Search

Background: Lipid metabolites may partially explain the inverse association between the Mediterranean diet (MedDiet) and cardiovascular disease (CVD).Objective: We evaluated the associations between 1) lipid species and the risk of CVD (myocardial infarction, stroke, or cardiovascular death); 2) a MedDiet intervention [supplemented with extra virgin olive oil (EVOO) or nuts] and 1-y changes in these molecules; and 3) 1-y changes in lipid species and subsequent CVD.Design: With the use of a case-cohort design, we profiled 202 lipid species at baseline and after 1 y of intervention in the PREDIMED (PREvencion con DIeta MEDiterranea) trial in 983 participants [230 cases and a random subcohort of 790 participants (37 overlapping cases)].Results: Baseline concentrations of cholesterol esters (CEs) were inversely associated with CVD. A shorter chain length and higher saturation of some lipids were directly associated with CVD. After adjusting for multiple testing, direct associations remained significant for 20 lipids, and inverse associations remained significant for 6 lipids. When lipid species were weighted by the number of carbon atoms and double bonds, the strongest inverse association was found for CEs [HR: 0.39 (95% CI: 0.22, 0.68)] between extreme quintiles (P-trend = 0.002). Participants in the MedDiet + EVOO and MedDiet + nut groups experienced significant (P < 0.05) 1-y changes in 20 and 17 lipids, respectively, compared with the control group. Of these changes, only those in CE(20:3) in the MedDiet + nuts group remained significant after correcting for multiple testing. None of the 1-y changes was significantly associated with CVD risk after correcting for multiple comparisons.Conclusions: Although the MedDiet interventions induced some significant 1-y changes in the lipidome, they were not significantly associated with subsequent CVD risk. Lipid metabolites with a longer acyl chain and higher number of double bonds at baseline were significantly and inversely associated with the risk of CVD.

Health effects of dietary fats have been extensively studied for decades. However, controversies exist on the effects of various types of fatty acids, especially saturated fatty acid (SFA), on cardiovascular disease (CVD). Current evidence supports that different types of dietary fatty acids have divergent effects on CVD risk, and the effects also depend strongly on the comparison or replacement macronutrient. A significant reduction in CVD risk can be achieved if SFAs are replaced by unsaturated fats, especially polyunsaturated fatty acids. Intake of industrially produced trans fat is consistently associated with higher CVD risk. Both n-6 and n-3 polyunsaturated fatty acids are associated with lower CVD risk, although the effects of fish oil supplementation remains inconsistent. The 2015–2020 Dietary Guidelines for Americans place greater emphasis on types of dietary fat than total amount of dietary fat and recommend replacing SFAs with unsaturated fats, especially polyunsaturated fatty acids for CVD prevention.

Background: Metabolomics technologies can efficiently profile a large number of structurally diverse lipids, e.g., glycerophospholipids, sphingolipids, and glycerolipids, that may play differential roles in pathogenesis of cardiovascular disease (CVD). However, existing studies were focused more on discovering individual lipid metabolites for CVD risk prediction than inferring perturbed pathways responsible for the pathological processes. Hypothesis: We hypothesized that different lipid metabolic pathways, captured by network analysis, were divergently associated with CVD risk; the associations could be modified by the Mediterranean diet (MedDiet) intervention. Methods: We conducted this study in the PREDIMED trial with participants randomized to three intervention diets: MedDiet with extra-virgin olive oil, MedDiet with nuts, or a low-fat control diet. This study comprises a subcohort of 788 participants randomly selected from the PREDIMED cohort and 230 cases. The outcome was a composite endpoint of non-fatal acute myocardial infarction, non-fatal stroke and cardiovascular death. We performed network analysis using Gaussian graphic model among 200 targeted lipid metabolites and subsequent dimensionality reduction using Greedy Modularity Optimization to detect subnetworks. We calculated the subnetwork scores by summing up the products of the topological connectivity weight (representing network structure) and metabolite level and included the scores into Cox proportional hazards model with simultaneous adjustment for other subnetwork scores and covariates. The Benjamini-Hochberg procedure was applied to detect smaller subnetworks of specific interest for further investigation. Results: We detected 4 major subnetworks of lipid metabolic pathway. Most lipid metabolites with larger numbers of carbon atom and double bond clustered within a same subnetwork (subnetwork 2), while those with smaller numbers of carbon atom and double bond clustered within other 3 subnetworks (subnetworks 1, 3 and 4). The hazard ratio (HR) of CVD across quartiles of the subnetwork score 2 was 0.56 (95% CI, 0.35, 0.91, P trend =0.008) after multivariable adjustment. The HRs of CVD comparing extreme quartiles of subnetwork scores 3 and 4 were 1.85 (95% CI, 1.15, 2.97, P trend =0.02) and 1.93 (95% CI, 1.19, 3.14, P trend =0.01), respectively. The MedDiet appeared to enhance the inverse association between subnetwork score 2 and CVD ( P interaction =0.03). We detected several smaller subnetworks with functional interpretation related to CVD pathogenesis such as the ceramide pathway and the pathway including phospholipids with high unsaturation. Conclusions: Based on topological structure of lipid metabolic pathways, we detected biologically meaningful pathways. We found divergent associations between subnetworks and CVD and smaller subnetworks with functional interpretation.

Introduction: The role of dietary fat intake in body weight regulation remains controversial and few studies have examined long-term changes in types of dietary fat and weight change in longitudinal studies. Methods: We examined the association between changes in energy from dietary fat and weight change in three large, prospective cohorts including 102, 123 U.S. women and men who were free of diabetes, cardiovascular disease and cancer at baseline. Linear mixed model was used to assess the association between changes in energy from specific dietary fat and weight changes at 4-year intervals with multivariable adjustment for age, baseline body-mass index at each period, and simultaneous changes in dietary factors (total energy, energy from protein, cereal fiber) and lifestyle factors (smoking, physical activity, television watching, sleep duration). Results: Increased intake of polyunsaturated fatty acid (PUFA) was inversely associated with weight gain. A 5% increment in energy from total PUFA was associated with less weight gain (-1.8 lb, 95% CI: -1.95 to -1.65, ptrans -fat was associated with 1.97 lb (95% CI: 1.86 to 2.08) greater weight gain within each 4-year period. Conclusion: Different types of dietary fats have divergent associations with long-term weight change: higher intakes of PUFA (both n-6 and n-3 PUFA) and plant-based MUFA were associated with less weight gain, whereas increasing saturated and trans -fat intakes were associated with greater weight gain. Our results support the current dietary guidelines that recommend unsaturated fats as replacements for saturated and trans -fats.

Background: Metabolites associated with betaine and choline metabolism and the gut-microbiota-dependent metabolite trimethylamine N-oxide (TMAO) have been linked to the risk of cardiovascular disease (CVD). However, the relationship between plasma concentrations of other gut microbiota-related metabolites and major CVD endpoints remains unclear. Objectives: To evaluate the association between gut microbiota-related metabolites and risk of incident CVD and the potential modifying effect of Mediterranean diet (MedDiet) interventions. Methods: We designed a case-cohort study nested within the PREDIMED trial. We used liquid chromatography–tandem mass spectrometry to measure plasma gut microbiota-related metabolites. A score including the sum of quartile values of 8 metabolites was constructed (TMAO, betaine, choline, phosphocholine, alphaglycerophosphocholine, proline, hydroxyproline, allantoin). The primary outcome was a composite of myocardial infarction, stroke, and cardiovascular death. Blood samples from a randomly selected PREDIMED sub-cohort (n=751) and all available incident CVD cases (n=229) after 4.8-y of follow-up were included in the analysis. We used weighted Cox regression models to estimate multivariable-adjusted hazard ratios (HR) and their 95% confidence intervals (CI). Models were adjusted for age, sex, BMI, family history of premature heart disease, and smoking, physical activity (metabolic equivalent tasks in min/d), hypertension, dyslipidemia, diabetes and was stratified by intervention group. Results: Baseline plasma concentrations of choline and hydroxyproline were associated with higher CVD risk independent of traditional risk factors, while no significant association between plasma concentrations of TMAO and CVD was found. The HRs comparing extreme quartiles (lowest quartile as the reference) were 1.72 (95% CI: 1.05, 2.81; P for trend=0.01) and 1.65 (95% CI: 1.03, 2.65; P for trend =0.04), respectively. The microbiota metabolite score was associated with a 2.13-fold higher risk of CVD across extreme quartiles (95% CI: 1.32, 3.43; P for trend Conclusions: Plasma gut microbiota-related metabolites were associated with an increased risk of CVD in a Mediterranean population at high cardiovascular risk, independent of traditional CVD risk factors.

Background: During development of cardiovascular disease (CVD), interferon-γ-mediated inflammation accelerates degradation of tryptophan into downstream metabolites. A Mediterranean diet (MedDiet) consisting of a high intake of extra-virgin olive oil (EVOO), nuts, fruits, vegetables, and cereals has been demonstrated to lower the risk of CVD. The longitudinal relation between tryptophan and its downstream metabolites and CVD in the context of a MedDiet is unstudied.Objective: We sought to investigate the relation between metabolites in the tryptophan-kynurenine pathway and CVD in the context of a MedDiet pattern.Methods: We used a case-cohort design nested in the Prevención con Dieta Mediterránea randomized controlled trial. There were 231 CVD cases (stroke, myocardial infarction, cardiovascular death) among 985 participants over a median of 4.7 y of follow-up [mean ± SD age: 67.6 ± 6.1 y; 53.7% women; mean ± SD body mass index (in kg/m2): 29.7 ± 3.7]. We assessed plasma tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid concentrations at baseline and after 1 y of intervention with a MedDiet. We combined these metabolites in a kynurenine risk score (KRS) by weighting each metabolite by the adjusted coefficient of its associations with CVD. Cox models were used in the primary analysis.Results: Increases in tryptophan after 1 y were associated with a lower risk of composite CVD (HR per SD: 0.79; 95% CI: 0.63, 0.98). The baseline kynurenic acid concentration was associated with a higher risk of myocardial infarction and coronary artery disease death but not stroke. A higher KRS was more strongly associated with CVD in the control group than in the 2 intervention groups (P-interaction = 0.003). Adjustment for changes in plasma tryptophan attenuated the inverse association between MedDiet+EVOO and CVD.Conclusions: An increase in the plasma tryptophan concentration was significantly associated with a decreased risk of CVD. A MedDiet may counteract the deleterious effects of a high kynurenine risk score. This study was funded by the National Institutes of Health of the United States (1R01HL118264), Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional (Projects CNIC-06/2007, RTIC G03/140, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2009-12304 and AGL2010-22319-C03-03 ) and by the Generalitat Valenciana (ACOMP2010-181, AP111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159 and ACOMP/213/165)

CONTEXT: Arginine, its methylated metabolites, and other metabolites related to the urea cycle have been independently associated with cardiovascular risk, but the potential causal meaning of these associations (positive for some metabolites and negative for others) remains elusive due to a lack of studies measuring metabolite changes over time. OBJECTIVE: To examine the association between baseline and 1-year concentrations of urea cycle metabolites and cardiovascular disease (CVD) in a case-cohort setting. DESIGN: A case-cohort study was nested within the Prevención con Dieta Mediterránea trial. We used liquid chromatography-tandem mass spectrometry to assess metabolite levels at baseline and after 1-year follow-up. The primary CVD outcome was a composite of myocardial infarction, stroke and cardiovascular death. We used weighted Cox regression models (Barlow weights) to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). SETTING: Multicenter randomized trial in Spain. PARTICIPANTS: Participants were 984 participants accruing 231 events over 4.7 years' median follow-up. MAIN OUTCOME MEASURE: Incident CVD. RESULTS: Baseline arginine/asymmetric dimethylarginine ratio [HR per standard deviation (SD) = 0.80; 95% CI, 0.67 to 0.96] and global arginine availability [arginine / (ornithine + citrulline)] (HR per SD = 0.83; 95% CI, 0.69 to 1.00) were significantly associated with lower risk of CVD. We observed no significant association for 1-year changes in these ratios or any effect modification by the Mediterranean diet (MD) intervention. CONCLUSIONS: A higher baseline arginine/asymmetric dimethylarginine ratio was associated with lower CVD incidence in a high cardiovascular risk population. The intervention with the MD did not change 1-year levels of these metabolites.

Little is known about the risk factors for peripheral artery disease (PAD) among diabetic patients in Saudi Arabia. We therefore investigated the association of traditional and non-traditional PAD risk factors, as well as clinical markers, with the prevalence of PAD in 598 diabetic patients in Saudi Arabia. PAD was diagnosed as an ankle–brachial index (ABI)

SCOPE: The relationship between red wine (RW) consumption and metabolism is poorly understood. We aimed to assess the systemic metabolomic profiles in relation to frequent RW consumption as well as the ability of a set of metabolites to discriminate RW consumers. METHODS AND RESULTS: Cross-sectional analysis of 1,157 participants. Subjects were divided as non-RW consumers versus RW consumers (> 1 glass/day RW (100 mL/day)). Plasma metabolomics analysis was performed using LC-MS. Associations between 386 identified metabolites and RW consumption were assessed using elastic net regression analysis taking into consideration baseline significant covariates. Ten-cross-validation (CV) was performed and receiver operating characteristic curves were constructed in each of the validation datasets based on weighted models. A subset of 13 metabolites was consistently selected and discriminated RW consumers versus non-consumers. Based on the multi-metabolite model weighted with the regression coefficients of metabolites, the area under the curve was 0.83 (95% CI: 0.80–0.86). These metabolites mainly consisted of lipid species (e.g. triglycerides and phosphatidylcholines), some organic acids and alkaloids. CONCLUSIONS: A multi-metabolite model identified in a Mediterranean population appeared useful to discriminate between frequent RW consumers and non-consumers. Further studies are needed to assess the contribution of these metabolites in health and disease.

Aims: To examine the nationally-representative dietary patterns and their joint effects with physical activity on the likelihood of metabolic syndrome (MS) among 20,827 Chinese adults. Methods and results: CNNHS was a nationally representative cross-sectional observational study. Metabolic syndrome was defined according to the Joint Interim Statement definition. The "Green Water" dietary pattern, characterized by high intakes of rice and vegetables and moderate intakes in animal foods was related to the lowest prevalence of MS (15.9%). Compared to the "GreenWater" dietary pattern, the "Yellow Earth" dietary pattern, characterized by high intakes of refined cereal products, tubers, cooking salt and salted vegetable was associated with a significantly elevated odds of MS (odds ratio 1.66, 95% CI: 1.40e1.96), after adjustment of age, sex, socioeconomic status and lifestyle factors. The "Western/new affluence" dietary pattern characterized by higher consumption of beef/lamb, fruit, eggs, poultry and seafood also significantly associated with MS (odds ratio: 1.37, 95% CI: 1.13e1.67). Physical activity showed significant interactions with the dietary patterns in relation to MS risk (P for interaction = 0.008). In the joint analysis, participants with the combination of sedentary activity with the "Yellow Earth" dietary pattern or the "Western/new affluence" dietary pattern both had more than three times (95% CI: 2.8-6.1) higher odds of MS than those with active activity and the "Green Water" dietary pattern. Conclusions: Our findings from the large Chinese national representative data indicate that dietary patterns affect the likelihood of MS. Combining healthy dietary pattern with active lifestyle may benefit more in prevention of MS. (C) 2012 Elsevier B.V. All rights reserved.

The levels of persistent organic pollutants (POPs) were determined in 50 samples of Korean human milk. POPs include organochlorine pesticides (OCPs) [aldrin, chlordanes, dieldrin, dichlorodiphenyltrichloroethanes (DDTs), endrins, heptachlors, hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs), mirex, and toxaphenes] and marker PCBs (PCB28, PCB52, PCB101, PCB138, PCB153 and PCB180). In all samples, p,p'-DDE were determined as 75.5-1115.3 ng/g fat. The compounds β-HCH and p,p'-DDT were detected at 72% and 60% of the samples, respectively. Chlordanes (nd-84.9 ng/g fat) heptachlors (nd-40.1 ng/g fat), HCB (nd-42.9 ng/g fat) and PCBs (nd-38.3 ng/g fat) were detected in several samples. The ratio of dichlorodiphenyltrichloroethylene (DDE)/DDT was 6.8, which explained that exposure of volunteers to DDT did not occur recently. Compared with the previous monitoring data, the level of marker PCBs generally decreased in the milk samples. The levels of OCPs are significantly correlated to the residential periods of the mothers but not with their dietary habits. Considering the daily intake of each OCPs, 18% of infants would ingest the amount of heptachlor exceeding the acceptable daily intake (ADI) proposed by World Health Organization (WHO). There was no sample surpassing the WHO ADI for DDTs, HCB and chlordanes.