- CHO
carbohydrate
- Med-Diet
Mediterranean diet
- PREDIMED
PREvención con DIeta MEDiterránea
CVD is the main cause of death worldwide at the turn of the 21st century. Western countries, including the USA, currently continue to exhibit unacceptably high absolute rates of cardiovascular morbidity and mortality, but incidence rates show marked geographical differences(Reference Rosamond, Flegal and Friday1). Surprisingly, a low incidence of CHD is found in some developed countries such as France, Spain, Greece, Italy and Portugal, leading to a higher life expectancy as compared with Northern European countries or the USA(Reference Rosamond, Flegal and Friday1,Reference Tunstall-Pedoe, Kuulasmaa and Mahonen2). The Mediterranean food pattern (Mediterranean diet (Med-Diet)) has been the factor most frequently invoked to explain this health advantage.
The Med-Diet was identified as the traditional dietary pattern found in olive-growing areas of Crete, Greece and southern Italy in the late 1950s and early 1960s. Its major characteristics are (a) high consumption of non-refined grains, legumes, nuts, fruits and vegetables; (b) relatively high fat consumption (even greater than 40% of total energy intake) mostly from MUFA, which accounts for 20% or more of the total energy intake; (c) olive oil used to cook and for dressing salads as the principal source of fat; (d) moderate to high consumption of fish; (e) low to moderate consumption of poultry and dairy products (usually as yoghurt or cheese); (f) low consumption of red meats, processed meats or meat products; and (g) moderate alcohol intake, usually in the form of red wine consumed with meals(Reference Trichopoulou, Kouris-Blazos and Wahlqvist3, Reference Serra-Majem, Roman and Estruch4).
The background of a long and ancient tradition with no evidence of harm makes the Med-Diet very promising for public health. The high fruit and vegetable intake adds other mechanistic benefits provided by their polyphenolic content to its high antioxidant content. Other components of the Med-Diet such as virgin olive oil and red wine gather antioxidant and anti-inflammatory actions that may contribute to the healthy effects of this diet on the heart(Reference Covas, Nyyssönen and Poulsen5, Reference Badía, Sacanella and Fernández-Solá6). Accordingly, many scientists agree that the Med-Diet may exert a protective effect on the cardiovascular system. This hypothesis fits well into the current paradigm of studying overall dietary patterns instead of simply assessing isolated nutrients in nutritional epidemiology. The rationale is that food items and nutrients may have synergistic or antagonistic effects when they are consumed in combination. Additionally, overall patterns better represent the dietary practices found in free-living populations and therefore provide more useful epidemiological information(Reference Jacques and Tucker7, Reference Jacobs and Steffen8). Consequently, they have a higher potential for acceptability, palatability and future compliance when they are recommended in behaviour counselling. In spite of its relatively high fat content, or precisely because of it, the use of olive oil or other full-fat salad dressings in the Med-Diet increases vegetable consumption, because it makes vegetables more palatable. The sautéing or stir frying of vegetables with variable amounts of olive oil instead of using low-fat spreads or steaming increases taste and results in long-term maintenance of a vegetable-rich diet. These preparation and cooking techniques are typical of the Med-Diet, where the custom is to cook vegetables in olive oil to enhance flavour. Hence, in health promotion and nutritional education, better compliance with the Med-Diet can be expected. In fact, trials of weight loss reported better adherence to a Med-Diet than to a low-fat diet(Reference McManus, Antinoro and Sacks9). Participants viewed this diet as tastier than low-fat regimens, which may explain the increased long-term compliance.
Evidence available on the Mediterranean diet and CVD prevention
Findings from large European cohort studies(Reference Trichopoulou, Costacou and Bamia10, Reference Knoops, de Groot and Kromhout11) suggest that a high degree of adherence to the Med-Diet is associated with a reduction in both total and CHD mortality. A Med-Diet was inversely associated with mortality from all causes in several small observational cohort studies of elderly people(Reference Trichopoulou, Kouris-Blazos and Wahlqvist3, Reference Kouris-Blazos, Gnardellis and Wahlqvist12, Reference Lasheras, Fernandez and Patterson13). Findings from the Greek European Prospective Investigation into Cancer cohort including more than 22 000 participants suggested that a higher adherence to the Med-Diet is associated with a reduction in total mortality and, more specifically, in coronary mortality(Reference Trichopoulou, Costacou and Bamia10). Two recent case–control studies also found an inverse association between adherence to the Med-Diet and incidence of non-fatal coronary events(Reference Martínez-González, Fernández-Jarne and Serrano-Martínez14, Reference Panagiotakos, Pitsavos and Chrysohoou15). A unique secondary prevention trial found a significant reduction in re-infarction or death when coronary patients were assigned to a so-called ‘Mediterranean diet’(Reference de Lorgeril, Salen and Martin16). This trial, the Lyon Diet Heart Study, found a 50–70% relative reduction in the risk of mortality or re-infarction when patients who had had a myocardial infarction were assigned to an experimental diet rich in bread, vegetables, fish and fruit and low in red meat (replaced with poultry). Butter and cream were replaced with a margarine enriched in α-linolenic acid. The 50–70% reduction in cardiac events observed after 46 months in the experimental group of the Lyon trial leads to the consideration that if these results were generalized to non-Mediterranean populations, substantially enhanced and efficient methods to reduce CHD would be available. It would be short-sighted not to acknowledge the vast public health benefit that a Med-Diet could provide with its adoption by the healthy population-at-large if the findings of the secondary trials are also confirmed in primary prevention trials. The American Heart Association has given attention to the Med-Diet as potentially useful for the prevention of CHD, but a cautious recommendation has been issued highlighting that more studies are needed before advising people to follow a Med-Diet. These studies will help to clarify whether the diet itself or other factors (such as more physical activity, a beneficial genetic background or stronger social support systems) account for the lower incidence of CHD in the Mediterranean countries(Reference Kris-Etherton17).
Olive oil, a rich source of MUFA, is a main component of the Med-Diet. Virgin olive oil retains all the lipophilic components of the fruit, small amounts of α-tocopherol and sizeable amounts of phenolic compounds with strong antioxidant properties, while refined olive oil loses most of its antioxidants during the refining process(Reference Visioli and Galli18). Tree nuts are also typical Med-Diet foods. Epidemiological studies have consistently shown that frequent nut consumption decreases the risk for CHD(Reference Kris-Etherton, Zhao and Binkoski19). Besides having a favourable fatty acid profile, nuts are a rich source of nutrients and other bioactive compounds that may beneficially influence the risk for CHD, such as fibre, phytosterols, folic acid and antioxidants(Reference Kris-Etherton, Zhao and Binkoski19). Walnuts differ from all other nuts in their high content of PUFA, particularly α-linolenic acid, a vegetable n-3 fatty acid(Reference Exler and Weihrauch20), which might confer additional antiatherogenic properties(Reference Harris21). However, the limited capacity for conversion to longer-chain n-3 fatty acids, and the lack of efficacy in ameliorating CVD risk factors and inflammatory markers in man, suggests that increased consumption of α-linolenic acid may be of little benefit in altering EPA (20:5n-3)+DHA (22:6n-3) status or in improving health outcomes compared with other dietary interventions(Reference Burdge and Calder22).
High-fat diets based on MUFA in diabetics, overweight subjects and high-risk individuals
Traditionally, nutritional advice to diabetics, obese subjects and those with cardiovascular risk factors emphasized the avoiding of animal fat and, preferably, all kinds of dietary fat, and their replacement with carbohydrates (CHO). The rationale was that fats provided excess energy, thought to promote obesity. However, in the last two decades, scientific evidence has accumulated on the beneficial role of diets with a relatively high MUFA content on cardiovascular risk factors, obesity and diabetes. These beneficial MUFA are provided by the Med-Diet and, specifically, by olive oil and most nuts(Reference Ros23). In fact, the frequent intake of simple CHO in many otherwise low-fat foods is associated with weight gain. However, when nutritional advice is given to people with obesity or diabetes, a reluctance still exists to recommend high-fat, high-MUFA diets as an alternative to the traditional (and less palatable) low-fat diets. Since obesity is the epidemic of the new century(Reference Yoon, Lee and Kim24), it is important to recognize that there is no evidence that a higher percentage of fat in the diet in the form of MUFA results in increased body weight. The lack of a fattening effect of such MUFA-rich diets has been shown in the context of controlled diets(Reference Ros23), weight-reduction programmes(Reference McManus, Antinoro and Sacks9) and ad libitum diets(Reference Sabaté25). Similarly, in a 2-year trial, 322 obese subjects were randomized to one of these three diets: low-fat, restricted-energy; the Med-Diet, restricted-energy; or low-CHO, non-restricted-energy. The authors concluded that the Med-Diet and low-CHO diets may be effective alternatives to low-fat diets. The more favourable effects on lipids (with the low-CHO diet) and on glycemic control (with the Med-Diet) suggest that personal preferences and metabolic considerations might allow individualized tailoring of dietary interventions(Reference Shai, Schwarzfuchs and Henkin26). Thus, we have compelling evidence that the Med-Diet may be a useful tool in the dietary treatment of obese, diabetic and high-risk subjects.
Protective mechanisms of the Mediterranean diet on CVD
Adoption of healthy lifestyles, such as the Med-Diet, is critical for the prevention and treatment of conventional risk factors, such as blood pressure, serum lipids and insulin resistance(Reference Perona, Cañizares and Montero27–Reference Fuentes, López-Miranda and Sánchez30). Since classical cardiovascular risk factors explain about 50% of the cardiovascular outcomes and multiple studies have demonstrated that about 20–25% of all future events occur in individuals with only one of these factors, some studies have been focused on the analysis of the Med-Diet on other alternative mechanisms such as the anti-inflammatory effects of this diet or its main components(Reference Giugliano, Ceriello and Esposito31).
The PREvención con DIeta MEDiterránea (PREDIMED) study is a large, parallel group, multi-centre, controlled, randomized 5-year clinical trial aimed at assessing the effects of the Med-Diet on the primary prevention of CVD(Reference Estruch, Martinez-Gonzalez and Corella32). Almost 7500 high-risk participants have been recruited and assigned to three interventions: Med-Diet supplemented with virgin olive oil, Med-Diet supplemented with mixed nuts, and low-fat diet. The main outcome is an aggregate of cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). The anticipated completion date of the PREDIMED trial is December 2011. In the pilot study of this trial, the 3-month effects of the three interventions on cardiovascular risk factors were assessed in the first 772 high-risk participants included in the trial. Both Med-Diets were associated with significant blood pressure lowering in hypertensive individuals already on anti-hypertensive medication (mean reduction of about 5%; Table 1). Observational studies(Reference Psaltopoulou, Naska and Orfanos33, Reference Alonso and Martínez-González34) and small feeding trials(Reference Strazzullo, Ferro-Luzzi and Siani35, Reference Ferrara, Raimondi and d'Episcopo36) have suggested that increased olive oil consumption helps lower blood pressure. In addition, the OmniHeart study(Reference Appel, Sacks and Obarzanek37) has shown that a healthy diet enriched with MUFA from various sources also has an anti-hypertensive effect. No effects on blood pressure have been reported for diets enriched with nuts in small trials(Reference Kris-Etherton, Zhao and Binkoski38). However, walnuts have favourable effects on endothelial function(Reference Ros, Núñez and Pérez-Heras39); thus it is plausible that nut intake had a blood pressure-lowering effect. A likely explanation for the blood pressure reduction observed with the two Med-Diets is the composite dietary change achieved, which was similar to that advocated in the dietary approaches to stop hypertension trial(Reference Appel, Moore and Obarzanek40), with the exception of the high content of olive oil. Salt intake was not restricted in our study. The blood pressure-lowering effect of the Med-Diets was higher than that obtained by partial substitution of CHO for MUFA in the OmniHeart trial(Reference Appel, Sacks and Obarzanek37), comparable to that of the unrestricted sodium dietary approaches to stop hypertension diets(Reference Appel, Moore and Obarzanek40) and of lesser magnitude than that of the low-sodium dietary approaches to stop hypertension diet(Reference Sacks, Svetkey and Vollmer41).
Changes in physiological and cardiovascular parameters in 772 high-risk subjects included in the PREDIMED study(Reference Estruch, Martinez-Gonzalez and Corella32)
(Mean values and standard deviations)
Med-Diet, Mediterranean-style diet; %, mean percent change from baseline; BP, blood pressure.
Three-month changes, including centre as a stratification factor, were analysed using a multivariate model, controlled for potential confounding by age, gender and baseline body weight. a, significant (P<0·05) differences between Med-Diet+Virgin Olive Oil and Control; b, significant (P<0·05) differences between Med-Diet+Mixed Nuts and Control; c, significant (P<0·05) differences between Med-Diet+Virgin Olive Oil and Med-Diet+Mixed Nuts.
The Med-Diet with olive oil was associated with decreased blood glucose (about 3%), and the two Med-Diets reduced fasting insulin and insulin resistance in non-diabetic participants (mean reduction of 8% in homeostasis model assessment score; Table 2), thereby extending previous observations on the effects of a Med-Diet on insulin sensitivity in subjects with the metabolic syndrome(Reference Esposito, Marfella and Ciotola42). Insulin resistance and diabetes are linked to excess energy intake, particularly in the form of saturated fatty acids and simple sugars, and to increased adiposity(Reference Franz, Bantle and Beebe43). Low-fat, high-CHO diets have traditionally been advised for medical nutrition therapy in diabetes. However, such diets may worsen metabolic control, an untoward effect that is not observed when using high-fat diets based on MUFA-rich oils or nuts(Reference Ros23). Frequent nut consumption has been inversely associated with diabetes risk(Reference Jiang, Manson and Stampfer44). Additionally, decreased intake of meat and dairy products and increased fibre intake, as observed in the Med-Diet groups, have been shown, in conjunction with other beneficial lifestyle measures, to prevent the evolution of glucose intolerance to diabetes(Reference Tuomilehto, Lindström and Eriksson45, 46). The results observed in our pilot study further support a beneficial role of healthy diets on insulin resistance.
Changes in plasma glucose and insulin concentrations in 772 high-risk subjects included in the PREDIMED study(Reference Estruch, Martinez-Gonzalez and Corella32)
(Mean values and standard deviations)
Med-Diet, Mediterranean-style diet; %, Mean percent change from baseline; HOMA, homeostasis model assessment.
Three-month changes, including centre as a stratification factor, were analysed using a multivariate model, controlled for potential confounding by age and gender.
a significant (P<0·05) differences between Med-Diet+Virgin Olive Oil and Control; b, significant (P<0·05) differences between Med-Diet+Mixed Nuts and Control; c, significant (P<0·05) differences between Med-Diet+Virgin Olive Oil and Med-Diet+Mixed Nuts.
It is well known that replacement of CHO with dietary fat lowers TAG and raises HDL cholesterol, while substituting MUFA for saturated fatty acids lowers LDL cholesterol(Reference Mensink, Zock and Kester47, Reference Clarke, Frost and Collins48). Total fat intake was high both at baseline and after 3 months and a similar reduction in saturated fatty acids intake of approximately 1% of energy was observed in the three arms of the study. However, the lipid profile was unchanged in the low-fat diet group, while LDL cholesterol decreased (about 4%) and HDL cholesterol increased (about 6%) in the Med-Diet groups, especially when olive oil was supplemented (Table 3). While diets enriched with a variety of nuts have an established hypocholesterolaemic effect(Reference Kris-Etherton, Zhao and Binkoski19, Reference Zambón, Sabaté and Muñoz28, Reference Ros, Núñez and Pérez-Heras39), it is unknown why substituting virgin for refined olive oil has such beneficial lipid effects. Minor olive oil constituents that are enriched in virgin oils(Reference Visioli and Galli18) might explain these effects and merit further study. Since low-fat diets usually lower both LDL and HDL cholesterol concentrations(Reference Yu-Poth, Zhao and Etherton49–Reference Gardner, Coulston and Chatterjee51), a fat-rich Med-Diet may be a better nutritional option for high-risk individuals.
Changes in plasma lipid parameters in 772 high-risk subjects included in the PREDIMED study (Modified from Estruch et al.(Reference Estruch, Martinez-Gonzalez and Corella32))
(Mean values and standard deviations)
Med-Diet, Mediterranean-style diet; %, Mean percent change from baseline.
Three-month changes, including centre as a stratification factor, were analysed using a multivariate model, controlled for potential confounding by age and gender.
a significant (P<0·05) differences between Med-Diet+Virgin Olive Oil and Control; b, significant (P<0·05) differences between Med-Diet+Mixed Nuts and Control; c, significant (P<0·05) differences between Med-Diet+Virgin Olive Oil and Med-Diet+Mixed Nuts.
In conclusion, our results suggest that the salutary health effects of the Med-Diet observed in epidemiological studies are exerted in part through plausible mechanisms: improved lipid profiles and reductions in blood pressure, and insulin resistance.
Anti-inflammatory effects of the Mediterranean diet
Up to now, the beneficial effect of the Med-Diet against CVD has been attributed to its effects controlling classical atherosclerosis risk factors, but, recently, some authors have suggested that an anti-inflammatory effect in the vascular wall may be another important mechanism to explain the link between the Med-Diet and low cardiovascular mortality(Reference Esposito, Marfella and Ciotola42). Indeed, atherosclerosis has long been considered the result of lipid accumulation in the artery wall, but there is currently compelling evidence that inflammation plays a key role at all stages of the disease(Reference Hansson52). Early phases of atherosclerosis involve the recruitment of inflammatory cells from the circulation, their adhesion to endothelium and finally migration to sub-endothelial space, a complex process mediated by inflammatory stimuli, which involves cytokine production and up-regulation of adhesion molecules on endothelial cells and leucocytes(Reference Blankenberg, Barbaux and Tiret53). Ongoing inflammation is also crucial in the development of instability and rupture of atheromatous plaques and the subsequent appearance of ischaemic events in advanced stages of the disease(Reference Hansson52, Reference Blankenberg, Barbaux and Tiret53).
The important role of inflammation in the pathogenesis of atherosclerosis has led to the belief that dietary preventive measures act in part by modifying related inflammatory pathways(Reference Giugliano, Ceriello and Esposito31). Indeed, results from cross-sectional studies(Reference Chrysohoou, Panagiotakos and Pitsavos54, Reference Salas-Salvadó, Garcia-Arellano and Estruch55) and a previous feeding trial(Reference Esposito, Marfella and Ciotola42) in Mediterranean populations suggest that the Med-Diet has anti-inflammatory effects, as was also ascertained in the US population(Reference Fung, McCullough and Newby56).
In the pilot study of the PREDIMED trial(Reference Estruch, Martinez-Gonzalez and Corella32), we also analysed the effects of the three mentioned interventions on soluble adhesion molecules and cytokines related to atherosclerosis. Recent epidemiological and clinical studies have shown that the Med-Diet or its main components are associated with a lower inflammatory status and/or improved endothelial function(Reference Trichopoulou, Costacou and Bamia10–Reference Kouris-Blazos, Gnardellis and Wahlqvist12, Reference Trichopoulou, Costacou and Bamia10–Reference Kouris-Blazos, Gnardellis and Wahlqvist12, Reference Ros, Núñez and Pérez-Heras39, Reference Hansson52). Similar findings have recently been reported for other healthy dietary patterns(Reference Blankenberg, Barbaux and Tiret53). Our findings of reduced circulating levels of cell adhesion molecules support the anti-inflammatory effects of Med-Diets.
In another sub-study of the PREDIMED trial(Reference Mena, Sacanella and Vazquez-Agell57), we analysed the effects of the three mentioned interventions on immune cell activation and soluble inflammatory biomarkers related to atherogenesis in 106 subjects at high risk for CVD. Changes from baseline in cellular and serum inflammatory biomarkers were assessed (Table 4). At 3 months, monocyte expression of CD49d, an adhesion molecule crucial for leucocyte homing, and of CD40, a pro-inflammatory ligand, decreased (P<0·05) after both Med-Diets but not after the low-fat diet. Serum IL-6 and soluble intercellular adhesion molecule-1 decreased in both Med-Diet groups (P<0·05). Soluble vascular cellular adhesion molecule-1 and C-reactive protein decreased only after the Med-Diet with virgin olive oil (P<0·05), whereas IL-6, soluble vascular cellular adhesion molecule-1 and soluble intercellular adhesion molecule-1 increased (P<0·05) after the low-fat diet. The effects of the Med-Diet on adhesion molecule expression on circulating peripheral blood mononuclear cells, a crucial step for their firm adhesion to endothelial cells during the inflammatory wall reaction, linked to atherosclerosis development(Reference Hansson52, Reference Blankenberg, Barbaux and Tiret53) has not been previously investigated.
Changes in peripheral blood mononuclear cells expression of cell surface inflammatory mediators (adhesion molecules and CD40) after 3 months of intervention (PREDIMED Study)(Reference Mena, Sacanella and Vazquez-Agell57)
(Mean values and standard deviations)
Med-Diet: Mediterranean diet.
* P<0·05 compared to baseline.
Significant interactions between diets were analysed by the simple effects test with multiple contrasts of Bonferroni. Med-Diets supplemented with olive oil and nuts down-regulate cellular (inflammatory biomarkers related to atherogenesis: CD49d molecules in peripheral lymphocyte and CD11b, CD49d and CD40 in monocytes.
Experimental and clinical studies have shown that olive oil down-regulates vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-selectin expression in the endothelium(Reference Dell'Agli, Fagnani and Mitro58) and decreases the plasma levels of soluble intercellular adhesion molecule-1, soluble E-selectin, IL-6 and high-sensitive C-reactive protein in high-risk patients(Reference Cortés, Núñez and Cofán59–Reference Carluccio, Siculella and Ancora61). Another diet was with mixed nuts, a classical Mediterranean food rich in antioxidants, with walnuts as the major component. A frequent intake of nuts has been associated with decreased levels of IL-6, C-reactive protein and fibrinogen in a population free of CVD(Reference Jiang, Jacobs and Mayer-Davis62), while a Med-Diet supplemented with walnuts decreased the levels of soluble vascular cell adhesion molecule-1 in hypercholesterolaemic and healthy subjects(Reference Ros, Núñez and Pérez-Heras63).
The recruitment and adhesion of peripheral blood mononuclear cells to the endothelium is an early event in fatty streak formation in which adhesion molecules and IL have a key role, but thereafter resident macrophages and lymphocytes become activated and secrete abundant amounts of cytokines that in turn can activate other cell types leading to a self-perpetuating inflammatory process in the vascular wall that is instrumental in more advanced stages of the disease: plaque formation, vulnerability and rupture leading to thrombosis and acute ischaemic episodes(Reference Hansson52, Reference Blankenberg, Barbaux and Tiret53). Inhibition of both cell-mediated and humoral inflammatory pathways, as shown in our study, provides a molecular mechanism for an anti-atherosclerotic effect of the Med-Diet. Interestingly, these changes were opposite to those observed in our study after the recommended low-fat diet, which, given the little changes in nutrients from baseline, was essentially a control diet, similar to the Med-Diets except for the olive oil and nut supplements. Noticeably, the beneficial effects of the Med-Diet on inflammatory markers were essentially similar in subjects under stable treatment with risk-reducing agents that have demonstrable anti-inflammatory properties, namely angiotensin-converting enzyme inhibitors and statins, and in those not treated with these drugs(Reference Ros, Núñez and Pérez-Heras63). Thus, the anti-inflammatory effect of the Med-Diet appears to be complementary to that of pharmacological treatment. Moreover, the benefit of dietary change occurred in older individuals with a sizeable burden of risk factors for CVD. This suggests that the potential anti-atherosclerotic effect of healthy foods is not limited to early disease.
In conclusion, Med-Diet supplemented with olive oil or nuts reduce the potency of cardiovascular risk factors and down-regulate cellular and humoral inflammatory pathways related to atherosclerosis. The fact that these beneficial effects are observed in older subjects at high cardiovascular risk suggests that it is never too late to change dietary habits for improving health status. These results support the recommendation of the Med-Diet as a useful tool against CVD in all stages of the disease.
Acknowledgements
The author thanks the researchers of the PREDIMED study group for their enthusiastic collaboration and all the PREDIMED personnel for excellent assistance with all aspects of the trial. CIBEROBN is an initiative from the Instituto de Salud Carlos III. This work has been supported by the following grants: RETICS RD06/0045, Ministerio de Ciencia e Innovación (AGL2006-14228-C03-01/ALI, AGL2007-66638-C02-02/ALI, AGL2009-13906-C02-02 and FIS 070473) and Centro Nacional de Investigaciones Cardiovasculares (CNIC-06-2007). The author declares no conflict of interest.
