure (HF) and atrial fibrillation (AF). We evaluated the association between plasma acylcarnitine levels and the incidence of HF or AF, and whether the mediterranean diet (MedDiet) may attenuate the association between acylcarnitines and HF or AF risk.Two case-control studies nested within the Prevención con dieta mediterránea (PREDIMED) trial. High cardiovascular risk participants were recruited in Spain: 326 incident HF and 509 AF cases individually matched to 1 to 3 controls. Plasma acylcarnitines were measured with high-throughput liquid chromatography-tandem mass spectrometry. Conditional logistic regression models were fitted to estimate multivariable OR and 95%CI. Additive and multiplicative interactions were assessed by intervention group, obesity (body mass index ≥ 30 kg/mElevated levels of medium- and long-chain acylcarnitines were associated with increased HF risk (adjusted ORAmong individuals at high cardiovascular risk, elevated long-chain acylcarnitines were associated with a higher risk of incident HF and AF. An intervention with MedDiet+extra-virgin olive oil may reduce AF risk associated with long-chain acylcarnitines. This trial was registered at controlled-trials.com (Identifier: ISRCTN35739639).

BACKGROUND: Intake of nuts has been inversely associated with risk of type 2 diabetes and cardiovascular disease, partly through inducing a healthy lipid profile. How nut intake may affect lipid metabolites remains unclear. OBJECTIVE: The aim of this study was to identify the plasma lipid metabolites associated with habitual nut consumption in US men and women. METHODS: We analyzed cross-sectional data from 1099 participants in the Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study. Metabolic profiling was conducted on plasma by LC–mass spectrometry. Nut intake was estimated from food-frequency questionnaires. We included 144 known lipid metabolites that had CVs ≤25%. Multivariate linear regression was used to assess the associations of nut consumption with individual plasma lipid metabolites. RESULTS: We identified 17 lipid metabolites that were significantly associated with nut intake, based on a 1 serving (28 g)/d increment in multivariate models [false discovery rate (FDR) P value

Background: Findings among randomized controlled trials evaluating the effect of red meat on cardiovascular disease risk factors are inconsistent. We provide an updated meta-analysis of randomized controlled trials on red meat and cardiovascular risk factors and determine whether the relationship depends on the composition of the comparison diet, hypothesizing that plant sources would be relatively beneficial. Methods: We conducted a systematic PubMed search of randomized controlled trials published up until July 2017 comparing diets with red meat with diets that replaced red meat with a variety of foods. We stratified comparison diets into high-quality plant protein sources (legumes, soy, nuts); chicken/poultry/fish; fish only; poultry only; mixed animal protein sources (including dairy); carbohydrates (low-quality refined grains and simple sugars, such as white bread, pasta, rice, cookies/biscuits); or usual diet. We performed random-effects meta-analyses comparing differences in changes of blood lipids, apolipoproteins, and blood pressure for all studies combined and stratified by specific comparison diets. Results: Thirty-six studies totaling 1803 participants were included. There were no significant differences between red meat and all comparison diets combined for changes in blood concentrations of total, low-density lipoprotein, or high-density lipoprotein cholesterol, apolipoproteins A1 and B, or blood pressure. Relative to the comparison diets combined, red meat resulted in lesser decreases in triglycerides (weighted mean difference [WMD], 0.065 mmol/L; 95% CI, 0.000–0.129; P for heterogeneity P P =0.003). In comparison with fish, red meat yielded greater decreases in low-density lipoprotein (WMD, –0.173 mmol/L; 95% CI, –0.260 to –0.086; P P =0.004). In comparison with carbohydrates, red meat yielded greater decreases in triglycerides (WMD, –0.181 mmol/L; 95% CI, –0.349 to –0.013). Conclusions: Inconsistencies regarding the effects of red meat on cardiovascular disease risk factors are attributable, in part, to the composition of the comparison diet. Substituting red meat with high-quality plant protein sources, but not with fish or low-quality carbohydrates, leads to more favorable changes in blood lipids and lipoproteins.