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Aims Physical activity has consistently been shown to improve cardiovascular health and high-density lipoprotein-cholesterol levels. However, only small and heterogeneous studies have investigated the effect of exercise on high-density lipoprotein functions. Our aim is to evaluate, in the largest observational study to date, the association between leisure time physical activity and a range of high-density lipoprotein functional traits. Methods The study sample consisted of 296 Spanish adults at high cardiovascular risk. Usual leisure time physical activity and eight measures of high-density lipoprotein functionality were averaged over two measurements, one year apart. Multivariable linear regression models were used to explore the association between leisure time physical activity (exposure) and each high-density lipoprotein functional trait (outcome), adjusted for cardiovascular risk factors. Results Higher levels of leisure time physical activity were positively and linearly associated with average levels over one year of plasma high-density lipoprotein-cholesterol and apolipoprotein A-I, paraoxonase-1 antioxidant activity, high-density lipoprotein capacity to esterify cholesterol and cholesterol efflux capacity in individuals free of type 2 diabetes only. The increased cholesterol esterification index with increasing leisure time physical activity reached a plateau at around 300 metabolic equivalents.min/day. In individuals with diabetes, the relationship with cholesteryl ester transfer protein followed a U-shape, with a decreased cholesteryl ester transfer protein activity from 0 to 300 metabolic equivalents.min/day, but increasing from there onwards. Increasing levels of leisure time physical activity were associated with poorer high-density lipoprotein vasodilatory capacity. Conclusions In a high cardiovascular risk population, leisure time physical activity was associated not only with greater circulating levels of high-density lipoprotein-cholesterol, but also with better markers of high-density lipoprotein functionality, namely cholesterol efflux capacity, the capacity of high-density lipoprotein to esterify cholesterol and paraoxonase-1 antioxidant activity in individuals free of diabetes and lower cholesteryl ester transfer protein activity in individuals with type 2 diabetes.

OBJECTIVE: To examine the effects of two Mediterranean eating plans (Med-EatPlans) versus a low-fat eating plan on the need for glucose-lowering medications. RESEARCH DESIGN AND METHODS: From the Prevención con Dieta Mediterránea (PREDIMED) trial, we selected 3,230 participants with type 2 diabetes at baseline. These participants were randomly assigned to one of three eating plans: Med-EatPlan supplemented with extra-virgin olive oil (EVOO), Med-EatPlan supplemented with mixed nuts, or a low-fat eating plan (control). In a subgroup (15%), the allocation was done in small clusters instead of using individual randomization, and the clustering effect was taken into account in the statistical analysis. In multivariable time-to-event survival models, we assessed two outcomes: 1) introduction of the first glucose-lowering medication (oral or injectable) among participants on lifestyle management at enrollment and 2) insulin initiation. RESULTS: After a median follow-up of 3.2 years, in multivariable analyses adjusting for baseline characteristics and propensity scores, the hazard ratios (HRs) of starting a first glucose-lowering medication were 0.78 (95% CI 0.62-0.98) for Med-EatPlan + EVOO and 0.89 (0.71-1.12) for Med-EatPlan + nuts, compared with the control eating plan. After a median follow-up of 5.1 years, the adjusted HRs of starting insulin treatment were 0.87 (0.68-1.11) for Med-EatPlan + EVOO and 0.89 (0.69-1.14) for Med-EatPlan + nuts compared with the control eating plan. CONCLUSIONS: Among participants with type 2 diabetes, a Med-EatPlan + EVOO may delay the introduction of new-onset glucose-lowering medications. The Med-EatPlan did not result in a significantly lower need for insulin. The supplemental foods used in the study were donated by Patrimonio Comunal Olivarero and Hojiblanca, Madrid, Spain (EVOO); the California Walnut Commission, Sacramento, CA (walnuts); and Borges SA (almonds) and La Morella Nuts (hazelnuts), Reus, Spain. The PREDIMED trial was supported by Instituto de Salud Carlos III, the official funding agency for biomedical research of the Spanish government, through grants provided to research networks specifically developed for the trial (RTIC RD 06/0045 [coordinator: M.A.M.-G.] and RTIC G03/140 [coordinator: R.E.]). All investigators of the PREDIMED trial belong to CIBER, an initiative of Instituto de Salud Carlos III. The authors also acknowledge grants from the National Institutes of Health Clinical Center (1R01-HL-118264-01 and 1R01-DK-102896), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04/0233, PI05/0976, PI07/0240, PI10/01407, PI10/02658, PI11/00049, PI11/02505, and AGL2010-22319-C03-03), Consejería de Salud Junta de Andalucía (PI0105/2007), and the Generalitat Valenciana, Valencia, Spain (ACOMP/2013/165 and COMP/2013/159).

Scope To assess whether following a Mediterranean diet (MedDiet) improves atherothrombosis biomarkers in high cardiovascular risk individuals. Methods and results In 358 random volunteers from the PREvención con DIeta MEDiterránea trial, the 1‐year effects on atherothrombosis markers of an intervention with MedDiet, enriched with virgin olive oil (MedDiet‐VOO; n = 120) or nuts (MedDiet‐Nuts; n = 119) versus a low‐fat control diet (n = 119), and whether large increments in MedDiet adherence (≥3 score points, versus compliance decreases) and intake changes in key food items are associated with 1‐year differences in biomarkers. Differences are observed between 1‐year changes in the MedDiet‐VOO intervention and control diet on the activity of platelet activating factor acetylhydrolase in high‐density lipoproteins (HDLs) (+7.5% [95% confidence interval: 0.17; 14.8]) and HDL‐bound α1‐antitrypsin levels (−6.1% [−11.8; −0.29]), and between the MedDiet‐Nuts intervention and the control arm on non‐esterified fatty acid concentrations (−9.3% [−18.1; −0.53]). Large MedDiet adherence increments are associated with less fibrinogen (−9.5% [−18.3; −0.60]) and non‐esterified fatty acid concentrations (−16.7% [−31.7; −1.74]). Increases in nut, fruit, vegetable, and fatty fish consumption, and decreases in processed meat intake are linked to enhancements in biomarkers. Conclusion MedDiet improves atherothrombosis biomarkers in high cardiovascular risk individuals., This work was supported by grants of Instituto de Salud Carlos III [OBN17PI02, PIE14/00045_INFLAMES, CB06/03/0019, CB06/03/0028, and CD17/00122 (A.H.)], and Agència de Gestió d'Ajuts Universitaris i de Recerca (2017 SGR 222).

Background: The effect of dietary fat intake on the metabolic syndrome (MetS) and in turn on cardiovascular disease (CVD) remains unclear in individuals at high CVD risk. Objective: To assess the association between fat intake and MetS components in an adult Mediterranean population at high CVD risk. Design: Baseline assessment of nutritional adequacy in participants (n = 6560, men and women, 55&ndash, 75 years old, with overweight/obesity and MetS) in the PREvenci&oacute, n con DIeta MEDiterr&aacute, nea (PREDIMED)-Plus randomized trial. Methods: Assessment of fat intake (total fat, monounsatured fatty acids: MUFA, polyunsaturated fatty acids: PUFA, saturated fatty acids: SFA, trans-fatty acids: trans-FA, linoleic acid, &alpha, linolenic acid, and &omega, 3 FA) using a validated food frequency questionnaire, and diet quality using 17-item Mediterranean dietary questionnaire and fat quality index (FQI). Results: Participants in the highest quintile of total dietary fat intake showed lower intake of energy, carbohydrates, protein and fiber, but higher intake of PUFA, MUFA, SFA, TFA, LA, ALA and &omega, 3 FA. Differences in MetS components were found according to fat intake. Odds (5th vs. 1st quintile): hyperglycemia: 1.3&ndash, 1.6 times higher for total fat, MUFA, SFA and &omega, 3 FA intake, low high-density lipoprotein cholesterol (HDL-c): 1.2 higher for LA, hypertriglyceridemia: 0.7 lower for SFA and &omega, 3 FA intake. Conclusions: Dietary fats played different role on MetS components of high CVD risk patients. Dietary fat intake was associated with higher risk of hyperglycemia.

[Background] High-density lipoprotein (HDL) functionality and low-density lipoprotein (LDL) atherogenic traits can describe the role of both particles on cardiovascular diseases more accurately than HDL- or LDL-cholesterol levels. However, it is unclear how these lipoprotein properties are particularly affected by different cardiovascular risk factors., [Objective] To determine which lipoprotein properties are associated with greater cardiovascular risk scores and each cardiovascular risk factor., [Methods] In two cross-sectional baseline samples of PREDIMED trial volunteers, we assessed the associations of HDL functionality (N = 296) and LDL atherogenicity traits (N = 210) with: 1) the 10-year predicted coronary risk (according to the Framingham-REGICOR score), and 2) classical cardiovascular risk factors., [Results] Greater cardiovascular risk scores were associated with low cholesterol efflux values; oxidized, triglyceride-rich, small HDL particles; and small LDLs with low resistance against oxidation (P-trend, [Conclusions] Dysfunctional HDL and atherogenic LDL particles are present in high cardiovascular risk patients. Dyslipidemia and male sex are predominantly linked to HDL dysfunctionality, whilst diabetes and advanced age are associated with LDL atherogenicity., This work was supported by: Agència de Gestió d’Ajuts Universitaris i de Recerca (2017 SGR 222), Fundació La Marató de TV3 (201512.31), and Instituto de Salud Carlos III (CB06/03/0028 and PI15/00047). A.H. was funded by Instituto de Salud Carlos III (CD17/00122), M.-T.S.-F. was supported by Agència de Gestió d’Ajuts Universitaris i de Recerca (2015 FI_B 01042), and M. Fitó was supported by Instituto de Salud Carlos III (CES12/025). CIBERs of Pathophysiology of Obesity and Nutrition (CIBEROBN) and Cardiovascular Diseases (CIBERCV) are initiatives of the Instituto de Salud Carlos III, Madrid, Spain.

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

[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 (, [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., PREDIMED trial was supported by the official funding agency for biomedical research of the Spanish government (Instituto de Salud Carlos III) RTIC G03/140 (Coordinator: Dr Estruch) and RTIC RD 06/0045 (Coordinator: Dr Martínez-González). We also acknowledge grants from the National Institutes of Health, United States (1R01HL118264-01); Fondo de Investigación Sanitaria– Fondo Europeo de Desarrollo Regional (PI04/0233, PI05/0976, PI07/0240, PI10/01407, PI10/02658, PI11/00049, PI11/02505 and AGL2010-22319-C03-03); Consejería de Salud de la Junta de Andalucía (PI0105/2007), and by the Generalitat Valenciana, Spain (ACOMP/2013/165 and ACOMP/2013/159).

[Scope] To evaluate whether increases in the consumption of cardioprotective food groups (virgin olive oil, nuts, fruits/vegetables, legumes, whole grains, fish, and wine) are associated with improvements in high‐density lipoprotein (HDL) functions in high cardiovascular risk subjects., [Methods and Results] The association between 1‐year changes in food group consumption and HDL functionality traits in 296 high cardiovascular risk subjects is assessed. Increases in virgin olive oil (10 g d–1) and whole grain consumption (25 g d–1) are associated with increments in cholesterol efflux capacity (+0.7%, P = 0.026, and +0.6%, P = 0.017, respectively). Increases in nut (30 g d–1) and legume intake (25 g d–1) are linked to increments in paraoxonase‐1 activity (+12.2%, P = 0.049, and +11.7%, P = 0.043, respectively). Legume intake increases are also related to decreases in cholesteryl ester transfer protein activity (–4.8%, P = 0.028). Fish consumption increments (25 g d–1) are associated with increases in paraoxonase‐1 activity (+3.9%, P = 0.030) and declines in cholesteryl ester transfer protein activity (–1.6%, P = 0.021), HDL cholesterol concentrations (–1.1%, P = 0.039), and functions related to HDL levels (cholesterol efflux capacity, –1.1%, P = 0.010)., [Conclusion] Increases in the consumption of virgin olive oil, nuts, legumes, whole grains, and fish (achievable through a regular diet) were associated with improvements in HDL functions in high cardiovascular risk subjects., This work was supported by: Agència de Gestió d'Ajuts Universitaris i de Recerca (2014‐SGR‐240) and the Instituto de Salud Carlos III (CB06/03/0028, CD17/00122, CES12/025, JR14/00008, OBN17PI02, PI11/01647, and PI15/00047).

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 Prevencion con Dieta Mediterranea (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.

[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., Dr. Jordi Salas-Salvadó has have received grants from the International Nut and Dried Fruit Foundation and is a non-paid member of the scientific advisory board of the International Nut and Dried Fruit Foundation. Dr. Marta Guasch-Ferré was supported by a postdoctoral fellowship granted by the Lilly Foundation European Association of Diabetes (EASD) through the Institut d’Investigacions Sanitàries Pere i Virgili (IISPV), Spain, Tarragona, Spain. Dr. Christopher Papandreou was supported by a postdoctoral fellowship granted by the Autonomous Government of Catalonia, Spain (PERIS 2016–2020 Incorporació de Científics I Tecnòlegs, SLT002/0016/00428).

Few studies have examined the association of a wide range of metabolites with total and subtypes of coffee consumption. The aim of this study was to investigate associations of plasma metabolites with total, caffeinated, and decaffeinated coffee consumption. We also assessed the ability of metabolites to discriminate between coffee consumption categories. This is a cross-sectional analysis of 1664 participants from the PREDIMED study. Metabolites were semiquantitatively profiled using a multiplatform approach. Consumption of total coffee, caffeinated coffee and decaffeinated coffee was assessed by using a validated food frequency questionnaire. We assessed associations between 387 metabolite levels with total, caffeinated, or decaffeinated coffee consumption (&ge, 50 mL coffee/day) using elastic net regression analysis. Ten-fold cross-validation analyses were used to estimate the discriminative accuracy of metabolites for total and subtypes of coffee. We identified different sets of metabolites associated with total coffee, caffeinated and decaffeinated coffee consumption. These metabolites consisted of lipid species (e.g., sphingomyelin, phosphatidylethanolamine, and phosphatidylcholine) or were derived from glycolysis (alpha-glycerophosphate) and polyphenol metabolism (hippurate). Other metabolites included caffeine, 5-acetylamino-6-amino-3-methyluracil, cotinine, kynurenic acid, glycocholate, lactate, and allantoin. The area under the curve (AUC) was 0.60 (95% CI 0.56&ndash, 0.64), 0.78 (95% CI 0.75&ndash, 0.81) and 0.52 (95% CI 0.49&ndash, 0.55), in the multimetabolite model, for total, caffeinated, and decaffeinated coffee consumption, respectively. Our comprehensive metabolic analysis did not result in a new, reliable potential set of metabolites for coffee consumption.

Our purpose was to study the relationship of adherence to the Mediterranean diet (MedDiet) with urinary factors that favor the formation of renal calcium and uric acid stones in overweight and obese participants who had metabolic syndrome. This cross-sectional study examined 267 participants. A well-known MedDiet score (range 0&ndash, 9) was calculated for each patient, and patients were then categorized has having low (&le, 3), medium (4&ndash, 5), or high (&ge, 6) adherence to the MedDiet. Baseline characteristics and urinary parameters were also analyzed. High calcium salt urinary crystallization risk (CaUCR) and high uric acid urinary crystallization risk (UrUCR) were calculated from urinary parameters using pre-defined criteria. More than half of patients with MedDiet scores &le, 3 had high UrUCR (55.4%) and high CaUCR (53.8%). In contrast, fewer patients with high adherence (&ge, 6) to the MedDiet had high UrUCR (41.2%) and high CaUCR (29.4%). Relative to those with low adherence, individuals with high adherence had a prevalence ratio (PR) of 0.77 for a high UrUCR (95% CI: 0.46&ndash, 1.12, p for trend: 0.069) and a PR of 0.51 for a high CaUCR (95% CI: 0.26&ndash, 0.87, p for trend: 0.012) after adjusting for age, sex, body mass index, type 2 diabetes, and total energy intake. Our findings indicate that greater adherence to the MedDiet was associated with a reduced CaUCR and a reduced UrUCR. This suggests that adequate dietary management using the MedDiet patterns may prevent or reduce the incidence and recurrence of calcium salt and uric acid renal stones.

[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., Supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to R.E.; RTIC RD 06/0045, to Miguel A. Martínez-González) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (Proyecto de Investigación (PI) 04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, PI13/00615, PI13/01090, PI14/01668, PI14/01798, PI14/01764), Ministerio de Ciencia e Innovación (Recursos y teconologia agroalimentarias(AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083-C3-1- R), Fundación Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (Generalitat Valenciana Ayuda Complementaria (GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151), Conselleria de Sanitat y, PI14/01764 AP; Atención Primaria (CS) 2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).). Drs. Shivappa and Hébert were supported by grant number R44DK103377 from the United States National Institute of Diabetes and Digestive and Kidney Diseases.

Background Sarcopenia is a progressive age-related skeletal muscle disorder associated with increased likelihood of adverse outcomes. Muscle wasting is often accompanied by an increase in body fat, leading to 'sarcopenic obesity'. The aim of the present study was to analyse the association of lifestyle variables such as diet, dietary components, physical activity (PA), body composition, and inflammatory markers, with the risk of sarcopenic obesity. Methods A cross-sectional analysis based on baseline data from the PREDIMED-Plus study was performed. A total of 1535 participants (48% women) with overweight/obesity (body mass index: 32.5 +/- 3.3 kg/m(2); age: 65.2 +/- 4.9 years old) and metabolic syndrome were categorized according to sex-specific tertiles (T) of the sarcopenic index (SI) as assessed by dual-energy X-ray absorptiometry scanning. Anthropometrical measurements, biochemical markers, dietary intake, and PA information were collected. Linear regression analyses were carried out to evaluate the association between variables. Results Subjects in the first SI tertile were older, less physically active, showed higher frequency of abdominal obesity and diabetes, and consumed higher saturated fat and less vitamin C than subjects from the other two tertiles (all P < 0.05). Multiple adjusted linear regression models evidenced significant positive associations across tertiles of SI with adherence to the Mediterranean dietary score (P-trend < 0.05), PA (P-trend < 0.0001), and the 30 s chair stand test (P-trend < 0.0001), whereas significant negative associations were found with an inadequate vitamin C consumption (P-trend < 0.05), visceral fat and leucocyte count (all P-trend < 0.0001), and some white cell subtypes (neutrophils and monocytes), neutrophil-to-lymphocyte ratio, and platelet count (all P-trend < 0.05). When models were additionally adjusted by potential mediators (inflammatory markers, diabetes, and waist circumference), no relevant changes were observed, only dietary variables lost significance. Conclusions Diet and PA are important regulatory mediators of systemic inflammation, which is directly involved in the sarcopenic process. A healthy dietary pattern combined with exercise is a promising strategy to limit age-related sarcopenia. This work was supported by the official Spanish institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación para la Salud (FIS), co‐funded by the European Regional Development Fund (ERDF) (four coordinated FIS projects leaded by J.S.‐S. and J.V., including the following projects: PI13/00462, PI13/01090, PI13/02184, PI14/00853, PI14/00728, PI14/01919, PI16/00501, PI16/00381, PI16/01522, PI17/00525, PI17/00532, PI17/00215, and PI17/00926), and through specific grants: the Astra Zeneca Young Investigators Award in Category of Obesity and Diabetes 2017 (D.R.); Juan de la Cierva‐formación research grant (FJCI‐2015‐24058) of the Spanish Ministry of Economy, Industry and Competitiveness and European Social Funds (J.K.), the ‘FOLIUM’ programme within the FUTURMed project; and talent for the medicine within the future from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands) (J.K.). None of the funding sources took part in the design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. This work is supported by the European Research Council (Advanced Research Grant 2014–2019; agreement #340918 granted to MAM‐G).

Scope: To examine the association between milk and dairy products intake and the prevalence of cognitive decline among Spanish individuals at high cardiovascular risk. Methods and results: Cross-sectional analyses are performed on baseline data from 6744 adults (aged 55-75 years old). Intake of milk and dairy products is estimated using a food frequency questionnaire grouped into quartiles. The risk of developing cognitive impairment is based on the Mini-Mental State Examination (MMSE). A higher prevalence of cognitive decline was found in subjects who consumed more grams. Patients with worse MMSE score (10-24) consumed a mean of 395.14 ± 12.21 g, while patients with better MMSE score (27-30) consumed a mean of 341.23 ± 2.73 g (p < 0.05). Those subjects with the lower milk consumption (

There is little information on the dietary modulation of thrombosis-related risk factors such as platelet count. We aimed to assess the effects of Mediterranean diet (MedDiet) on platelet count and related outcomes in an older population at high cardiovascular risk. In participants of the PREDIMED (PREvención con DIeta MEDiterránea) study, we assessed whether an intervention with a MedDiet enriched with extra-virgin olive oil or nuts, relative to a low-fat control diet, modulated platelet count (n = 4189), the risk of developing thrombocytosis and thrombocytopenia (n = 3086), and the association between these alterations and all-cause mortality (median follow-up time: 3.0 years). Although platelet count increased over time (+0.98·109 units/L·year [95% confidence interval: 0.12, 1.84]), MedDiet interventions moderated this increase, particularly in individuals with near-high baseline count (both MedDiets combined: −3.20·109 units/L·year [−5.81, −0.59]). Thrombocytopenia incidence was lower in the MedDiet interventions (incidence rates: 2.23% in control diet, 0.91% in MedDiets combined, hazard ratio: 0.44 [0.23, 0.83]). Finally, thrombocytopenia was associated with a higher risk of all-cause mortality (hazard ratio: 4.71 [2.69, 8.24]), but this relationship was attenuated in those allocated to MedDiet (p-interaction = 0.018). In brief, MedDiet maintained platelet counts within a healthy range and attenuated platelet-related mortality in older adults at high cardiovascular risk.

Summary Background Because of the high density of fat, high-fat diets are perceived as likely to lead to increased bodyweight, hence health-care providers are reluctant to recommend them to overweight or obese individuals. We assessed the long-term effects of ad libitum, high-fat, high-vegetable-fat Mediterranean diets on bodyweight and waist circumference in older people at risk of cardiovascular disease, most of whom were overweight or obese. Methods PREDIMED was a 5 year parallel-group, multicentre, randomised, controlled clinical trial done in primary care centres affiliated to 11 hospitals in Spain. 7447 asymptomatic men (aged 55–80 years) and women (aged 60–80 years) who had type 2 diabetes or three or more cardiovascular risk factors were randomly assigned (1:1:1) with a computer-generated number sequence to one of three interventions: Mediterranean diet supplemented with extra-virgin olive oil (n=2543); Mediterranean diet supplemented with nuts (n=2454); or a control diet (advice to reduce dietary fat; n=2450). Energy restriction was not advised, nor was physical activity promoted. In this analysis of the trial, we measured bodyweight and waist circumference at baseline and yearly for 5 years in the intention-to-treat population. The PREDIMED trial is registered with ISRCTN.com, number ISRCTN35739639. Findings After a median 4·8 years (IQR 2·8–5·8) of follow-up, participants in all three groups had marginally reduced bodyweight and increased waist circumference. The adjusted difference in 5 year changes in bodyweight in the Mediterranean diet with olive oil group was −0·43 kg (95% CI −0·86 to −0·01; p=0·044) and in the nut group was −0·08 kg (–0·50 to 0·35; p=0·730), compared with the control group. The adjusted difference in 5 year changes in waist circumference was −0·55 cm (–1·16 to −0·06; p=0·048) in the Mediterranean diet with olive oil group and −0·94 cm (–1·60 to −0·27; p=0·006) in the nut group, compared with the control group. Interpretation A long-term intervention with an unrestricted-calorie, high-vegetable-fat Mediterranean diet was associated with decreases in bodyweight and less gain in central adiposity compared with a control diet. These results lend support to advice not restricting intake of healthy fats for bodyweight maintenance. Funding Spanish Government, CIBERobn, Instituto de Salud Carlos III, Hojiblanca, Patrimonio Comunal Olivarero, California Walnut Commission, Borges SA, and Morella Nuts.

Background: Higher consumption of some polyphenols has been associated with a reduced risk of diabetes. However, no studies have evaluated the relation between all polyphenol subclasses and the incidence of diabetes.Objective: We aimed to prospectively examine the associations between the intake of total polyphenols and different groups of polyphenols (flavonoids, phenolic acids, stilbenes, lignans, and others) on the risk of incident diabetes in the PREDIMED (Prevencion con Dieta Mediterranea) trial.Methods: This was an observational cohort analysis of the nondiabetic participants in the PREDIMED trial. This study was a multicenter, controlled, randomized, parallel-group feeding trial to assess the effects of either a Mediterranean diet that was supplemented with extra-virgin olive oil or nuts or advice to adhere to a low-fat control diet on cardiovascular outcomes in elderly men and women at high cardiovascular disease risk. From the 7447 randomly assigned participants, 3430 were selected because they were free of diabetes at baseline and filled out the food-frequency questionnaires (FFQs). Polyphenol intake was calculated by matching food consumption data from repeated FFQs with the Phenol-Explorer database on the polyphenol content of each reported food. HRs and 95% CIs for diabetes according to tertiles of polyphenol intake were estimated with the use of time-dependent Cox proportional hazards models.Results: Over a mean of 5.51 y of follow-up (18,900 person-years), there were 314 new cases of diabetes. After multivariable adjustment, we observed a 28% reduction in new-onset diabetes in the highest compared with the lowest tertile of total polyphenol intake (HR: 0.72; 95% CI: 0.52, 0.99; P-trend = 0.05). The intake of subclasses of polyphenols also was inversely associated with diabetes risk, including for total flavonoids (HR: 0.67; 95% CI: 0.48, 0.93; P-trend = 0.02), stilbenes (HR: 0.57; 95% CI: 0.38, 0.84; P-trend = 0.003), dihydroflavonols (HR: 0.59; 95% CI: 0.40, 0.88; P-trend = 0.003), and flavanones (HR: 0.69; 95% CI: 0.49, 0.97; P-trend = 0.03).Conclusions: A high intake of total polyphenols, total flavonoids (specifically flavanones and dihydroflavonols), and stilbenes is associated with a reduced risk of diabetes in elderly persons at high risk of cardiovascular disease. This trial was registered at http://www.controlled-trials.com as ISRCTN35739639.

Background: When promoting physical activity practice, it is important to consider the plausible environmental determinants that may affect this practice. We aimed to explore the impact of objectively measured Public Open Spaces (POS) on objectively measured and self-reported physical activity and the influence of weather on this association, in a Mediterranean sample of senior adults with overweight or obesity and the metabolic syndrome. Method: Cross-sectional analyses based on 218 PREDIMED-Plus trial participants aged 55 to 75 years, from Palma de Mallorca (Spain). Indicators of access to POS were assessed in a 1.0 km sausage network walkable buffer around each participant’s residence address using geographic information systems. Mean daily minutes of self-reported leisure-time brisk walking, and accelerometer objectively measured moderate-to-vigorous physical activity in bouts of at least 10 min (OM-MVPA) were measured. To investigate the association between access to POS and physical activity, generalized additive models with Gaussian link function were used. Results: Better access to POS was not statistically significantly associated with self-reported leisure-time brisk walking. A positive significant association was only observed between the distance of healthy routes contained or intersected by buffer and OM-MVPA. This association was only evident on non-rainy days. Conclusions: In this elderly population living in a Mediterranean city, only healthy routes contained or intersected by a 1 km sausage network walkable buffer influenced the accelerometer objectively measured moderate-to-vigorous physical activity in bouts of at least 10 min and rainy conditions during the accelerometer period appeared to be an important factor related to active ageing.

Some imperfections in the randomization procedures affecting a small subset of participants in the Prevencion con Dieta Mediterranea (PREDIMED) trial (at most 14%) have been reported in a recent republication of the main PREDIMED article (see Estruch et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 2018;378:e34). For this reason, the authors wish to make the …

A 48-year-old man with a history of smoking, high blood pressure, moderate alcoholism, occasional cocaine consumer, sleep apnea syndrome and family history of ischemic heart disease.

Background and aims The PREDIMED (PREvencion con DIeta MEDiterranea) 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 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 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.

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. Centro de Investigacion Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds (CB06/03). Supported by the official funding agency for biomedical research of the Spanish government, ISCIII, through grants provided to research networks specifically developed for the trial (RTIC G03/140 and RD 06/0045 through CIBEROBN, and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigacion Sanitaria eFondo Europeo de Desarrollo Regional (PI04e2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and PI11/02505; PI13/00462), Ministerio de Ciencia e Innovacion (AGL- 2009e13906-C02 and AGL2010e22319-C03), Fundacion Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010e181, GVACOMP2011e151, CS2010- AP-111, and CS2011-AP-042), and the Navarra Regional Government (27/2011). The Fundacion Patrimonio Comunal Olivarero and Hojiblanca SA (Malaga, Spain), California Walnut Commission (Sac- ramento, CA), Borges SA (Reus, Spain), and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study

BACKGROUND: Perturbed lipid metabolic pathways may play important roles in the development of cardiovascular disease (CVD). However, existing epidemiological studies have focused more on discovering individual lipid metabolites for CVD risk prediction rather than assessing metabolic pathways. METHODS: This study included a subcohort of 787 participants and all 230 incident CVD cases from the PREDIMED trial. Applying a network-based analytical method, we identified lipid subnetworks and clusters from a global network of 200 lipid metabolites and linked these subnetworks/clusters to CVD risk. RESULTS: Lipid metabolites with more double bonds clustered within one subnetwork, whereas lipid metabolites with fewer double bonds clustered within other subnetworks. We identified 10 lipid clusters that were divergently associated with CVD risk. The hazard ratios [HRs, 95% confidence interval (CI)] of CVD per a 1-standard deviation (SD) increment in cluster score were 1.39 (1.17-1.66) for the hydroxylated phosphatidylcholine (HPC) cluster and 1.24 (1.11-1.37) for a cluster that included diglycerides and a monoglyceride with stearic acyl chain. Every 1-SD increase in the score of cluster that included highly unsaturated phospholipids and cholesterol esters was associated with an HR for CVD of 0.81 (95% CI, 0.67-0.98). Despite a suggestion that MedDiet modified the association between a subnetwork that included most lipids with a high degree of unsaturation and CVD, changes in lipid subnetworks/clusters during the first-year follow-up were not significantly different between intervention groups. CONCLUSIONS: The degree of unsaturation was a major determinant of the architecture of lipid metabolic network. Lipid clusters that strongly predicted CVD risk, such as the HPC cluster, warrant further functional investigations. This work was supported by a research grant from the National Institutes of Health [R01 HL118264]. The Prevención con Dieta Mediterránea (PREDIMED) trial was supported by the official funding agency for biomedical research of the Spanish government, the Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial (RTIC G03/140 to R.E. and RTIC RD 06/0045 to Dr. Miguel A. Martínez-González) and through the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición and by grants from: the Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007); the Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505 and PI13/00462); the Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03); the Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007); the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010–181, GVACOMP2011–151, CS2010-AP-111, and CS2011-AP-042); and the Regional Government of Navarra (P27/2011). Dr. Dong D Wang was supported by a postdoctoral fellowship granted by the American Heart Association (16POST31100031)

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., The authors disclose no conflict of interest related with the article. Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds (CB06/03). Supported by the official funding agency for biomedical research of the Spanish government, ISCIII, through grants provided to research networks specifically developed for the trial (RTIC G03/140 and RD 06/0045) through CIBEROBN, and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–FondoEuropeo de Desarrollo Regional (PI04–2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and PI11/02505; PI13/00462), Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, and CS2011-AP-042), and the Navarra Regional Government (27/2011). The Fundación Patrimonio Comunal Olivarero and Hojiblanca SA (Málaga, Spain), California Walnut Commission (Sacramento, CA), Borges SA (Reus, Spain), and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study. None of the funding sources played a role in the design, collection, analysis or interpretation of the data or in the decision to submit the manuscript for publication. Acknowledgements: The authors thank all the participants for their collaboration, all the PREDIMED personnel for their assistance and all the personnel of affiliated primary care centers for making the study possible. CIBEROBN is an initiative of ISCIII, Spain.

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.

A moderately high-fat Mediterranean diet does not promote weight gain. This study aimed to investigate the association between dietary intake of specific types of fat and obesity and body weight. A prospective cohort study was performed using data of 6942 participants in the PREDIMED trial, with yearly repeated validated food-frequency questionnaires, and anthropometric outcomes (median follow-up: 4.8 years). The effects of replacing dietary fat subtypes for one another, proteins or carbohydrates were estimated using generalized estimating equations substitution models. Replacement of 5% energy from saturated fatty acids (SFA) with monounsaturated fatty acids (MUFA) or polyunsaturated fatty acids (PUFA) resulted in weight changes of &minus, 0.38 kg (95% Confidece Iinterval (CI): &minus, 0.69, &minus, 0.07), and &minus, 0.51 kg (95% CI: &minus, 0.81, &minus, 0.20), respectively. Replacing proteins with MUFA or PUFA decreased the odds of becoming obese. Estimates for the daily substitution of one portion of red meat with white meat, oily fish or white fish showed weight changes up to &minus, 0.87 kg. Increasing the intake of unsaturated fatty acids at the expense of SFA, proteins, and carbohydrates showed beneficial effects on body weight and obesity. It may therefore be desirable to encourage high-quality fat diets like the Mediterranean diet instead of restricting total fat intake.

Prospective studies have reported an inverse association between the consumption of total dairy products and milk and the risk of colorectal cancer (CRC). Nonetheless, there is little and inconsistent evidence regarding subtypes of dairy product and CRC risk. We assessed the associations between the consumption of total dairy products, their different subtypes and CRC risk in older Mediterranean individuals at high cardiovascular risk. We analyzed data from 7,216 men and women (55-80 years) without CRC at baseline from the PREvencion con DIeta MEDiterranea study. Individuals were recruited between 2003 and 2009 and followed up until December 2012. At baseline and yearly thereafter, consumption of total and specific dairy products was assessed using a validated 137-item food-frequency questionnaire. Cox proportional hazards ratios (HRs) of CRC incidence were estimated for tertiles of mean consumption of dairy products during the follow-up. During a median [interquartile range] follow-up of 6.0 [4.4-7.3] years, we documented 101 incident CRC cases. In the multivariable-adjusted models, HRs and 95% confidence intervals (CIs) of CRC for the comparison of extreme tertiles of total dairy product and low-fat milk consumption were 0.55 (95% CI: 0.31-0.99; p-trend = 0.037) and 0.54 (95% CI: 0.32-0.92; p-trend = 0.022), respectively. No significant associations with other dairy products (whole-fat and low-fat dairy products; total, low-fat and whole-fat yogurt; cheese; total, low-fat and whole-fat milk; concentrated full-fat dairy products, sugar-enriched dairy products and fermented dairy products) were found. A high consumption of total dairy products and low-fat milk was significantly associated with a reduced CRC risk.

PURPOSE: The aim of the present study was to assess the association between the dietary total antioxidant capacity, the dietary intake of different antioxidants and mortality in a Mediterranean population at high cardiovascular disease risk. METHODS: A total of 7,447 subjects from the PREDIMED study (multicenter, parallel group, randomized controlled clinical trial), were analyzed treating data as an observational cohort. Different antioxidant vitamin intake and total dietary antioxidant capacity were calculated from a validated 137-item food frequency questionnaire at baseline and updated yearly. Deaths were ascertained through contact with families and general practitioners, review of medical records and consultation of the National Death Index. Cox regression models were fitted to assess the relationship between dietary total antioxidant capacity and mortality. Dietary total antioxidant capacity was estimated using ferric-reducing antioxidant power assays./nRESULTS: A total of 319 deaths were recorded after a median follow-up of 4.3 years. Subjects belonging to the upper quintile of antioxidant capacity were younger, ex-smokers, with high educational level, and more active and had higher alcohol intake. Multivariable-adjusted models revealed no statistically significant difference between total dietary antioxidant capacity and mortality (Q5 vs. Q1 ref HR 0.85; 95 % CI 0.60-1.20) neither for the intake of all the vitamins studied. CONCLUSIONS: No statistically significant association was found between antioxidant capacity and total mortality in elderly subjects at high cardiovascular risk. This study was funded by the Spanish Ministry of Health (ISCIII), CIBEROBN, PI1001407, G03/140, RD06/0045 and the Autonomous Government of Catalonia, and Caixa Tarragona (10-1343).

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-The relationship between plasma concentrations of betaine and choline metabolism and major cardiovascular disease (CVD) end points remains unclear. We have evaluated the association between metabolites from the choline pathway and risk of incident CVD and the potential modifying effect of Mediterranean diet interventions. Methods and Results-We designed a case-cohort study nested within the PREDIMED (Prevention With Mediterranean Diet) trial, including 229 incident CVD cases and 751 randomly selected participants at baseline, followed up for 4.8 years. We used liquid chromatography-tandem mass spectrometry to measure, at baseline and at 1 year of follow-up, plasma concentrations of 5 metabolites in the choline pathway: trimethylamine N-oxide, betaine, choline, phosphocholine, and a-glycerophosphocholine. We have calculated a choline metabolite score using a weighted sum of these 5 metabolites. We used weighted Cox regression models to estimate CVD risk. The multivariable hazard ratios (95% confidence intervals) per 1-SD increase in choline and alpha-glycerophosphocholine metabolites were 1.24 (1.05-1.46) and 1.24 (1.03-1.50), respectively. The baseline betaine/choline ratio was inversely associated with CVD. The baseline choline metabolite score was associated with a 2.21-fold higher risk of CVD across extreme quartiles (95% confidence interval, 1.36-3.59; P, This work was supported by NIH research grant HL118264. The PREDIMED trial was supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial (RTIC G03/140 to Estruch; RTIC RD 06/0045 to Martinez-Gonzalez) and through Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y Nutricion; and by grants from Centro Nacional de Investigaciones Cardiovasculares (06/2007), Fondo de Investigacion Sanitaria-Fondo Europeo de Desarrollo Regional (PI04-2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, and PI13/00462), Ministerio de Ciencia e Innovacion (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundacion Mapfre 2010, Consejeria de Salud de la Junta de Andalucia (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010-181, GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011). Guasch-Ferre was supported by a postdoctoral fellowship granted by the Agency for Administration of University and Research Grants of the Autonomous Government of Catalonia (2014-BP-A 00017). None of the funding sources played a role in the design, collection, analysis, or interpretation of the data or in the decision to submit the article for publication.

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

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

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

Objectives: To assess the association between potato consumption, blood pressure changes and the risk of hypertension in two Mediterranean populations. Design: Separate analyses were performed in the PREDIMED (PREvención con DIeta MEDiterránea), a multicenter nutrition intervention trial, and the SUN (“Seguimiento Universidad de Navarra”) project, an open, prospective cohort, both in Spain. Participants: The PREDIMED trial included 6,940 participants aged 55-80 years at high risk for cardiovascular disease. The SUN project included 13,837 middle-aged participants who were university graduates. Main outcome measures: In PREDIMED, generalized estimating equations adjusted for lifestyle and dietary characteristics were used to assess changes in blood pressure across quintiles of total potato consumption during a 4-year follow-up. Controlled blood pressure levels during follow-up were also assessed. For SUN, multivariable-adjusted hazard ratios (HR) for incident hypertension during an average 6.7-year follow-up were calculated. Results: In PREDIMED, the mean (SD) total potato intake was 81.9 (40.6) g/day. No overall significant differences in blood pressure changes were detected based on consumption of potatoes. For total potatoes, the mean change in systolic BP after multivariate adjustment was quintile 5 (Q5) vs. quintile 1 (Q1): -0.90, 95% CI: (-2.56 to 0.76) mmHg, p for trend=0.14 and for diastolic BP it was Q5 vs. Q1: -0.02, 95% CI: (-0.93 to 0.89) mmHg, p for trend=0.81. In SUN, the mean (SD) total potato consumption was 52.7 (33.6) g/day and no significant association between potato consumption and hypertension incidence was observed: HR: for total potato consumption, Q5 vs. Q1: 0.98, 95% CI: (0.80 to 1.19), p for trend=0.84. Conclusions: Potato consumption is not associated with changes in blood pressure or risk of hypertension in Mediterranean populations and this might be explained by relatively low consumption of potatoes and characteristics of the traditional Mediterranean diet, particularly the custom of accompanying potatoes with vegetables or legumes and dressing them with olive oil.

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 PREvencion con DIeta MEDiterranea (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.

Background: Substantial evidence suggests that consuming 1-2 servings of fish per week, particularly oily fish (e.g., salmon, herring, sardines) is beneficial for cardiovascular health due to its high n-3 polyunsaturated fatty acid content. However, there is some concern that the mercury content in fish may increase cardiovascular disease risk, but this relationship remains unclear. Methods: The PREDIMED trial included 7477 participants who were at high risk for cardiovascular disease at baseline. In this study, we evaluated associations between mercury exposure, fish consumption and cardiovascular disease. We randomly selected 147 of the 288 cases diagnosed with cardiovascular disease during follow-up and matched them on age and sex to 267 controls. Instrumental neutron activation analysis was used to assess toenail mercury concentration. In-person interviews, medical record reviews and validated questionnaires were used to assess fish consumption and other covariates. Information was collected at baseline and updated yearly during follow-up. We used conditional logistic regression to evaluate associations in the total nested case-control study, and unconditional logistic regression for population subsets. Results: Mean (+/- SD) toenail mercury concentrations (mu g per gram) did not significantly differ between cases (0.63 (+/- 0.53)) and controls (0.67 (+/- 0.49)). Mercury concentration was not associated with cardiovascular disease in any analysis, and neither was fish consumption or n-3 fatty acids. The fully-adjusted relative risks for the highest versus lowest quartile of mercury concentration were 0.71 (95% Confidence Interval [CI], 0.34, 1.14; p(trend) = 0.37) for the nested case-control study, 0.74 (95% CI, 0.32, 1.76; p(trend) = 0.43) within the Mediterranean diet intervention group, and 0.50 (95% CI, 0.13, 1.96; p(trend) = 0.41) within the control arm of the trial. Associations remained null when mercury was jointly assessed with fish consumption at baseline and during follow-up. Results were similar in different sensitivity analyses. Conclusions: We found no evidence that mercury exposure from regular fish consumption increases cardiovascular disease risk in a population of Spanish adults with high cardiovascular disease risk and high fish consumption. This implies that the mercury content in fish does not detract from the already established cardiovascular benefits of fish consumption., This study was funded by the Spanish Ministry of Health (ISCIII), PI1001407, Thematic Network G03/140, RD06/0045, FEDER (Fondo Europeo de Desarrollo Regional), and the Centre Catala de la Nutricio de l'Institut d'Estudis Catalans. The Fundacion Patrimonio Comunal Olivarero and Hojiblanca SA (Malaga, Spain), California Walnut Commission (Sacramento, CA), Borges SA (Reus, Spain) and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds and hazelnuts, respectively, used in the study.

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. The Prevención con Dieta Mediterránea (PREDIMED) trial was supported by the official funding agency for biomedical research of the Spanish government, the Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial [grant RTIC G03/140 (to RE); grant RTIC RD 06/0045 (to MAM-G)] and through the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición and by grants from Centro Nacional de Investigaciones Cardiovasculares (grant CNIC 06/2007), the Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (grants PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, I07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, and PI13/00462), the Ministerio de Ciencia e Innovación (grants AGL-2009–13906-C02 and AGL2010–22319-C03), the Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (grant PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (grants ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, and CS2011-AP-042), and the Regional Government of Navarra (grant P27/2011).

Importance Cataract, one of the most frequent causes of blindness in developed countries, is strongly associated with aging. The exact mechanisms underlying cataract formation are still unclear, but growing evidence suggests a potential role of inflammatory and oxidative processes. Therefore, antioxidant and anti-inflammatory factors of the diet, such as vitamin K 1 , could play a protective role. Objective To examine the association between dietary vitamin K 1 intake and the risk of incident cataracts in an elderly Mediterranean population. Design, Setting, and Participants A prospective analysis was conducted in 5860 participants from the Prevencion con Dieta Mediterranea Study, a randomized clinical trial executed between 2003 and 2011. Participants were community-dwelling men (44.2%) and women (55.8%), and the mean (SD) age was 66.3 (6.1) years. Main Outcomes and Measures Dietary vitamin K 1 intake was evaluated using a validated food frequency questionnaire. The time to the cataract event was calculated as the time between recruitment and the date of the occurrence to cataract surgery, the time to the last visit of the follow-up, date of death, or the end of the study. Hazard ratios and 95% CIs for cataract incidence were estimated with a multivariable Cox proportional hazards model. Results Participants were community-dwelling men (44.2%; n = 868) and women (55.8%; n = 1086), and the mean (SD) age was 66.3 (6.1) years. After a median of 5.6 years follow-up, we documented a total of 768 new cataracts. Participants in the highest tertile of dietary vitamin K 1 intake had a lower risk of cataracts than those in the lowest tertile (hazard ratio, 0.71; 95% CI, 0.58-0.88; P = .002), after adjusting for potential confounders. Conclusions and Relevance High intake of dietary vitamin K 1 was associated with a reduced risk of cataracts in an elderly Mediterranean population even after adjusting by other potential confounders. Trial Registration isrctn.org:ISRCTN35739639

unster, MGermany Background: We will focus our attention in this article in the ECG changes of classical Prinzmetal angina that occur during occlusive proximal coronary spasm usually in patients with normal or noncritical coronary stenosis. Results: The most important ECG change during a focal proximal coronary spasm is in around 50% of cases the appearance of peaked and symmetrical T wave that is followed, if the spasm persist, by progressive ST-segment elevation that last for a few minutes, and later progressively resolve. The most frequent ECG changes associated with ST-segment elevation are: (a) increased height of the R wave, (b) coincident S-wave diminution, (c) upsloping TQ in many cases, and (d) alternans of the elevated ST-segment and negative T wave deepness in 20% of cases. The presence of arrhythmias is very frequent during Prinzmetal angina crises, especially ventricular arrhythmias. The prevalence and importance of ventricular arrhythmias were related to: (a) duration of episodes, (b) degree of ST-segment elevation, (c) presence of ST-T wave alternans, and (d) the presence of >25% increase of the R wave. Conclusions: The incidence of Prinzmetal angina is much lower then 50 years ago for many reasons including treatment with calcium channel blocks to treat hypertension and ischemia heart disease and the decrease of smoking habits. Ann Noninvasive Electrocardiol 2014;19(5):442-453 electrocardiography; Prinzmethal angina; coronary spasm; ST elevation

Background For many years was considered that negative T wave in ischemic heart disease represents ischemia and for many authors located in subepicardial area. Methods We performed a review based in the literature and in the experience of the authors commenting the real significance of the presence of negative T wave in patients with ischemic heart disease. Results The negative T wave may be of primary or secondary type. Negative T wave observed in ischemic heart disease are of primary origin, therefore not a consequence of abnormal repolarization pattern. The negative T wave of ischemic origin presents the following characteristics: (1) are symmetrical and of variable deepness; (2) present mirror patterns; (3) starts in the second part of repolarization; and (4) may be accompanied by positive or negative U wave. The negative T wave of ischemic origin may be seen in the following clinical settings: (1) postmyocardial infarction due to a window effect of necrotic zone and (2) as a consequence of reperfusion in case of aborted MI when the artery has opened spontaneously, or after fibrinolysis, PCI, or coronary spasm. Conclusion Acute ongoing ischemia do not cause negative T wave. This pattern appears when the ongoing ischemia is vanishing or in the chronic phase. In all these cases the cause of negative T wave is not located in the subepicardial area. Furthermore, positive exercise testing is expressed by ST depression never by isolated negative T wave. There are many circumstances that may present negative T wave outside ischemic heart disease and that have been discussed in this paper.

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. This trial was registered at controlled-trials.com as ISRCTN35739639. © 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 (multivariableadjusted 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. Am J Clin Nutr 2014;100(suppl):320S–8S.

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. Clinical trial registry: International Standard Randomized Controlled Trial Number (ISRCTN of London, England) 35739639. © 2014 Elsevier B.V., We would like to thank all the volunteers involved in the PREDIMED study for their valuable cooperation. This study was supported by CICYT (AGL2010-22319-C03) from the Spanish Ministry of Science and Innovation (MICINN), and the Instituto de Salud Carlos III, ISCIII (CIBERobn-CB06/03, PI1002658, and PI1001407). CIBERobn is an initiative of ISCIII, Spain. AT-R received support from ISCIII (FI10/00265).

Aims Scarce data are available on the effect of the traditional Mediterranean diet (TMD) on heart failure biomarkers. We assessed the effect of TMD on biomarkers related to heart failure in a high cardiovascular disease risk population. Methods and Results A total of 930 subjects at high cardiovascular risk (420 men and 510 women) were recruited in the framework of a multicentre, randomized, controlled, parallel-group clinical trial directed at testing the efficacy of the TMD on the primary prevention of cardiovascular disease (The PREDIMED Study). Participants were assigned to a low-fat diet (control, n = 310) or one of two TMDs [TMD + virgin olive oil (VOO) or TMD + nuts]. Depending on group assignment, participants received free provision of extra-virgin olive oil, mixed nuts, or small non-food gifts. After 1 year of intervention, both TMDs decreased plasma N-terminal pro-brain natriuretic peptide, with changes reaching significance vs. control group (P

Resumen Introduccion y objetivos Analizar las diferencias en funcion del sexo en las caracteristicas clinicas, tratamiento y mortalidad a los 28 dias y a los 7 anos de un primer infarto de miocardio. Metodos Entre 2001 y 2003, 2.042 pacientes con un primer infarto de miocardio ingresaron consecutivamente en seis hospitales espanoles. Se recogen prospectivamente las caracteristicas clinicas, el tratamiento y la mortalidad a los 28 dias. Se dispone del estado vital a los 7 anos mediante consulta del Indice Nacional de Defunciones. Resultados Se incluyo a 449 mujeres y 1.593 varones con un primer infarto de miocardio. En comparacion con los varones, las mujeres eran mayores y tenian mayor prevalencia de hipertension y diabetes mellitus; tambien recibieron mas tratamiento con inhibidores de la enzima de conversion de la angiotensina, pero menos bloqueadores beta y trombolisis. No hubo diferencias en el uso de procedimientos invasivos. Las mujeres tuvieron mas infartos de miocardio sin elevacion del segmento ST o no clasificables (el 37,9 frente al 31,3% y el 9,8 frente al 6,1% respectivamente; p Conclusiones Hay diferencias clinicas y demograficas entre varones y mujeres que ingresan por un primer infarto de miocardio. El pronostico a corto plazo es similar en ambos sexos. La mortalidad a 7 anos de un primer infarto de miocardio es peor en varones que en mujeres. Estos resultados se observan en infartos agudos de miocardio con y sin elevacion del segmento ST.

Nutrigenetic studies analyzing gene-diet interactions of the TCF7L2-rs7903146 C > T polymorphism on type-2 diabetes (T2D) have shown controversial results. A reason contributing to this may be the additional modulation by obesity. Moreover, TCF7L2-rs7903146 is one of the most influential variants in T2D-genetic risk scores (GRS). Therefore, to increase the predictive value (PV) of GRS it is necessary to first see whether the included polymorphisms have heterogeneous effects. We comprehensively investigated gene-obesity interactions between the TCF7L2-rs7903146 C > T polymorphism on T2D (prevalence and incidence) and analyzed other T2D-polymorphisms in a sub-sample. We studied 7018 PREDIMED participants at baseline and longitudinally (8.7 years maximum follow-up). Obesity significantly interacted with the TCF7L2-rs7903146 on T2D prevalence, associations being greater in non-obese subjects. Accordingly, we prospectively observed in non-T2D subjects (n = 3607) that its association with T2D incidence was stronger in non-obese (HR: 1.81; 95% CI: 1.13-2.92, p = 0.013 for TT versus CC) than in obese subjects (HR: 1.01; 95% CI: 0.61-1.66; p = 0.979; p-interaction = 0.048). Accordingly, TCF7L2-PV was higher in non-obese subjects. Additionally, we created obesity-specific GRS with ten T2D-polymorphisms and demonstrated for the first time their higher strata-specific PV. In conclusion, we provide strong evidence supporting the need for considering obesity when analyzing the TCF7L2 effects and propose the use of obesity-specific GRS for T2D., This study was funded by the Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economia y Competitividad-Fondo Europeo de Desarrollo Regional (projects PI051839, PI070240, PI1001407, G03/140, CIBER 06/03, RD06/0045 PI07-0954, CNIC-06, PI11/02505, SAF2009-12304, AGL2010-22319-C03-03, and PRX14/00527; contract JR14/00008), by the University Jaume I (Project P1-1B2013-54) and by the Generalitat Valenciana (AP111/10, AP-042/11, BEST/2015/087, GVACOMP2011-151, ACOMP/2011/145, ACOMP/2012/190, and ACOMP/2013/159). CIBEROBN is an initiative of Institute of Health Carlos III of Spain which is supported by FEDER funds (CB06/03). This material is based upon work supported by the U.S. Department of Agriculture-Agricultural Research Service (ARS), under Agreement No. 58-1950-4-003. Dolores Corella acknowledges the collaboration of the Real Colegio Complutense at Harvard University, Cambridge. MA, USA. The PREDIMED study was registered at controlled-trials.com (http://www.controlledtrials.com/ISRCTN35739639; ethics approval by the Institutional Review Board of the Hospital Clinic at Barcelona, Spain, 16/07/2002, under the protocol number G03/140). The Institutional Review Board of each participating center approved the study protocol, and all participants provided written informed consent. The Institutional Review Board of the Valencia University (protocol number G03/140, 22/05/2003) approved the PREDIMED-Valencia study protocol, and all participants provided written informed consent.