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The objective of this study was to evaluate the prospective associations between dietary glycemic index (GI) and glycemic load (GL) and the risk for invasive breast cancer incidence in postmenopausal women at high cardiovascular disease (CVD) risk. This study was conducted within the framework of the PREvención con DIeta MEDiterránea (PREDIMED) study, a nutritional intervention trial for primary cardiovascular prevention. We included 4010 women aged between 60 and 80 years who were initially free from breast cancer but at high risk for CVD disease. Dietary information was collected using a validated 137-item food frequency questionnaire. We assigned GI values using the International Tables of GI and GL values. Cases were ascertained through yearly consultation of medical records and through consultation of the National Death Index. Only cases confirmed by results from cytology tests or histological evaluation were included. We estimated multivariable-adjusted hazard ratios for invasive breast cancer risk across tertiles of energy-adjusted dietary GI/GL using Cox regression models. We repeated our analyses using yearly repeated measures of GI/GL intakes. No associations were found between baseline dietary GI/GL and invasive breast cancer incidence. The multivariable hazard ratio and 95% confidence interval (CI) for the top tertile of dietary GI was 1.02 (95% CI: 0.42-2.46) and for dietary GL was 1.00 (95% CI: 0.44-2.30) when compared with the bottom tertile. Repeated-measures analyses yielded similar results. In sensitivity analyses, no significant associations were observed for women with obesity or diabetes. Dietary GI and GL did not appear to be associated with an increased risk for invasive breast cancer in postmenopausal women at high CVD risk.

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: 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.

9 Páginas; 2 Tablas; 3 Figuras. Publicado online : 08 October 2015, Purpose Serum nitric oxide (NO) reduction and increased endothelin-1 (ET-1) play a pivotal role in endothelial dysfunction and hypertension. Considering that traditional Mediterranean diet (TMD) reduces blood pressure (BP), the aim of this study was to analyze whether TMD induced changes on endothelial physiology elements such as NO, ET-1 and ET-1 receptors which are involved in BP control. Methods Non-smoking women with moderate hypertension were submitted for 1 year to interventions promoting adherence to the TMD, one supplemented with extra virgin olive oil (EVOO) and the other with nuts versus a control low-fat diet (30 participants/group). BP, NO, ET-1 and related gene expression as well as oxidative stress biomarkers were measured. Results Serum NO and systolic BP (SBP) or diastolic BP (DBP) were negatively associated at baseline, as well as between NO and ET-1. Our findings also showed a DBP reduction with both interventions. A negative correlation was observed between changes in NO metabolites concentration and SBP or DBP after the intervention with TMD + EVOO (p = 0.033 and p = 0.044, respectively). SBP reduction was related to an impairment of serum ET-1 concentrations after the intervention with TMD + nuts (p = 0.008). We also observed changes in eNOS, caveolin 2 and ET-1 receptors gene expression which are related to NO metabolites levels and BP. Conclusions The changes in NO and ET-1 as well as ET-1 receptors gene expression explain, at least partially, the effect of EVOO or nuts on lowering BP among hypertensive women., The authors thank the participants in the PREDIMED study for their continued collaboration. The Fundación Patrimonio Comunal Olivarero, Hojiblanca SA (Málaga, Spain), California Walnut Commission (Sacramento, CA, USA), Borges SA (Reus, Spain) and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds and hazelnuts, respectively. We also thank the Scientific and Technical services of the University of Barcelona for malondialdehyde determinations. This study was supported by the Spanish Ministry of Health (FIS PI10/0082, G03/140, RD06/0045), Fondo Europeo de Desarrollo Regional, the Spanish Ministry of Science (BFU2007-61727/BFI) and the Generalitat de Catalunya (2009SGR00438).

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 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

Some slight departures from the protocol of individual randomization affecting only a small subset of participants in the Prevencion con Dieta Mediterranea (PREDIMED) trial (at most 14%) occurred and prompted a thorough reanalysis of data and republication of the main PREDIMED paper (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). The authors report the …

To the Editor: Because of irregularities in the randomization procedures, we wish to retract the following article: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90. DOI: 10.1056/NEJMoa1200303.1 We have reanalyzed the data and have published a new report: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N Engl J Med. DOI: 10.1056/NEJMoa1800389.2 . . .

OBJECTIVE Transcription factor 7-like 2 (TCF7L2) polymorphisms are strongly associated with type 2 diabetes, but controversially with plasma lipids and cardiovascular disease. Interactions of the Mediterranean diet (MedDiet) on these associations are unknown. We investigated whether the TCF7L2-rs7903146 (C>T) polymorphism associations with type 2 diabetes, glucose, lipids, and cardiovascular disease incidence were modulated by MedDiet. RESEARCH DESIGN AND METHODS A randomized trial (two MedDiet intervention groups and a control group) with 7,018 participants in the PREvención con DIetaMEDiterránea study was undertaken and major cardiovascular events assessed. Data were analyzed at baseline and after a median follow-up of 4.8 years. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for cardiovascular events. RESULTS The TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes (odds ratio 1.87 [95% CI 1.62–2.17] for TT compared with CC). MedDiet interacted significantly with rs7903146 on fasting glucose at baseline (P interaction = 0.004). When adherence to the MedDiet was low, TT had higher fasting glucose concentrations (132.3 ± 3.5 mg/dL) than CC+CT (127.3 ± 3.2 mg/dL) individuals (P = 0.001). Nevertheless, when adherence was high, this increase was not observed (P = 0.605). This modulation was also detected for total cholesterol, LDL cholesterol, and triglycerides (P interaction < 0.05 for all). Likewise, in the randomized trial, TT subjects had a higher stroke incidence in the control group (adjusted HR 2.91 [95% CI 1.36–6.19]; P = 0.006 compared with CC), whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes (adjusted HR 0.96 [95% CI 0.49–1.87]; P = 0.892 for TT compared with CC). CONCLUSIONS Our novel results suggest that MedDiet may not only reduce increased fasting glucose and lipids in TT individuals, but also stroke incidence.

15 Páginas; 6 Figuras, Several important biological activities have been attributed to the pentacyclic triterpene ursolic acid (UA), being its antitumoral effect extensively studied in human adenocarcinomas. In this work, we focused on the efficacy and molecular mechanisms involved in the antitumoral effects of UA, as single agent or combined with doxorubicin (DXR), in human soft tissue sarcoma cells. UA (5–50 μM) strongly inhibited (up to 80%) the viability of STS cells at 24 h and its proliferation in soft agar, with higher concentrations increasing apoptotic death up to 30%. UA treatment (6–9 h) strongly blocked the survival AKT/GSK3β/β-catenin signalling pathway, which led to a concomitant reduction of the anti-apoptotic proteins c-Myc and p21, altogether resulting in the activation of intrinsic apoptosis. Interestingly, UA at low concentrations (10–15 μM) enhanced the antitumoral effects of DXR by up to 2-fold, while in parallel inhibiting DXR-induced AKT activation and p21 expression, two proteins implicated in antitumoral drug resistance and cell survival. In conclusion, UA is able to induce intrinsic apoptosis in human STS cells and also to sensitize these cells to DXR by blocking the AKT signalling pathway. Therefore, UA may have beneficial effects, if used as nutraceutical adjuvant during standard chemotherapy treatment of STS., Research was supported by the Institute of Health Carlos III through the subprogramme “CIBERobn (Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición)”. VHV was supported by a predoctoral fellowship from ‘Govern de les Illes Balears, Conselleria d’Educació, Cultura i Universitats’ under a program of joint financing with the European Social Fund.

Virgin olive oil phenolic compounds have been revealed to be potent antioxidants as part of the Mediterranean diet. To test the hypothesis that these phenolics can modulate the serum and very low-density lipoprotein (VLDL) triacylglycerol concentrations in humans, a double-blind, randomized, crossover trial was designed. Thirty-three participants received 25 mL/d of refined olive oil (devoid of phenolic content [PC]), common olive oil (PC = 370 mmol/kg), and virgin olive oil (PC = 825 mmol/kg) in a Latin square design. The 3 olive oils were administered over 3 periods of 3 weeks, each one preceded by 2-week washout periods. All analyses were carried out on an intention-to-treat basis. The interventions did not modify the concentrations of serum and low-density lipoprotein cholesterol and triacylglycerol; but they exerted changes in the cholesterol, triacylglycerol, and phospholipid content of VLDL. The virgin olive oil consumption led to increased oleic and palmitic acids, as well as decreased linoleic acid, in VLDL. The main outcome was the significant dose-dependent linear trend between the PC in the olive oils and the palmitic (16:0) and linoleic (18:2 n-6) acid and their corresponding triacylglycerol molecular species in VLDL. © 2011 Elsevier Inc. All rights reserved., Supported in part by grants from Comision Interministerial de Ciencia y Tecnologia (CICYT; ALI97-1607-CO2-01 and AGL2008-02258), CSIC (200870I208), Instituto de Salud Carlos III (SNS Contract CP06/00100 and RD06/0045), and Comissió Interdepartamental de Recerca i Technologia (CIRIT) and by Federació de Cooperatives Agràries de Catalunya (1999SGR00243) and contract Miguel Servet (CP06/00100 for MF), Spanish Heath System.

6 páginas, 4 figuras, 1 tabla., Terpenic acids are under development as therapeutic agents in numerous treatments. In support of pharmacokinetic and toxicological evaluations, a robust assay based on high-performance liquid chromatography (HPLC) was developed for the analysis of the terpenoids in human serum. For a clear understanding of the differences in biological activity of these compounds, the interactions between oleanolic or betulinic acids and human serum protein have been studied by ultraviolet−visible (UV−vis) absorption under physiological conditions. A combination of liquid/liquid extraction, centrifugation, and consecutive HPLC resulted in simultaneous separation, identification, and quantification of the oleanolic, betulinic, and ursolic acids. The validity of the developed method was established by determining linearity, recovery, precision, accuracy, limit of detection, and quantification. Detection limits were in the range of 3.3−4.3 ng/mL, and linearity values ranged up to 1 μg/mL. The repeatability of the method was good. All compounds can be well-distinguished by order of elution during liquid chromatography. The pentacyclic triterpenoids have been identified by retention time comparison to pure standards and quantified by an internal standard. The results by UV−vis absorption spectra experiments (240−340 nm) indicate that protein structures have been perturbed in the presence of oleanolic and betulinic acids., This work was supported in part by grants from Comision Interministerial de Ciencia y Tecnologia (CICYT, AGL2008-02258), Instituto de Salud Carlos III (RETICS, RD06/0045), and Exxentia Group (110101080017 21).

OBJECTIVE To test the effects of two Mediterranean diet (MedDiet) interventions versus a low-fat diet on incidence of diabetes. RESEARCH DESIGN AND METHODS This was a three-arm randomized trial in 418 nondiabetic subjects aged 55–80 years recruited in one center (PREDIMED-Reus, northeastern Spain) of the Prevención con Dieta Mediterránea [PREDIMED] study, a large nutrition intervention trial for primary cardiovascular prevention in individuals at high cardiovascular risk. Participants were randomly assigned to education on a low-fat diet (control group) or to one of two MedDiets, supplemented with either free virgin olive oil (1 liter/week) or nuts (30 g/day). Diets were ad libitum, and no advice on physical activity was given. The main outcome was diabetes incidence diagnosed by the 2009 American Diabetes Association criteria. RESULTS After a median follow-up of 4.0 years, diabetes incidence was 10.1% (95% CI 5.1–15.1), 11.0% (5.9–16.1), and 17.9% (11.4–24.4) in the MedDiet with olive oil group, the MedDiet with nuts group, and the control group, respectively. Multivariable adjusted hazard ratios of diabetes were 0.49 (0.25–0.97) and 0.48 (0.24–0.96) in the MedDiet supplemented with olive oil and nuts groups, respectively, compared with the control group. When the two MedDiet groups were pooled and compared with the control group, diabetes incidence was reduced by 52% (27–86). In all study arms, increased adherence to the MedDiet was inversely associated with diabetes incidence. Diabetes risk reduction occurred in the absence of significant changes in body weight or physical activity. CONCLUSIONS MedDiets without calorie restriction seem to be effective in the prevention of diabetes in subjects at high cardiovascular risk.

Dietary virgin olive oil may help to reduce blood pressure in hypertensive individuals, but little is known about the effect on type 2 diabetic patients. For the present study, 17 type 2 diabetic elderly subjects and 23 healthy elderly controls received a diet rich in virgin olive oil for 4 weeks. Blood pressure, biochemical parameters, low-density lipoprotein (LDL), and oxidized LDL lipids and fatty acids were measured. Systolic blood pressure was reduced after virgin olive oil consumption in both controls and diabetic patients. Although the biochemical parameters were not modified, the intervention protected LDL from oxidation and restored the levels of dihomo-γ-linolenic acid (20:3, n-6) in serum cholesterol esters and phospholipids of diabetic patients. In conclusion, the present study provides new evidence of the effects of dietary virgin olive oil on blood pressure and LDL oxidation in type 2 diabetics. It is likely that the components responsible for the observed effects are the monounsaturated fatty acids and the presence of antioxidants in the oil, but this needs further investigation., This work was supported by funds from Comision Interministerial de Ciencia y Tecnologia (CICYT, AGL2008-02258/ALI), Instituto de Salud Carlos III (Thematic Network RD06/0045/002) and Consejo Superior de Investigaciones Cientificas (CSIC, 200870I208).

OBJECTIVE: Many studies have shown that the nature of the lipid consumed in the diet significantly affects the development of inflammatory diseases. In this study, we compared the effect of diets supplemented with 15% by weight of fish oil (FO), refined olive oil (ROO), and pomace olive oil (POO) with that of a low-fat diet, 2% by weight of corn oil, considered as the basal diet (BD), on the ability to modify reactive oxidative species and proinflammatory mediator generation by stimulated murine macrophages. METHODS: Mice were fed the different oil-enriched diets for 8 wk. Peritoneal macrophages were isolated from these mice and subsequently stimulated. Reactive oxygen species and proinflammatory mediators were measured in the corresponding supernatants. Data were statistically treated by one-way analysis of variance and Tukey's multiple comparison post hoc test. RESULTS: The ROO and POO significantly reduced the hydrogen peroxide production compared with BD, whereas FO stimulated its production. Moreover, the generation of nitric oxide was significantly prevented in all the experimental oil-enriched dietary groups. The ROO and FO groups showed significantly reduced cytokine (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6) and prostaglandin E(2) production. CONCLUSION: These results confirm the prevention action on proinflammatory mediator generation exerted by FO and demonstrate the protective antioxidant properties not only of olive oil but also of POO. The consumption of these olive oils may help to prevent cellular oxidative stress and inflammation., This study has been supported by founds from the Comisión Interministerial de Ciencia y Tecnología (to V. Ruiz-Gutierrez, AGL 2002-00192 and AGL 2005-00572).

This study was supported by grants from the Danish Heart Foundation (04-10-B116-A304-22197), and by funds from the projects (AGL2002-00195, AGL2005-00572 (CICYT) and G03/140-2002 (Red FIS de Investigacion Corporativa).

We have previously reported the anticarcinogenic effects of an olive fruit extract composed of pentacyclic triterpenes, the main components of which are maslinic acid (73.25%) and oleanolic acid (25.75%). Here we examined the effects of the individual components on proliferation, necrosis and apoptosis rates by fluorescence-based techniques in human HT-29 colon cancer cells. Oleanolic acid showed moderate antiproliferative activity, with an EC50 of 160.6 (SE 10.6) μmol/l, and moderate cytotoxicity at high concentrations (≥250 μmol/l). On the other hand, maslinic acid inhibited cell growth with an EC50 of 101.2 (SE 7.8) μmol/l, without necrotic effects. Oleanolic acid, which lacks a hydroxyl group at the carbon 2 position, failed to activate caspase-3 as a prime apoptosis protease. In contrast, maslinic acid increased caspase-3-like activity at 10, 25 and 50 μmol/l by 3-, 3.5- and 5-fold over control cells, respectively. The detection of ROS in the mitochondria, which serve as pro-apoptotic signal, evidenced the different bioactivity of the two triterpenes. Confocal microscopy analysis revealed that maslinic acid generated superoxide anions while oleanolic acid-treated cells did not differ from the control. Completion of apoptosis by maslinic acid was confirmed microscopically by the increase in plasma membrane permeability, and detection of DNA fragmentation. In conclusion, the anticancer activity observed for olive fruit extracts seems to originate from maslinic acid but not from oleanolic acid. Maslinic acid therefore is a promising new compound for the chemoprevention of colon cancers. © The Authors 2008., Supported by grant AGL2005-05728 from the Ministerio de Ciencia y Tecnología and grant 2005-SGR-00632 from the Generalitat de Catalunya, Spain.

BACKGROUND: The effect of dietary pomace olive oil, which has the same concentration of oleic acid but a higher proportion of oleanolic acid (OA) than olive oil, was examined on animal models of hypertension for the first time. METHODS: During 12 weeks, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were fed with either a control 2% corn oil diet (BD), or high-fat diets containing 15% of refined olive oil (OL), pomace olive oil (POM), or pomace olive oil supplemented in OA (up to 800 ppm) (POMO). Then, vascular reactivity and endothelial nitric oxide (NO) synthase (eNOS) expression were studied in aortic rings. Plasma nitrite + nitrate levels were also determined. RESULTS: Diets had no effects on blood pressure (BP). In contrast to the BD and OL dietary groups, POM intake improved relaxation evoked by acetylcholine in SHR aorta. The POMO intake increased vasodilatation to acetylcholine and attenuated phenylephrine-induced contractions in both strains of rats associated with a major NO participation revealed by inhibition of NOS. The enhanced relaxation shown in POM and POMO SHR aorta was attributed to an increased eNOS protein expression. Plasma nitrite levels were also increased in these groups. Although olive and pomace oils used in diets contained similar fatty acid composition, beneficial effects on endothelial function were absent in the OL group. Therefore, these effects must be associated with some minor components from pomace olive oil such as OA. CONCLUSIONS: Chronic intake of diets rich in pomace olive oil improves endothelial dysfunction in SHR aorta by mechanisms associated with enhanced eNOS expression. Important evidence is provided regarding the effects of pomace olive oil and OA on endothelial function in hypertensive animals.

We appreciate the interest and kind comments by Gonzalez-Salvado et al regarding our published article on extravirgin olive oil (EVOO) consumption and a reduced risk of atrial fibrillation (AF).1 The answer to their questions about the quantity of EVOO that should be consumed to observe a reduction in the risk of AF and the between-subject variability in EVOO consumption can be found in our online-only Data Supplement published in Circulation. In the per protocol analyses shown in Table II in the online-only Data Supplement (including the 3 arms of the trial together), we demonstrated that the risk of AF was only 6.6 cases/1000 person-years when the attained consumption reached the 3 upper quintiles of consumption, whereas it was 15.5 when the consumption was in the 2 lower quintiles. This cutoff corresponded to a consumption of at least 25 g/d. More specifically, and taking into account the between-subject variability in total energy intake and after controlling for other potential confounding factors, we observed a significant reduction in the risk of AF when EVOO consumption represented ≥15% of total energy intake (please check Figure IB in the online-only Data Supplement). We acknowledge that we did not specify whether EVOO was consumed raw or cooked. Specifically we included both possibilities in our educational recommendations to participants, but we also gave the advice to our participants to frequently consume EVOO for salad dressings and as a spread. Please check http://www.predimed.es, and previous articles on our interventions in the Prevención con Dieta …

© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society. Objectives To evaluate how glycemic index (GI) and glycemic load (GL) are associated with the metabolic syndrome (MetS) and its features in middle-aged and elderly adults at high cardiovascular risk. Design Prospective, longitudinal, population-based cohort. Setting PREvenciõn con DIeta MEDiterránea study. Participants Men and women (N = 6,606) divided into three age groups (, Funded by: Centro Nacional de Investigaciones Cardiovasculares. Grant Number: 06/2007; Instituto de Salud Carlos III; Fondo de Investigación Sanitaria PI. Grant Number: 07/0473; Ministerio de Ciencia e Innovación. Grant Numbers: AGL-2009–13906-C02, AGL2010–22319-C03; Ministerio de Sanidad-Plan Nacional de Drogas. Grant Number: 2010/087; Fondo de Investigaciones Sanitarias. Grant Number: PI1002658 Fundación Mapfre 2010 Government of the Basque Country. Grant Number: IT386–10 University of the Basque Country. Grant Number: UFI 11/32 Catalan government Miguel Servet. Grant Number: 06/00100

© 2014 Elsevier B.V. Background and aim: Hypertension is one of the main cardiovascular risk factors in the elderly. The aims of this work were to evaluate if a one-year intervention with two Mediterranean diets (Med-diet) could decrease blood pressure (BP) due to a high polyphenol consumption, and if the decrease in BP was mediated by plasma nitric oxide (NO) production. Methods and results: An intervention substudy of 200 participants at high cardiovascular risk was carried out within the PREDIMED trial. They were randomly assigned to a low-fat control diet or to two Med-diets, one supplemented with extra virgin olive oil (Med-EVOO) and the other with nuts (Med-nuts). Anthropometrics and clinical parameters were measured at baseline and after one year of intervention, as well as BP, plasma NO and total polyphenol excretion (TPE) in urine samples. Systolic and diastolic BP decreased significantly after a one-year dietary intervention with Med-EVOO and Med-nuts. These changes were associated with a significant increase in TPE and plasma NO. Additionally, a significant positive correlation was observed between changes in urinary TPE, a biomarker of TP intake, and in plasma NO (Beta=4.84; 95% CI: 0.57-9.10). Conclusions: TPE in spot urine sample was positively correlated with plasma NO in Med-diets supplemented with either EVOO or nuts. The statistically significant increases in plasma NO were associated with a reduction in systolic and diastolic BP levels, adding to the growing evidence that polyphenols might protect the cardiovascular system by improving the endothelial function and enhancing endothelial synthesis of NO., We would like to thank all the volunteers involved in the PREDIMED study for their valuable cooperation. This study was supported in part by CICYT (AGL2010-22319-C03 and AGL2013-49083-C3-1-R), RD06/0045 and CIBEROBN from the ISCIII (Spanish Ministry of Science and Innovation, MICINN), Quality Group from Generalitat de Catalunya 2009-SGR-724 and 2014-SGR-773, and Grant of support to research groups no.35/2011 (Balearic Islands Gov. and EU FEDER funds). A.M.-R. thanks the “Juan de la Cierva” postdoctoral program (JCI-2012-13463) from MEC. A.T.-R. would like to thank the ISCIII for granting her a predoctoral fellowship (FI10/00265).

The influence of the fatty acid composition of chylomicron remnant-like particles (CRLPs) on their uptake and induction of lipid accumulation in macrophages was studied. CRLPs containing triacylglycerol enriched in saturated, monounsaturated, n−6 or n−3 polyunsaturated fatty acids derived from palm, olive, corn or fish oil, respectively, and macrophages derived from the human monocyte cell line THP-1 were used. Lipid accumulation (triacylglycerol and cholesterol) in the cells was measured after incubation with CRLPs for 5, 24 and 48 h, and uptake over 24 h was determined using CRLPs radiolabelled with [3H]triolein. Total lipid accumulation in the macrophages was significantly greater with palm CRLPs than with the other three types of particle. This was mainly due to increased triacylglycerol concentrations, whereas changes in cholesterol concentrations did not reach significance. There were no significant differences in lipid accumulation after incubation with olive, corn or fish CRLPs. Palm and olive CRLPs were taken up by the cells at a similar rate, which was considerably faster than that observed with corn and fish CRLPs. These findings demonstrate that CRLPs enriched in saturated or monounsaturated fatty acids are taken up more rapidly by macrophages than those enriched in n−6 or n−3 polunsaturated fatty acids, and that the faster uptake rate results in greater lipid accumulation in the case of saturated fatty acid-rich particles, but not monounsaturated fatty acid-rich particles. Thus, dietary saturated fatty acids carried in chylomicron remnants may enhance their propensity to induce macrophage foam cell formation.

Hydroxytyrosol is a phenol found in olive oil. To verify the effect of hydroxytyrosol on the development of atherosclerosis, two groups of apo E deficient male mice on a standard chow diet were used: the control group receiving only water, and the second group an aqueous solution of hydroxytyrosol in order to provide a dose of 10 mg/kg/day to each mouse. This treatment was maintained for 10 weeks. At the moment of sacrifice, blood was drawn and heart removed. Plasma lipids, apolipoproteins and monocyte Mac-1 expression were assayed as well as aortic atherosclerotic areas in both groups. Data showed no significant changes in HDL cholesterol, paraoxonase, apolipoprotein B or triglyceride levels. However, hydroxytyrosol administration decreased apolipoprotein A-I and increased total cholesterol, atherosclerotic lesion areas and circulating monocytes expressing Mac-1. The latter was highly correlated with lesion areas (r = 0.65, P < 0.01). These results indicate that administration of hydroxytyrosol in low cholesterol diets increases atherosclerotic lesion associated with the degree of monocyte activation and remodelling of plasma lipoproteins. Our data supports the concept that phenolic-enriched products, out of the original matrix, could be not only non useful but also harmful. Our results suggest that the formulation of possible functional foods should approximate as much as possible the natural environment in which active molecules are found., This research was supported by grants FEGA-FEOGA (CAO99-0014), CICYT (SAF2004-08173-C03-02 and AGL2002-00495), Junta de Andalucía (CAO01-002), FISS 01/0202, Redes DGA (A-26) and FISS de investigación cooperativa C03-01 and G03-140 and by Fundación Española del Corazón., This research was supported by grants FEGA-FEOGA (CAO99-0014), CICYT (SAF2004-08173-C03-02 and AGL2002-00495), Junta de Andalucía (CAO01-002), FISS 01/0202, Redes DGA (A-26) and FISS de investigación cooperativa C03-01 and G03-140 and by Fundación Española del Corazón. R.C., S.A., M.A.N. and N.G. were recipient of DGA, FEGA-FEOGA and Fundación Cuenca Villoro fellowships.

Cholesteryl esters (CE), triacylglycerols (TG), free cholesterol (FC), monoacylglycerols (MG), and phospholipids (PL) were simultaneously determined by high performance liquid chromatography (HPLC) coupled to a light-scattering detector (ELSD) in Iberian pig fat from adipose tissue and Masseter muscle. The precision of the HPLC system was excellent, showing RSD values of repeatability lower than 5.27% for detector response and 0.12% for retention times. TG was the major lipid class detected, accounting for nearly 80% in the muscle and 86% in adipose tissue. The fatty acid compositions of total lipids, TG, and PL in the tissues studied were characterized for high concentrations of oleic (18:1, n-9), palmitic (16:0), and stearic (18:0) acids. We conclude that the method reported here is suitable for rapid and precise determination of lipid classes in Iberian pig fat and may be suitable for the analysis of the sensory quality of this and other meat products., This work was financed by grants from Comisión Interministerial de Ciencia y Tecnología (CICYT) (AGL2002‐00195) and Junta de Andalucia (CAO01‐002) and an I3P contract to JSP (European Social Funds).

Hypertension development in the spontaneously hypertensive rat (SHR) leads to vascular wall widening by smooth muscle cell proliferation. In these cells, triglycerides (TG) and cholesteryl esters (CE) can accumulate until they become foam cells. We administrated two oleic rich oils, virgin olive (VOO) and high oleic sunflower oils (HOSO), to Wistar−Kyoto rats (WKY) and SHR because these oils have been reported to reduce the risk for coronary heart disease in hypertensive patients and SHR. After 12 weeks of feeding, we analyzed the TG and CE composition and the lipolytic (lipoprotein lipase, LPL, and non-LPL) activity in aortas of these animals. HOSO increased the content of linoleic acid in CE and TG of aortas from both WKY and SHR as compared with animals fed VOO by proportionally decreasing the content of oleic acid. Conversely, VOO reduced the LPL and non-LPL lipolytic activities, hence limiting the free fatty acids available for the synthesis of TG and CE in the vascular wall.

This work has received the prize ‘II Premio Nacional de la Asociación Española de Municipios del Olivo a la Investigación sobre Aceite y Salud 2003’., The developing CNS, and in particular the visual system, is very sensitive to the effects of alcohol. Alcohol causes lipid peroxidation. Squalene, the major olive oil hydrocarbon, is a quencher of singlet oxygen and prevents the corresponding lipid peroxidation. We presumed that squalene can protect against the alcohol-induced damage already observed during the development of the chick retina. Alcohol+squalene was administered directly into the yolk sac of the egg of White Leghorn chicks at day 6 of incubation. The lipid composition of the retina was analyzed in embryos at E7, E11, E15 and E18. The proportions of phospholipids, free and esterified cholesterol, diacylglycerides and free fatty acids were estimated using the Iatroscan TLC/FID procedure. Gas chromatography and mass spectrometry were used to determine the fatty acid composition. The morphological study was carried out at E11 using semithin sections, and by means of immunohistochemical techniques at E19. Comparing the results obtained in control embryos, the administration of alcohol+squalene reduces the effects of alcohol on the total lipid composition of the retina during development. The effects were, in fact, of less magnitude than in embryos treated only with alcohol. The major phospholipid species of alcohol+squalene-treated embryos exhibited total recuperation at E15. As far as fatty acids are concerned, no significant changes were observed with regard to control embryos during development. From a morphological point of view, the retinas of alcohol+squalene-treated embryos show at E11 fewer cellular alterations than the retinas of alcohol-treated embryos. In this respect, the retinas of alcohol+squalene-treated embryos exhibited: a columnar cell arrangement similar to that observed in control retinas; few pycnotic cells and very few alterations in ganglion cell layers and in the optic nerve fibers layer. At E19 the recuperation of the expression of myelin oligodendrocyte specific protein (MOSP) in alcohol+squalene-treated embryos was recorded. Since squalene reduces the deleterious effects caused by alcohol on the lipid composition and the structure of the retina, squalene could act as a naturally occurring agent for the prevention of damage caused by abusive alcohol ingestion during pregnancy., This work was supported by funds from the Comisión Interministerial de Ciencia y Tecnología (CICYT) (AGL2002-00495) and (BFI2002-04481-C02-01); Consejería de Agricultura y Pesca (CAO01-002) and Red FIS.S de investigatión cooperativa G03-140 (PREDIMED).

OBJECTIVE: We examined the effects of virgin olive oil (VOO) triacylglycerols (TGs) on the lipid composition of human very low-density lipoprotein (VLDL). METHODS: Twenty-one normocholesterolemic, normotensive, non-diabetic elderly subjects were recruited for the study. Two VOOs (VOO1 and VOO2) of the same variety, with an equivalent composition in minor components and differing only in the oleic and linoleic acid concentrations, were administered for 4 wk each to assess the effect of their TG molecular species compositions. Blood was collected after an overnight fast, VLDLs were isolated by ultracentrifugation, and lipid classes, TG molecular species, and TG fatty acid composition were determined. RESULTS: Dietary VOOs significantly differed in TG molecular species composition. VOO1 represented larger amounts of triolein (P < 0.01), whereas VOO2 was significantly enriched with dilinoleoyl-oleoyl-glycerol, linoleoyl-dioleoyl-glycerol, and linoleoyl-oleoyl-palmitoyl-glycerol (P < 0.01). For VLDL, intake of VOO1 caused an increase of total TG (P < 0.01) due mainly to increases in triolein and linoleoyl-dioleoyl-glycerol. Conversely, VOO2 increased VLDL cholesteryl esters (P < 0.01) and TG rich in arachidonic acid (P < 0.01). Conclusions: The different TG molecular species compositions of dietary oils may be an independent determinant of the lipid composition of VLDL in elderly people and therefore may play a role in regulating lipoprotein metabolism in these subjects.

The present study was conducted in order to evaluate the influence of hypertension on the triacylglycerol (TG) molecular species composition and other lipid classes of rat adipose tissue. In addition, the effect of two dietary oils, with a similar content in oleic acid but different TG moieties, was studied. Virgin olive oil (VOO) or high-oleic sunflower oil (HOSO) was added to a baseline diet (BD) and administrated to Wistar−Kyoto and spontaneously hypertensive rats (SHR) for 12 weeks. Both VOO and HOSO normalized the altered composition of TG molecular species and phospholipid (PL) fatty acids in SHR compared to animals fed BD, although the effect exhibited by VOO was greater. Rats fed HOSO showed a greater palmitic (p < 0.05) and lower linoleic acid (p < 0.05) incorporation into PL but a greater accumulation of linoleic acid-containing TG species, particularly dioleoyl-linoleoyl-glycerol, with a concomitant displacement of trilinolein. Both oils were capable of increasing the lipoprotein lipase (LPL) activity in normotensive rats, but only VOO did so in the SHR. Therefore, it was concluded that although oleic acid-rich diets improve some of the altered parameters of SHR adipose tissue, VOO is more effective than HOSO in this regard.

The aim of the present study was to investigate the applicability of a previously developed method for the analysis of triacylglycerol molecular species to the simultaneous determination of triacylglycerols, diacylglycerols and monoacylglycerols of human very-low-density lipoproteins (VLDL). Ten elderly women were recruited for the study. Blood was obtained in fasting conditions and VLDL were isolated by ultracentrifugation. Neutral lipids were separated by solid-phase extraction and were subsequently injected on a reversed-phase HPLC system, with an elution system composed of acetone in acetonitrile. The method allowed the separation of four monoacylglycerols, 18 diacylglycerols and 24 triacylglycerols, including the resolution of positional isomers of diacylglycerols. Monoacylglycerols were composed of oleic, linoleic, palmitic and stearic acids. The major diacylglycerols were 1,2-dilinoleoyl-glycerol and 1,3-dilinoleoyl-glycerol (14.24±1.02 and 17.93±1.42%, respectively). The main triacylglycerols quantified were dioleoyl-stearoyl-glycerol (OOS), oleoyl-dipalmitoyl-glycerol (OPP), trilinoleoyl-glycerol (LLL) and linoleoyl-distearoyl-glycerol (LSS), accounting for 11.25±2.15, 10.14±2.05, 9.35±2.30 and 8.56±1.56%, respectively. An inverse relationship between polarity and fatty acid disappearance from triacylglycerols (r2=0.82, P, This work was supported by FEDER funds from the European Community (FEDER 1FD97-2288) and by grants (ALI99-0863 and AGL2002-00195) from the Comisión Interministerial de Ciencia y Tecnologı́a (CICYT).

Postprandial triacylglycerol-rich lipoproteins (TRL) have been implicated in the pathophysiology of atherosclerosis, but the intracellular processes by which TRL could affect vascular function are still unknown. Incubation of TRL obtained at 2 h postprandial period with vascular smooth muscle cells (VSMC) produced a tyrosine phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) that belong to the mitogen-activated protein kinase (MAPK) family. The activation of ERK1 and ERK2 had a maximum at 15 min, returned to baseline by 60 min, and was partially depleted after incubation of cells with a MAPKK inhibitor (PD 098059). In addition, postprandial TRL did competent VSMC for DNA replication through a MAPK pathway. These effects were dependent of the lipid composition of TRL. Our observations suggest that postprandial TRL can trigger activation of the MAPK pathway and induce a mitogenic response in VSMC in a lipid-dependent fashion., This study was supported by the grant of CICYT (OLI96-2126 and ALI99-0863).

Na+-dependent D-glucose transport was studied in brush-border membrane vesicles from duodenum, jejunum, and ileum of 5- to 6-wk-old chickens. Regional differences were found, and both initial rates and accumulation ratio of D-glucose were higher in the proximal part of the small intestine than in the ileum. To establish the mechanism(s) underlying these differences we have studied the density of Na+-dependent D-glucose cotransporter (SGLT1) as well as lipid composition and fluidity. Phlorizin-specific binding and Western blot analysis indicated a decrease in the amount of SGLT1 in the ileum when compared to the duodenum and jejunum. The distal part of the small intestine also showed a decrease in free cholesterol content and saturated-to-unsaturated fatty acid ratio together with an increase in lipid content and phosphatidylcholine-to-sphingomyelin ratio. These results were associated with a decrease in the diphenylhextriene fluorescence polarization found in brush-border membranes of the ileum. We can conclude that the decrease in the apical D-glucose transport found in the ileum is primarily due to a reduction in the amount of SGLT1 present in the brush-border membrane rather than the differences in the lipid composition and fluidity., This work was supported by grants PB96/1255 from the Ministerio de Educación y Cultura and 1999-SGR-00271 from the Generalitat de Catalunya (Spain).

[Background] Whilst it is well known that psychosocial determinants may contribute to cardiovascular diseases (CVD), data from specific groups are scarce. The present study aims to determine the contribution of psychosocial determinants in increasing the risk of cardiovascular events (myocardial infarction and stroke), and death from CVD, in a high risk adult population., [Methods] Longitudinal prospective study of 7263 patients (57.5% women), mean age 67.0 (SD 6.2) free from CVD but at high risk, with a median follow-up of 4.8 years (from October 2003 to December 2010). The Hazard Ratios (HRs) of cardiovascular events (myocardial infarction, stroke, and death from cardiovascular causes) related to educational attainment, diagnosed depression (based on medical records), and low social support (number of people living in the household) were estimated by multivariate Cox regression models., [Results] Stroke incidence was associated with low educational level in the whole population (HR: 1.83, 95% CI: 1.09–3.09), and especially in men (HR: 2.11, 95% CI 1.09–4.06). Myocardial infarction and CVD mortality were not associated with any of the psychosocial factors considered., [Conclusion] Adults with low educational level had a higher risk of stroke. Depression and low social support were not associated with CVD incidence., [Trial registration] Clinical trial registration information unique identifier: ISRCTN35739639., Instituto de Salud Carlos III, and Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Centro Nacional de Investigaciones Cardiovasculares, Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional, Ministerio de Ciencia e Innovación, Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía, Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana, and the Regional Government of Navarra. None of the institutions described above have influenced the design, collection, analysis, and interpretation of data; the writing of the manuscript; and the decision to submit the manuscript for publication.

High blood pressure (BP) has been ranked as the most important risk factor worldwide regarding attributable deaths. Dietary habits are major determinants of BP. Among them, frequent intake of low-fat dairy products may protect against hypertension. Our aim was to assess the relationship between low-fat dairy product intake and BP levels and their changes after 12-month follow-up in a cohort of asymptomatic older persons at high cardiovascular risk recruited into a large-scale trial assessing the effects of Mediterranean diets on cardiovascular outcomes. Data from 2290 participants, including 1845 with hypertension, were available for analyses. Dairy products were not a specific part of the intervention; thus, data were analysed as an observational cohort. Dietary information was collected with validated semi-quantitative FFQ and trained personnel measured BP. To assess BP changes, we undertook cross-sectional analyses at baseline and at the end of follow-up and longitudinal analyses. A statistically significant inverse association between low-fat dairy product intake and systolic BP was observed for the 12-month longitudinal analysis. In the longitudinal analysis, the adjusted systolic and diastolic BP were significantly lower in the highest quintile of low-fat dairy product intake (-4.2 (95% CI -6.9, -1.4) and -1.8 (95% CI -3.2, -0.4) mmHg respectively), whereas the point estimates for the difference in diastolic BP indicated a modest non-significant inverse association. Intake of low-fat dairy products was inversely associated with BP in an older population at high cardiovascular risk, suggesting a possible protective effect against hypertension. © The Author 2008., The PREDIMED study is funded by public resources from the Spanish Ministry of Health (Fondo de Investigación Sanitaria PI04233, PI051839, PI070240, PI052368, PI052584, PI051458, PI042234, RTIC G03/140, RD06/0045/0000 and CIBER CB06/03 Fisiopatología de la Obesidad y Nutrición) and from the Generalitat Valenciana (GRUPOS2004-43 and ACOMP06109).

[Background] Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk., [Methods] We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models., [Results] Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids)., [Conclusions] Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality., [Clinical trial registration] ISRCTN35739639., This study was supported in part 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, RD 06/0045, PI1002658 and PI1001407). The CIBERobn is an initiative of the ISCIII, Spain. ATR received support from ISCIII (FI10/00265).

Background: A variant (rs3812316, C771G, and Gln241His) in the MLXIPL (Max-like protein X interacting protein-like) gene encoding the carbohydrate response element binding protein has been associated with lower triglycerides. However, its association with cardiovascular diseases and gene-diet interactions modulating these traits are unknown. Methods and Results: We studied 7166 participants in the PREvención with DIeta MEDiterránea trial testing a Mediterranean diet (MedDiet) intervention versus a control diet for cardiovascular prevention, with a median follow-up of 4.8 years. Diet, lipids, MLXIPL polymorphisms, and cardiovascular events were assessed. Data were analyzed at baseline and longitudinally. We used multivariable-adjusted Cox regression to estimate hazard ratios for cardiovascular outcomes. The MLXIPL-rs3812316 was associated with lower baseline triglycerides (P=5.5×10-5) and lower hypertriglyceridemia (odds ratio, 0.73; 95% confidence interval [CI], 0.63-0.85; P=1.4×10-6 in G-carriers versus CC). This association was modulated by baseline adherence to MedDiet. When adherence to MedDiet was high, the protection was stronger (odds ratio, 0.63; 95% CI, 0.51-0.77; P=8.6×10-6) than when adherence to MedDiet was low (odds ratio, 0.88; 95% CI, 0.70-1.09; P=0.219). Throughout the follow-up, both the MLXIPL-rs3812316 (P=3.8×10-6) and the MedDiet intervention (P=0.030) were significantly associated with decreased triglycerides. Likewise in G-carriers MedDiet intervention was associated with greater total cardiovascular risk reduction and specifically for myocardial infarction. In the MedDiet, but not in the control group, we observed lower myocardial infarction incidence in G-carriers versus CC (hazard ratios, 0.34; 95% CI, 0.12-0.93; P=0.036 and 0.90; 95% CI, 0.35-2.33; P=0.830, respectively). Conclusions: Our novel results suggest that MedDiet enhances the triglyceride-lowering effect of the MLXIPL-rs3812316 variant and strengthens its protective effect on myocardial infarction incidence. © 2014 American Heart Association, Inc., Study supported by the Ministry of Economy and the Fondo Europeo de Desarrollo Regional (projects CIBER 06/03, PI07-0954, CNIC-06, PI11/02505, SAF2009-12304 and AGL2010-22319-C03-03), by contracts 53-K06-5 to 10 and 58-1950-9-001 from the US Department of Agriculture Research Service, USA and by the Generalitat Valenciana, Spain (AP-042/11, ACOMP/2012/190, ACOMP/2013/159, and ACOMP/213/165). M. Fitó was supported by the Instituto de Salud Carlos III and the Catalan Government, CP06/00100.

The relation between dietary magnesium intake and cardiovascular disease (CVD) or mortality was evaluated in several prospective studies, but few of them have assessed the risk of all-cause mortality, which has never been evaluated in Mediterranean adults at high cardiovascular risk. The aim of this study was to assess the association between magnesium intake and CVD and mortality risk in a Mediterranean population at high cardiovascular risk with high averagemagnesium intake. The present study included 7216 men and women aged 55-80 y fromthe PREDIMED (Prevencíon con Dieta Mediterŕanea) study, a randomized clinical trial. Participants were assigned to 1 of 2 Mediterranean diets (supplemented with nuts or olive oil) or to a control diet (advice on a low-fat diet). Mortality was ascertained by linkage to the National Death Index and medical records. We fitted multivariable-adjusted Cox regressions to assess associations between baseline energy-adjusted tertiles of magnesium intake and relative risk of CVD and mortality. Multivariable analyses with generalized estimating equation models were used to assess the associations between yearly repeated measurements of magnesium intake and mortality. After a median follow-up of 4.8 y, 323 total deaths, 81 cardiovascular deaths, 130 cancer deaths, and 277 cardiovascular events occurred. Energy-adjusted baseline magnesium intake was inversely associated with cardiovascular, cancer, and all-cause mortality. Compared with lower consumers, individuals in the highest tertile of magnesium intake had a 34% reduction in mortality risk (HR: 0.66; 95% CI: 0.45, 0.95; P < 0.01). Dietary magnesium intake was inversely associated with mortality risk in Mediterranean individuals at high risk of CVD. © 2014 American Society for Nutrition., This study was funded in part by the Spanish Ministry of Health, Carlos III Institute of Health grant PI1001407, Thematic Network grants G03/140 and RD06/0045, the European Fund of Regional Development, and the Catalan Center for Nutrition of the Institute of Catalan Studies. The Communal Olive Heritage Foundation and Hojiblanca (Málaga, Spain), California Walnut Commission (Sacramento, CA), Borges (Reus, Spain), and Morella Nuts (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study. The Center for Biomedical Investigation in the Network Pathophysiology of Obesity and Nutrition is an initiative of Carlos III Institute of Health.

Background/Objectives: Although benefits have been attributed to the Mediterranean diet, its effect on glycaemic control has not been totally elucidated. The aim of this work was to compare the effect of two Mediterranean diets versus a low-fat diet on several parameters and indices related to glycaemic control in type 2 diabetic subjects. Subjects/Methods: A multicentric parallel trial was conducted on 191 participants (77 men and 114 women) of the PREDIMED study in order to compare three dietary interventions: two Mediterranean diets supplemented with virgin olive oil (n=67; body mass index (BMI)=29.4 ± 2.9) or mixed nuts (n = 74; BMI = 30.1 ± 3.1) and a low-fat diet (n = 50; BMI = 29.8 ± 2.8). There were no drop-outs. Changes in body weight and waist circumference were determined. Insulin resistance was measured by HOMA-IR index, adiponectin/leptin and adiponectin/HOMA-R ratios after 1 year of follow-up. Results: Increased values of adiponectin/leptin ratio (P = 0.043, P = 0.001 and P < 0.001 for low-fat, olive oil and nut diets, respectively) and adiponectin/HOMA-IR ratio (P = 0.061, P = 0.027 and P = 0.069 for low-fat, olive oil and nut diets, respectively) and decreased values of waist circumference (P = 0.003, P = 0.001 and P = 0.001 for low-fat, olive oil and nut diets, respectively) were observed in the three groups. In both Mediterranean diet groups, but not in the low-fat diet group, this was associated with a significant reduction in body weight (P = 0.347, P = 0.003 and P = 0.021 for low-fat, olive oil and nut diets, respectively). Conclusions: Mediterranean diets supplemented with virgin olive oil or nuts reduced total body weight and improved glucose metabolism to the same extent as the usually recommended low-fat diet. © 2014 Macmillan Publishers Limited., This study was funded by the Spanish Ministry of Health (PI1001407, AGL2009-130906-C02-02, AGL2010-22319-C03-02, G03/140, RD06/0045), by Carlos III Health Institute (PREDIMED; CIBERobn), by Public Health Division of the Department of Health of the Autonomous Government of Catalonia in collaboration with Merck Sharp & Dohme Laboratories, by the Government of the Basque Country (IT-572-13) and by the University of the Basque Country (EDUNANOTEK, UFI11/32).

Vitamin K has been related to cardiovascular disease and cancer risk. However, data on total mortality are scarce. The aimof the present study was to assess the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high cardiovascular disease risk. A prospective cohort analysis was conducted in 7216 participants from the PREDIMED (Prevención con Dieta Mediterránea) study (median follow-up of 4.8 y). Energy and nutrient intakes were evaluated using a validated 137-item food frequency questionnaire. Dietary vitamin K intake was calculated annually using the USDA food composition database and other published sources. Deaths were ascertained by an end-point adjudication committee unaware of the dietary habits of participants after they had reviewed medical records and linked up to the National Death Index. Cox proportional hazard models were fitted to assess the RR of mortality. Energy-adjusted baseline dietary phylloquinone intake was inversely associated with a significantly reduced risk of cancer and all-cause mortality after controlling for potential confounders (HR: 0.54; 95% CI: 0.30, 0.96; and HR: 0.64; 95% CI: 0.45, 0.90, respectively). In longitudinal assessments, individuals who increased their intake of phylloquinone or menaquinone during follow-up had a lower risk of cancer (HR: 0.64; 95% CI: 0.43, 0.95; and HR: 0.41; 95% CI: 0.26, 0.64, respectively) and all-cause mortality (HR: 0.57; 95%CI: 0.44, 0.73; and HR: 0.55; 95% CI: 0.42, 0.73, respectively) than individuals who decreased or did not change their intake. Also, individuals who increased their intake of dietary phylloquinone had a lower risk of cardiovascular mortality risk (HR: 0.52; 95% CI: 0.31, 0.86). However, no association between changes in menaquinone intake and cardiovascular mortality was observed (HR: 0.76; 95% CI: 0.44, 1.29). An increase in dietary intake of vitamin K is associated with a reduced risk of cardiovascular, cancer, or all-cause mortality in a Mediterranean population at high cardiovascular disease risk. © 2014 American Society for Nutrition., Supported by National Cardiovascular Research Center grant 06/2007, Health Research Fund grants PI07/0473 and PI1002658, Ministry of Science and Innovation grants AGL-2009-13906-C02 and AGL2010-22319-C03, Ministry of Health–National Drug Plan grant 2010/087, Mapfre Foundation 2010, Government of the Basque Country grant IT386-10, University of the Basque Country grant UFI 11/32, and the Autonomous Government of Catalonia [joint contract with Institute of Health Carlos III (Miguel Servet grant 06/00100)]. CIBER Physiopathology of Obesity and Nutrition and Thematic networks of cooperative health research grant RD 06/0045 are initiatives of the Institute of Health Carlos III.

[Background] The Fas apoptotic pathway has been implicated in type 2 diabetes and cardiovascular disease. Although a polymorphism (rs7138803; G > A) near the Fas apoptotic inhibitory molecule 2 (FAIM2) locus has been related to obesity, its association with other cardiovascular risk factors and disease remains uncertain., [Methods] We analyzed the association between the FAIM2-rs7138803 polymorphism and obesity, blood pressure and heart rate in 7,161 participants (48.3% with type 2 diabetes) in the PREDIMED study at baseline. We also explored gene-diet interactions with adherence to the Mediterranean diet (MedDiet) and examined the effects of the polymorphism on cardiovascular disease incidence per diabetes status after a median 4.8-year dietary intervention (MedDiet versus control group) follow-up., [Results] We replicated the association between the FAIM2-rs7138803 polymorphism and greater obesity risk (OR: 1.08; 95% CI: 1.01-1.16; P = 0.011; per-A allele). Moreover, we detected novel associations of this polymorphism with higher diastolic blood pressure (DBP) and heart rate at baseline (B = 1.07; 95% CI: 0.97-1.28 bmp in AA vs G-carriers for the whole population), that remained statistically significant even after adjustment for body mass index (P = 0.012) and correction for multiple comparisons. This association was greater and statistically significant in type-2 diabetic subjects (B = 1.44: 95% CI: 0.23-2.56 bmp; P = 0.010 for AA versus G-carriers). Likewise, these findings were also observed longitudinally over 5-year follow-up. Nevertheless, we found no statistically significant gene-diet interactions with MedDiet for this trait. On analyzing myocardial infarction risk, we detected a nominally significant (P = 0.041) association in type-2 diabetic subjects (HR: 1.86; 95% CI:1.03-3.37 for AA versus G-carriers), although this association did not remain statistically significant following correction for multiple comparisons., [Conclusions] We confirmed the FAIM2-rs7138803 relationship with obesity and identified novel and consistent associations with heart rate in particular in type 2 diabetic subjects. Furthermore, our results suggest a possible association of this polymorphism with higher myocardial infarction risk in type-2 diabetic subjects, although this result needs to be replicated as it could represent a false positive. © 2014 Corella et al.; licensee BioMed Central Ltd., This study has been supported by The Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministry of Economy and Innovation, Spain and Fondo Europeo de Desarrollo Regional (projects PI051839, PI070240, PI1001407, G03/140, CIBER 06/03, RD06/0045 PI07-0954, CNIC-06, PI11/02505, SAF2009-12304 and AGL2010-22319-C03-03), by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research, USA and by the Generalitat Valenciana, Spain (AP111/10, AP-042/11, BEST11-263, BEST/ 2011/261, GVACOMP2011-151, ACOMP/2011/145 and ACOMP/2012/190).

The PREvención con DIeta MEDiterránea (PREDIMED) trial showed that Mediterranean diets (MedDiets) supplemented with either extravirgin olive oil or nuts reduced cardiovascular events, particularly stroke, compared with a control, lower fat diet. The mechanisms of cardiovascular protection remain unclear. We evaluated the 1-year effects of supplemented MedDiets on 24-hour ambulatory blood pressure (BP), blood glucose, and lipids. Randomized, parallel-design, controlled trial was conducted in 2 PREDIMED sites. Diets were ad libitum, and no advice on increasing physical activity or reducing sodium intake was given. Participants were 235 subjects (56.5% women; mean age, 66.5 years) at high cardiovascular risk (85.4% with hypertension). Adjusted changes from baseline in mean systolic BP were -2.3 (95% confidence interval [CI], -4.0 to -0.5) mm Hg and -2.6 (95% CI, -4.3 to -0.9) mm Hg in the MedDiets with olive oil and the MedDiets with nuts, respectively, and 1.7 (95% CI, -0.1 to 3.5) mm Hg in the control group (P, This work was supported by grants from Instituto de Salud Carlos III (ISCIII; PI05/2584, PI07/1138, PI12/01231), Ministry of Science and Innovation (AGL 2010-22319 and AGL 2011-23430), Consejería de Salud de la Junta de Andalucía (PI015/2007), Sociedad Española de Medicina de Familia y Comunitaria, and Sociedad Andaluza de Medicina Familiar y Comunitaria. Dr Mónica Doménech was supported by Fundació per l’Estudi de la Hipertensió Arterial dels Hospitals Comarcals de Catalunya (FEHTACC). Dr Sala-Vila was supported by postdoctoral contract FIS CP12/03299. Dr Toledo was supported by a Rio Hortega postresidency fellowship from the ISCIII, Ministry of Economy and Competitiveness, Spanish Government.

A higher heart rate (HR) has been associated with increased total and cardiovascular mortality [1] and [2]. Clinical trials support the beneficial effect of decreasing HR in patients with heart failure [3] and ischaemic heart disease [4]. A recent cross-sectional study showed that closer adherence to the Mediterranean diet (MeDiet) was related to lower HR [5]. We evaluated the association between adherence to the MeDiet (measured with a score from 0 to 14 obtained by a validated screener [6]) and HR using both a cross-sectional and a longitudinal analysis of the PREDIMED trial [7] and [8]., This study was funded by the Spanish Ministry of Health (ISCIII), CIBEROBN, PI1001407, PI11/02505, G03/140, RD06/0045, the Autonomous Government of Catalonia, Caixa Tarragona (10-1343) and by the Generalitat Valenciana (ACOMP/2013/165). 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. None of the funding sources played a role in the design, collection, analysis, interpretation or publication of the data. ET is supported by a Rio Hortega fellowship (ISCIII, Spanish Government).

Monounsaturated oils, virgin olive oil (VOO) and high oleic sunflower oil (HOSO) are suggested to have selective physiologic effects on humans in the fasting state. The aim of the study was to evaluate whether two oils with equal amounts of oleic acid but with different compositions of minor fatty acids and triacylglycerol molecular species (TAG) could produce different triacylglycerol-rich lipoprotein (TRL)-TAG responses in the postprandial state. Eight normolipidemic men consumed the following three meals in random order on separate occasions with 2 wk between meals: control meal, control meal plus VOO and control meal plus HOSO. Plasma total TAG and TRL-TAG were measured hourly for 7 h after ingestion. TAG and sn-2 positional fatty acids within TAG were analyzed in the TRL fraction. Plasma total TAG concentrations in response to the dietary oils did not differ. However, TRL triglyceridemia was significantly lower after VOO intake (P < 0.05). The molecular species in the TRL fraction returned toward basal levels more quickly (P < 0.05) after VOO than HOSO intake. 2-Positional fatty acid analysis demonstrated higher proportions of stearic and palmitic acids and a lower proportion of oleic acid (P < 0.05) in TRL-TAG derived from HOSO. This study shows that VOO intake results in attenuated postprandial TAG concentration and faster TRL-TAG disappearance from blood compared with HOSO, suggesting that the oleic acid content may not be the main factor affecting TAG metabolism. Minor fatty acids such as linoleic acid and the 2-positional distribution of saturated stearic and palmitic acids into the TAG molecule may be important determinants of postprandial lipemia in normolipidemic men., Supported by CICYT OLI96–2126 and ALI99–0863