Rosa M. Lamuela-Raventós

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet

BACKGROUND Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events. METHODS In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years. RESULTS A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported. CONCLUSIONS Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish governments Instituto de Salud Carlos III and others; Controlled-Trials.com number, ISRCTN35739639.).

Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory

Abstract Research has shown that fruits and vegetables containing high levels of polyphenolics (flavonoids) display high total antioxidant activity. Our laboratory found that various fruit and vegetable extracts, particularly blueberry (BB), were effective in reversing age-related deficits in neuronal signaling and behavioral parameters following 8 weeks of feeding, possibly due to their polyphenolic content. However, it was unclear if these phytonutrients were able to directly access the brain from dietary BB supplementation (BBS). The present study examined whether different classes of polyphenols could be found in brain areas associated with cognitive performance following BBS. Thus, 19 month old F344 rats were fed a control or 2% BB diet for 8–10 weeks and tested in the Morris water maze (MWM), a measure of spatial learning and memory. LC–MS analyses of anthocyanins in the diet and subsequently in different brain regions of BBS and control rats were carried out. Several anthocyanins (cyanidin-3- O -ß-galactoside, cyanidin-3- O -ß-glucoside, cyanidin-3- O -ß-arabinose, malvidin-3- O -ß-galactoside, malvidin-3- O -ß-glucoside, malvidin-3- O -ß-arabinose, peonidin-3- O -ß-arabinose and delphinidin-3- O -ß-galactoside) were found in the cerebellum, cortex, hippocampus or striatum of the BBS rats, but not the controls. These findings are the first to suggest that polyphenolic compounds are able to cross the blood brain barrier and localize in various brain regions important for learning and memory. Correlational analyses revealed a relationship between MWM performance in BBS rats and the total number of anthocyanin compounds found in the cortex. These findings suggest that these compounds may deliver their antioxidant and signaling modifying capabilities centrally.

A Short Screener Is Valid for Assessing Mediterranean Diet Adherence among Older Spanish Men and Women

Ensuring the accuracy of dietary assessment instruments is paramount for interpreting diet-disease relationships. The present study assessed the relative and construct validity of the 14-point Mediterranean Diet Adherence Screener (MEDAS) used in the Prevención con Dieta Mediterránea (PREDIMED) study, a primary prevention nutrition-intervention trial. A validated FFQ and the MEDAS were administered to 7146 participants of the PREDIMED study. The MEDAS-derived PREDIMED score correlated significantly with the corresponding FFQ PREDIMED score (r = 0.52; intraclass correlation coefficient = 0.51) and in the anticipated directions with the dietary intakes reported on the FFQ. Using Bland Altmans analysis, the average MEDAS Mediterranean diet score estimate was 105% of the FFQ PREDIMED score estimate. Limits of agreement ranged between 57 and 153%. Multiple linear regression analyses revealed that a higher PREDIMED score related directly (P < 0.001) to HDL-cholesterol (HDL-C) and inversely (P < 0.038) to BMI, waist circumference, TG, the TG:HDL-C ratio, fasting glucose, and the cholesterol:HDL-C ratio. The 10-y estimated coronary artery disease risk decreased as the PREDIMED score increased (P < 0.001). The MEDAS is a valid instrument for rapid estimation of adherence to the Mediterranean diet and may be useful in clinical practice.

Cohort Profile: Design and methods of the PREDIMED study

The Spanish Ministry of Health—Instituto de Salud Carlos III (ISCIII) funded the project for the period 2003–05 (RTIC G03/140). In 2006 a new funding modality was established by ISCIII through the CIBER (Centros de Investigacion Biomedica En Red). Fisiopatologia de la Obesidad y Nutricion (CIBERobn), which is providing funding for 7 of the original research groups, whereas the other 12 were funded by a new research network (RTIC RD 06/0045). Other official funds from Spanish government agencies have been obtained for subprojects related to intermediate outcomes (lipoproteins, inflammatory markers, vascular imaging, genomic and proteomic studies, etc.). Obviously, the donation by food companies of all the VOO and mixed nuts needed throughout the duration of the study is a substantial contribution.

Isoflavones, lignans and stilbenes – origins, metabolism and potential importance to human health

Interest in the physiological role of the bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the class of compounds known as the phytoestrogens, which embody several groups of non-steroidal oestrogens including isoflavones, lignans and stilbenes that are widely distributed within the plant kingdom. These compounds have a wide range of hormonal and non-hormonal activities in animals or in vitro and these suggest plausible mechanisms for potential health effects of diets rich in these compounds in humans. In addition, experimental and epidemiological data are available to support the concept that phytoestrogen-rich diets exert physiological effects, and preliminary human studies suggest a potential role for dietary phytoestrogens in affecting hormone-dependent disease rates. © 2000 Society of Chemical Industry

Prevention of Diabetes With Mediterranean Diets: A Subgroup Analysis of a Randomized Trial

Context Can changes in diet prevent diabetes in older adults? Contribution This subgroup analysis of a multicenter trial involved older adults with high risk for heart disease who were randomly assigned to a Mediterranean diet supplemented with either extra-virgin olive oil or mixed nuts or to a low-fat control diet. Neither energy restriction nor increased physical activity was advised. After 4 years of follow-up, fewer persons in the Mediterranean diet groups developed diabetes than in the control group. Implication Changes in dietary patterns that do not necessarily lead to weight loss or include energy restrictions could help prevent diabetes in some older adults. The Editors Type 2 diabetes mellitus represents a major health problem because worldwide prevalence has more than doubled in the past 3 decades, with nearly 347 million persons with diabetes in 2010 (1), and is a potent risk factor for cardiovascular disease (CVD), blindness, renal failure, and lower limb amputation (2). Compelling evidence shows that diabetes can be prevented with lifestyle changes. Intensive lifestyle modification promoting weight loss through energy-restricted diets together with increased physical activity can decrease incident diabetes to as low as 50% (3). Indeed, lifestyle modification has performed better than pharmacologic approaches (such as metformin or rosiglitazone) in diabetes prevention (46). Of interest, the benefit of lifestyle changes in decreasing diabetes risk seems to extend beyond the termination of active intervention (68). However, there is little information on whether changes in the overall dietary pattern, without energy restriction, increased physical activity, and ensuing weight loss, may also be effective to prevent diabetes. Prospective epidemiologic studies strongly suggest that dietary patterns characterized by high consumption of fruit, vegetables, whole grains, and fish and reduced consumption of red and processed meat, sugar-sweetened beverages, and starchy foods delay diabetes onset (9). In the last 6 years, the traditional Mediterranean diet has emerged as a healthy dietary pattern that is also associated with a decreased risk for diabetes (1012). The Mediterranean diet is moderately rich in fat (35% to 40% of energy), especially from vegetable sources (rich in olive oil and nuts), and relatively low in dairy products. Moderate consumption of alcohol, mostly wine, and frequent use of sauces with tomato, onions, garlic, and spices for meal preparation are also typical. Preliminary data from the PREDIMED (Prevencin con Dieta Mediterrnea) study (1317) showed that traditional Mediterranean diets enriched with high-fat foods of vegetable origin decreased the incidence of diabetes (18). However, that report studied participants only from 1 of the 11 PREDIMED recruiting centers. In this analysis, we provide the final results on diabetes incidence in the whole multicenter trial after a median follow-up of 4.1 years. Methods Design Overview The PREDIMED study is a parallel-group, randomized, primary cardiovascular prevention trial done in Spain in persons at high risk but without CVD at baseline. The protocol, design, objectives, and methods have been reported in detail elsewhere (13, 14). Briefly, participants were randomly assigned in a 1:1:1 ratio to 1 of 3 nutrition interventions: Mediterranean diet supplemented with extra-virgin olive oil (EVOO), Mediterranean diet supplemented with mixed nuts, or a control diet consisting of advice to reduce intake of all types of fat. A complete list of PREDIMED study investigators is available in Supplement 1. The local institutional review boards approved the protocol at each study location, and all participants provided written informed consent. Supplement. Original Version (PDF) Supplement 1. List of Prevencin con Dieta Mediterrnea Study Investigators Setting and Participants Eligible participants were community-dwelling men (aged 55 to 80 years) and women (aged 60 to 80 years) without CVD at baseline who had either type 2 diabetes or at least 3 or more cardiovascular risk factors, namely current smoking, hypertension, hypercholesterolemia, low high-density lipoprotein cholesterol levels, overweight or obesity, and family history of premature CVD. Exclusion criteria have previously been reported (13). Randomization and Intervention From October 2003 to June 2009, 7447 suitable candidates were enrolled in the trial. The study nurse from each recruiting center randomly assigned each participant to the corresponding intervention group following computer-generated random numbers for allocation contained in sealed envelopes, which were centrally prepared for each center by the coordinating unit. Four strata of randomization were built by sex and age (cutoff, 70 years) but not by baseline diabetes status. The primary care physicians did not participate in the randomization process. The study nurses were independent of the nursing staff of the primary care health centers. Therefore, they were not involved in the usual clinical care of participants, and their exclusive role was to collect data for the trial. Given the nature of the interventions (nutritional advice and provision of foods), only investigators assessing outcomes were blinded with respect to intervention assignment. This was done by providing them with coded data sets and medical records blinded with respect to the personal identity of the participant and without any information on treatment allocation. Because our main objective was to determine the effect of the 3 interventions on diabetes incidence, this report includes data only on participants who did not have diabetes at baseline and for whom we could ascertain the incidence of diabetes during follow-up (n= 3541) (Figure 1). Figure 1. Study flow diagram. EVOO = extra-virgin olive oil; MedDiet = Mediterranean diet. A behavioral intervention promoting the Mediterranean diet was implemented in the corresponding groups of the trial, as described (13). Dietitians gave personalized advice to participants about the amount and use of EVOO for cooking and dressing; weekly intake of nuts; increased consumption of vegetables, fruits, legumes, and fish; recommended intake of white meat instead of red or processed meat; avoidance of butter, fast food, sweets, pastries, or sugar-sweetened beverages; and the dressing of dishes with sofrito sauce (using tomato, garlic, onion, and spices simmered in olive oil). Reduction of alcoholic beverages other than wine was advised to all participants. Wine with meals was recommended with moderation only to habitual drinkers. At baseline and quarterly thereafter, dietitians conducted individual and group dietary training sessions to provide information on typical Mediterranean foods, seasonal shopping lists, meal plans, and recipes for each group. In each session, a 14-item questionnaire was used to assess adherence to the Mediterranean diet (13, 14) so that personalized advice could be provided to upgrade participants adherence. The same questionnaire was assessed yearly in the control group. Participants assigned to the 2 Mediterranean diet groups received allotments of either EVOO (50 mL/d) or mixed nuts (30 g/d: 15 g of walnuts, 7.5 g of almonds, and 7.5 g of hazelnuts) at no cost. Participants assigned to the control diet received recommendations to reduce intake of all types of fat (from both animal and vegetable sources) and received nonfood gifts (kitchenware, tableware, aprons, or shopping bags). Through October 2006, participants in the control group received only a leaflet describing the low-fat diet. Thereafter, participants assigned to the control diet also received personalized advice and were invited to group sessions with the same frequency and intensity as those in the Mediterranean diet groups. A separate 9-item dietary questionnaire (14) was used to assess adherence to the low-fat diet. Neither energy restriction nor increased physical activity was advised for any intervention group. At baseline examination and yearly during follow-up, we administered a 137-item validated semiquantitative food-frequency questionnaire (19); the validated Spanish version of the Minnesota Leisure-time Physical Activity Questionnaire (20); and a 47-item questionnaire about education, lifestyle, medical history, and medication use. At baseline, trained personnel performed electrocardiography and anthropometric and blood pressure measurements. Blood pressure was measured in triplicate by using a validated semiautomatic oscillometer with a 5-minute interval between measurements and the participant in a sitting position (Omron HEM-705CP, Omron, Hoofddorp, the Netherlands). Fasting blood and spot urine were sampled at baseline and follow-up years 1, 3, 5, and 7. After an overnight fast, tubes for EDTA plasma, citrate plasma, and serum and urine samples were collected and aliquots were coded and stored at 80C in the central laboratory until analysis. Serum glucose, cholesterol, and triglyceride levels were measured using standard enzymatic methods. High-density lipoprotein cholesterol was measured after precipitation with phosphotungstic acid and magnesium chloride. Biomarkers of adherence to the supplemental foods, including urine hydroxytyrosol levels and plasma -linolenic acid proportions, which are reliable biomarkers of EVOO and walnut intake, respectively, were measured in random subsamples of participants during the first 5 years of follow-up (by gas chromatographymass spectrometry and by gas chromatography, respectively). Laboratory technicians were blinded to intervention group. Outcomes and Follow-up Diabetes was a prespecified secondary outcome of the PREDIMED trial. IT was considered to be present at baseline by clinical diagnosis or use of antidiabetic medication. New-onset diabetes during follow-up was diagnosed using the American Diabetes Association criteria, namely fasting plasma glucose levels of 7.0 mmol/L or g

Wine, beer, alcohol and polyphenols on cardiovascular disease and cancer.

Since ancient times, people have attributed a variety of health benefits to moderate consumption of fermented beverages such as wine and beer, often without any scientific basis. There is evidence that excessive or binge alcohol consumption is associated with increased morbidity and mortality, as well as with work related and traffic accidents. On the contrary, at the moment, several epidemiological studies have suggested that moderate consumption of alcohol reduces overall mortality, mainly from coronary diseases. However, there are discrepancies regarding the specific effects of different types of beverages (wine, beer and spirits) on the cardiovascular system and cancer, and also whether the possible protective effects of alcoholic beverages are due to their alcoholic content (ethanol) or to their non-alcoholic components (mainly polyphenols). Epidemiological and clinical studies have pointed out that regular and moderate wine consumption (one to two glasses a day) is associated with decreased incidence of cardiovascular disease (CVD), hypertension, diabetes, and certain types of cancer, including colon, basal cell, ovarian, and prostate carcinoma. Moderate beer consumption has also been associated with these effects, but to a lesser degree, probably because of beer’s lower phenolic content. These health benefits have mainly been attributed to an increase in antioxidant capacity, changes in lipid profiles, and the anti-inflammatory effects produced by these alcoholic beverages. This review summarizes the main protective effects on the cardiovascular system and cancer resulting from moderate wine and beer intake due mainly to their common components, alcohol and polyphenols.

Inhibition of circulating immune cell activation: a molecular antiinflammatory effect of the Mediterranean diet

BACKGROUND Adherence to the Mediterranean diet (Med-Diet) is associated with a reduced risk of cardiovascular disease (CVD). However, the molecular mechanisms involved are not fully understood. OBJECTIVE The objective was to compare the effects of 2 Med-Diets with those of a low-fat diet on immune cell activation and soluble inflammatory biomarkers related to atherogenesis in subjects at high risk of CVD. DESIGN In a controlled study, we randomly assigned 112 older subjects with diabetes or > or =3 CVD risk factors to 3 dietary intervention groups: Med-Diet with supplemental virgin olive oil (VOO), Med-Diet with supplemental nuts, and low-fat diet. Changes from baseline in cellular and serum inflammatory biomarkers were assessed at 3 mo. RESULTS One hundred six participants (43% women; average age: 68 y) completed the study. At 3 mo, monocyte expression of CD49d, an adhesion molecule crucial for leukocyte homing, and of CD40, a proinflammatory ligand, decreased (P < 0.05) after both Med-Diets but not after the low-fat diet. Serum interleukin-6 and soluble intercellular adhesion molecule-1, inflammatory mediators crucial in firm adhesion of leukocytes to endothelial surfaces, decreased (P < 0.05) in both Med-Diet groups. Soluble vascular cellular adhesion molecule-1 and C-reactive protein decreased only after the Med-Diet with VOO (P < 0.05), whereas interleukin-6, soluble vascular cellular adhesion molecule-1, and soluble intercellular adhesion molecule-1 increased (P < 0.05) after the low-fat diet. CONCLUSIONS Med-Diets supplemented with VOO or nuts down-regulate cellular and circulating inflammatory biomarkers related to atherogenesis in subjects at high risk of CVD. The results support the recommendation of the Med-Diet as a useful tool against CVD.

A 14-Item Mediterranean Diet Assessment Tool and Obesity Indexes among High-Risk Subjects: The PREDIMED Trial

Objective Independently of total caloric intake, a better quality of the diet (for example, conformity to the Mediterranean diet) is associated with lower obesity risk. It is unclear whether a brief dietary assessment tool, instead of full-length comprehensive methods, can also capture this association. In addition to reduced costs, a brief tool has the interesting advantage of allowing immediate feedback to participants in interventional studies. Another relevant question is which individual items of such a brief tool are responsible for this association. We examined these associations using a 14-item tool of adherence to the Mediterranean diet as exposure and body mass index, waist circumference and waist-to-height ratio (WHtR) as outcomes. Design Cross-sectional assessment of all participants in the “PREvención con DIeta MEDiterránea” (PREDIMED) trial. Subjects 7,447 participants (55–80 years, 57% women) free of cardiovascular disease, but with either type 2 diabetes or ≥3 cardiovascular risk factors. Trained dietitians used both a validated 14-item questionnaire and a full-length validated 137-item food frequency questionnaire to assess dietary habits. Trained nurses measured weight, height and waist circumference. Results Strong inverse linear associations between the 14-item tool and all adiposity indexes were found. For a two-point increment in the 14-item score, the multivariable-adjusted differences in WHtR were −0.0066 (95% confidence interval, –0.0088 to −0.0049) for women and –0.0059 (–0.0079 to –0.0038) for men. The multivariable-adjusted odds ratio for a WHtR>0.6 in participants scoring ≥10 points versus ≤7 points was 0.68 (0.57 to 0.80) for women and 0.66 (0.54 to 0.80) for men. High consumption of nuts and low consumption of sweetened/carbonated beverages presented the strongest inverse associations with abdominal obesity. Conclusions A brief 14-item tool was able to capture a strong monotonic inverse association between adherence to a good quality dietary pattern (Mediterranean diet) and obesity indexes in a population of adults at high cardiovascular risk.

Protective effect of olive oil and its phenolic compounds against low density lipoprotein oxidation.

The protective effect of phenolic compounds from an olive oil extract, and of olive oils with (extra-virgin) and without (refined) phenolic components, on low density lipoprotein (LDL) oxidation was investigated. When added to isolated LDL, phenolics [0.025–0.3 mg/L caffeic acid equivalents (CAE)] increased the lag time of conjugated diene formation after copper-mediated LDL oxidation in a concentration-dependent manner. Concentrations of phenolics greater than 20 mg/L inhibited formation of thiobarbituric-acid reactive substances after AAPH-initiated LDL oxidation. LDL isolated from plasma after preincubation with phenolics (25–160 mg/L CAE) showed a concentration-dependent increase in the lag time of conjugated diene formation after copper-mediated LDL oxidation. Refined olive oil (0 mg/L CAE) and extra-virgin olive oil (0.1 and 0.3 mg/L CAE) added to isolated LDL caused an increase in the lag time of conjugated diene formation after copper-mediated LDL oxidation that was related to olive oil phenolic content. Multiple regression analysis showed that phenolics were significantly associated with the increase in lag time after adjustment for effects of other antioxidants; α-tocopherol also achieved a statistically significant effect. These results indicate that olive oil phenolic compounds protect LDL against peroxyl radical-dependent and metal-induced oxidation in vitro and could associate with LDL after their incubation with plasma. Both types of olive oil protect LDL from oxidation. Olive oil containing phenolics, however, shows more antioxidant effect on LDL oxidation than refined olive oil.