Curr Cardiol Rep (2015) 17:26 DOI 10.1007/s11886-015-0583-y

LIPID ABNORMALITIES AND CARDIOVASCULAR PREVENTION (G DE BACKER, SECTION EDITOR)

New Insights into the Role of Nutrition in CVD Prevention Aleix Sala-Vila & Ramon Estruch & Emilio Ros

# Springer Science+Business Media New York 2015

Abstract Nutrition plays an increasingly significant role in lifestyle strategies for cardiovascular prevention. Foods and dietary patterns that encompass specific foods and beverages and their combinations, with synergies among their components, are the subject of much epidemiologic and clinical research in relation to health issues, including cardiovascular disease. Foods with the highest evidence for beneficial effects on cardiovascular outcomes (mainly fatal and nonfatal coronary artery disease and stroke) and intermediate risk markers (principally cholesterol and blood pressure) are fruits and vegetables, legumes, nuts, whole grains, dairy products, fish, and alcohol consumed in moderation. Epidemiologic and clinical trial evidence on cardiovascular health issues is reviewed for these foods and for the dietary pattern with the highest probability of a causal link with cardiovascular protection, namely This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention A. Sala-Vila : E. Ros Lipid Clinic, Endocrinology and Nutrition Service, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, C. Villarroel 170, 08036 Barcelona, Spain A. Sala-Vila e-mail: [email protected] A. Sala-Vila : R. Estruch : E. Ros Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain R. Estruch e-mail: [email protected] R. Estruch Department of Internal Medicine, IDIBAPS, Hospital Clinic, C. Villarroel 170, 08036 Barcelona, Spain E. Ros (*) Lipid Clinic, Endocrinology and Nutrition Service, (IDIBAPS) Hospital Clínic, C. Villarroel 170, 08036 Barcelona, Spain e-mail: [email protected]

the Mediterranean diet. When pertinent, mechanisms of protection derived from specific nutrients in foods are also examined. The explosion of knowledge in cardioprotective foods and diets needs to be translated to the public, as dietary quality is still far from optimal in large segments of the population. Keywords Cardiovascular disease . Diet . Fruits and vegetables . Seeds . Legumes . Nuts . Whole grains . Dairy products . Fish . Alcohol . Dietary patterns . Mediterranean diet

Introduction Consistent evidence from landmark epidemiological studies supports the concept that an unhealthy lifestyle (smoking, physical inactivity, abstention or excess alcohol, poor diets, and not being at ideal body weight) contributes nearly 80 % of population-attributable risk of cardiovascular diseases (CVD) [1–3]. That a salutary lifestyle will afford close to 80 % protection from CVD has been confirmed recently by data from a large community cohort in Sweden [4]. Consequently, lifestyle modification is of paramount importance in population-based strategies for cardiovascular prevention, as discussed in the 2012 European guidelines on CVD prevention [5] and the 2013 American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines on lifestyle management to reduce cardiovascular risk [6]. Among lifestyle strategies for reduction of CVD and diabetes, nutrition plays an increasingly significant role [7–9]. Foods, rather than nutrients in isolation, are the fundamental unit in nutrition; nevertheless, by encompassing all foods and their nutrient components with possible synergies and antagonisms between them, dietary patterns are best suited to explore associations between diet and disease [10, 11]. In the last

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years, there has been an explosion of research into dietary components and patterns that have an impact on cardiovascular prevention and on underlying mechanisms. This review is necessarily limited to significant developments into common foods and diet patterns as they relate to CVD prevention. There are novel and expanding aspects to food that cannot be dealt with for reasons of space, such as the importance of meal frequency (i.e., skipping breakfast) for cardiometabolic outcomes [12], nutritional effect on telomere length, a surrogate for biologic aging [13], the influence of diet on the intestinal microbiota [14], or gene–diet interactions in the modulation of CVD phenotypes [15]. The scope of this review also prevents discussing culinary fats and oils and some foods that are consistently recognized as harmful when consumed too often, such as sugars in solid form or in beverages, which would deserve a complete review on its own [16]. The scientific evidence on nutrition and CVD derives mainly from epidemiologic studies relating exposure to foods and diets to CVD outcomes in different cohorts and from randomized clinical trials (RCTs), which usually examine effects of diet components on intermediate markers. Present evidence indicates that foods with a beneficial effect on cardiovascular health are fruits, vegetables, legumes, nuts, whole grains, low-fat dairy products, fish, and alcoholic beverages consumed in moderation [5–10]. Recent findings on these foods in relation to CVD prevention will be summarized. Up-to-date evidence on dietary patterns and CVD, particularly new results from the landmark PREDIMED (PREvención con DIeta MEDiterránea) clinical trial of nutrition intervention with the Mediterranean diet (MeDiet) for CVD prevention [17••], will also be summarized.

Foods Specific foods influence the risk of CVD and diabetes through the synergy and interaction of their main nutrient and bioactive phytochemical components (Table 1). Fruits and Vegetables The evaluation of effects of vegetables and fruits on health outcomes is complicated because there is a large variability at the global level, effects for fruits need not be similar to those of vegetables, cooking for many vegetables may change their composition, and there are multiple possibilities of interactions among them. Nevertheless, fruit and vegetable consumption has long been associated with reduced CVD risk based on evidence from observational studies, as shown in a 2006 metaanalysis [18]. Indeed, plant-based diets widely recommended for health are based on abundant fruits and vegetables [5–10]. Recent reports from large prospective studies and metaanalyses are largely confirmatory [19–23]. Data from 10,000

Table 1 Effects of bioactive components of cardioprotective foods on intermediate risk factors Foods

Bioactive components

Fruits and vegetables Slow-release carb and fiber Legumes Saponins (legumes) Non-sodium minerals Polyphenols Nuts

Effects ↑ Glycemic control ↓ Cholesterol ↓ blood pressure ↓ Oxidation

↓ cholesterol ↓ Blood pressure ↓ Oxidation ↑ Glycemic control ↓ Cholesterol ↓ Oxidation = Cholesterol ↓ Blood pressure ↓ Blood pressure Antiarrhythmic ↑ HDL-cholesterol ↓ Fibrinogen Polyphenols (wine and beer) ↓ Oxidation ↓ Blood pressure

Unsaturated fatty acids Non-sodium minerals Polyphenols Whole grains Slow-release carb and fiber - beta-glucan (oats) Polyphenols Dairy products Saturated fatty acids Non-sodium minerals Whey and casein peptides Fish Long-chain n-3 fatty acids Alcoholic beverages Ethanol

Carb carbohydrate

Norwegian men with an exceptional follow-up of four decades shows that those who consumed more vegetables, fruits, and berries had an 8–10 % reduced risk of all-cause mortality and a 20 % reduced risk of stroke mortality compared to lower consumption groups [21]. This study puts berries, low-energy and polyphenol-rich fruits customarily consumed in Northern Europe, into focus for cardiovascular benefit. Regarding stroke, a meta-analysis of 20 observational studies [22] shows a protective effect for these two categories of plant foods; a linear dose–response relationship showed stroke risk to be reduced by 32 % [95 % confidence interval (CI) 18–44] for each 200-g/day increment in consumption of fruits and 11 % (CI 2–19) for a daily increase in the same amount of vegetables. Another meta-analysis assessed total and cardiovascular mortality in relation to exposure to fruits and vegetables in 16 prospective cohort studies and found that each additional serving/day was associated with a 4–5 % reduced risk of allcause and CVD mortality [23]. Regarding diabetes risk, meta-analyses of fruit and vegetable consumption, either combined or separately, indicate no significant benefit, except for green leafy vegetables [24•]. However, findings from large prospective studies suggest that consumption of specific fruits, such as apples, blueberries, and grapes, is associated with a lower diabetes risk [25]. Fiber is a main component of plant foods that independently relates to a range of health benefits, including a lower risk of diabetes, but this association is mainly driven by fiber from whole grains, with a weaker effect of fruit fiber and no effect of vegetable

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fiber [24•]. There is little evidence that increased fruit and vegetable consumption relates to reduced adiposity [26] or less weight gain with time [27]. Epidemiologic evidence suggests that consumption of fruits and vegetables is associated with stronger protection of stroke than coronary artery disease (CAD). An underlying reason may be that these plant foods are low-sodium and highpotassium and lower blood pressure, as exemplified by Dietary Approaches to Stop Hypertension (DASH)-style diets [28]. However, the association with other cardiovascular risk factors is not clear. No RCTs have specifically evaluated effects on CVD. It is assumed that the health effects of fruits and vegetables, as of plant foods in general, are due to their high fiber, antioxidant, and non-sodium mineral content. These properties underlie the general recommendation of consuming >5 servings/day. Legumes Like nuts and cereal grains, legumes (dry beans, chickpeas, lentils, and soybeans) are seeds, energy- and nutrient-dense foods made of complex matrices containing nutritive components to sustain the future seedling and bioactive phytochemicals to protect the plant’s DNA [29•]. Legumes are low in fat but rich in protein, complex carbohydrates, fiber, non-sodium minerals, micronutrients such as folate, and phytochemicals such as saponins (glycosylated triterpenes with cholesterollowering properties) and polyphenolic compounds, a composition in beneficial nutrients that predicts a health benefit of their consumption. In a meta-analysis of five cohort studies, legume consumption was inversely associated with incident CAD, with a relative risk (RR) per four weekly 100-g servings of 0.86 (CI 0.78–0.94), but was not significantly associated with stroke or diabetes in fewer studies [30]. Epidemiologic observations have also related bean consumption to lower body weight, smaller waist circumference, and lower systolic blood pressure [31, 32]. RCTs have shown beneficial effects of legume diets on cardiovascular risk factors, such as lipids, glycemic control, and blood pressure. A meta-analysis of 10 RCTs evaluating the lipid effects of non-soy legume consumption indicates significant mean decreases in total cholesterol of 0.31 mmol/L and LDL-cholesterol of 0.21 mmol/L [33]. Another meta-analysis of 11 feeding studies found mean 7.2 and 6.2 % reductions in total and LDL-cholesterol, respectively, with a 16.6 % reduction in triglycerides [34]. Data from feeding studies suggest that legumes reduce postprandial blood glucose and insulin excursions, an effect that is mediated by slow carbohydrate absorption and results in improved glycemic control [35]. Indeed, to this end, legumes have been recommended for a long time in the diet of patients with diabetes. A slight blood pressure-lowering effect of legumes has been suggested in a meta-analysis of RCTs, but marked

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heterogeneity among studies precludes drawing firm conclusions [36]. The legume doses used in these studies ranged from 46 to 150 g/day in isocaloric exchange for other foods and no weight gain was reported. The conclusion from available evidence is that legumes should be incorporated into healthy diets to further cardiovascular protection. Nuts Like others seeds, nuts are particularly nutrient-dense foods. Most energy in nuts derives from fat, but fatty acids are mainly unsaturated, predominantly oleic acid; walnuts contain sizable amounts of polyunsaturates, including linoleic acid (18:2n-6) and α-linolenic acid (ALA, C18:3n-3), the principal plant n-3 fatty acid. Nuts are also rich in complex carbohydrate and fiber, protein, tocopherols, non-sodium minerals, and polyphenols [37]. The term nuts encompasses tree nuts, such as almonds, walnuts, hazelnuts, and pistachios, and also peanuts, which botanically are legumes but have a similar nutrient profile to tree nuts. Several large prospective studies have reported on incident CAD in relation to frequency of nut consumption (including peanuts and peanut butter). Attesting to the interest of the topic for the nutrition community, three meta-analyses of prospective studies were published recently in a single issue of a leading nutrition journal [30, 38•, 39]. Six studies consistently described a protective effect of nut consumption on fatal and nonfatal CAD, resulting in an inverse association with fatal CAD (RR 0.76; CI 0.69–0.84) and with nonfatal CAD (RR 0.78; CI 0.67–0.92) per four servings of nuts/week (one serving equals 28.4 g). Expressing the results for each serving/day resulted in a pooled RR for CAD (fatal and nonfatal) of 0.72 (CI 0.64–0.81). A dose–response relationship between nut consumption and reduced CAD outcomes was observed in all studies. The consistency of findings in all prospective studies strongly suggests a causal association between nut consumption and cardioprotection. The consumption of nuts was also inversely associated with diabetes in six studies, with an RR per four weekly servings of 0.87 (CI 0.81–0.94) [30]. On the other hand, the metaanalysis of prospective studies suggests no association between nut consumption and stroke risk [30, 38•]. The results of the PREDIMED trial, however, indicate that nut consumption within the MeDiet reduces the risk of stroke [17••]. The meta-analysis of four observational studies in which exposure to nuts was related to incident hypertension also shows a protective effect [39]. Noticeably, pooled RRs for each serving/ day were 0.83 (CI 0.76–0.91) for all-cause mortality, ascertained in five studies [38•, 39]. Cohort studies have also reported an association between nut consumption and reduced circulating levels of inflammatory biomarkers [37]. Many short-term RCTs have compared the effects of nutenriched versus nut-free diets on the lipid profile. A pooled

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analysis of 25 RCTs using various nuts indicates a consistent cholesterol-lowering effect, with a mean 7.4 % LDLcholesterol reduction for an average consumption of 67 g (2.4 oz) of nuts, which was independent of the type of nut tested [40]. Nut diets also reduced triglycerides when they were elevated at baseline. Other studies have shown beneficial effects of nut diets on oxidation, inflammation, and endothelial function [37]. In the PREDIMED trial, the MeDiet enriched with one serving of nuts/day resulted in a 30 % reduction in incident of CVD (Fig. 1) and, among components of the CVD outcome, a 49 % reduction in stroke [17••], thus providing first-level evidence of the cardiovascular benefit of nuts. Based on these findings, the recent AHA/American Stroke Association guidelines for the primary prevention of stroke recommend a MeDiet enriched with nuts as a strategy to reduce stroke risk [41]. Because nuts are high-fat foods, they are often perceived as providing excess energy and promoting obesity. However, there is no epidemiologic or RCT evidence; on the contrary, reports of large cohorts show inverse associations between nut consumption and BMI or weight gain over time [42, 43]. Furthermore, frequent nut eaters had a lower prevalence of metabolic syndrome in a preliminary report of the PRED IMED study [44] and higher reversion rates in a report of the full cohort [45], and the main driver was decreased visceral adiposity. Finally, a recent meta-analysis of RCTs showed small non-significant associations of nut intake with reduced, not increased, adiposity measures [46]. Mechanistically, the lack of weight gain after consuming nuts is largely due to their Fig. 1 Incidence of cardiovascular disease by intervention group in the PRED IMED study [17••]. Med Diet, Mediterranean diet; EVOO, extravirgin olive oil. (From Estruch et al. [17••]. Copyright © (2013) Massachusetts Medical Society. Reprinted with permission)

prominent satiating effect [37]. The accumulating evidence on the cardiovascular benefit of nuts has prompted the inclusion of this food group in many guidelines, including the newest AHA/ACC document on lifestyle management to reduce cardiovascular risk [6]. Whole Grains Whole grains are seeds composed of bran (the outer layer), germ (the origin of the seedling), and endosperm (store of starch and protein to nourish the future plant). Bran is a concentrated source of fiber and nutrients, including vitamins, minerals, and phytochemicals, which together are thought to provide most of the health benefits of whole grains [47•]. In contrast, refining removes both the germ and bran along with most fiber and micronutrients, leaving almost exclusively the macronutrients carbohydrate and protein. The unique composition of whole grains is believed to confer beneficial effects on chronic disease risk via mechanisms shared by all seeds [29•]. A good example of the profound effect that refining has on the health benefits of grains is the diabetogenic effect of white rice, which primarily consists of starch and provides a significant glycemic load. Thus, a recent meta-analysis of observational studies shows a pooled RR of 1.55 (CI 1.20 to 2.01) comparing the highest with the lowest category of white rice intake in Asian populations, where white rice is a staple [48]. A comprehensive review [47•] and the latest meta-analysis [49] of 11 major prospective studies show that, compared with

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individuals who rarely or never consumed whole grains, those consuming 48 to 80-g/day had a 21 % lower risk of CVD; with similar estimates for CAD, stroke, and fatal CVD; a 26 % lower risk of diabetes; and less weight gain. An increase in consumption of 20 and 30 g/day provided a 26 and 36 % drop in CAD incidence, respectively, indicating a dose–response effect. Besides a benefit on diabetes, whole grains and their bran part are important mediators of colonic health [47•]. Short-term RCTs have also shown that whole grain interventions have a modest lowering effect on fasting blood glucose and total and LDL-cholesterol [49]. A recent meta-analysis of RCTs using beta-glucan-rich oats and barley shows that dose >3 g/day reduce LDL-cholesterol by 0.30 mmol/L (CI 0.24– 0.35) [50]. The benefit on CAD risk associated with whole grains is similar to that suggested for fruit and vegetable consumption of >5 servings/day. An expert panel has recently recommended that 8-g of whole grain per 30-g serving (27 g/100 g) be considered a minimum content of whole grains that is nutritionally meaningful and that a food providing at least 8 g of whole grains/30-g serving be defined as a whole-grain food [51].

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products and yogurt, and relate to reduced risk of weight gain and obesity as well [56, 57, 59]. In RCTs, high-fat dairy products such as cheese do not exert the negative effects on blood lipids that would have been predicted based on saturated fat content. Recent trials testing different dairy foods for outcomes of blood lipids at similar intakes of dairy fat suggest that hard cheese has a lesser LDLcholesterol-raising effect than butter or milk [56]. In one study, eating 143-g/day of 27 %-fat cheese did not increase LDLcholesterol from baseline and lowered levels versus 47-g butter/day [60]. The high calcium content of cheese promoting fecal fat excretion and the fermentation process, leading to prebiotic effects on the colon, have been proposed as mechanisms for its lack of cholesterol-raising effect [53, 60]. In summary, a reappraisal of the effects of milk and derived products on both the risk of CVD and intermediate markers is changing the view towards a neutral or even beneficial effect, independently of fat content. As dairy products are a nutritious staple contributing to better diet quality for many populations, there are accruing reasons for promoting their consumption, especially that of fermented species. Fish

Dairy Products Dairy products contribute important nutrients to the diet, including carbohydrate, protein, calcium, potassium, and micronutrients such as vitamin D. Dairy fat contains saturated fatty acids, traditionally believed to be harmful, a reason why dietary guidelines usually recommend low-fat products. However, recent evidence from observational studies suggests that consumption of milk or dairy products does not increase and might even reduce CVD risk, regardless of fat content [52, 53]. In a meta-analysis of 17 studies [53], milk consumption was not associated with risk of CAD or stroke, but a modest inverse association existed with overall CVD risk (RR 0.94; CI 0.89–0.99 per 200 mL/day). There were no associations of total dairy products or of total high-fat and total low-fat dairy products with CAD. That even dairy products high in fat, hence high in saturated fat, do not increase risk concurs with recent meta-analytical evidence for no overall association of intake of saturated fatty acids with incident CAD [54, 55]. Still, the weak protective effect against CVD could be due to a blood pressure-lowering effect, as observed in prospective studies, although not convincingly shown in small RCTs [56]. The anti-hypertensive effect of the DASH diet was ascribed in part to low-fat dairy products, a key component of this dietary pattern [28]. Milk minerals such as calcium and blockade of the angiotensin-converting enzyme by peptides derived from milk proteins (casein and whey) are believed to play a role in the anti-hypertensive effect [57, 58]. There is also suggestive evidence that dairy products have beneficial effects on the metabolic syndrome and diabetes, driven mainly by low-fat

There is a large body of evidence regarding the cardioprotective properties of long-chain n-3 polyunsaturated fatty acids (LCn3PUFA), mainly eicosapentaenoic (C20:5n3, EPA) and docosahexaenoic (C22:6n3, DHA) acids [61]. The main source of these fatty acids is seafood. LCn3PUFA abound in the flesh of fatty fish (mackerel, herring, salmon, tuna, sardines), while in lean fish (such as cod) they are confined to the liver, which is a natural source of fish oil. Whereas LCn3PUFA effects on plasma lipids and vascular function are only seen at pharmacological doses (>3 g/day), cardiac effects, particularly protection against sudden cardiac death due to an antiarrhythmic effect, can be observed at regular intakes of 250 mg/day [62]. This amount is easily achievable by meeting the AHA recommendation to consume at least two servings/week of fish, preferably fatty fish [63]. Main findings of studies published within the last 3 years on the relationship between fish intake (not fish oil or LCn3PUFA supplements) and CVD will be summarized. Two meta-analyses dealt with fish consumption and stroke risk [64, 65]. After pooling data from 19 cohorts, there was evidence of a modest beneficial association, in particular against ischemic stroke [64]. An increment of two servings/ week of any fish type was associated with a 4 % (CI 1–7) reduced risk of cerebrovascular disease [65]. A metaanalysis of 17 prospective studies in cohorts without prior CAD reported that, compared to individuals with the lowest consumption, those who consumed fish 1/week showed a 16 % (CI 5–25) lower risk of fatal CHD [66]. Finally, in a dose–response analysis of data from eight prospective studies,

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each additional 100-g serving of fish/week was associated with a 5 % reduced risk (CI 3–8) of acute coronary syndrome [67]. These data reinforce the cardiovascular benefit of fish consumption. However, as summarized in a recent meta-analysis of observational studies, neither consumption of fish/seafood nor intake of EPA+DHA was significantly associated with diabetes risk [68]. Two issues deserve attention concerning fish consumption to reduce CVD risk. First, the extent to which the observed effects are solely attributable to LCn3PUFA or should be ascribed to an interplay of bioactive compounds found in the parent food, either beneficial (LCn3PUFA, iodine, taurine, peptides) or harmful (polychlorinated biphenyls and heavy metals). The latter notion seems plausible given the publication since 2010 of the results of several RCTs showing no cardioprotective effects of LCn3PUFA. However, methodological issues in these trials (in particular the length of intervention, background diet, and drug use) might preclude drawing firm conclusions, as recently pointed out [69]. The second issue relates to the increased consumer demand for fish and derived LCn3PUFA, which, coupled with an increasing global population, will likely impact on the sustainability of fish supply in the near future. This has prompted the search for alternative sources of EPA and DHA. In this regard, plant-derived n3PUFA appear to be good candidates. They include two fatty acids. First, ALA (C18:3n3), a shorter-chain n3PUFA supplied by soybeans, flaxseed, and walnuts. ALA is poorly converted to EPA in the body, translating into modest increases of EPA, but not DHA, in plasma and cell pools [70], but cardioprotective effects of ALA on its own have been suggested [71•]. Second, stearidonic acid (SDA, C18:4n3), an n3PUFA found in some oil seeds, particularly in oil of crops genetically modified to express the enzyme delta-6-desaturase. By skipping the first rate-limiting delta-6-desaturase step, transformation of SDA to EPA is more efficient than from ALA [72]. Because they are plant-derived, the supply of either ALA or SDA is certainly more sustainable than that of fatty fish, besides being devoid of marine pollutants. Ongoing research into the cardioprotective properties of these fatty acids will eventually define their role as substitutes of marine-derived LCn3PUFA. Alcoholic Beverages Excessive alcohol consumption is a major global risk factor for morbidity and mortality [73]. However, evidence from both epidemiologic studies and RCTs shows that drinking alcohol in moderation, mainly in the form of wine or beer, is cardioprotective [74], a reason why it is considered an integral part of a healthful lifestyle [1–10]. Many observational studies have examined the association of exposure to alcoholic beverages and CVD outcomes. A meta-analysis of 84 prospective studies concluded that, in comparison to non-drinking, light-

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to-moderate alcohol consumption reduced fatal and nonfatal CAD by close to 30 % and overall mortality by 13 %, but had no effect on stroke [75]. An updated narrative review focused on drinking patterns confirms these findings while showing that individuals with episodic heavy (binge) drinking had a risk similar to lifetime abstainers [76]. The relationship between alcohol consumption and CVD outcomes may be curvilinear, U-shaped, or a flattered-out inverse association [76]. Moderate alcohol consumption also protects from diabetes, as shown in a meta-analysis of 20 cohort studies, where a Ushaped relationship was found for both sexes [77]. The evidence, however, is inconclusive regarding the issue of alcohol consumption and body weight [78]. A meta-analysis of RCTs examining the effects of moderate alcohol consumption on intermediate markers of CVD confirmed that the most consistent effect is increased HDLcholesterol, which is dose-dependent and occurs with any type of alcoholic beverage; thus, it may be ascribed to ethanol itself [79]; as HDL-cholesterol relates inversely to CVD risk, this has traditionally been considered the main mechanism for the cardiovascular protection of alcoholic beverages. In addition, alcohol consumption has been associated with a reduced risk of venous thrombosis and lower fibrinogen levels [79]. A meta-analysis including studies with different alcoholic beverages suggests that moderate daily intake of wine and beer may confer higher protection against CVD than moderate intake of liquors and spirits, mainly due to the higher polyphenolic content of fermented alcoholic beverages [80]. A higher protective effect of moderate consumption of wine compared to liquors and spirits has been suggested in some epidemiological studies, but not in others [81, 82]. The discrepancies may be due to confounding factors difficult to control in prospective studies but solvable by RCTs. In relation to blood pressure, in a recent 4-week intervention crossover trial, moderate doses of dealcoholized red wine decreased systolic and diastolic blood pressure while increasing plasma nitric oxide (NO) concentrations [83•]. Red wine tended to have effects similar to those of dealcoholized red wine, but the changes did not achieve statistical significance, and gin had no effect. Thus, the blood pressure-lowering and NOraising effects should be attributed to red wine polyphenols and not to alcohol. The cardiovascular benefit of moderate wine intake has been related to beneficial effects on oxidative status and arterial wall inflammation. Although alcohol itself induces oxidative stress, wine and beer polyphenols are strong antioxidants and might therefore counteract the pro-oxidant properties of ethanol. RCTs have shown that red wine increases plasma antioxidant capacity, suppresses reactive oxygen species, and decreases LDL oxidation and oxidative DNA damage [84]. Postprandial reduction of oxidative stress has also been observed after red wine consumption, an interesting effect that supports the Mediterranean way of drinking wine with meals [85]. Finally, red wine and dealcoholized red wine

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significantly reduced plasma and monocyte inflammatory biomarkers related to early stages of atherosclerosis, suggesting that wine polyphenols (not alcohol) exert an antiinflammatory effect on the vascular endothelium [86]. In summary, epidemiological studies suggest that moderate alcohol consumption protects against CAD and results of small RCTs have added plausibility to this effect. Whether fermented beverages such as wine and beer have higher protective effects than liquors and spirits is a matter of debate. To solve these issues, RCT assessing the long-term effects of different type of alcoholic beverages on hard cardiovascular endpoints are warranted. Meat and Meat Products Based on the expected raising effect of total and LDLcholesterol of saturated fatty acids in red meat, a major source of protein and fat, dietary recommendations for health have always included a limitation in red meat consumption or advice to substitute it for white (poultry) meat, which has lower fat content [1–10]. However, recent evidence from epidemiological studies indicates a neutral or weak direct association of red unprocessed meat consumption with the risk of CAD, stroke, diabetes, or cardiovascular and all-cause mortality, while consumption of processed meat, such as sausages, salami, and bacon, consistently relates to adverse cardiovascular outcomes and mortality [87–89]. An underlying reason for these differences in health effects between unprocessed meat and processed meat products is that the latter are treated by salting, curing, or smoking, having much higher sodium content, besides harmful additives such as nitrites, nitrates, and nitrosamines [90]. Also, meat is characterized by high saturated fat content, but presently intake of saturated fatty acids is considered neutral regarding CVD risk [54, 55], which may help explain the lack of harm of unprocessed meat, while pointing to preservatives in processed meat as the culprit. Besides a null effect on cardiovascular health outcomes, (lean) red meat has little effect on the lipid profile, blood pressure, or body weight [91]. Thus, current evidence suggests that moderate consumption of lean red meat is not harmful for CVD or diabetes risk.

Dietary Patterns Dietary patterns comprise all foods and beverages as they are actually consumed in various characteristic combinations by different populations across the world. The science of nutritional epidemiology uses theoretical constructs of nutritional variables grouped according to a priori criteria, usually corresponding to prevalent nutrition knowledge and representing current dietary guidelines and recommendations, or food patterns empirically derived from cluster or factor analysis made

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after data collection [10]. Based on a growing body of evidence from such analyses, the general consensus is that dietary patterns beneficial for cardiovascular health are plant-based, consisting of fruits, vegetables, legumes, nuts, and whole grains as main sources of energy, the paradigm being the vegetarian diet, in which low-fat dairy products are also consumed [92]. Customary consumption of seafood, moderate consumption of poultry, and infrequent consumption of red and processed meat, sweets, and sweetened beverages are also part of (non-vegetarian) healthy diets [8–10]. Currently, DASH-type diets [28, 93], the Alternate Healthy Eating Index (AHEI) 2010 (an update of the Healthy Eating Index, which measures adherence to the 2005 Dietary Guidelines for Americans) [94], and the MeDiet [95] are among the most popular healthy diets based on the above principles. It must be noted that the AHEI 2010 and the MeDiet incorporate moderate consumption of alcohol as a critical component. A traditional dietary approach to prevent CVD has been the low-fat diet, which entails a reduction of all dietary fat and usually a concomitant increase in carbohydrates, but it proved futile to reduce cardiovascular outcomes in two large RCTs of nutritional intervention: the Women’s Health Initiative Dietary Modification Trial [96] and the Look AHEAD trial of lifestyle intervention in diabetic patients [97]. In sharp contrast, the MeDiet, a high-fat, high unsaturated fat dietary pattern, has shown a remarkable efficacy to reduce incident CVD by 30 % in the high-risk cohort recruited into the PREDIMED trial [17••]. As the characteristics of the MeDiet and of the PRED IMED trial were recently reviewed in the journal [98], only the latest results will be discussed. Mediterranean Diet and the PREDIMED Trial: New Findings The PREDIMED trial demonstrated that, compared to advice on a low-fat (control) diet, an energy-unrestricted MeDiet enriched with extra-virgin olive oil or nuts reduced incident CVD by 30 % in a cohort of nearly 7,500 high-risk individuals after a mean follow-up of 4.8 years (Fig. 1), thus providing the highest level of scientific evidence for a food pattern in the primary prevention of CVD [17••]. Regarding other cardiovascular outcomes, the MeDiet intervention also reduced the risk of peripheral arterial disease [99] and atrial fibrillation [100], although the antiarrhythmic effect (38 % protection) in this post hoc analysis was limited to the MeDiet enriched with extra-virgin olive oil. Three further PREDIMED studies provide mechanistic evidence for protection against CVD. In a pre-specified study with the whole non-diabetic cohort, the MeDiet with olive oil reduced incident diabetes by 40 % compared with the control diet [101]. In a PREDIMED sub-cohort, after intervention for 1 year, the MeDiet reduced 24-h ambulatory blood pressure, the gold standard for blood pressure assessment, compared to the control diet [102]. The

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changes of nearly −4 mmHg for mean systolic blood pressure and −2 mmHg for mean diastolic blood pressure were remarkable given that most participants were hypertensive and received standard anti-hypertensive medications. Finally, in a carotid ultrasound study at 2 years, participants allocated the MeDiet plus nuts showed plaque regression and those in the MeDiet plus olive oil arm showed delayed progression of atherosclerotic lesions, compared with progression in the control group [103]. In conclusion, the landmark PREDIMED trial is providing first class scientific evidence of the power of food to influence cardiovascular outcomes and mechanisms thereof. Because the mean age of the participants at the beginning of the trial was 67 years [17••], the results also show that it is never too late to change dietary habits to improve cardiovascular health.

Conclusions Decades of sound nutritional epidemiological research and feeding intervention RCTs have provided high-quality evidence on the power of foods and dietary patterns to influence cardiovascular outcomes. The present paradigm is that plantbased diets in general, together with specific healthy foods such as fish and low-fat or fermented dairy products, and the MeDiet in particular are optimal for CVD prevention and should be an integral part of a healthy lifestyle. The dietary approach to CVD is necessarily cost-effective compared with standard cardiovascular drugs and procedures, which could be avoided by many individuals if diet-focused strategies are implemented. There is still much work to be done in this respect, as shown by a recent investigation of trends in dietary quality, as assessed from 1999 to 2010 by the AHEI2010 in a large US adult population sample, which concludes that the overall dietary quality remains poor [104]. Importantly, better dietary quality was associated with higher family income and education, and the gap between low and high socioeconomic status widened with time, indicating where efforts should be directed to attempt to solve these disparities. Nevertheless, even highly educated health professionals who survived a myocardial infarction improved only marginally average dietary quality, as assessed by the AHEI2010 [105]. Still, for those who did best, there was a 29 % reduction in all-cause mortality and a 40 % reduction in CVD mortality. These data indicate that a great effort needs to be made at the public health level to foster the knowledge of cardioprotective foods and diets among the population, not forgetting health professionals. Acknowledgments Aleix Sala-Vila was supported by post-doctoral contract FIS CP12/03299. CIBEROBN is an initiative of ISCIII, Spain. Ramon Estruch has received grant support and travel expenses from Spanish Institute of Health BCarlos III^ (Government of Spain).

Compliance with Ethics Guidelines Conflict of Interest Aleix Sala-Vila declares that he has no conflict of interest. Ramon Estruch is on the advisory board for FIVIN—Spain, European Foundatino for Alcohol and Research (ERAB), and Beer and Health Foundation. He has received grant support from Novartis Farmaceutica, SA; has received payment for educational conferences from Cerveceros de España, Sanofi-Aventis, and FIVIN Spain. He has received fees from NuGO Meeting, Foro Sanidad, Madrid, Fundación Dieta Mediterranea, Aguas de Barcelona, ECO Congress, 38 Congress of SAEN, World Congress of Nutrition, and Semana de Nutrición. Emilio Ros reports grants from California Walnut Commission, personal fees from Nuts for Life, personal fees from La Asturiana S.A., grants and personal fees from Merck, Sharp & Dohme, personal fees from Rubió, personal fees from Alter, grants and personal fees from Sinageva, grants and personal fees from Aegerion, grants and personal fees from Sanofi-Aventis, grants and personal fees from Ferrer International, and grants from Amgen. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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