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Background: Knowledge of the safety and efficacy of disease-modifying therapies (DMTs) in older patients with Multiple Sclerosis (pwMS) is limited due to their exclusion from clinical trials. Our purpose is to evaluate the choice of DMTs in pwMS older than 50 years old in a real-world setting., Methods: Cross-sectional study of pwMS from the Argentine MS and NMOSD Registry. We included patients under 35 and above 50 years old prescribed DMTs. Disease activity was categorized as highly active (HA) or not highly active (NHA), and DMTs were classified as low efficacy therapies (LET) or high efficacy therapies (HET)., Results: 1460 patients (65% females) were enrolled. The HA group comprised 241 patients, 198 young (82.2%) and 43 older (17.8%). The NHA group included 1219 patients, 893 young (73%) and 326 older (27%). In the NHA group, older patients received LET more frequently than younger patients (66% versus 44%; p < 0.01). In the HA group, older patients received LET in 61% of cases, whereas younger patients received HET in 71% (p = 0.01)., Conclusion: The study shows the preference of LET in older patients regardless of disease activity. However it does not demonstrate a difference in disability in older patients based on low vs high efficacy DMTs used, probably due to the design of the study. Further longitudinal studies are warranted to address this issue., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aim: Certain trace elements have been associated with increased cardiovascular risk. The aim of this study was to evaluate the association between serum copper (S-Cu) levels and the risk of a first event of cardiovascular disease (CVD) in a population of older adults with high cardiovascular risk., Methods and Results: We conducted a case-control study nested within the PREDIMED trial. During a median follow-up of 4.8 years, a total of 207 incident cases diagnosed with CVD were matched for sex, age, and intervention group with 436 controls. Personal interviews, reviews of medical records, and validated questionnaires were used to assess known CVD risk factors. Biological serum samples were collected annually. Inductively coupled plasma mass spectrometry analysis was used to determine S-Cu levels. Adjusted odds ratios were calculated using multivariate conditional logistic regression models. All participants had S-Cu levels within the reference values, 750 μg/L to 1450 μg/L. Among men, but not among women, the mean S-Cu concentration was higher in cases 1014.1 μg/L than in controls 959.3 μg/L; (p = 0.004). In men, the multivariable-adjusted odds ratio for CVD was 2.36 (95% CI 1.07-5.20 for the comparison of the highest vs. the lowest quartile; p for trend = 0.02), in women, it was 0.43 (95% CI 0.11-1.70; p for trend = 0.165)., Conclusion: In older Spanish men with high cardiovascular risk, a significant association was observed between high S-Cu levels, but still within the reference values, and an increased risk of a first event of CVD. Our findings suggest a sex difference in CVD risk and S-Cu levels. To confirm this relationship and to analyze the differences observed between men and women, further studies are needed., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The American Heart Association proposed 7 ideal cardiovascular health metrics (Life's Simple 7 [LS7]) namely, not smoking, body mass index <25 kg/m 2 , healthy diet, moderate physical activity ≥150 min/week, total blood cholesterol <200 mg/dL, blood pressure <120/80 mmHg and fasting blood glucose <100 mg/dL. Our objective was to assess the association between these LS7 metrics and the incidence of atrial fibrillation (AF)., Methods and Results: A total of 6,479 participants of the PREDIMED study were included. We calculated the participants' baseline LS7 index ranging 0-7 points to categorize them according to their adherence to these LS7 health metrics. Multivariable Cox regression models were used to estimate Hazard Ratios (HR) and their 95% Confidence Intervals (95% CI). After a median follow-up of 4.8 years, we identified 250 incident cases of AF. After adjusting for potential confounders, adherence to LS7 index was not associated with the incidence of AF (adjusted HR 0.90 [95% CI: 0.56-1.45] for highest vs. lowest LS7 categories). Body mass index <25 kg/m 2 was the only health metric individually associated with a lower risk of AF (HR 0.36 [95% CI: 0.16-0.78])., Conclusions: In a high cardiovascular risk Spanish population, adherence to American Heart Association's LS7 metrics was not associated with the risk of incident AF., Clinical Trials Number: ISRCTN35739639., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 <0.001 for all). A higher risk of CVD was also found for a 1-SD increment of a combined score of these 3 metabolites (HR = 1.60; 95%CI: 1.32-1.94, p trend <0.001). This result was replicated using plasma measurements after one-year. No interactions were detected with the nutritional intervention., Conclusion: Plasma 2-hydroxyglutarate, fumarate and malate levels were prospectively associated with increased cardiovascular risk., Clinical Trial Number: ISRCTN35739639., Competing Interests: Declaration of competing interest Authors declare no conflict of interest in this article., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

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 (Pinteraction = 0.006), kynurenic acid (Pinteraction = 0.008), and quinolinic acid (Pinteraction = 0.033) with HF and the association between kynurenic acid and AF (Pinteraction = 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objective: To examine associations between intake of simple sugars and cancer incidence, cancer mortality, and total mortality in a prospective cohort study based on the PREDIMED trial conducted from 2003 to 2010., Methods: Participants were older individuals at high cardiovascular risk. Exposures were total sugar, glucose and fructose from solid or liquid sources, and fructose from fruit and 100% fruit juice. Cancer incidence was the primary outcome; cancer mortality and all-cause mortality were secondary outcomes. Multivariable-adjusted, time-dependent Cox proportional hazard models were used., Results: Of 7447 individuals enrolled, 7056 (94.7%) were included (57.6% women, aged 67.0 ± 6.2 years). 534 incident cancers with 152 cancer deaths and 409 all-cause deaths were recorded after a median follow-up of 6 years. Intake of simple sugars in solid form was unrelated to outcomes. Higher cancer incidence was found per 5 g/day increase in intake of liquid sugars, with multivariable-adjusted HR of 1.08 (95% CI, 1.03-1.13) for total liquid sugar, 1.19 (95% CI, 1.07-1.31) for liquid glucose, 1.14 (95% CI, 1.05-1.23) for liquid fructose, and 1.39 (95% CI, 1.10-1.74) for fructose from fruit juice. Cancer and all-cause mortality increased to a similar extent with intake of all sugars in liquid form. In categorical models, cancer risk was dose-related for all liquid sugars., Conclusions: Simple sugar intake in drinks and fruit juice was associated with an increased risk of overall cancer incidence and mortality and all-cause mortality. This suggests that sugary beverages are a modifiable risk factor for cancer and all-cause mortality., Competing Interests: Conflict of interest Jordi Salas-Salvadó reports serving on the board of and receiving grant support through his institution from the International Nut and Dried Fruit Council, and Eroski Foundation; serving in the Executive Committee of Instituto Danone Spain; has received research support from the Instituto de Salud Carlos III, Spain; Ministerio de Economía y Competitividad, Spain; Departament de Salut Pública de la Generalitat de Catalunya, Catalonia, Spain; European Commission. He has received research support from the California Walnut Commission, Folsom, CA, USA; Patrimonio Comunal Olivarero, Spain; La Morella Nuts, Spain; and Borges S.A., Spain. Reports receiving consulting fees and travel expenses from Danone; California Walnut Commission, Eroski Foundation, Instituto Danone - Spain, Nestle and Abbot Laboratories. Ramon Estruch reports personal fees from Brewers of Europe (Belgium), Fundación Cerveza y Salud (Spain), Pernaud Richard (Mexico), “Fundación Domingo Martínez" (Barcelona, Spain), Wine and Culinary International Forum (Valencia, Spain), Instituo Cajal (Alburquerque, USA; Tokyo, Japan; and Milan, Italy), other funding from “Cerveza y Salud” (Madrid, Spain) and non-financial support from ERAB (Belgium), Sociedad Española de Nutrición (Madrid, Spain) and Fundación Bosch y Gimpera (Barcelona, Spain). Emilio Ros reports grants, personal fees, non-financial support and other from California Walnut Commission; grants, personal fees, non-financial support and other from Alexion; personal fees, non-financial support and other from Danone; and personal fees from Amarin. The other authors report no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Imbalanced dietary intake is related to increased adiposity, which is linked to increased metabolic risk even in the absence of obesity. BMI is traditionally used to classify body fatness and weight range, but it only considers body weight and height. The Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) equation has appeared as an additional tool to estimate adiposity considering also other relevant parameters, i.e., sex and age., Objectives: We aimed to determine whether the CUN-BAE index could estimate adiposity-related metabolic risk in apparently healthy, normoglycemic adults., Methods: In this case-control study, men and women (18-45 y old) were classified as normal-weight (NW) [n = 20; BMI (in kg/m2) <25] or overweight-obese (OW-OB) (n = 34; BMI ≥25). The primary outcome was body fat content and clinical circulating parameters to assess by correlation analysis CUN-BAE's usefulness as a predictor of metabolic risk. In addition, transcriptomic biomarkers of lipid metabolism were analyzed in peripheral blood mononuclear cells (PBMCs) as secondary outcome indicators of metabolic impairment. Data were analyzed by correlation analysis and comparison of means., Results: CUN-BAE values correlated directly with body fatness obtained by DXA (r = 0.89, P < 0.01), with classical molecular biomarkers of metabolic risk, and with PBMC gene expression of carnitine palmitoyltransferase 1A (CPT1A), sterol regulatory element binding transcription factor 1c (SREBP-1c), and fatty acid synthase (FASN), early markers of metabolic impairment (P < 0.05). Moreover, CUN-BAE allowed identification of NW individuals with excessive body fatness, who were not yet presenting obesity-related molecular alterations. In these subjects, visceral fat correlated directly with circulating glucose, triglycerides, and total and LDL cholesterol, and with triglyceride-glucose and fatty liver indexes (P < 0.05). This is indicative of a metabolically obese NW phenotype., Conclusions: Data obtained in our cohort of young normoglycemic volunteers support the use of the CUN-BAE index as a tool to estimate accurately body fat mass, but also as a first easy/effective screening tool to identify lean people with increased fat mass and increased metabolic risk.This trial was registered at clinicaltrials.gov as NCT04402697., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background & Aims: Ultra-processed food and drink products (UPF) consumption has been associated with obesity and its-related comorbidities. Excess of visceral fat, which appears with increasing age, has been considered as the culprit contributing to adiposity-associated adverse health outcomes. However, none of previous studies elucidated the link between UPF and directly quantified adiposity and its distribution. We aimed to prospectively investigate the association between concurrent changes in UPF consumption and objectively assessed adiposity distribution., Methods: A subsample of 1485 PREDIMED-Plus participants (Spanish men and women aged 55-75 years with overweight/obesity and metabolic syndrome) underwent body composition measurements. Consumption of UPF at baseline, 6 and 12 months was evaluated using a validated 143-item semi-quantitative Food Frequency Questionnaire. Food items (g/day) were categorized according to their degree of processing using NOVA system. Regional adiposity (visceral fat (in g) and android-to-gynoid fat ratio) and total fat mass (in g) at three time points were measured with dual-energy X-ray absorptiometry (DXA) and were normalized using sex-specific z-scores. The association of changes in UPF consumption, expressed as the percentage of total daily intake (daily g of UPF/total daily g of food and beverage intake∗100), with adiposity changes was evaluated using linear mixed-effects models., Results: On average, the consumption of UPF accounted for 8.11% (SD 7.41%) of total daily intake (in grams) at baseline. In multivariable-adjusted model, 10% daily increment in consumption of UPF was associated with significantly (all p-values <0.05) greater accumulation of visceral fat (β 0.09 z-scores, 95% CI 0.05; 0.13), android-to-gynoid fat ratio (0.05, 0.00; 0.09) and total fat (0.09, 0.06; 0.13)., Conclusion: A higher consumption of UPF was associated with greater age-related visceral and overall adiposity accumulation. Further studies are warranted to confirm these results in other populations and settings., Trial Registration: The trial was registered at the International Standard Randomized Controlled Trial (ISRCTN: http://www.isrctn.com/ISRCTN89898870) with number 89898870 and registration date of 24 July 2014, retrospectively registered., Competing Interests: Conflicts of interest E.R. reports outside the submitted work: serving on the advisory board and receiving financial support other than grants or personal fees from Cerveza y Salud, Spain; personal fees from Brewers of Europe, Belgium; personal fees from Fundación Cerveza y Salud, Spain; financial support from Instituto Cervantes, Albuquerque, USA; personal fees from Instituto Cervantes, Milan, Italy; personal fees from Instituto Cervantes, Tokyo, Japan; non-financial support from Fundación Bosch i Gimpera, Spain; grants from Spanish Institute of Health “Carlos III”; personal fees from Pernaud Richart, Mexico; personal fees from Fundación Dieta Mediterranea, Barcelona, Spain; non-financial support from ERAB, Belgium; non-financial support from Sociedad Española de Nutrición (SEN); non-financial support from Wine and Culinary International Forum; grant from Grant–Fountain Laboratories, Spain; and grant from Uriach Laboratories. The rest of the authors, JK, MM, IA, MB-R, MR-C, JVioque, SG-P, LD, JS-S(,) MF, VM, RE, JVidal, MAM-G, SC, AJJ, TF-V, RC, RO, PB-C, NB, HS, JAM, and DR, declare that they have no potential conflicts of interests., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: Epidemiological data on iron status and cardiovascular disease (CVD) are still controversial. The aim of this study was to determine whether low serum iron (SI) levels are associated with an increased odds of first CVD event in a population at high cardiovascular risk., Methods: Case-control study design nested within the "PREvención con DIeta MEDiterránea" (PREDIMED) trial. A total of 207 participants diagnosed with CVD (myocardial infarction, stroke or cardiovascular death) during follow-up period (2003-2010) were matched by sex, age and intervention group to 436 controls by incidence density sampling. Median time between serum sample collection and subsequent CVD event occurrence was 0.94 years. Inductively coupled plasma mass spectrometry analysis was used to determine SI levels. In-person interviews, medical record reviews, and validated questionnaires were used to assess covariates. Multivariable-adjusted odds ratios (ORs) of CVD were calculated with conditional logistic regression., Results: Mean SI levels were higher in men than in women (1224.0 μg/L vs. 1093.8 μg/L; p < 0.001). Among women, but not in men, the mean SI concentration was lower in cases than in controls (1008.5 μg/L vs. 1132.9 μg/L; p = 0.030). There was a gradual decrease in the multivariable-adjusted ORs of CVD with increasing SI levels (highest vs. lowest quartile: OR = 0.55, 95% CI: 0.32-0.93; p trend  = 0.020). This inverse relationship was more pronounced among women (highest vs. lowest quartile: OR = 0.15, 95% CI: 0.03-0.69; p trend  = 0.011)., Conclusions: The present findings are consistent with previously reported inverse associations between SI and CVD. SI levels as an independent marker of short-term cardiovascular risk may be useful for risk assessment in older populations., Trial Registration: www.controlled-trials.com; International Standard Randomized Controlled Trial Number (ISRCTN): 35,739,639. Registered 5 October 2005. Retrospectively registered., Competing Interests: Conflicts of interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The quality of carbohydrate consumed, assessed by the glycemic index (GI), glycemic load (GL), or carbohydrate quality index (CQI), affects the postprandial glycemic and insulinemic responses, which have been implicated in the etiology of several chronic diseases. However, it is unclear whether plasma metabolites involved in different biological pathways could provide functional insights into the role of carbohydrate quality indices in health., Objectives: We aimed to identify plasma metabolomic profiles associated with dietary GI, GL, and CQI., Methods: The present study is a cross-sectional analysis of 1833 participants with overweight/obesity (mean age = 67 y) from 2 case-cohort studies nested within the PREDIMED (Prevención con Dieta Mediterránea) trial. Data extracted from validated FFQs were used to estimate the GI, GL, and CQI. Plasma concentrations of 385 metabolites were profiled with LC coupled to MS and associations of these metabolites with those indices were assessed with elastic net regression analyses., Results: A total of 58, 18, and 57 metabolites were selected for GI, GL, and CQI, respectively. Choline, cotinine, γ-butyrobetaine, and 36:3 phosphatidylserine plasmalogen were positively associated with GI and GL, whereas they were negatively associated with CQI. Fructose-glucose-galactose was negatively and positively associated with GI/GL and CQI, respectively. Consistent associations of 21 metabolites with both GI and CQI were found but in opposite directions. Negative associations of kynurenic acid, 22:1 sphingomyelin, and 38:6 phosphatidylethanolamine, as well as positive associations of 32:1 phosphatidylcholine with GI and GL were also observed. Pearson correlation coefficients between GI, GL, and CQI and the metabolomic profiles were 0.30, 0.22, and 0.27, respectively., Conclusions: The GI, GL, and CQI were associated with specific metabolomic profiles in a Mediterranean population at high cardiovascular disease risk. Our findings may help in understanding the role of dietary carbohydrate indices in the development of cardiometabolic disorders. This trial was registered at isrctn.com as ISRCTN35739639., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Although the association between glutamate and glutamine in relation to cardiometabolic disorders has been evaluated, the role of these metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unknown., Objectives: We examined associations of glutamate, glutamine, and the glutamine-to-glutamate ratio with AF and HF incidence in a Mediterranean population at high cardiovascular disease (CVD) risk., Methods: The present study used 2 nested case-control studies within the PREDIMED (Prevención con Dieta Mediterránea) study. During ∼10 y of follow-up, there were 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma concentrations of glutamate and glutamine were semiquantitatively profiled with LC-tandem MS. ORs were estimated with multivariable conditional logistic regression models., Results: In fully adjusted models, per 1-SD increment, glutamate was associated with a 29% (95% CI: 1.08, 1.54) increased risk of HF and glutamine-to-glutamate ratio with a 20% (95% CI: 0.67, 0.94) decreased risk. Glutamine-to-glutamate ratio was also inversely associated with HF risk (OR per 1-SD increment: 0.80; 95% CI: 0.67, 0.94) when comparing extreme quartiles. Higher glutamate concentrations were associated with a worse cardiometabolic risk profile, whereas a higher glutamine-to-glutamate ratio was associated with a better cardiometabolic risk profile. No associations between the concentrations of these metabolites and AF were observed., Conclusions: Our findings suggest that high plasma glutamate concentrations possibly resulting from alterations in the glutamate-glutamine cycle may contribute to the development of HF in Mediterranean individuals at high CVD risk.This trial was registered at www.isrctn.com as ISRCTN35739639., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background & Aims: Little is known about the impact of specific dietary patterns on the development of obesity phenotypes. We aimed to determine the association of longitudinal changes in adherence to the traditional Mediterranean diet (MedDiet) with the transition between different obesity phenotypes., Methods: Data of 5801 older men and women at high cardiovascular risk from PREDIMED trial were used. Adherence to MedDiet was measured with the validated 14p-Mediterranean Diet Adherence Screener (MEDAS). Using the simultaneous combination of metabolic health- and body size-related parameters participants were categorized into one of four phenotypes: metabolically healthy and abnormal obese (MHO and MAO), metabolically healthy and abnormal non-obese (MHNO and MANO). Cox regression models with yearly repeated measures during 5-year of follow-up were built with use of Markov chain assumption., Results: Each 2-point increase in MEDAS was associated with the following transitions: in MAO participants, with a 16% (95% CI 3-31%) greater likelihood of becoming MHO; in MHO participants with a 14% (3-23%) lower risk of becoming MAO; in MHNO participants with a 18% (5-30%) lower risk of becoming MHO. In MANO women, but not in men, MEDAS was associated with 20% (5-38%) greater likely of becoming MHNO (p for interaction by gender 0.014). No other significant associations were observed., Conclusions: Better adherence to the traditional MedDiet is associated with transitions to healthier phenotypes, promoting metabolic health improvement in MAO, MANO (only in women), and MHO, as well as protecting against obesity incidence in MHNO subjects., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Overall quality of dietary carbohydrate intake rather than total carbohydrate intake may determine the risk of cardiovascular disease (CVD)., Objective: We examined 6- and 12-mo changes in carbohydrate quality index (CQI) and concurrent changes in several CVD risk factors in a multicenter, randomized, primary-prevention trial (PREDIMED-Plus) based on an intensive weight-loss lifestyle intervention program., Methods: Prospective analysis of 5373 overweight/obese Spanish adults (aged 55-75 y) with metabolic syndrome (MetS). Dietary intake information obtained from a validated 143-item semiquantitative food-frequency questionnaire was used to calculate 6- and 12-mo changes in CQI (categorized in quintiles), based on 4 criteria (total dietary fiber intake, glycemic index, whole grain/total grain ratio, and solid carbohydrate/total carbohydrate ratio). The outcomes were changes in intermediate markers of CVD., Results: During the 12-mo follow-up, the majority of participants improved their CQI by increasing their consumption of fruits, vegetables, legumes, fish, and nuts and decreasing their consumption of refined cereals, added sugars, and sugar-sweetened beverages. After 6 mo, body weight, waist circumference (WC), systolic and diastolic blood pressure (BP), fasting blood glucose, glycated hemoglobin (HbA1c), triglyceride levels, triglycerides and glucose (TyG) index, and TyG-WC decreased across successive quintiles of improvement in the CQI. After 12 mo, improvements were additionally observed for HDL cholesterol and for the ratio of total to HDL cholesterol. Favorable improvements (expressed in common units of SD and 95% CI) for quintile 5 compared with quintile 1 of CQI change were observed for most risk factors, including TyG-WC (SD -0.20; 95% CI -0.26, -0.15), HbA1c (SD -0.16; 95% CI -0.23, -0.10), weight (SD -0.12; 95% CI -0.14, -0.09), systolic BP (SD -0.11; 95% CI -0.19, -0.02) and diastolic BP (SD -0.11; 95% CI -0.19, -0.04)., Conclusions: Improvements in CQI were strongly associated with concurrent favorable CVD risk factor changes maintained over time in overweight/obese adults with MetS. This trial was registered as ISRCTN 89898870., (Copyright © The Author(s) 2019.)

Background and Aims: Glutamate, glutamine are involved in energy metabolism, and have been related to cardiometabolic disorders. However, their roles in the development of type-2 diabetes (T2D) remain unclear. The aim of this study was to examine the effects of Mediterranean diet on associations between glutamine, glutamate, glutamine-to-glutamate ratio, and risk of new-onset T2D in a Spanish population at high risk for cardiovascular disease (CVD)., Methods and Results: The present study was built within the PREDIMED trial using a case-cohort design including 892 participants with 251 incident T2D cases and 641 non-cases. Participants (mean age 66.3 years; female 62.8%) were non diabetic and at high risk for CVD at baseline. Plasma levels of glutamine and glutamate were measured at baseline and after 1-year of intervention. Higher glutamate levels at baseline were associated with increased risk of T2D with a hazard ratio (HR) of 2.78 (95% CI, 1.43-5.41, P for trend = 0.0002). In contrast, baseline levels of glutamine (HR: 0.64, 95% CI, 0.36-1.12; P for trend = 0.04) and glutamine-to-glutamate ratio (HR: 0.31, 95% CI, 0.16-0.57; P for trend = 0.0001) were inversely associated with T2D risk when comparing extreme quartiles. The two Mediterranean diets (MedDiet + EVOO and MedDiet + mixed nuts) did not alter levels of glutamine and glutamate after intervention for 1 year. However, MedDiet mitigated the positive association between higher baseline plasma glutamate and T2D risk (P for interaction = 0.01)., Conclusion: Higher levels of glutamate and lower levels of glutamine were associated with increased risk of T2D in a Spanish population at high risk for CVD. Mediterranean diet might mitigate the association between the imbalance of glutamine and glutamate and T2D risk. This trial is registered at http://www.controlled-trials.com, ISRCTN35739639., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Excess adiposity is associated with poor cardiometabolic (CM) health. To date, several techniques and indicators have been developed to determine adiposity. We aimed to compare the ability of traditional anthropometric, as well as standard and novel DXA-derived parameters related to overall and regional adiposity, to evaluate CM risk., Methods: Using the cross-sectional design in the context of the PREDIMED-Plus trial, 1207 Caucasian senior men and women with overweight/obesity and metabolic syndrome (MetS) were assessed. At baseline, anthropometry- and DXA-measured parameters of central, visceral, peripheral and central-to-peripheral adiposity together with comprehensive set of CM risk factors were obtained. Partial correlations and areas under the ROC curve (AUC) were estimated to compare each adiposity measure with CM risk parameters, separately for men and women, and in the overall sample., Results: DXA-derived indicators, other than percentage of total body fat, showed stronger correlations (rho -0.172 to 0.206, p < 0.001) with CM risk than anthropometric indicators, after controlling for age, diabetes and medication use. In both sexes, DXA-derived visceral adipose tissue measures (VAT, VAT/Total fat, visceral-to-subcutaneous fat) together with lipodystrophy indicators (Trunk/Legs fat and Android/Gynoid fat) were strongly and positively correlated (p < 0.001) with glycated hemoglobin (HbA1c), the triglyceride and glucose index (TyG), triglycerides (TG), the ratio TG/HDL-cholesterol (TG/HDL-C), and were inversely related to HDL-C levels (p < 0.001). Furthermore, in AUC analyses for both sexes, VAT/Total fat showed the highest predictive ability for abnormal HbA1c levels (AUC = 0.629), VAT for TyG (AUC = 0.626), both lipodystrophy indicators for TG (AUCs = 0.556), and Trunk/Legs fat for HDL-C (AUC = 0.556) and TG/HDL-C (AUC = 0.581)., Conclusions: DXA regional adiposity measures offer advantages beyond traditional anthropometric and DXA overall adiposity indicators for CM risk assessment in senior overweight/obese subjects with MetS. In particular, in both sexes, visceral adiposity better stratifies individuals at risk for glucose abnormalities, and indicators of lipodystrophy better predict markers of dyslipidemia., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background and Aims: There is ongoing controversy about the effect of a low to moderate alcohol consumption on atrial fibrillation (AF). Our aim is to assess the association between adherence to a Mediterranean alcohol drinking pattern and AF incidence., Methods and Results: A total 6527 out of the 7447 participants in the PREDIMED trial met our inclusion criteria. A validated frequency food questionnaire was used to measure alcohol consumption. Participants were classified as non-drinkers, Mediterranean alcohol drinking pattern (MADP) (10-30 g/d in men and 5-15 g/day in women, preferably red wine consumption with low spirits consumption), low-moderate drinking (<30 g/day men y and < 15 g/day women), and heavy drinking. We performed multivariable Cox regression models to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) of incident AF according to alcohol drinking patterns. After a mean follow up of 4.4 years, 241 new incident AF cases were confirmed. Alcohol consumption was not associated to AF incidence among low-moderate drinkers (HR: 0.96; 95%CI: 0.67-1.37), adherents to MADP (HR: 1.15 95%CI: 0.75-1.75), or heavy drinkers (HR: 0.92; 95%CI: 0.53-1.58), compared with non-drinkers., Conclusions: In a high cardiovascular risk adult population, a Mediterranean alcohol consumption pattern (low to moderate red wine consumption) was not associated with an increased incidence of AF., Clinical Trials: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN35739639., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Inflammation is known to be related to the leading causes of death including cardiovascular disease, several types of cancer, obesity, type 2 diabetes, depression-suicide and other chronic diseases. In the context of whole dietary patterns, the Dietary Inflammatory Index (DII ® ) was developed to appraise the inflammatory potential of the diet., Objective: We prospectively assessed the association between DII scores and all-cause mortality in two large Spanish cohorts and valuated the consistency of findings across these two cohorts and results published based on other cohorts., Design: We assessed 18,566 participants in the "Seguimiento Universidad de Navarra" (SUN) cohort followed-up during 188,891 person-years and 6790 participants in the "PREvencion con DIeta MEDiterránea" (PREDIMED) randomized trial representing 30,233 person-years of follow-up. DII scores were calculated in both cohorts from validated FFQs. Higher DII scores corresponded to more proinflammatory diets. A total of 230 and 302 deaths occurred in SUN and PREDIMED, respectively. In a random-effect meta-analysis we included 12 prospective studies (SUN, PREDIMED and 10 additional studies) that assessed the association between DII scores and all-cause mortality., Results: After adjusting for a wide array of potential confounders, the comparison between extreme quartiles of the DII showed a positive and significant association with all-cause mortality in both the SUN (hazard ratio [HR] = 1.85; 95% CI: 1.15, 2.98; P-trend = 0.004) and the PREDIMED cohort (HR = 1.42; 95% CI: 1.00, 2.02; P-trend = 0.009). In the meta-analysis of 12 cohorts, the DII was significantly associated with an increase of 23% in all-cause mortality (95% CI: 16%-32%, for the highest vs lowest category of DII)., Conclusion: Our results provide strong and consistent support for the hypothesis that a pro-inflammatory diet is associated with increased all-cause mortality. The SUN cohort and PREDIMED trial were registered at clinicaltrials.gov as NCT02669602 and at isrctn.com as ISRCTN35739639, respectively., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Insulin resistance is a complex metabolic disorder and is often associated with type 2 diabetes (T2D)., Objectives: The aim of this study was to test whether baseline metabolites can additionally improve the prediction of insulin resistance beyond classical risk factors. Furthermore, we examined whether a multimetabolite model predicting insulin resistance in nondiabetics can also predict incident T2D., Methods: We used a case-cohort study nested within the Prevención con Dieta Mediterránea (PREDIMED) trial in subsets of 700, 500, and 256 participants without T2D at baseline and 1 and 3 y. Fasting plasma metabolites were semiquantitatively profiled with liquid chromatography-tandem mass spectrometry. We assessed associations between metabolite concentrations and the homeostasis model of insulin resistance (HOMA-IR) through the use of elastic net regression analysis. We subsequently examined associations between the baseline HOMA-IR-related multimetabolite model and T2D incidence through the use of weighted Cox proportional hazard models., Results: We identified a set of baseline metabolites associated with HOMA-IR. One-year changes in metabolites were also significantly associated with HOMA-IR. The area under the curve was significantly greater for the model containing the classical risk factors and metabolites together compared with classical risk factors alone at baseline [0.81 (95% CI: 0.79, 0.84) compared with 0.69 (95% CI: 0.66, 0.73)] and during a 1-y period [0.69 (95% CI: 0.66, 0.72) compared with 0.57 (95% CI: 0.53, 0.62)]. The variance in HOMA-IR explained by the combination of metabolites and classical risk factors was also higher in all time periods. The estimated HRs for incident T2D in the multimetabolite score (model 3) predicting high HOMA-IR (median value or higher) or HOMA-IR (continuous) at baseline were 2.00 (95% CI: 1.58, 2.55) and 2.24 (95% CI: 1.72, 2.90), respectively, after adjustment for T2D risk factors., Conclusions: The multimetabolite model identified in our study notably improved the predictive ability for HOMA-IR beyond classical risk factors and significantly predicted the risk of T2D., (© 2019 American Society for Nutrition.)

Background & Aims: Limited prospective studies have examined the association between legumes consumption and mortality, whereas scarce, if at all, previous studies have evaluated such associations taking into consideration specific grain legumes. We aimed to investigate the association between total legumes consumption and grain legumes species (dry beans, chickpeas, lentils, and fresh peas) with all-cause, cardiovascular disease (CVD), cancer and other-cause mortality among elderly Mediterranean individuals at high CVD risk., Methods: We prospectively assessed 7216 participants from the PREvención con DIeta MEDiterránea study. Dietary intake was assessed at baseline and yearly during follow-up by using a validated food frequency questionnaire., Results: During a median follow-up of 6.0 years, 425 total deaths, 103 CVD deaths, 169 cancer deaths and 153 due to other-causes deaths occurred. Hazard ratios (HRs) [95% confidence interval (CI)] of CVD mortality were 1.52 (1.02-2.89) (P-trend = 0.034) and 2.23 (1.32-3.78) (P-trend = 0.002) for the 3rd tertile of total legumes and dry beans consumption, respectively, compared with the 1st tertile. When comparing extreme tertiles, higher total legumes and lentils consumption was associated with 49% (HR: 0.51; 95% CI: 0.31-0.84; P-trend = 0.009) and 37% (HR: 0.63; 95% CI: 0.40-0.98; P-trend = 0.049) lower risk of cancer mortality. Similar associations were observed for CVD death in males and for cancer death in males, obese and diabetic participants., Conclusions: These findings support the benefits of legumes consumption for cancer mortality prevention which may be counterbalanced by their higher risk for CVD mortality., Trial Registration: The trial is registered at http://www.controlled-trials.com (ISRCTN35739639). Registration date: 5th October 2005., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: To assess clinical and/or imaging features useful to distinguish between Susac syndrome (SuS) and primary angiitis of central nervous system (PACNS)., Methods: Multicenter retrospective analysis of two cohorts of Argentine patients diagnosed with SuS and PACNS., Results: 13 patients diagnosed with SuS (6 women and 7 men, mean age 35 ± 10 years) and 15 with PACNS (10 women and 5 men, mean age 44 ± 18 years) were analyzed. Cognitive impairment (11 out of 13 patients vs. 5 out of 15, p = .006), ataxia (7 out of 13 vs. 2 out of 15, p = .042) and auditory disturbances (7 out of 13 vs. 0 out of 15, p = .003) were more frequent in SuS patients; whereas seizures were more frequent in PACNS patients (8 out of 15 vs. 1 out of 13, p = .035). On MRI, corpus callosum (CC) involvement was observed more often in SuS, with abnormalities in CC genu, in 13 out of 13 SuS patients vs. only 2 out of 15 PACNS patients (p < .001); in CC body these were present in 13 out of 13 SuS patients vs. 1 out of 15 PACNS patients, (p < .001); and in CC splenium in 12 out of 13 Sus patients vs. 1 of 15 PACNS, p < .001). Cortical lesions were more frequent in PACNS patients (10 out of 15 vs. 3 out of 13 SuS patients, p = .02), as were hemorrhages (5 out of 15 vs. 0 out of 13 SuS, p = .04) and multiple basal ganglia infarcts (7 out of 15 vs. 1 out of 13 Sus, p = .037)., Conclusion: Specific clinical and/or MRI findings may help distinguish SuS from PACNS with potential therapeutic implications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: The PREDIMED (PREvención con DIeta MEDiterránea) is a multicentre trial analyzed as a prospective cohort study. A total of 7122 participants (aged 55-80 years) at high risk of cardiovascular disease in the PREDIMED trial were recruited in 11 centres in Spain. The prevalence of subjects with type 2 diabetes was 50%. Our objective was to determine the contribution of lifestyle factors to the development of peripheral artery disease (PAD)., Methods: Incident clinical PAD in relation to a healthy lifestyle 5-point score defined as adherence to a Mediterranean diet (MedDiet), moderate alcohol intake, regular physical activity, normal weight (BMI<25) and non-smoking was measured., Results: Eighty-seven incident PAD cases were diagnosed during a median follow-up of 4.8 years. Compared with participants with 0 or 1 healthy lifestyle factor, the multivariable hazard ratio for PAD was 0.65 (95% confidence interval (CI) 0.37 to 1.14) for 2 factors, and 0.40 (0.22-0.72) for 3 or more. Moderate alcohol consumption, non-smoking, physical activity and following a MedDiet were significantly inversely associated with PAD whereas no association was found for normal weight (BMI<25 kg/m 2 ). PAD risk monotonically decreased with an increasing number of lifestyle factors, and the greatest reduction was found for a score combining moderate alcohol consumption, MedDiet and physical activity or non-smoking. The multivariable-adjusted population attributable risk percent for the combination of these 4 factors was 80.5% (95% CI: 21.3%-95.1%)., Conclusions: Our results demonstrate that a simple healthy lifestyle score is associated with a substantially reduced risk of PAD in a high cardiovascular risk population with a high prevalence (50%) of subjects with type 2 diabetes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial., Objective: The aim of this study was to investigate associations between TMAO and related metabolites with T2D risk in subjects at high risk of cardiovascular disease., Design: This is a case-cohort design study within the Prevención con Dieta Mediterránea (PREDIMED) study, with 251 incident T2D cases and a random sample of 694 participants (641 noncases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 y). We used liquid chromatography-tandem mass spectrometry to measure plasma TMAO, l-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) species, phosphocholine, α-glycerophosphocholine, and choline at baseline and after 1 y. We examined associations with the use of weighted Cox proportional hazard models, accounting for the weighted case-cohort design by the Barlow method., Results: After adjustment for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and α-glycerophosphocholine had a lower risk of T2D [HR (95% CI): 0.52 (0.29, 0.89) and 0.46 (0.24, 0.89), respectively]. The HR (95% CI) comparing the extreme quartiles of betaine was 0.41 (0.23, 0.74). Similar trends were observed for C16:0 LPC, C18:1 LPC, C18:0 LPC, C20:4 LPC, C22:6 LPC, C18:1 LPC plasmalogen, and C16:0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-y changes in oleic acid LPC plasmalogen concentrations had a lower T2D risk than the reference quartile., Conclusion: Whether the associations between plasma TMAO and certain metabolite concentrations with T2D risk reflect its pathophysiology or represent an epiphenomenon needs to be elucidated. This trial is registered at http://www.controlled-trials.com as ISRCTN35739639.

Background & Aims: Legumes, a low-energy, nutrient-dense and low glycemic index food, have shown beneficial effects on glycemic control and adiposity. As such, legumes are widely recommended in diabetic diets, even though there is little evidence that their consumption protects against type 2 diabetes. Therefore the aim of the present study was to examine the associations between consumption of total legumes and specific subtypes, and type 2 diabetes risk. We also investigated the effect of theoretically substituting legumes for other protein- or carbohydrate-rich foods., Methods: Prospective assessment of 3349 participants in the PREvención con DIeta MEDiterránea (PREDIMED) study without type 2 diabetes at baseline. Dietary information was assessed at baseline and yearly during follow-up. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for type-2 diabetes incidence according to quartiles of cumulative average consumption of total legumes, lentils, chickpeas, dry beans and fresh peas., Results: During a median follow-up of 4.3 years, 266 new cases of type 2 diabetes occurred. Individuals in the highest quartile of total legume and lentil consumption had a lower risk of diabetes than those in the lowest quartile (HR: 0.65; 95% CI: 0.43, 0.96; P-trend = 0.04; and HR: 0.67; 95% CI: 0.46-0.98; P-trend = 0.05, respectively). A borderline significant association was also observed for chickpeas consumption (HR 0.68; 95% CI: 0.46, 1.00; P-trend = 0.06). Substitutions of half a serving/day of legumes for similar servings of eggs, bread, rice or baked potato was associated with lower risk of diabetes incidence., Conclusions: A frequent consumption of legumes, particularly lentils, in the context of a Mediterranean diet, may provide benefits on type 2 diabetes prevention in older adults at high cardiovascular risk., Trial Registration: The trial is registered at http://www.controlled-trials.com (ISRCTN35739639). Registration date: 5th October 2005., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Oxidatively induced DNA damage, an important factor in cancer etiology, is repaired by oxyguanine glycosylase 1 (OGG1). The lower repair capacity genotype (homozygote Cys326Cys) in the OGG1-rs1052133 (Ser326Cys) polymorphism has been associated with cancer risk. However, no information is available in relation to cancer mortality, other causes of death, and modulation by diet., Objective: Our aim was to evaluate the association of the OGG1-rs1052133 with total, cancer, and cardiovascular disease (CVD) mortality and to analyze its modulation by the Mediterranean diet, focusing especially on total vegetable intake as one of the main characteristics of this diet., Design: Secondary analysis in the PREDIMED (Prevención con Dieta Mediterránea) trial is a randomized, controlled trial conducted in Spain from 2003 to 2010., Participants/setting: Study participants (n=7,170) were at high risk for CVD and were aged 55 to 80 years., Intervention: Participants were randomly allocated to two groups with a Mediterranean diet intervention or a control diet. Vegetable intake was measured at baseline., Main Outcome Measures: Main outcomes were all-cause, cancer, and CVD mortality after a median follow-up of 4.8 years., Statistical Analyses: Multivariable-adjusted Cox regression models were fitted., Results: Three hundred eighteen deaths were detected (cancer, n=127; CVD, n=81; and other, n=110). Cys326Cys individuals (prevalence 4.2%) presented higher total mortality rates than Ser326-carriers (P=0.009). The multivariable-adjusted hazard ratio for Cys326Cys vs Ser326-carriers was 1.69 (95% CI 1.09 to 2.62; P=0.018). This association was greater for CVD mortality (P=0.001). No relationship was detected for cancer mortality in the whole population (hazard ratio 1.07; 95% CI 0.47 to 2.45; P=0.867), but a significant age interaction (P=0.048) was observed, as Cys326Cys was associated with cancer mortality in participants <66.5 years (P=0.029). Recessive effects limited our ability to investigate Cys326Cys×diet interactions for cancer mortality. No statistically significant interactions for total or CVD mortality were found for the Mediterranean diet intervention. However, significant protective interactions for CVD mortality were found for vegetable intake (hazard ratio interaction per standard deviation 0.42; 95% CI 0.18 to 0.98; P=0.046)., Conclusions: In this population, the Cys326Cys-OGG1 genotype was associated with all-cause mortality, mainly CVD instead of cancer mortality. Additional studies are needed to provide further evidence on its dietary modulation., (Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: The study of the plasma lipidome may help to better characterize molecular mechanisms underlying cardiovascular disease. The identification of new lipid biomarkers could provide future targets for prevention and innovative therapeutic approaches. In the frame of the PREDIMED trial, our aim was to examine the associations of baseline lipidome patterns or their changes with the risk of clinical CVD events., Methods: We included 983 participants in our case-cohort study. The end-point was the incidence of major CVD during 4.8years of median follow-up. We repeatedly measured 202 plasma known lipid metabolites at baseline and after 1-year of intervention. Principal component analysis was used to identify lipidome factors. Among the 15 identified factors, 7 were significantly associated with CVD. Considering common patterns among factors, lipids were grouped (summed) into scores., Results: After adjustment for traditional CVD risk factors, scores of baseline polyunsaturated phosphatidylcholines (PC)/lysoPC/PC-plasmalogens and polyunsaturated cholesterol esters (CE) showed inverse associations with CVD (p=0.036 and 0.012, respectively); whereas scores of monoacylglycerols (MAGs)/diacylglycerols (DAGs) and short triacylglycerols (TAGs) showed a direct association with CVD (p=0.026 and 0.037, respectively). Baseline phosphatidylethanolamines (PEs) and their 1-y changes tended to be associated with higher CVD risk (p=0.066 and 0.081, respectively). We did not find a significant effect of the intervention with the Mediterranean Diet on these scores., Conclusions: Our study suggests that polyunsaturated PCs and CEs may confer protection against CVD. In contrast, MAGs, DAGs, TAGs and PEs appeared to be associated with higher CVD risk., (Copyright © 2017 Elsevier B.V. All rights reserved.)

One of the biggest challenges in multiple sclerosis (MS) is the definition of treatment response/failure in order to optimize treatment decisions in affected patients. The objective of this consensus was to review how disease activity should be assessed and to propose recommendations on the identification of treatment failure in RRMS patients in Argentina., Methods: A panel of experts in neurology from Argentina, dedicated to the diagnosis and care of MS patients, gathered both virtually and in person during 2016 and 2017 to carry out a consensus recommendation on the identification of treatment failure in RRMS patients. To achieve consensus, the methodology of "formal consensus-RAND/UCLA method" was used., Results: Recommendations were established based on published evidence and the expert opinion. Recommendations focused on disease management, disease activity markers and treatment failure identification were determined. Main consensus were: ≥2 relapses during the first year of treatment and/or ≥3 new or enlarged T2 or T1 GAD+ lesions and/or sustained increase of ≥2 points in EDSS or ≥100% in T25FW defines treatment failure in RRMS patients., Conclusions: The recommendations of this consensus guidelines attempts to optimize the health care and management of patients with MS in Argentina., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Potatoes have a high glycemic load but also antioxidants, vitamins, and minerals. It is unclear what mechanisms are involved in relation to their effect on blood pressure (BP) and hypertension. Objectives: This study aimed to assess the association between potato consumption, BP changes, and the risk of hypertension in 2 Spanish populations. Methods: Separate analyses were performed in PREDIMED (PREvención con DIeta MEDiterránea), a multicenter nutrition intervention trial of adults aged 55-80 y, and the SUN (Seguimiento Universidad de Navarra) project, a prospective cohort made up of university graduates and educated adults with ages (means ± SDs) of 42.7 ± 13.3 y for men and 35.1 ± 10.7 y for women. In PREDIMED, generalized estimating equations adjusted for lifestyle and dietary characteristics were used to assess changes in BP across quintiles of total potato consumption during a 4-y follow-up. Controlled BP values (systolic BP <140 mm Hg and diastolic BP <90 mm Hg) during follow-up were also assessed. For SUN, multivariate-adjusted HRs for incident hypertension during a mean 6.7-y follow-up were calculated. Results: In PREDIMED, the total potato intake was 81.9 ± 40.6 g/d. No overall differences in systolic or diastolic BP changes were detected based on consumption of potatoes. For total potatoes, the mean difference in change between quintile 5 (highest intake) and quintile 1 (lowest intake) in systolic BP after multivariate adjustment was -0.90 mm Hg (95% CI: -2.56, 0.76 mm Hg; P -trend = 0.1) and for diastolic BP was -0.02 mm Hg (95% CI: -0.93, 0.89 mm Hg; P -trend = 0.8). In SUN, the total potato consumption was 52.7 ± 33.6 g/d, and no significant association between potato consumption and hypertension incidence was observed in the fully adjusted HR for total potato consumption (quintile 5 compared with quintile 1: 0.98; 95% CI: 0.80, 1.19; P -trend = 0.8). Conclusions: Potato consumption is not associated with changes over 4 y in blood pressure among older adults in Spain or with the risk of hypertension among Spanish adults. This trial was registered at www.controlled-trials.com as ISRCTN35739639., Competing Interests: Author disclosures: EAH, MAM-G, JS-S, DC, M Fitó, AG-R, FA, M Fiol, JL, LS-M, XP, MR-C, CR, MB, JVS, HS, CMR, and ET, no conflicts of interest. RE reports grants from Spanish Institute of Health “Carlos III” Patrimonio Comunal Olivarero, Spain; California Walnut Commission; Borges SA, Spain; FIS, Government of Spain; Fundacion Bosch i Gimpera, Spain, during the conduct of the study; nonfinancial support from Cerveza y Salud, Spain; nonfinancial support from FIVIN, Spain; nonfinancial support from Fundacion Dieta Mediterranea, Spain, nonfinancial support from Universidad Internacional de Catalunya, Spain; grants from Bicentury SA, Spain; grants from Grand Fountaine, Spain; grants from Novartis SA, Spain; personal fees from Brewers of Europe, Belgium; personal fees from Fundacional Cerveza y Salud, Spain; personal fees from FIVIN, Spain; personal fees from Instituto Cervantes, Alburquerque, NM; personal fees from Instituto Cervantes, Milan, Italy; personal fees from Lilly Laboratories; personal fees from Prodeca: Generalitate de Catalunya; personal fees from Wine and Culinary International International Forum; Harvard School of Public Health, Boston, MA; and University of Columbia, NYC, outside the submitted work. ER reports grants, nonfinancial and other support from California Walnut Commission; grants, personal fees, nonfinancial and other support from Merck, Sharp & Dohme; grants, personal fees, nonfinancial and other support from Alexion; personal fees, nonfinancial and other support from Aegerion; grants and personal fees from Sanofi Aventis; grants, personal fees, nonfinancial and other support from Ferrer International; grants from Amgen; grants from Pfizer; and personal fees from Akcea, outside the submitted work. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript., (© 2017 American Society for Nutrition.)

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 (PREvención con DIeta MEDiterránea) 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., (© 2017 American Society for Nutrition.)

Background: Eggs are a major source of dietary cholesterol and their consumption has been sometimes discouraged. A relationship between egg consumption and the incidence of cardiovascular disease (CVD) has been suggested to be present exclusively among patients with type2 diabetes., Aims: To assess the association between egg consumption and CVD in a large Mediterranean cohort where approximately 50% of participants had type 2 diabetes., Methods: We prospectively followed 7216 participants (55-80 years old) at high cardiovascular risk from the PREDIMED (PREvención con DIeta MEDiterránea) study for a mean of 5.8 years. All participants were initially free of CVD. Yearly repeated measurements of dietary information with a validated 137-item food-frequency questionnaire were used to assess egg consumption and other dietary exposures. The endpoint was the rate of major cardiovascular events (myocardial infarction, stroke or death from cardiovascular causes)., Results: A major cardiovascular event occurred in 342 participants. Baseline egg consumption was not significantly associated with cardiovascular events in the total population. Non-diabetic participants who ate on average >4 eggs/week had a hazard ratio (HR) of 0.96 (95% confidence interval, 0.33-2.76) in the fully adjusted multivariable model when compared with non-diabetic participants who reported the lowest egg consumption (<2 eggs/week). Among diabetic participants, the HR was 1.33 (0.72-2.46). There was no evidence of interaction by diabetic status. HRs per 500 eggs of cumulative consumption during follow-up were 0.94 (0.66-1.33) in non-diabetics and 1.18 (0.90-1.55) in diabetics., Conclusions: Low to moderated egg consumption was not associated with an increased CVD risk in diabetic or non-diabetic individuals at high cardiovascular risk. This trial was registered at controlled-trials.com as ISRCTN35739639., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Hydroxytyrosol is a phenolic compound that is present in virgin olive oil (VOO) and wine. Hydroxytyrosol-related foods have been shown to protect against cardiovascular disease (CVD). Objective: We investigated the associations between hydroxytyrosol and its biological metabolite, 3- O -methyl-hydroxytyrosol, also known as homovanillyl alcohol (HVAL), with CVD and total mortality. Design: We included 1851 men and women with a mean ± SD age of 66.8 ± 6 y at high risk of CVD from prospective cohort data. The primary endpoint was a composite of myocardial infarction, stroke, and death from cardiovascular causes; the secondary endpoint was all-cause mortality. Twenty-four-hour urinary hydroxytyrosol and HVAL and catechol- O -methyltransferase ( COMT ) rs4680 genotypes were measured. Results: After multivariable adjustment, all biomarkers were associated, as a continuous variable, with lower CVD risk, but only HVAL showed a strong inverse association (HR: 0.44; 95% CI: 0.25, 0.80) for the comparison between quintiles. Only HVAL, as a continuous variable, was associated with total mortality (HR: 0.81; 95% CI: 0.70, 0.95). Individuals in the highest quintile of HVAL compared with the lowest had 9.2 (95% CI: 3.5, 20.8) and 6.3 (95% CI: 2.3, 12.1) additional years of life or years free of CVD, respectively, after 65 y. Individuals with the rs4680GG genotype had the highest HVAL concentrations ( P = 0.05). There was no association between COMT genotypes and events or interaction between COMT genotypes and HVAL concentrations. Conclusions: We report, for the first time to our knowledge, an independent association between high urinary HVAL concentrations and a lower risk of CVD and total mortality in elderly individuals. VOO and wine consumption and a high metabolic COMT capacity for methylation are key factors for high HVAL concentrations. The association that stems from our results reinforces the benefits of 2 key components of the Mediterranean diet (wine and VOO). This trial was registered at www.predimed.es as ISRCTN35739639., (© 2017 American Society for Nutrition.)

Background: The study of dietary patterns is gaining interest. Although the health benefits of yogurt and lignans have been investigated separately, to our knowledge there are no studies on their associative effects., Objective: The aim of this study was to evaluate a possible association between yogurt and lignans using biomarkers of cardiovascular disease risk in an elderly population., Design: We conducted a cross-sectional analysis of the association between baseline dietary information and cardiovascular risk parameters using food frequency questionnaires., Participants: We enrolled 7,169 Spanish participants of the PREDIMED (Prevención con Dieta Mediterránea) study (elderly men and women at high cardiovascular risk) from June 2003 to June 2009., Main Outcome Measures: Cardiovascular risk parameters, including cholesterol, triglycerides, glucose, body mass index, weight, waist circumference, and blood pressure were measured., Statistical Analysis: General linear models were used to assess the relationship between categorical variables (yogurt, total dairy intake, lignans, and yogurt plus lignans) and cardiovascular risk parameters., Results: The consumption of either yogurt or lignans seems to have beneficial effects on human health, but the consumption of both showed greater improvement in some cardiovascular health parameters. Indeed, participants with a higher consumption of both yogurt and lignans showed lower total cholesterol (estimated β-coefficients=-6.18; P=0.001) and low-density lipoprotein cholesterol levels (β=-4.92; P=0.005). In contrast, participants with lower yogurt and lignan consumption had a higher body mass index (β=0.28; P=0.007) and weight (β=1.20; P=0.008)., Conclusions: High lignan and yogurt consumption is associated with a better cardiovascular risk parameters profile in an elderly Mediterranean population. Further research is warranted to determine the mechanisms and consequences of this potential effect., (Copyright © 2017 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: The associations between dietary fat and cardiovascular disease have been evaluated in several studies, but less is known about their influence on the risk of diabetes. Objective: We examined the associations between total fat, subtypes of dietary fat, and food sources rich in saturated fatty acids and the incidence of type 2 diabetes (T2D). Design: A prospective cohort analysis of 3349 individuals who were free of diabetes at baseline but were at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study was conducted. Detailed dietary information was assessed at baseline and yearly during the follow-up using a food frequency questionnaire. Multivariable Cox proportional hazards models were used to estimate T2D HRs and 95% CIs according to baseline and yearly updated fat intake. Results: We documented 266 incident cases during 4.3 y of follow-up. Baseline saturated and animal fat intake was not associated with the risk of T2D. After multivariable adjustment, participants in the highest quartile of updated intake of saturated and animal fat had a higher risk of diabetes than the lowest quartile (HR: 2.19; 95% CI: 1.28, 3.73; and P- trend = 0.01 compared with HR: 2.00; 95% CI: 1.29, 3.09; and P- trend < 0.01, respectively). In both the Mediterranean diet and control groups, participants in the highest quartile of updated animal fat intake had an ∼2-fold higher risk of T2D than their counterparts in the lowest quartile. The consumption of 1 serving of butter and cheese was associated with a higher risk of diabetes, whereas whole-fat yogurt intake was associated with a lower risk. Conclusions: In a Mediterranean trial focused on dietary fat interventions, baseline intake of saturated and animal fat was not associated with T2D incidence, but the yearly updated intake of saturated and animal fat was associated with a higher risk of T2D. Cheese and butter intake was associated with a higher risk of T2D, whereas whole-fat yogurt intake was associated with a lower risk of T2D. This trial was registered at www.isrctn.com as ISRCTN35739639., (© 2017 American Society for Nutrition.)

Background & Aims: Few studies have assessed the association between consumption of red meat (RM) and processed red meats (PRM) and the incidence of metabolic syndrome (MetS) and results have been inconsistent. We investigated associations between total consumption of meat and its subtypes and incident MetS and estimated the effect of substituting RM or PRM for alternative protein-rich foods., Methods: We analyzed 1868 participants (55-80 years-old) recruited into the PREDIMED study who had no MetS at baseline and were followed for a median of 3.2 years. MetS was defined using updated harmonized criteria. Anthropometric variables, dietary habits, and blood biochemistry were determined at baseline and yearly thereafter. Multivariable-adjusted hazard ratios (HRs) of MetS were estimated for the two upper tertiles (versus the lowest one) of mean consumption of meat and its subtypes during the follow-up as exposure., Results: Comparing the highest vs the lowest tertile of consumption, we observed an increased risk of MetS incidence, with HRs of 1.23 (95% confidence interval [CI]: 1.03-1.45) and 1.46 (CI: 1.22-1.74) for total meat and pooled RM and PRM, respectively. Compared with participants in the lowest tertile, those in the highest tertile of poultry and rabbit consumption had a lower risk of MetS incidence. The risk of MetS was lower when one-serving/day of RM or PRM was replaced by legumes, poultry and rabbit, fish or eggs., Conclusion: RM and PRM consumption was associated with higher risk of MetS. Replacing RM or PRM with other protein-rich foods related to a lower risk of MetS and should, therefore, be encouraged. This trial was registered at controlled-trials.com as ISRCTN35739639., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The relation between the consumption of sweetened beverages and metabolic syndrome (MetS) is controversial., Objective: This analysis evaluated the associations between intakes of sugar-sweetened beverages (SSBs), artificially sweetened beverages, and natural and bottled fruit juices and the incidence of MetS in elderly individuals at high risk of cardiovascular disease (CVD) and without MetS at baseline., Methods: We prospectively examined 1868 participants free of MetS at baseline from the PREDIMED (PREvención con DIeta MEDiterránea) study. MetS was defined by using the updated harmonized criteria of the International Diabetes Federation, the American Heart Association, and National Heart, Lung, and Blood Institute. Energy and nutrient intakes were evaluated at baseline and then yearly by using a validated 137-item food-frequency questionnaire. Multivariable-adjusted HRs for MetS and its components were estimated from mean intakes during follow-up. We compared the 2 highest consumption categories (1-5 and >5 servings/wk) with the lowest category (<1 serving/wk)., Results: A total of 930 incident cases of MetS were documented during a median follow-up of 3.24 y. When we compared consumption of >5 servings/wk with consumption of <1 serving/wk, multivariable HRs (95% CIs) for MetS incidence were 1.43 (1.00, 2.15), 1.74 (1.26, 2.41), 1.30 (1.00, 1.69), and 1.14 (1.04, 1.65) for SSBs, artificially sweetened beverages, natural fruit juices, and bottled fruit juices, respectively., Conclusions: The occasional consumption of SSBs and artificially sweetened beverages (1-5 servings/wk) was not associated with the incidence of MetS in middle-aged and elderly individuals at high risk of CVD. The consumption of >5 servings/wk of all of the types of beverages analyzed was associated with an increased risk of MetS and some of its components. However, for SSBs and bottled fruit juices these associations must be interpreted with caution because of the low frequency of consumption in this population. This trial was registered at clinicaltrials.gov as ISRCTN35739639., (© 2016 American Society for Nutrition.)

Background and Aims: Evidence on the association yogurt consumption and obesity is not conclusive. The aim of this study was to prospectively evaluate the association between yogurt consumption, reversion of abdominal obesity status and waist circumference change in elderly., Methods and Results: 4545 individuals at high cardiovascular risk were prospectively followed. Total, whole-fat and low-fat yogurt consumption were assessed using food frequency questionnaires. Generalized estimating equations were used to analyze the association between yogurt consumption and waist circumference change (measured at baseline and yearly during the follow-up). Logistic regression models were used to evaluate the odds ratios (ORs) and 95% CIs of the reversion rate of abdominal obesity for each quintile of yogurt consumption compared with the lowest quintile. After multivariable adjustment, the average yearly waist circumference change in the quintiles of whole-fat yogurt consumption was: Q1: 0.00, Q2: 0.00 (-0.23 to 0.23), Q3: -0.15 (-0.42 to 0.13), Q4: 0.10 (-0.21 to 0.42), and Q5: -0.23 (-0.46 to -0.00) cm; p for trend = 0.05. The ORs for the reversion of abdominal obesity for whole-fat yogurt consumption were Q1: 1.00, Q2: 1.40 (1.04-1.90), Q3: 1.33 (0.94-1.89), Q4: 1.21 (0.83-1.77), and Q5: 1.43 (1.06-1.93); p for trend = 0.26., Conclusion: Total yogurt consumption was not significantly associated with reversion of abdominal obesity status and a lower waist circumference. However, consumption of whole-fat yogurt was associated with changes in waist circumference and higher probability for reversion of abdominal obesity. Therefore, it seems that whole-fat yogurt has more beneficial effects in management of abdominal obesity in elderly population at high cardiovascular risk., (Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies have suggested that metabolite profiles of elevated acylcarnitines were associated with increased risk of cardiovascular disease (CVD) in populations with established coronary disease. However, to our knowledge, this association has not been evaluated in the context of primary cardiovascular prevention., Objectives: We evaluated the association between 28 plasma acylcarnitine species and risk of incident CVD and the potential modifying effect of Mediterranean diet (MedDiet) interventions., Design: We measured plasma acylcarnitines with the use of high-throughput liquid chromatography-tandem mass spectrometry at baseline and after 1 y of follow-up, both individually and classified into short-, medium-, or long-chain scores, in a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED) study, which is a randomized Mediterranean dietary intervention for primary cardiovascular prevention. A randomly selected subcohort (n = 751) and all available incident CVD cases (n = 229) after 4.8 y of follow-up were included in the current study., Results: After adjustment for age, sex, body mass index, and other CVD risk factors, participants in the highest quartile of baseline short- and medium-chain acylcarnitines had a higher risk of CVD than did participants in the lowest quartile [HRs: 1.80 (95% CI: 1.11, 2.91; P-trend 0.01) and 1.55 (95% CI: 1.01, 2.48; P-trend = 0.04), respectively]. Increased short-chain acylcarnitines after 1 y were associated with higher risks of total CVD and stroke. Participants with higher baseline concentrations of short-, medium-, and long-chain acylcarnitines who were randomly assigned to the control group had a higher risk of CVD than did subjects with lower concentrations of acylcarnitines who were assigned to the MedDiet group., Conclusions: Our data support the conclusion that metabolite profiles characterized by elevated concentrations of acylcarnitines are independently associated with risks of total CVD and stroke alone in participants at high risk of CVD. MedDiet interventions may mitigate the adverse associations shown between higher concentrations of acylcarnitines and CVD. This trial was registered at www.controlled-trials.com as ISRCTN35739639., (© 2016 American Society for Nutrition.)

Background & Aims: High dietary protein diets are widely used to manage overweight and obesity. However, there is a lack of consensus about their long-term efficacy and safety. Therefore, the aim of this study was to assess the effect of long-term high-protein consumption on body weight changes and death outcomes in subjects at high cardiovascular risk., Methods: A secondary analysis of the PREDIMED trial was conducted. Dietary protein was assessed using a food-frequency questionnaire during the follow-up. Cox proportional hazard models were used to estimate the multivariate-adjusted hazard ratio (HR) and 95% confidence intervals (95%CI) for protein intake in relation to the risk of body weight and waist circumference changes, cardiovascular disease, cardiovascular death, cancer death and total death., Results: Higher total protein intake, expressed as percentage of energy, was significantly associated with a greater risk of weight gain when protein replaced carbohydrates (HR: 1.90; 95%CI: 1.05, 3.46) but not when replaced fat (HR: 1.69; 95%CI: 0.94, 3.03). However, no association was found between protein intake and waist circumference. Contrary, higher total protein intake was associated with a greater risk of all-cause death in both carbohydrate and fat substitution models (HR: 1.59; 95%CI: 1.08, 2.35; and HR: 1.66; 95%CI: 1.13, 2.43, respectively). A higher consumption of animal protein was associated with an increased risk of fatal and non-fatal outcomes when protein substituted carbohydrates or fat., Conclusions: Higher dietary protein intake is associated with long-term increased risk of body weight gain and overall death in a Mediterranean population at high cardiovascular risk., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Dietary fat quality and fat replacement are more important for cardiovascular disease (CVD) prevention than is total dietary fat intake., Objective: The aim was to evaluate the association between total fat intake and fat subtypes with the risk of CVD (myocardial infarction, stroke, or death from cardiovascular causes) and cardiovascular and all-cause death. We also examined the hypothetical effect of the isocaloric substitution of one macronutrient for another., Design: We prospectively studied 7038 participants at high CVD risk from the PREvención con DIeta MEDiterránea (PREDIMED) study. The trial was conducted from 2003 to 2010, but the present analysis was based on an expanded follow-up until 2012. At baseline and yearly thereafter, total and specific fat subtypes were repeatedly measured by using validated food-frequency questionnaires. Time-dependent Cox proportional hazards models were used., Results: After 6 y of follow-up, we documented 336 CVD cases and 414 total deaths. HRs (95% CIs) for CVD for those in the highest quintile of total fat, monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA) intake compared with those in the lowest quintile were 0.58 (0.39, 0.86), 0.50 (0.31, 0.81), and 0.68 (0.48, 0.96), respectively. In the comparison between extreme quintiles, higher saturated fatty acid (SFA) and trans-fat intakes were associated with 81% (HR: 1.81; 95% CI: 1.05, 3.13) and 67% (HR: 1.67; 95% CI: 1.09, 2.57) higher risk of CVD. Inverse associations with all-cause death were also observed for PUFA and MUFA intakes. Isocaloric replacements of SFAs with MUFAs and PUFAs or trans fat with MUFAs were associated with a lower risk of CVD. SFAs from pastries and processed foods were associated with a higher risk of CVD., Conclusions: Intakes of MUFAs and PUFAs were associated with a lower risk of CVD and death, whereas SFA and trans-fat intakes were associated with a higher risk of CVD. The replacement of SFAs with MUFAs and PUFAs or of trans fat with MUFAs was inversely associated with CVD. This trial was registered at www.controlled-trials.com as ISRCTN 35739639., (© 2015 American Society for Nutrition.)

Background & Aims: There is little evidence on post hoc-derived dietary patterns (DP) and all-cause mortality in Southern-European populations. Furthermore, the potential effect modification of a DP by a nutritional intervention has not been sufficiently assessed. We assessed the association between a posteriori defined baseline major DP and total mortality or cardiovascular events within each of the three arms of a large primary prevention trial (PREDIMED) where participants were randomized to two active interventions with Mediterranean-type diets or to a control group (allocated to a low-fat diet)., Design: We followed-up 7216 participants for a median of 4.3 years. A validated 137-item food-frequency questionnaire was administered. Baseline DP were ascertained through factor analysis based on 34 predefined groups. Cox regression models were used to estimate multivariable-adjusted hazard ratios (HR) for cardiovascular disease (CVD) or mortality across quartiles of DP within each of the three arms of the trial., Results: We identified two major baseline DP: the first DP was rich in red and processed meats, alcohol, refined grains and whole dairy products and was labeled Western dietary pattern (WDP). The second DP corresponded to a "Mediterranean-type" dietary pattern (MDP). During follow-up, 328 participants died. After controlling for potential confounders, higher baseline adherence to the MDP was associated with lower risk of CVD (adjusted HR for fourth vs. first quartile: 0.52; 95% CI (Confidence Interval): 0.36, 0.74; p-trend <0.001) and all-cause mortality (adjusted HR: 0.53; 95% CI: 0.38, 0.75; p-trend <0.001), regardless of the allocated arm of the trial. An increasing mortality rate was found across increasing quartiles of the WDP in the control group (allocated to a low-fat diet), though the linear trend was not statistically significant (p = 0.098)., Conclusions: Higher adherence to an empirically-derived MDP at baseline was associated with a reduced risk of CVD and mortality in the PREDIMED trial regardless of the allocated arm. The WDP was not associated with higher risk of mortality or cardiovascular events., (Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The association between consumption of dairy products and the risk of developing metabolic syndrome (MetS) is unclear., Objective: The purpose of this study was to evaluate the associations between consumption of dairy products (total and different subtypes) and incident MetS in a Mediterranean population at high cardiovascular disease risk., Methods: We prospectively analyzed 1868 men and women (55-80 y old) without MetS at baseline, recruited from different PREDIMED (Prevención con Dieta Mediterránea) centers between October 2003 and June 2009 and followed up until December 2010. MetS was defined according to updated, harmonized criteria. At baseline and yearly thereafter, we determined anthropometric variables, dietary habits by a 137-item validated food-frequency questionnaire, and blood biochemistry. Multivariable-adjusted HRs of MetS or its components were estimated for each of the 2 upper tertiles (vs. the lowest one) of mean consumption of dairy products during the follow-up., Results: During a median follow-up of 3.2 y, we documented 930 incident MetS cases. In the multivariable-adjusted model, HRs (95% CIs) of MetS for the comparison of extreme tertiles of dairy product consumption were 0.72 (0.61, 0.86) for low-fat dairy, 0.73 (0.62, 0.86) for low-fat yogurt, 0.78 (0.66, 0.92) for whole-fat yogurt, and 0.80 (0.67, 0.95) for low-fat milk. The respective HR for cheese was 1.31 (1.10, 1.56)., Conclusions: Higher consumption of low-fat dairy products, yogurt (total, low-fat, and whole-fat yogurt) and low-fat milk was associated with a reduced risk of MetS in individuals at high cardiovascular disease risk from a Mediterranean population. Conversely, higher consumption of cheese was related to a higher risk of MetS. This trial was registered at controlled-trials.com as ISRCTN35739639., (© 2015 American Society for Nutrition.)

Background and Aim: We tested the hypothesis that an intervention with a Mediterranean diet (MeDiet) could mitigate the well-known harmful effects of abdominal obesity on cardiovascular health., Methods and Results: We assessed the relationship between baseline waist-to-height ratio (WHtR) and major cardiovascular events during a median follow-up of 4.8 years in the Prevention with Mediterranean Diet (PREDIMED) randomized primary prevention trial, which tested a MeDiet against a control diet (advice on a low-fat diet). We also examined whether the MeDiet intervention was able to counteract the detrimental cardiovascular effects of an increased WHtR. The trial included 7447 participants (55-80 years old, 57% women) at high cardiovascular risk but free of cardiovascular disease (CVD) at enrollment. An increased risk of CVD events (myocardial infarction, stroke, or cardiovascular death) was apparent for the highest versus the lowest quartile of WHtR (multivariable-adjusted hazard ratio: 1.98) (95% confidence interval: 1.10-3.57; linear trend: p = 0.019) only in the control-diet group, but not in the two groups allocated to intervention with MeDiet (p for interaction = 0.034). This apparent interaction suggesting that the intervention counterbalanced the detrimental cardiovascular effects of adiposity was also significant for body mass index (BMI) (p = 0.01) and waist circumference (p = 0.043)., Conclusions: The MeDiet may counteract the harmful effects of increased adiposity on the risk of CVD., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Few observational studies have examined the effect of dietary fiber intake and fruit and vegetable consumption on total mortality and have reported inconsistent results. All of the studies have been conducted in the general population and typically used only a single assessment of diet., Objective: We investigated the association of fiber intake and whole-grain, fruit, and vegetable consumption with all-cause mortality in a Mediterranean cohort of elderly adults at high cardiovascular disease (CVD) risk by using repeated measurements of dietary information and taking into account the effect of a dietary intervention., Design: We followed up 7216 men (55-75 y old) and women (60-75 y old) at high CVD risk in the Prevención con Dieta Mediterránea (PREDIMED) trial for a mean of 5.9 y. Data were analyzed as an observational cohort. Participants were initially free of CVD. A 137-item validated food-frequency questionnaire administered by dietitians was repeated annually to assess dietary exposures (fiber, fruit, vegetable, and whole-grain intakes). Deaths were identified through the continuing medical care of participants and the National Death Index. An independent, blinded Event Adjudication Committee adjudicated causes of death. Cox regression models were used to estimate HRs of death during follow-up according to baseline dietary exposures and their yearly updated changes., Results: In up to 8.7 y of follow-up, 425 participants died. Baseline fiber intake and fruit consumption were significantly associated with lower risk of death [HRs for the fifth compared with the first quintile: 0.63 (95% CI: 0.46, 0.86; P = 0.015) and 0.59 (95% CI: 0.42, 0.82; P = 0.004), respectively]. When the updated dietary information was considered, participants with fruit consumption >210 g/d had 41% lower risk of all-cause mortality (HR: 0.59; 95% CI: 0.44, 0.78). Associations were strongest for CVD mortality than other causes of death., Conclusion: Fiber and fruit intakes are associated with a reduction in total mortality. PREDIMED was registered at controlled-trials.com as ISRCTN35739639., (© 2014 American Society for Nutrition.)

Background: MicroRNAs have emerged as important epigenetic regulators in cardiovascular diseases (CVDs). Using an observational meta-analysis design, we previously characterized a gain-of-function microRNA-410 target site polymorphism (rs13702T>C) in the 3'untranslated region of the lipoprotein lipase (LPL) gene. The C allele was associated with lower triglycerides, and this association was modulated by fat intake., Objectives: We aimed to extend our findings by assessing the interaction between the rs13702 polymorphism and fat intake on triglycerides at baseline and longitudinally by using a dietary intervention design. We also examined as a primary outcome the association of this variant with CVD incidence and its modulation by the Mediterranean diet (MedDiet)., Design: We studied 7187 participants in the PREDIMED (Prevención con Dieta Mediterránea) randomized trial that tested a MedDiet intervention compared with a control diet, with a median 4.8-y follow-up. LPL polymorphisms and triglycerides were determined and CVD assessed. Gene-diet interactions for triglycerides were analyzed at baseline (n = 6880) and after a 3-y intervention (n = 4131). Oxidative stress parameters were investigated in a subsample., Results: The rs13702T>C polymorphism was strongly associated with lower triglycerides in C allele carriers and interacted synergistically with dietary monounsaturated (P = 0.038) and unsaturated fat intake (P = 0.037), decreasing triglycerides at baseline. By 3 y, we observed a gene-diet interaction (P = 0.025) in which the C allele was associated with a greater reduction in triglycerides after intervention with MedDiet, high in unsaturated fat. Although the polymorphism was associated with lower stroke risk (HR: 0.74; 95% CI: 0.57, 0.97; P = 0.029 per C allele), this association reached statistical significance only in the MedDiet intervention (HR: 0.58; 95% CI: 0.37, 0.91; P = 0.019 in C compared with TT carriers), not in the control group (HR: 0.94; 95% CI: 0.55, 1.59; P = 0.805)., Conclusion: We report a novel association between a microRNA target site variant and stroke incidence, which is modulated by diet in terms of decreasing triglycerides and possibly stroke risk in rs13702 C allele carriers after a high-unsaturated fat MedDiet intervention., (© 2014 American Society for Nutrition.)

Background: Vegetarian diets have been associated with reduced mortality. Because a pure vegetarian diet might not easily be embraced by many individuals, consuming preferentially plant-derived foods would be a more easily understood message. A provegetarian food pattern (FP) emphasizing preference for plant-derived foods might reduce all-cause mortality., Objective: The objective was to identify the association between an a priori-defined provegetarian FP and all-cause mortality., Design: We followed 7216 participants (57% women; mean age: 67 y) at high cardiovascular risk for a median of 4.8 y. A validated 137-item semiquantitative food-frequency questionnaire was administered at baseline and yearly thereafter. Fruit, vegetables, nuts, cereals, legumes, olive oil, and potatoes were positively weighted. Added animal fats, eggs, fish, dairy products, and meats or meat products were negatively weighted. Energy-adjusted quintiles were used to assign points to build the provegetarian FP (range: 12-60 points). Deaths were confirmed by review of medical records and the National Death Index., Results: There were 323 deaths during the follow-up period (76 from cardiovascular causes, 130 from cancer, 117 for noncancer, noncardiovascular causes). Higher baseline conformity with the provegetarian FP was associated with lower mortality (multivariable-adjusted HR for ≥ 40 compared with <30 points: 0.59; 95% CI: 0.40, 0.88). Similar results were found with the use of updated information on diet (RR: 0.59; 95% CI: 0.39, 0.89)., Conclusions: Among omnivorous subjects at high cardiovascular risk, better conformity with an FP that emphasized plant-derived foods was associated with a reduced risk of all-cause mortality. This trial was registered at www.controlled-trials.com as ISRCTN35739639., (© 2014 American Society for Nutrition.)

Background and Aims: Epidemiologic and biological evidence supports an inverse association between polyphenol consumption and the risk of cardiovascular disease (CVD). However, no previous studies have prospectively evaluated the relationship between polyphenol intake and the incidence of CVD in such a comprehensive way. The aim was to evaluate the association between intakes of total polyphenol and polyphenol subgroups, and the risk of major cardiovascular events (myocardial infarction, stroke or death from cardiovascular causes) in the PREDIMED study., Methods and Results: The present work is an observational study within the PREDIMED trial. Over an average of 4.3 years of follow-up, there were 273 confirmed cases of CVD among the 7172 participants (96.3%) who completed a validated 137-item food frequency questionnaire (FFQ) at baseline. Polyphenol consumption was calculated by matching food consumption data from the FFQ with the Phenol-Explorer database on polyphenol content of each reported food. After multivariate adjustment, a 46% reduction in risk of CVD risk was observed comparing Q5 vs. Q1 of total polyphenol intake (HR = 0.54; 95% confidence interval [CI] = 0.33-0.91; P-trend = 0.04). The polyphenols with the strongest inverse associations were flavanols (HR = 0.40; CI 0.23-0.72; P-trend = 0.003), lignans (HR = 0.51; CI 0.30-0.86; P-trend = 0.007), and hydroxybenzoic acids (HR = 0.47; CI 0.26-0.86; P-trend 0.02)., Conclusion: Greater intake of polyphenols, especially from lignans, flavanols, and hydroxybenzoic acids, was associated with decreased CVD risk. Clinical trials are needed to confirm this effect and establish accurate dietary recommendations., (Copyright © 2014 Elsevier B.V. All rights reserved.)