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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

BackgroundPlasma fatty acids (FAs) have been associated with cardiovascular disease (CVD) risk. Diet and endogenous metabolism influence the FA profile of the plasma phospholipid (PL) fraction. In the PREDIMED trial, we examined 1-year changes in the FA profile of plasma PL according to a nutritional intervention with Mediterranean diets, either supplemented with extra-virgin olive oil (MedDiet + EVOO) or mixed nuts (MedDiet + nuts), in a high cardiovascular risk population. We also analyzed if 1-year changes in PL FAs were associated with subsequent cardiovascular risk.MethodsWe included 779 participants in our case-cohort study: 185 incident cases and 594 participants in the subcohort (including 31 overlapping cases). The end point was the incidence of CVD. We measured the FAs of plasma PL at baseline and after 1 year of intervention.ResultsMedDiet + EVOO increased C17:0 and C20:3n9 in linear regression models [β coefficientperSD : 0.215 (95% CI, 0.032–0.399) and 0.271 (0.107–0.434), respectively] and decreased 16:1n7 and C22:4n6 [βperSD: −0.239 (95% CI, −0.416 to −0.061) and −0.287 (95% CI, −0.460 to −0.113), respectively] vs the control group. MedDiet + nuts increased C18:3n3 [βperSD: 0.382 (95% CI, 0.225 – 0.539)], C18:2n6 [βper SD: 0.250 (95% CI, 0.073 — 0.428)], C18:0 [βperSD: 0.268 (95% CI, 0.085—0.452)], and C22:0 [βper SD: 0.216 (95% CI, 0.031—0.402)]; and decreased the sum of six n6 FAs [βper SD: −0.147 (95% CI, −0.268 to −0.027)] vs the control group. The 1-year increase in C18:2n6 was inversely associated with the subsequent CVD risk (HRperSD: 0.64 (95% CI, 0.44–0.92)).ConclusionsMedDiet interventions changed n6 FAs and C16:1n7c; other changes were specific for each group: MedDiet + EVOO increased C17:0 and C20:3n9, and MedDiet + Nuts C18:3n3, C18:2n6, C18:0, and C22:0 FAs.

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.

BackgroundLifestyles influence atrial fibrillation (AF) risk. Blood biomarkers can characterize the atrial substrate that facilitates the development of AF. Therefore, determining the effect of lifestyle interventions on blood concentrations of biomarkers of AF-related pathways could help understand AF pathophysiology and contribute to AF prevention.MethodsWe studied 471 participants enrolled in the PREDIMED-Plus trial, a Spanish randomized trial conducted in adults (55-75 years) with metabolic syndrome and body mass index between 27-40 kg/m2. Eligible participants were randomized 1:1 to an intensive lifestyle intervention, emphasizing physical activity, weight loss, and adherence to an energy-reduced Mediterranean diet or to a control group. Serum biomarkers [carboxy-terminal propeptide of procollagen type I (PICP), high-sensitivity troponin T (hsTnT), high-sensitivity C reactive protein (hsCRP), 3-nitrotyrosine (3-NT), and N-terminal propeptide of B-type natriuretic peptide (NT-proBNP)] were measured at baseline, 3 and 5 years after randomization. Mixed models were used to evaluate the effect of intervention on changes in biomarkers through year 5. Mediation analysis was performed to examine the proportion mediated by each component of the intervention.ResultsAt baseline, participants’ mean age was 65, 41% were female, and 50% were assigned to the intervention. After five years, mean changes in log-transformed biomarkers were -0.03 (PICP), 0.19 (hsTnT), -0.15 (hsCRP), 0.12 (3-NT), and 0.30 (NT-proBNP). Compared to the control group, participants in the intervention group experienced greater decreases in hsCRP (−16%, 95% confidence interval (CI) -28%, - 1%) or smaller increases in 3-NT (−15%, 95% CI -25%, -4%) and NT-proBNP (−13%, 95% CI -25%, 0%). The intervention had minimal impact on hsTnT (−3%, 95% CI -8%, 2%) or PICP concentrations (−0%, 95% CI -9%, 9%). The effect of the intervention on hsCRP was primarily mediated by weight loss (73% and 66% at years 3 and 5).ConclusionOver five years, a dietary and lifestyle intervention for weight-loss favorably affected concentrations of hsCRP, 3-NT, and NT-proBNP, pointing to specific mechanisms in pathways linking lifestyles and AF.

Introduction and objectives Telomeres are noncoding regions located at the end of chromosomes and their shortening has been associated with risk factors and cardiovascular disease. The aim of this study was to evaluate the association between ideal cardiovascular health (Life's simple 7) and the odds of having short telomeres in a subsample of participants older than 55 years from the Seguimiento Universidad de Navarra (SUN) study. Methods We included 886 participants older than 55 years (645 men and 241 women). Telomere length was measured using a real-time quantitative polymerase chain reaction. Cardiovascular health score was defined by the American Heart Association as a composite score of 7 key risk factors (smoking status, physical activity, diet, body mass index , blood pressure, total cholesterol, and fasting blood glucose) with 0 to 2 points for each factor. We categorized this score in tertiles as poor (0-9 points), intermediate (10-11 points) and ideal (12-14 points). The odds of having short telomeres was defined as telomere length below the 20th percentile. Results Individuals with higher ideal cardiovascular health had a lower prevalence of having short telomeres (adjusted OR, 0.60; 95%CI, 0.34-1.05; P trend = .052). This association was statistically significant in men (adjusted OR, 0.37; 95%CI, 0.17-0.83; P trend = .025) but not in women. Conclusions An inverse association between cardiovascular health score and short telomeres was found especially for men older than 55 years in the SUN population. The SUN project was registered at ClinicalTrials.gov (Identifier: NCT02669602).

Resumen Introduccion y objetivos Los telomeros son regiones no codificantes localizadas al final de los cromosomas de celulas eucariotas, y su acortamiento se ha visto relacionado con la enfermedad cardiovascular y sus factores de riesgo. El objetivo de este estudio es evaluar la asociacion entre el indice de salud cardiovascular ideal y el riesgo de telomero corto en una poblacion de sujetos de edad avanzada de la cohorte Seguimiento Universidad de Navarra (SUN). Metodos Se valoro a 886 adultos mayores de 55 anos (645 varones y 241 mujeres). La longitud telomerica se midio utilizando qPCR (quantitative protein chain reaction) en tiempo real y reaccion unica. El indice de salud cardiovascular «Life's simple 7» se definio segun la American Heart Association mediante la puntuacion de 7 items con valores de 0 a 2 para cada uno: tabaquismo, actividad fisica, dieta, indice de masa corporal, presion arterial, colesterol total y glucosa en sangre. La maxima puntuacion del indice corresponde a 14 puntos. Se categorizo en terciles: pobre (0-9 puntos), intermedio (10-11 puntos) e ideal (12-14 puntos). El riesgo de telomero corto se definio como una longitud telomerica por debajo del percentil 20. Resultados Sujetos con altos valores en el indice de salud cardiovascular ideal tenian menos riesgo de telomero corto (OR ajustada = 0,60; IC95%, 0,34-1,05; p de tendencia lineal = 0,052). Esta asociacion fue significativa en varones (OR ajustada = 0,37; IC95%, 0,17-0,83; p de tendencia lineal = 0,025), pero no en mujeres. Conclusiones En varones mayores de 55 anos, existe una asociacion inversa entre el indice de salud cardiovascular y el riesgo de tener telomeros cortos. El proyecto SUN fue registrado en ClinicalTrials.gov (Identificador: NCT02669602).

The potential role of the lipidome in atrial fibrillation (AF) development is still widely unknown. We aimed to assess the association between lipidome profiles of the Prevención con Dieta Mediterránea (PREDIMED) trial participants and incidence of AF. We conducted a nested case–control study (512 incident centrally adjudicated AF cases and 735 controls matched by age, sex, and center). Baseline plasma lipids were profiled using a Nexera X2 U-HPLC system coupled to an Exactive Plus orbitrap mass spectrometer. We estimated the association between 216 individual lipids and AF using multivariable conditional logistic regression and adjusted the p values for multiple testing. We also examined the joint association of lipid clusters with AF incidence. Hitherto, we estimated the lipidomics network, used machine learning to select important network-clusters and AF-predictive lipid patterns, and summarized the joint association of these lipid patterns weighted scores. Finally, we addressed the possible interaction by the randomized dietary intervention.Forty-one individual lipids were associated with AF at the nominal level (p per+1SD of 1.32 (95% confidence interval: 1.16–1.51; p Current Controlled Trials number, ISRCTN35739639.

Background: Lifestyles influence atrial fibrillation (AF) risk. Blood biomarkers can characterize the atrial substrate that facilitates the development of AF. Therefore, determining the effect of lifestyle interventions on blood concentrations of biomarkers of AF-related pathways could help understand AF pathophysiology and contribute to AF prevention. Methods: The PREDIMED-PLUS study is a Spanish multicenter randomized trial in adults (55-75 years) with metabolic syndrome and body mass index between 27-40 kg/m 2 . Participants were randomized 1:1 to an intensive lifestyle intervention (ILI) program, emphasizing physical activity, weight loss, and adherence to the Mediterranean diet, or a control intervention. In a sub-sample, serum biomarkers including carboxy-terminal propeptide of procollagen type I (PICP), high-sensitivity troponin T (hsTnT), high-sensitivity C reactive protein (hsCRP), N-terminal propeptide of B-type natriuretic peptide (NT-proBNP), and 3-nitrotyrosine (3-NT) were measured at baseline and years 3 and 5 after randomization. Mixed models were used to evaluate the effect of ILI on changes in biomarkers through years 3 and 5. Follow-up time was modeled as a categorical and continuous variable. Results: Of 481 participants (65 mean age, 40% female, 49% assigned to ILI), 453 (94%) and 442 (92%) had available samples at years 3 and 5. After 5 years, mean changes in log-transformed biomarkers were -0.01 (PICP), 0.20 (hsTnT), -0.17 (hsCRP), 0.12 (3-NT), and 0.25 (NT-proBNP). Participants in the ILI group experienced greater decreases in hsCRP or smaller increases in 3-NT, NT-proBNP, and in hsTnT to a lesser extent, as compared to the control group (Table). The ILI did not affect PICP concentrations. Results were consistent when modeling follow-up time as a continuous variable. Conclusion: Over five years, an ILI favorably affected concentrations of hsCRP, 3-NT, and NT-proBNP, and of hs-TnT to a lesser degree, pointing to specific mechanisms in the pathways linking lifestyles and AF.

Introduction: Higher consumption of coffee and caffeine has been linked to less weight gain and lower body mass index in prospective cohort studies, usually with exposure assessment limited to baseline values. As BMI is a proxy for adiposity but does not capture fat tissue or its metabolically relevant distribution, precise measurements of distinct adipose tissues are needed, so the cardiometabolic impact of an anti-obesity effect can be assessed. Hypothesis: We assessed the hypothesis that an increase in coffee consumption is associated with a reduction in body fat, in particular with trunk fat and visceral adipose tissue (VAT). Methods: In the setting of a large, randomized trial of Mediterranean diet and physical activity intervention, we evaluated 1483 participants with metabolic syndrome. Changes in the consumption of caffeinated and decaffeinated coffee were derived from validated food frequency questionnaires at baseline, 6 months and yearly during follow-up. Fat tissue was measured with dual x-ray absorptiometry at baseline and after 6, 12 months and three years. Linear multilevel mixed effect models were used to investigate the relationship between changes in coffee consumption and corresponding concurrent changes in fat tissue over three years. Results: After adjustment for intervention group, and other potential confounders, an increase in caffeinated coffee consumption from no or infrequent consumption (≤ 3 cups/ month) to moderate consumption (1-7 cups/week) was associated with reductions in total body fat (Δ z-score: -0.06; 95 % CI: -0.11 to -0.02), trunk fat (Δ z-score: -0.07; 95 % CI: -0.12 to -0.02), and VAT (Δ z-score: -0.07; 95 % CI: -0.13 to -0.01). However, changes to even higher levels (> 1 cup/day) showed no significant association. Conclusions: Moderate consumption of caffeinated coffee, but not high consumption, was associated with reductions in total body fat, trunk fat and VAT in a Mediterranean cohort with metabolic syndrome. Decaffeinated coffee was not linked to adiposity indicators. In conclusion, moderate consumption of caffeinated coffee may be part of a weight management strategy.

Background: Dietary flavonoid intake is associated with a reduced risk of some cardiometabolic disorders, attributed in part to their claimed anti-inflammatory activity. Our aim was to investigate the potential association between specific urine flavonoid metabolites, liver enzymes, and inflammatory status in individuals with metabolic syndrome (MetS). Methods: In this cross-sectional study, clinical and dietary data from 267 participants, aged 55 to 75 years, participating in the PREDIMED Plus study (PREvención con DIeta MEDiterránea) were analyzed. At the baseline, spot urine samples were collected and seven urinary flavonoid metabolites were quantified using ultra-performance liquid chromatography coupled to triple quadrupole mass spectrometry (UPLC-Q-q-Q MS). Liver enzymes, inflammatory scores, and urinary flavonoid concentrations were inverse normally transformed. Results: Adjusted linear regression models showed an inverse association between urinary citrus flavanone concentrations and gamma-glutamyl transferase (GGT) (all p-values

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).

BACKGROUND Dementia is projected to affect 135 million by 2050. Diet is a pertinent target for primary prevention, but firm recommendations for dementia prevention are not available yet. Our aim was to address the association between exploratory (empirically derived) dietary patterns (DP) and changes in the Spanish Telephone Interview for Cognitive Status (STICS-m, maximum score = 41 points) over 6 years. METHOD Information on diet was collected with a validated 136-item food-frequency questionnaire from 803 participants in the Mediterranean cohort "Seguimiento Universidad de Navarra." We used principal component analysis to derive exploratory DP. The derived DP were associated with change in STICS-m scores over 6 years, through adjusted multiple linear regression models. RESULTS Two main DP were identified. The first DP resembled a Western dietary pattern (WDP)-high in sugar, fat, processed foods, and red meat-and the second DP resembled a Mediterranean dietary pattern (MDP)-high in vegetables, fruits, nuts, fish, and olive oil. Adherence to the WDP (tertile 3 vs tertile 1) was significantly associated with negative STICS-m changes after 6 years (between-tertile difference in changes: -0.80 points; 95% confidence interval [CI] -1.51, -0.08, p value = 0.03). Meanwhile, the MDP showed a positive +0.71 point (95% CI 0.15, 1.26, p value = 0.01) between-tertile difference in changes in the STICS-m score. CONCLUSIONS A healthy, prudent, MDP was associated with less decline in cognitive function and, thus, could help to lower dementia incidence. Western-type diets were associated with a greater decline in cognitive performance and could increase dementia incidence.

Background: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive. Objective: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort. Methods: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype. Results: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE ɛ4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score β= 0.76 95% CI 0.15,1.36; p trend = 0.011) and a high LTPA (Q4 versus Q1 β= 0.63; 95% CI –0.01,1.26; p trend = 0.030) were associated with more favorable changes in cognitive function over time among APOE ɛ4 non-carriers with statistically significant interactions in both cases (p for interaction = 0.042 for PA score, and p = 0.039 for LTPA). Conclusion: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE ɛ4 non-carriers.

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

The global growing rates of cognitive decline and dementia, together with the absence of curative therapies for these conditions, support the interest in researching potential primary prevention interventions, with particular focus on dietary habits. The aim was to assess the association between polyphenol intake and 6-year change in cognitive function in the ‘Seguimiento Universidad de Navarra’ (SUN) Project, a Spanish prospective cohort study. Changes (final – initial) in cognitive function were evaluated in a subsample of 806 participants (mean age 66 (sd 5) years, 69·7 % male) of the SUN Project using the validated Spanish Telephone Interview for Cognitive Status-modified score. Polyphenol intake was derived from a validated semi-quantitative FFQ and matching food composition data from the Phenol-Explorer database. Multivariable linear regression models were used to evaluate the association between total polyphenol intake, polyphenol subclasses and cognitive changes. No significant association between total polyphenol intake and changes in cognitive function was found. However, a higher intake of lignans (βQuintile (Q) 5 v. Q1 0·81; 95 % CI 0·12, 1·51; Ptrend = 0·020) and stilbenes (βQ5 v. Q1 0·82; 95 % CI 0·15, 1·49; Ptrend = 0·028) was associated with more favourable changes in cognitive function over time, particularly with respect to immediate memory and language domains. Olive oil and nuts were the major sources of variability in lignan intake, and wine in stilbene intake. The results suggest that lignan and stilbene intake was associated with improvements in cognitive function.

Background: Severe cognitive decline is one of the major public health problems in developed countries. Finding modifiable risk factors could become essential to develop strategies to prevent or de...

Exposure to persistent organic pollutants (POPs) may influence telomere length (TL), which is considered as a marker of biological age associated with the risk of chronic disease. We hypothesized that dietary exposure to polychlorinated biphenyls (PCBs) and dioxins could affect TL. Our aim was to evaluate the association of dietary exposure to PCBs and dioxins with TL. In this cross-sectional study of 886 subjects older than 55 y (mean age: 67.7; standard deviation (SD): 6.1; 27% women) from the “Seguimiento Universidad de Navarra” (SUN) project. TL was determined by real-time quantitative polymerase chain reaction and dietary PCBs and dioxins exposure was collected using a validated 136-item Food Frequency Questionnaire. Multivariable linear regression models were used to control for potential confounding factors. Shorter TL was associated with dietary total PCBs (SD of T/S ratio/(ng/day) = −0.30 × 10−7; 95% CI, −0.55 × 10−7 to −0.06 × 10−7), dioxin-like PCBs (DL-PCBs) (SD of T/S ratio/(pg WHO TEQ (Toxic Equivalents)/day) = −6.17 × 10−7; 95% CI, −11.30 × 10−7 to −1.03 × 10−7), and total TEQ exposure (SD of T/S ratio/(pg WHO TEQ/day) = −5.02 × 10−7; 95% CI, −9.44 × 10−7 to −0.61 × 10−7), but not with dioxins (SD of T/S ratio/(pg WHO TEQ/day) = −13.90 × 10−7; 95% CI, −37.70 × 10−7 to 9.79 × 10−7). In this sample of middle-aged and older Spanish adults, dietary exposure to total PCBs and DL-PCBs alone and together with dioxins was associated with shorter TL. Further longitudinal studies, preferably with POPs measured in biological samples, are needed to confirm this finding.

Effective prevention and risk prediction are important for peripheral artery disease (PAD) due to its poor prognosis and the huge disease burden it produces. Circulating amino acids (AA) and their metabolites may serve as biomarkers of PAD risk, but they have been scarcely investigated. The objective was to prospectively analyze the associations of baseline levels of plasma AA (and their pathways) with subsequent risk of PAD and the potential effect modification by a nutritional intervention with the Mediterranean diet (MedDiet). A matched case-control study was nested in the PREDIMED trial, in which participants were randomized to three arms: MedDiet with tree nut supplementation group, MedDiet with extra-virgin olive oil (EVOO) supplementation group or control group (low-fat diet). One hundred and sixty-seven PAD cases were matched with 250 controls. Plasma AA was measured with liquid chromatography/mass spectrometry at the Broad Institute. Baseline tryptophan, serine and threonine were inversely associated with PAD (ORfor 1 SD increase = 0.78 (0.61–0.99); 0.67 (0.51–0.86) and 0.75 (0.59–0.95), respectively) in a multivariable-adjusted conditional logistic regression model. The kynurenine/tryptophan ratio was directly associated with PAD (ORfor 1 SD increase = 1.50 (1.14–1.98)). The nutritional intervention with the MedDiet+nuts modified the association between threonine and PAD (p-value interaction = 0.018) compared with the control group. However, subjects allocated to the MedDiet+EVOO group were protected against PAD independently of baseline threonine. Plasma tryptophan, kynurenine/tryptophan ratio, serine and threonine might serve as early biomarkers of future PAD in subjects at a high risk of cardiovascular disease. The MedDiet supplemented with EVOO exerted a protective effect, regardless of baseline levels of threonine.

Scope: Some very-low density lipoprotein (VLDL) properties may render them more pro-atherogenic. We aimed to assess whether a Mediterranean diet (MedDiet) or an energy-reduced MedDiet with increased physical activity improves them. Methods and results: In a sample of the PREvención con DIeta MEDiterránea (PREDIMED) study, a 1-year intervention with MedDiet with extra-virgin olive oil (n = 89) or nuts (MedDiet-Nuts; n = 79) is compared with a low-fat diet (n = 90). In the PREDIMED-Plus study, a 1-year intervention with energy-reduced MedDiet and physical activity (n = 103) is compared with an ad libitum MedDiet (n = 101). VLDL levels of apolipoprotein C-I, C-III, triglycerides, and cholesterol; the apolipoprotein E-/C-I ratio; and VLDL ex-vivo triglyceride transfer are measured. In PREDIMED participants in both MedDiet groups combined, VLDL apolipoprotein C-III levels are nominally reduced (-0.023 SD units, 95% CI -0.44 to -0.014, p = 0.037). VLDL triglyceride transfer is nominally increased in the MedDiet-Nuts group (+0.39 SD units, 95% CI 0.012-0.78, p = 0.045). In PREDIMED-Plus, no inter-group differences are detected. Conclusions: In older adults at high cardiovascular risk, MedDiet is associated with lower VLDL atherogenicity versus a low-fat diet. No differences are seen after an energy-reduced MedDiet with physical activity. The authors want to thank Daniel Muñoz-Aguayo, Gemma Blanchart, and Sònia Gaixas for their laboratory support, and Stephanie Lonsdale for her help in editing the English text. A full list of names of all PREDIMED and PREDIMED-Plus study collaborators is available in the Supporting files Appendix 1. The authors also thank the PREDIMED-Plus Biobank Network as a part of the National Biobank Platform of the ISCIII for storing and managing the PREDIMED-Plus biological samples. CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of Instituto de Salud Carlos III (Madrid, Spain), and is financed by the European Regional Development Fund. Acknowledgements to European Research Council (Grant 340918). This work was supported by the Instituto de Salud Carlos III (grant numbers: IFI20/00002, PI19/00017, PI15/00047, PI18/00020, PI16/00533, PI13/00233, PI21/00024, PI20/00012, and CP21/00097) and co-funded by the European Union. The funders played no role in study design, collection, analysis, or interpretation of data, and neither in the process of writing the manuscript and the publish process.

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.

Telomere length (TL) has been associated with aging and is determined by lifestyle. However, the mechanisms by which a dietary pattern such as the Mediterranean diet (MedDiet) affects TL homeostasis are still unknown. Our aim was to analyse the effect of an energy-restricted MedDiet with physical activity promotion (intervention group) versus an unrestricted-caloric MedDiet with no weight-loss advice (control group) on TL and 8-hydroxydeoxyguanosine (8-OHdG) plasma levels. In total, 80 non-diabetic participants with metabolic syndrome were randomly selected from the PREDIMED (PREvención con DIeta MEDiterránea)-Plus-Reus study. TL was measured by a hybridisation method and 8-OHdG levels by ELISA at baseline and after one year of intervention. Linear mixed models (LMM)—raw and after adjusting for potential confounders—were used to examine the associations between TL or 8-OHdG plasma levels by intervention group and/or time. A total of 69 subjects with available DNA samples were included in the analyses. A significant β-coefficient was found for time towards increasing values through the year of follow-up for TL (unadjusted β of 0.740 (95% CI: 0.529 to 0.951), and multivariable model β of 0.700 (95% CI: 0.477 to 0.922)). No significant βs were found, neither for the intervention group nor for the interaction between the intervention group and time. Regarding 8-OHdG plasma levels, no significant βs were found for the intervention group, time, and its interaction. Our results suggest that MedDiet could have an important role in preventing telomere shortening, but calorie restriction and exercise promotion did not provide an additional advantage concerning telomere length after one year of MedDiet intervention.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

BACKGROUND: Type 2 diabetes was related with larger cognitive decline. However, other glycemic dysregulations showed inconsistent results. Our aim was to examine longitudinal associations between diabetes/glycemic status and cognitive function in older adults with metabolic syndrome. METHODS: We conducted a 2-year prospective cohort study (n=6,874) within the framework of the PREDIMED-Plus study. The participants (with overweight/obesity and metabolic syndrome; mean age 64.9 years; 48.5% women) completed a battery of 8 cognitive tests, and a global cognitive function Z-score (GCF) was estimated. Participants were categorized by diabetes status (no-diabetes, prediabetes, and 1c) levels were measured and antidiabetic medications were recorded. Linear and logistic regression models, adjusted by potential confounders, were fitted to assess associations between glycemic status and changes in cognitive function. RESULTS: Prediabetes status was unrelated to cognitive decline. However, compared to participants without diabetes, those with ≥5-year diabetes duration had greater reductions in the GCF (β=-0.11 [95%CI -0.16;-0.06]), processing speed and executive function measurements. Inverse associations were observed between baseline HOMA-IR and changes in the GCF (β=-0.0094 [95%CI -0.0164;-0.0023]), but also between HbA1c levels and changes in the GCF (β=-0.0610 [95%CI -0.0889;-0.0331]), the Mini-Mental test, and other executive function tests. Poor diabetes control was inversely associated with phonologic fluency. Sulfonylureas, but especially insulin use, were related to cognitive decline.CONCLUSIONS: Insulin resistance, diabetes status, longer diabetes duration, poor glycemic control, and insulin treatment were associated with worsening cognitive function at short-term in a population at high cardiovascular risk.TRIAL REGISTRATION: ISRCTN, ISRCTN89898870. Registered 28 May 2014 - Retrospectively registered, http://www.isrctn.com/ISRCTN89898870

Background Consumption of certain foods is associated with long-term weight gains and abdominal fat accumulation in healthy, middle-aged and young, non-obese participants. Whether the same foods might be associated with changes in adiposity in elderly population at high cardiovascular risk is less known. Objective Using yearly repeated measurements of both food habits and adiposity parameters, we aimed to investigate how changes in the consumption of specific foods were associated with concurrent changes in weight or waist circumference (WC) in the PREDIMED trial. Design We followed-up 7009 participants aged 55-70 years at high cardiovascular risk for a median time of 4.8 years. A validated 137-item semi-quantitative Food Frequency Questionnaire was used for dietary assessment with yearly repeated measurements. We longitudinally assessed associations between yearly changes in food consumption (serving/d) and concurrent changes in weight (kg) or WC (cm). Results Yearly increments in weight were observed with increased consumption (kg per each additional increase in 1 serving/d) for refined grains (0.32 kg/serving/d), red meat (0.24), potatoes (0.23), alcoholic beverages (0.18), processed meat (0.15), white bread (0.07) and sweets (0.04); whereas inverse associations were detected for increased consumption of low-fat yogurt (- 0.18), and low-fat milk (- 0.06). Annual WC gain (cm per each additional increase in 1 serving/d) occurred with increased consumption of snacks, fast-foods and pre-prepared dishes (0.28), processed meat (0.18), alcoholic beverages (0.13), and sweets (0.08); whereas increased consumption of vegetables (- 0.23), and nuts (- 0.17), were associated with reductions in WC. Conclusions In this assessment conducted in high-risk subjects using yearly repeated measurements of food habits and adiposity, some ultra-processed foods, refined carbohydrates (including white bread), potatoes, red meats and alcohol were associated with higher weight and WC gain, whereas increases in consumption of low-fat dairy products and plant foods were associated with less gain in weight and WC., The research leading to these results was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), and through specific grants/contracts: the FOLIUM program within the FUTURMed project. Talent for the medicine within the future from the Fundacion Instituto de Investigacion Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014-2020 of the Balearic Islands) [JK]; ERC Advanced Research Grant (340918) [MAM-G as PI]. None of the funding sources took part in the design, collection, analysis or interpretation of the data, or in the decision to submit the manuscript for publication.

Background The prevalence of overweight/obesity and related manifestations such as metabolic syndrome (MetS) is increasing worldwide. High energy density diets, usually with low nutrient density, are among the main causes. Some high-quality dietary patterns like the Mediterranean diet (MedDiet) have been linked to the prevention and better control of MetS. However, it is needed to show that nutritional interventions promoting the MedDiet are able to improve nutrient intake. Objective To assess the effect of improving MedDiet adherence on nutrient density after 1 year of follow-up at the PREDIMED-Plus trial. Methods We assessed 5777 men (55-75 years) and women (60-75 years) with overweight or obesity and MetS at baseline from the PREDIMED-Plus trial. Dietary changes and MedDiet adherence were evaluated at baseline and after 1 year. The primary outcome was the change in nutrient density (measured as nutrient intake per 1000 kcal). Multivariable-adjusted linear regression models were fitted to analyse longitudinal changes in adherence to the MedDiet and concurrent changes in nutrient density. Results During 1-year follow-up, participants showed improvements in nutrient density for all micronutrients assessed. The density of carbohydrates (- 9.0%), saturated fatty acids (- 10.4%) and total energy intake (- 6.3%) decreased. These changes were more pronounced in the subset of participants with higher improvements in MedDiet adherence. Conclusions The PREDIMED-Plus dietary intervention, based on MedDiet recommendations for older adults, maybe a feasible strategy to improve nutrient density in Spanish population at high risk of cardiovascular disease with overweight or obesity.

Objective— To examine the associations between baseline levels of fatty acids in blood cell membranes and their 1-year changes with the incidence of coronary heart disease (CHD) in older adults at high cardiovascular disease risk. Approach and Results— This is a case-control study nested in the PREDIMED trial (Prevención con Dieta Mediterránea), with 136 CHD cases and 272 controls (matched on age, sex, body mass index, intervention group, and time of permanence in the study to the time event). We used gas chromatography to measure the proportion of 22 fatty acids in blood cell membranes at baseline and after 1 year. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs. After adjustment for classical CHD risk factors and multiple testing, 1 SD increase in baseline levels of C22:0, C24:0 and the sum of individual very long chain saturated fatty acids was associated with 56% (OR, 0.44 [95% CI, 0.28–0.69]), 59% (OR, 0.41 [95% CI, 0.25–0.65]), and 55% (OR, 0.45 [95% CI, 0.29–0.70]) a decreased odds of developing CHD, respectively. Baseline C20:1n9 was associated with higher odds of CHD (OR, 1.58 [95% CI, 1.25–2.00]). Conclusions— Higher levels of C22:0 and C24:0 were associated with a lower CHD incidence, whereas higher levels of C20:1n9 were associated with a higher risk. This study adds to the growing body of evidence suggesting potential differences in the cardiovascular disease effects of different types of circulating saturated fatty acids.

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: The tryptophan–kynurenine pathway is linked to inflammation. We hypothesize that metabolites implicated in this pathway may be associated with the risk of heart failure (HF) or atrial fibrillation (AF) in a population at high risk of cardiovascular disease. OBJECTIVES: We aimed to prospectively analyze the associations of kynurenine-related metabolites with the risk of HF and AF and to analyze a potential effect modification by the randomized interventions of the PREDIMED (Prevención con Dieta Mediterránea) trial with Mediterranean diet (MedDiet). METHODS: Two case–control studies nested within the PREDIMED trial were designed. We selected 324 incident HF cases and 502 incident AF cases individually matched with ≤3 controls. Conditional logistic regression models were fitted. Interactions with the intervention were tested for each of the baseline plasma metabolites measured by LC–tandem MS. RESULTS: Higher baseline kynurenine:tryptophan ratio (OR for 1 SD: 1.20; 95% CI: 1.01, 1.43) and higher levels of kynurenic acid (OR: 1.19; 95% CI: 1.01, 1.40) were associated with HF. Quinolinic acid was associated with AF (OR: 1.15; 95% CI: 1.01, 1.32) and HF (OR: 1.25; 95% CI: 1.04, 1.49). The MedDiet intervention modified the positive associations of kynurenine (P(interaction) = 0.006), kynurenic acid (P(interaction) = 0.008), and quinolinic acid (P(interaction) = 0.033) with HF and the association between kynurenic acid and AF (P(interaction) = 0.02). CONCLUSIONS: We found that tryptophan–kynurenine pathway metabolites were prospectively associated with higher HF risk and to a lesser extent with AF risk. Moreover, an effect modification by MedDiet was observed for the association between plasma baseline kynurenine-related metabolites and the risk of HF, showing that the positive association of increased levels of these metabolites and HF was restricted to the control group.

Systemic inflammation is associated with an increased risk of non-communicable diseases, such as cardiovascular diseases and diabetes. Circulating fatty acids (FA) are known to be related to these conditions, possibly through their role in inflammation, although different types of FAs can have opposite effects on inflammatory mediators. The aim of the present study was to analyze the association of plasma FAs with inflammatory biomarkers in a PREDIMED trial subsample after one year of intervention. In a one-year longitudinal study of 91 participants of the PREDIMED trial (Barcelona-Clinic center), plasma FAs and inflammatory biomarkers were analyzed using gas chromatography and ELISA, respectively. In baseline plasma, a multivariable-adjusted ordinary least squares regression model showed that n-3 polyunsaturated FAs concentrations were inversely associated with concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and E-selectin, whereas the level of the most abundant saturated FA, palmitic acid, was directly associated with concentrations of interleukin-6 (IL-6) (beta = 0.48 pg/mL, 95% CI: 0.03, 0.93 per 1-SD increase, p-value = 0.037). After one year of nutritional intervention, changes of plasma diet-derived total saturated FAs and palmitic acid were directly associated with changes in IL6 (beta = 0.59 pg/mL [95% CI: 0.28, 0.89] per 1-SD, p-value = 0.001; beta = 0.64 pg/mL, 95% CI: 0.31, 0.98, p-value = 0.001), respectively, after correction for multiple testing. Our findings suggest that saturated FAs of dietary origin, especially palmitic acid, are directly involved in the increase of IL-6 in plasma.