ischemic heart disease and the mediterranean diet

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ISCHEMIC HEART DISEASE (D MUKHERJEE, SECTION EDITOR) Ischemic Heart Disease and the Mediterranean Diet Thomas F. Whayne Jr. Published online: 18 April 2014 # Springer Science+Business Media New York 2014 Abstract Lifestyle modification is primary in cardiovascular (CV) disease prevention. A major contribution is the Mediter- ranean diet (MedDiet), defined by two of seven components. Italian investigators determined a significant decrease in pe- ripheral arterial disease of 56 % for a high score. Multiple specific CV risk factors are also favorably modified by the MedDiet. This includes beneficial effect on inflammation, vascular endothelium, and insulin resistance. There is also evidence that coronary heart disease, diabetes mellitus, and metabolic syndrome are decreased. Benefit appears to extend to new migrants in France. The economics of dietary adher- ence are favorable with decreased total lifetime health costs. Although mixed nuts appear to be a major factor in the MedDiet, special emphasis goes to extra virgin olive oil. Benefit also extends to other noncommunicable diseases with a decrease in cancer, Parkinsons disease, and Alzheimers disease. Further quantitation of benefit and understanding of mechanisms involved in dietary benefit is essential. Keywords Cardiovascular risk . Coronary heart disease . Ischemic heart disease . Lipoproteins . Mediterranean diet . Metabolic syndrome . Myocardial infarction . Peripheral arterial disease Abbreviations apoB apolipoprotein B CHD Coronary heart disease CI Confidence interval CV Cardiovascular DM Diabetes mellitus HbA1c Glycated hemoglobin HDL-C High-density lipoprotein cholesterol HOMA-IR Homeostatic model assessment-insulin resistance HR Hazard ratio LDL-C Low-density lipoprotein cholesterol MedDiet Mediterranean diet MI Myocardial infarction MetSyn Metabolic syndrome PAD Peripheral arterial disease PREDIMED Prevención con Dieta Mediterránea RR Relative risk VLDL-C Very low-density lipoprotein cholesterol Introduction Diet should always be first-line in any effort to reduce cardio- vascular (CV) risk. However, many published diets are limited in scope, emphasize one concept as a fad, or are so excessively involved in extreme restrictions, that adherence by any signif- icant number of individuals is highly improbable. On the other hand, the Mediterranean diet (MedDiet) involves many de- lightful and tasty choices and there is accumulating evidence of its value and practicality. The relationship of the MedDiet to ischemic heart disease and results with CV risk are considered in this article. Definition of Mediterranean Diet Rees et al. defined the MedDiet as follows after including 11 clinical trials involving 15 articles and made up of 52,044 randomized participants [1]. The definition involves seven This article is part of the Topical Collection on Ischemic Heart Disease T. F. Whayne Jr. (*) Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, 326 Wethington Building, 900 South Limestone Street, Lexington, KY 40536-0200, USA e-mail: [email protected] Curr Cardiol Rep (2014) 16:491 DOI 10.1007/s11886-014-0491-6

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Page 1: Ischemic Heart Disease and the Mediterranean Diet

ISCHEMIC HEART DISEASE (D MUKHERJEE, SECTION EDITOR)

Ischemic Heart Disease and the Mediterranean Diet

Thomas F. Whayne Jr.

Published online: 18 April 2014# Springer Science+Business Media New York 2014

Abstract Lifestyle modification is primary in cardiovascular(CV) disease prevention. A major contribution is the Mediter-ranean diet (MedDiet), defined by two of seven components.Italian investigators determined a significant decrease in pe-ripheral arterial disease of 56 % for a high score. Multiplespecific CV risk factors are also favorably modified by theMedDiet. This includes beneficial effect on inflammation,vascular endothelium, and insulin resistance. There is alsoevidence that coronary heart disease, diabetes mellitus, andmetabolic syndrome are decreased. Benefit appears to extendto new migrants in France. The economics of dietary adher-ence are favorable with decreased total lifetime health costs.Although mixed nuts appear to be a major factor in theMedDiet, special emphasis goes to extra virgin olive oil.Benefit also extends to other noncommunicable diseases witha decrease in cancer, Parkinson’s disease, and Alzheimer’sdisease. Further quantitation of benefit and understanding ofmechanisms involved in dietary benefit is essential.

Keywords Cardiovascular risk . Coronary heart disease .

Ischemic heart disease . Lipoproteins . Mediterranean diet .

Metabolic syndrome .Myocardial infarction . Peripheralarterial disease

AbbreviationsapoB apolipoprotein BCHD Coronary heart diseaseCI Confidence intervalCV Cardiovascular

DM Diabetes mellitusHbA1c Glycated hemoglobinHDL-C High-density lipoprotein cholesterolHOMA-IR Homeostatic model assessment-insulin

resistanceHR Hazard ratioLDL-C Low-density lipoprotein cholesterolMedDiet Mediterranean dietMI Myocardial infarctionMetSyn Metabolic syndromePAD Peripheral arterial diseasePREDIMED Prevención con Dieta MediterráneaRR Relative riskVLDL-C Very low-density lipoprotein cholesterol

Introduction

Diet should always be first-line in any effort to reduce cardio-vascular (CV) risk. However, many published diets are limitedin scope, emphasize one concept as a fad, or are so excessivelyinvolved in extreme restrictions, that adherence by any signif-icant number of individuals is highly improbable. On the otherhand, the Mediterranean diet (MedDiet) involves many de-lightful and tasty choices and there is accumulating evidenceof its value and practicality. The relationship of theMedDiet toischemic heart disease and results with CV risk are consideredin this article.

Definition of Mediterranean Diet

Rees et al. defined the MedDiet as follows after including 11clinical trials involving 15 articles and made up of 52,044randomized participants [1•]. The definition involves seven

This article is part of the Topical Collection on Ischemic Heart Disease

T. F. Whayne Jr. (*)Division of Cardiovascular Medicine, Gill Heart Institute, Universityof Kentucky, 326 Wethington Building, 900 South Limestone Street,Lexington, KY 40536-0200, USAe-mail: [email protected]

Curr Cardiol Rep (2014) 16:491DOI 10.1007/s11886-014-0491-6

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components to be considered with the presence of at least twoof these components to qualify as a MedDiet (Table 1). Theseven possible components are: a high ratio of monounsatu-rated to saturated fat, some red wine consumption defined aslow to moderate, high legume consumption, significant grainand cereal consumption, consumption of fruits and vegetablesin significant quantities, low consumption of meats and meatproducts with increased consumption of fish, and moderateconsumption of milk and dairy products. Therefore, individ-uals consistently consuming two of the seven componentswould qualify as following a Mediterranean diet. Rees et al.interpreted their analysis as showing limited evidence to sug-gest a favorable effect on CV risk factors [1•]. Theycommented that more comprehensive interventions involvinga description as MedDiet might have a more beneficial effecton plasma lipid levels than a dietary intervention withminimalcomponents. Dietary interventions should be considered first-line therapy for CV disease prevention and there is increasingevidence that the traditional MedDiet may decrease the risk ofCV disease [2]. The extent of coronary heart disease (CHD) ismajor and any nutritional approach that can contribute todecreasing CHD and improving CV health is essential.

Prevención Con Dieta Mediterránea (PREDIMED) Study

The Prevención con Dieta Mediterránea (PREDIMED) studywas a primary prevention dietary trial in Spain that wasrandomized and involved multiple centers [3, 4•, 5•]. The trialwas carried out from October 2003 until December 2010 [3]with a median follow up of 4.8 years [5•]. There was a blindedassessment of end points. The participants were men fromages 55 to 80 years and women from ages 60 to 80 years [3]and the female participants were 57 % of the total [5•]. Theprimary end point was the rate of major CVevents consistingof myocardial infarction (MI), stroke, or death from a CVetiology). The overall study showed that among persons atincreased CV risk, both the MedDiet supplemented withextra-virgin olive oil and MedDiet supplemented with 30 g/

day of mixed nuts decreased the incidence of major CVevents[5•]. A primary end-point event occurred in 288 of 7447individuals enrolled. The multivariable-adjusted hazard ratio(HR) was 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 theMedDiet/extra-virgin olive oil (96 events) and the groupassigned to the MedDiet/with nuts (83 events), respectively.Each of these two groups was compared to the control groupwhich had an occurrence of 109 events.

Also with PREDIMED, Ruiz-Canela et al. looked specifi-cally at individuals where the requirement was that the partic-ipants have no clinical evidence of peripheral arterial disease(PAD) or CV disease at baseline [3]. However, the participantshad to have either type 2 diabetes mellitus (DM) or otherwise,at least three CV risk factors. There were a total of threegroups: a MedDiet with extra-virgin olive oil (2539 patients);a MedDiet with mixed nuts; and the control group which wascounseled on a low-fat diet. There was an extensive programof dietary education for all participants on a quarterly basis.Each of the two MedDiet groups had a lower risk of PAD incomparison to the control group: 18 cases out of 2539 partic-ipants for MedDiet/extra-virgin olive oil group; 26 cases outof 2452 participants for the MedDiet/mixed nuts group; and45 cases out of 2444 participants in the controsl group. Afteradjusting for classic CV risk factors, the HR was 0.34 (95 %CI, 0.20-0.58) for the MedDiet/extra-virgin olive oil groupand HR 0.50 (95%CI, 0.30-0.81) for theMedDiet/mixed nutsgroup; both were compared to the control group. The Kaplan-Meier curves diverged early in the PREDIMED trial; therewas not a significant difference between the two diet interven-tion groups. The authors commented on this being the firstrandomized primary prevention trial that showed benefit froma specific diet in reducing PAD although they could notseparate true primary prevention from a decreased develop-ment of symptomatic PAD from an early stage of PAD [3].

In a fairly small substudy of PREDIMED, Estruch et al.assessed 772 asymptomatic subjects, ages 55-80 years whowere at high CV risk [6]. After following one of the followingfor 3months:MedDiet/extra-virgin olive oil (n=257),MedDiet/mixed nuts (n=258), or a control low fat diet (n=257), theoutcomes were evaluated. Compared to the control, the follow-ing results were obtained for MedDiet/extra-virgin olive oil,MedDiet/mixed nuts respectively: plasma glucose -7.02 mg/dL (95 % CI, -12.6 to -1.26 mg/dL) and -5.4 mg/dL (95 %CI, -01.44 to -0.18 mg/dL); systolic blood pressure -5.9 mmHg(95 % CI, -8.7 to -3.1 mmHg) and -7.1 mmHg (95 % CI, -10.0to -4.1 mmHg); and total cholesterol to high-density lipopro-tein cholesterol (HDL-C) ratio -.38 (95 % CI, -0.55 to -0.22)and -0.26 (CI, -0.422 to -0.10). In addition, compared to thecontrol, MedDiet/extra-virgin olive oil decreased C-reactiveprotein by 0.54 mg/L (95 % CI, 1.04 to 0.03 mg/L). The studyshows that even a short-term MedDiet can favorably affectsignificant CV risk factors [6].

Table 1 Definition of theMediterranean diet involves presence of at leasttwo of the following seven components [1•]

High ratio of monounsaturated to saturated fat

Some red wine consumption defined as low to moderate

High legume consumption

Significant grain and cereal consumption

Significant consumption of fruits and vegetables

Low consumption of meats and meat products with increased fishconsumption

Moderate consumption of milk and dairy products

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From PREDIMED, Sala-Vila et al. studied changes incarotid intima-media thickness (CIMT) in 175 subjects, 164with complete data [7]. They found that compared to a controllow fat diet where CIMT progressed, MedDiet/mixed nutsresulted in regression of CIMT after a mean intervention of2.4 years. There were no changes of CIMT in association withMedDiet/extra-virgin olive oil.

Dietary Scores and Indexes

Methodology to assess adherence to a MedDiet is essential inepidemiological studies. Diet indexes are used in an attempt todo a global evaluation of diet quality [8]. An index is supposedto be general and qualitative and in the case of the MedDiet, itis supposed to be based on a traditional MedDiet referencepattern. Therefore, MedDiet indices summarize the diet with asingle score that is the result of the contribution of differentcomponents such as food, food groups, food combinations,and nutrients. The methods can involve positive or negativescoring of components, subtraction or addition of standard-ized components, and a ratio between components. For exam-ple, an Italian cohort study looked at the risk of developingPAD in type 2 DM patients and the postulate was that a higherscore was better. A point was added according to food intakewith evidence of benefit in CHD prevention and a 0 was givenfor foods with potential harm [9]. These Italian investigatorsfound that a score of 11 or more resulted in a 56 % decreasedincidence of PAD. Dietary scores can be employed to assessmultiple associations between the Med Diet and observationssuch as life expectancy, incidence of obesity, CV diseasepresence, and association with some cancers [8]. However,better quantitation than such indices is essential to improve theaccuracy of measuring adherence.

Dietary Percent Benefit

The traditional MedDiet has been analyzed byWillett to showpercent benefit [10]. A half century ago, Keys and colleaguesdescribed very low rates of CHD in the Mediterranean region,an area with relatively high fat intake but principally fromolive oil. It has been noted that trans fat from partially hydro-genated vegetable oils is strongly related to CHD risk andsuch oils are absent in the traditional MedDiet. Epidemiologicevidence also supports a CHD benefit from increased intake offruits, vegetables, whole grains, and fish, as well as dailyconsumption of moderate amounts of alcohol. In the analysisof Willett, it was noted that associated with regular physicalactivity in nonsmokers, health food choices consistent with atraditional MedDiet can result in the avoidance of 80 % ofCHD, 70 % of stroke, and 90 % of type 2 diabetes [10].

Mediterranean Diet Effects on CV Risk Factors

Multiple analyses have assessed the value of the MedDiet inmodifying CV risk. Nordmann et al. searched multiple databases from their onset, including MEDLINE and CochraneCentral Register of Controlled Trials, until January 2011 and,in addition, contacted various experts to identify randomizedcontrolled trials that had compared the MedDiet to low-fatdiets in overweight or obese subjects [11]. Their analysis waslimited to a minimum 6month follow-up and intention-to-treatdata and its effect on CV risk factors. The inclusion criteria ofthe authors was met by 2650 subjects that consisted of 50 %women. After 2 years of follow-up, the subjects following theMedDiet (as compared to a low-fat diet) had morefavorable changes in weighted mean differences of bodyweight (-2.2 kg; 95 % CI, -3.9 to -0.6), body massindex (-0.6 kg/m2; 95 % CI, -1 to -0.1), systolic bloodpressure (-1.7 mmHg; 95 % CI, -3.3 to -.05), diastolicblood pressure (-1.5 mmHg; 95 % CI, -2.1 to -0.8), fastingplasma glucose (-3.8 mg/dL, 95 % CI, -7 to -0.6), totalcholesterol (-7.4 mg/dL; 95 % CI, -10.3 to -4.4), andhigh-sensitivity C-reactive protein (hsCRP) (-1.0 mg/L;95 % CI, -1.5 to-0.5). Therefore, Nordmann et al. con-cluded the MedDiet appeared to be more effective thana low-fat diet in effecting long-term change in CV riskfactors and inflammatory markers [11].

Much other data supports the advantage of the MedDiet.Martínez-González et al. performed a systematic review ofprospective studies that evaluated the relationship of fruit and/or vegetable consumption with occurrence of chronic disease[12]. They also evaluated 18,457 university graduates enrolledin a dynamic cohort with baseline data collected between 1999and 2010. This systematic review found that increased fruit andvegetable consumption was inversely associated with CV dis-ease incidence and mortality. However, even dealing withhealth-conscious university graduates, it was found that low fruitand vegetable consumption was relatively prevalent, emphasiz-ing the need for improvement strategies [12]. Sofi reviewed theeffectiveness of theMedDiet in primary or secondary preventionand focused on the effect of a complete dietary approach ratherthan focusing on single nutrients [13]. The significant healthbenefit to a general population from the MedDiet in decreasingoverall mortality and in decreasing the incidence of CV diseasewas emphasized. Estruch et al. studied 772 subjects (age 69±5 years) with high CV risk and assigned them to either a low-fatdiet or to one of two styles of theMedDiet [14]. They found thatbody weight, waist circumference, and mean systolic/diastolicblood pressure decreased (P<0.005). They also found a trend ofdecreases in fasting glucose and total cholesterol as well asincreases in high-density lipoprotein cholesterol (HDL-C) aswell as a trend for reduced C-reactive protein.

In a meta-analysis of randomized controlled trials compar-ing MedDiet effects to low-fat diets in overweight/obese

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subjects, Nordmann found results supporting an advantage ofthe MedDiet over low-fat diets for the improvement of mostCV risk factors. He found modest incremental effects of theMedDiet on individual CV risk factors but the consistentbenefit over a wide range of CV risk factors appeared to offeran advantage for decreasing CV complications [15]. Grossoet al. also performed a systematic review of the MedDiet andCV risk factors (Table 2) [16•]. They looked at a total of 58studies that evaluated the relationship between the MedDietand lipoprotein concentration, antioxidative capacity, inflam-matory markers, hypertension, obesity, diabetes, and metabol-ic syndrome (MetSyn). Most of the studies were found toshow a favorable effect of the MedDiet on CV risk althoughthey commented specifically on some remaining controversy,especially regarding obesity and emphasized the need formore randomized clinical trials, especially to elucidate mech-anisms [16•]. In another comparative MedDiet review, Serra-Majem et al. reviewed 43 articles corresponding to 35 studies.They found that with the Med Diet, there were favorableeffects on lipoprotein levels, vasodilatation of endothelium,insulin resistance, MetSyn, antioxidant capacity, cardiac mor-tality, CV mortality, cancer incidence in the obese, and onthose with previous MI [17]. These results appeared to revealpotential mechanisms despite the need for further corrobora-tion of the MedDiet. Sofi et al. in 2010 conducted an updatedversion of their previous meta-analysis with the addition thenof seven prospective studies [18]. They used a random-effectsmodel carried out after inclusion of the then seven new studiesand were able to show a 2-point increase in MedDiet adher-ence was associated with a significant decrease in overallmortality (Relative Risk [RR]=0.92; 95 % CI: 0.90-0.94)and decrease in CV incidence or mortality (RR=0.90; 95 %CI: 0.85-0.93). They also showed significant benefit in reduc-ing cancer incidence or mortality and in decreasing neurode-generative diseases. They commented that large sample sizemade a very significant contribution to their model due to asignificant effect on association of overall mortality.

Another contribution of the MedDiet is to emphasize thatfat quality is more important than the actual amount of fateaten with a significant risk of increased CV disease fromsaturated and trans fats [19]. Therefore, complex carbohy-drates or unsaturated fat should be substituted for saturatedand trans fats in order to decrease saturated and trans-fatintake. Population studies in Finland and the MedDiet, espe-cially emphasize the importance of monounsaturated andpolyunsaturated fats as very important nutrients to preventCV disease. There is accumulating knowledge also of theimportance of omega-3 (n-3) fatty acids [19]. Olive oil hassome omega-3 fatty acids. However, as studied by Benitoet al. in a characterization of different Spanish olive oils, itwas found that the predominant fatty acid in olive oil, oleicacid, can represent essentially 70-80 % of the fatty acids [20].

Van Horn et al., in 2008, wrote a comprehensive review ofavailable evidence for the dietary prevention of CV disease[21]. They focused on the need for individualized dietarypatterns to optimize a decrease in CV risk due to the fact thatmost patients present with multiple CV risk factors includingthe MetSyn. They summarized dietary considerations as fol-lows: low in saturated fatty acids, trans-fatty acids, and cho-lesterol; increased omega-3 fatty acids; sufficient total dietaryfiber; unsalted nuts as well as other vegetable protein sourceslike soy and legumes; low-fat dairy foods and other calcium/vitamin D-rich foods; a diet rich in vitamins, minerals, phy-tochemicals, and antioxidants; increased B vitamins and fiberfrom foods such as whole grains and vegetables; possibleinclusion of plant sterols in individuals at very high CV risk;and increased physical activity as well as maintenance ofappropriate energy balance.

Metabolic Syndrome

Decreased prevalence of the MetSyn has been associated witha MedDiet including diets rich in olive oil, legumes/othervegetables, fish, fruits, and nuts [22]. In addition, such dietsinclude those with a moderate alcohol intake while they arelow in whole-fat dairy products, processed carbohydrates, andred meat. Diets of the MedDiet class appear to favorablymodulate insulin resistance, blood pressure, and hyperlipid-emia while affecting an anti-inflammatory component relevantto the MetSyn. Kastorini et al. reviewed 35 original-researchstudies regarding the MedDiet and also found a possibleprotective effect on body weight and obesity, factors notalways confirmed with MedDiet studies [23]. Richard et al.performed a small study of 19 men with the MetSyn and theeffect of the MedDiet on apolipoprotein B (apoB) metabolismin these MetSyn patients, with and without weight loss.[24]They found that the MedDiet increased LDL-C particle sizewhile decreasing apoB concentration in particles of LDL-C.These two beneficial results occurred without weight loss in

Table 2 Specific individual benefits of the Mediterranean diet related tocardiovascular risk [16•, 17]

Favorable lipoprotein levels

Antioxidant capacity

Decreased inflammatory markers

Decreased hypertension

Decreased obesity

Decreased insulin resistance

Improvement in diabetes mellitus

Reduced metabolic syndrome

Improvement in cardiac mortality

Improvement in overall cardiovascular mortality

Decrease in incidence of some cancers

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the MetSyn patients. On the other hand, there was a veryminimal effect on very low-density lipoprotein cholesterol(VLDL-C) unless there was also associated weight loss.

In an extensive meta-analysis of 50 studies involving534,906 subjects, Kastorini et al. analyzed the effect of theMedDiet on the MetSyn in 50 epidemiological studies orrandomized controlled trials [25]. They also assessed the effectof the MedDiet on components of the MetSyn. Their analysisshowed adherence to a MedDiet decreased risk of MetSyn (HR-0.69, 95 % CI: -1.24 to -1.16). In addition, there was aprotective effect of the MedDiet on various components ofthe MetSyn. These included increase in HDL-C (1.17 mg/dL,95 % CI: 0.38 to 1.96), decrease in triglycerides (-6.14 mg/dL,95 % CI: -10.35 to -1.93), decrease in plasma glucose(-3.89 mg/dL, 95 % CI: -5.84 to -1.95), decrease in systolicblood pressure (-2.35 mmHg, 95 % CI: -3.51 to -1.18), de-crease in diastolic blood pressure (-1.58 mmHg, 95 %CI: -2.02 to -1.13), and decrease in waist circumference(-0.42 cm, 95 % CI: -0.82 to -0.02). It appeared that epidemi-ological studies confirmed the results of clinical trials.

Diabetes

There is also evidence for benefit of the MedDiet on type 2DM [26]. As shown, the MedDiet appears to have an inverserelationship with MetSyn, which, in turn, has a major associ-ation with DM. The MedDiet can be considered an option forthe DMpatient in association with increased exercise. There isa beneficial response of insulin, plasma glucose, plasma lipidsand, as already noted, a beneficial effect on overall CV risk.Esposito et al. looked at five randomized controlled trials thathad evaluated the effects of the MedDiet on glycemic controlindices in patients with type 2 DM [27]. They found improvedplasma glucose control ranging from 7 to 40 mg/dL and afavorable decrease in glycated hemoglobin (HbA1c) of 0.1 %to 0.6 %. In their analysis, they found no trial that had reportedworsening of glycemic control. Ajala et al. searched random-ized controlled trials involving an intervention for 6 months orover with comparisons of the following diets: low-carbohydrate, vegetarian, vegan, low-glycemic index, high-fiber, high-protein, and MedDiet with all compared to a con-trol diet [28]. The MedDiet had the greatest effect on decreas-ing HbA1c (-0.47 % (P<0.00001). They also found that theMedDiet led to the greatest weight loss (-1.84 kg (P<0.0001).

To further clarify the effect of the MedDiet on glycemiccontrol, Lasa et al. studied a small group (77 men and 114women) in the PREDIMED study, comparing three dietaryinterventions: low-fat diet, MedDiet/olive oil, and MedDiet/nuts. Low-fat diet, MedDiet/olive oil, and MedDiet/nuts re-sulted in increased adiponectin/leptin ratio (P=0.043, P=0.001, and P<0.001 respectively); increased adiponectin/homeostatic model assessment-insulin resistance (HOMA-

IR) ratio (P=0.061, P=0.027, and P=0.069 respectively);decreased waist circumference (P=0.003, P=0.001, and P=0.001 respectively) [29]. Both types of MedDiet yielded gen-erally favorable results relevant to DM.

Mediterranean Migrants

Another interesting evaluation of the MedDiet is to assessbenefit for outsiders as was done by Darmon and Khlat [30].They found that of those living in France, adult male migrantsfrom North Africa reported following diets similar to a typicalMedDiet. This appears to be at least a partial explanation for alow chronic disease rate and the high adult life expectancy thathas been observed in these adult Africanmen as compared to asimilar population in their native homeland.

Relationship of Mediterranean Diet to Food Supplements

Another consideration is whether there is evidence of benefitfor dietary supplements. Mead et al. performed a systematicreview of dietary advice for previous MI patients and found nosignificant evidence to support the use of antioxidant vitamins,therapies to decrease homocysteine, or the use of a low glyce-mic index diet [31]. Hooper also performed an extensivereview of dietary options and found no credible evidence tosupport the use of high-dose anti-oxidants (vitamin E and betacarotene) to decrease mortality or CV events [32]. Badimonet al. reported on nutraceuticals and atherosclerosis in humantrials [33]. They found several studies (but not all) supportingan inverse association between polyphenol consumption andCV mortality. They also found some evidence, but not in themajority of studies, of benefit from antioxidants, especiallyregarding high dietary intake of foods containing significantamounts of vitamin E, vitamin C, and beta-carotene. On theother hand, direct supplementation with antioxidants does notappear to show comparable benefit and the explanation may besuperiority of combined supplementation in food versus asingle supplement, failure to define the optimal dosage, andfailure to appropriately time supplementation. It appears thatthere is no significant evidence for augmentation of theestablished benefits of theMedDiet by nutritional supplements.

Economics of Mediterranean Diet

Consideration of cost is always relevant if a new diet ispushed. Von Schacky discussed that for secondary CV diseaseprevention, the MedDiet, optimal body weight, exercise, ter-mination of tobacco abuse, control of blood pressure, dietarymanagement of lipids, management of diabetes to get HbA1cto 7.0 % or less, omega-3 fatty acids, statins, platelet

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inhibitors, beta-blockers, and an angiotensin-converting en-zyme inhibitor (ACE-I) are all supported by strong evidence-based medicine and have favorable cost-benefit ratios [34].Saulle et al. specifically researched the financial cost of fol-lowing a MedDiet by assessing cost differences as determinedby low and high adherence rates [35]. They found that adop-tion of a MedDiet may lead to chronic disease prevention withassociated increased life expectancy including improvedhealth and decreased total costs over a lifetime.

Extra Virgin Olive Oil

It appears well established that the MedDiet, rich in extravirgin olive oil, can decrease CV disease risk. This appearsto result by favorable modulations of lipoprotein profile,blood pressure, glucose metabolism, hemostasis, antithrom-botic profile, endothelial function, inflammation, oxidativestress, and even may offer some protection againstAlzheimer’s disease and age-related cognitive decline. Manyof these benefits are associated with minor components ofextra virgin olive oil and many authors such as Perez-Jimenezet al. consider that the definition of the MedDiet shouldspecifically include virgin olive oil [36]. The MedDiet may,of course, be associated with mixed nuts instead of olive oil.However, in countries such as Spain, Italy, and Greece thatfollow a typical MedDiet, extra virgin olive oil is the majorsource of fat. Furthermore, it appears that CV protection fromextra virgin olive oil may be most important in the firstdecades of life, suggesting that the diet, including extra virginolive oil, should be initiated before puberty and maintainedthrough life [36]. Major extra virgin olive oil components areoleic acid and the polyphenol, dihydroxyphenylethanol. In astudy involvingWistar rats, Faine et al. compared the individ-ual effect of these components versus administration of extravirgin olive [37]. Extra virgin olive oil was more effective thanthe individual isolated components in improving lipid profile,increasing HDL-C, and decreasing LDL-C, consistent with anaugmented effect of the oil itself as compared to that of itscomponents. In another study involving rats, Brzosko et al.showed extra virgin olive oil appeared to contribute to inducedthrombosis prevention by decreasing fibrinogen concentra-tions and impairing platelet/vessel wall interactions [38]. Nev-ertheless, further proof regarding specific mechanisms thatfavorably modify CV risk associated with the various compo-nents associated with extra virgin olive need more research.

Overall Effect of the MedDiet on NoncommunicableDiseases

Awealth of evidence supports the benefit of the MedDiet forCV risk reduction. In addition, analytical reviews show that

following a MedDiet is also associated with decreased risk ofsome cancers, even in the elderly [39, 40]. Sofi et al. per-formed a meta-analysis of the effect of following a MedDieton various factors involved in overall health status, and in thecase of the following entities not specifically associated withCV disease, found decreasedmortality from cancer of 6% anddecreased incidence of Parkinson’s disease and Alzheimer’sdisease of 13 %. Benefits from the MedDiet appear to beextensive and to go beyond just CV-related diseases.

Conclusions

There is a wealth of information regarding the MedDiet withmajor continuing studies and much still to be learned. Thebottom line is that there is extensive evidence of a decrease inCV risk associated with adherence to the MedDiet. Severalcomponents associated with CV risk are beneficially affectedsuch as lipoproteins, thrombosis, and vascular reactivity. Inaddition, benefit of the MedDiet appears to extend far beyondCV disease and to involve some evidence of a beneficialdecrease in other chronic diseases such as cancer, Alzheimer’sdisease, and Parkinson’s disease. Benefit of at least somedietary modification in the direction of the Med Diet is hardto deny.

Compliance with Ethics Guidelines

Conflict of Interest Thomas F. Whayne, Jr. declares that he has noconflict of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance

1.• Rees K, Hartley L, Flowers N, et al. ‘Mediterranean’ dietary patternfor the primary prevention of cardiovascular disease. CochraneDatabase Syst Rev. 2013;8, CD009825. This article by Rees et al.is an excellent initial reference that gives background informationstarting with the Seven Countries study and then goes on to definethe MedDiet.

2. Bautista MC, Engler MM. The Mediterranean diet: is itcardioprotective? Prog Cardiovasc Nurs. 2005;20(2):70–6.

3. Ruiz-Canela M, Estruch R, Corella D, et al. Association ofMediterranean diet with peripheral artery disease: thePREDIMED randomized trial. JAMA. 2014;311(4):415–7.

4.• Martinez-Gonzalez MA, Corella D, Salas-Salvado J, et al. Cohortprofile: design and methods of the PREDIMED study. Int JEpidemiol. 2012;41(2):377–85. This description of the

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PREDIMED study is key in assessing the current status of theMedDiet.

5.• Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention ofcardiovascular disease with a Mediterranean diet. N Engl J Med.2013;368(14):1279–90. Estruch et al. define the importance ofextra virgin olive oil and/or mixed nuts assessed as supplementsto the MedDiet.

6. Estruch R, Martinez-Gonzalez MA, Corella D, et al. Effects of aMediterranean-style diet on cardiovascular risk factors: a random-ized trial. Ann Intern Med. 2006;145(1):1–11.

7. Sala-Vila A, Romero-Mamani ES, Gilabert R, et al. Changes inultrasound-assessed carotid intima-media thickness and plaque witha mediterranean diet: a substudy of the PREDIMED trial.Arterioscler Thromb Vasc Biol. 2014;34(2):439–45.

8. Bach A, Serra-Majem L, Carrasco JL, et al. The use of indexesevaluating the adherence to the Mediterranean diet in epidemiolog-ical studies: a review. Public Health Nutr. 2006;9(1A):132–46.

9. Ciccarone E, Di Castelnuovo A, Salcuni M, et al. A high-scoreMediterranean dietary pattern is associated with a reduced risk ofperipheral arterial disease in Italian patients with Type 2 diabetes. JThromb Haemost. 2003;1(8):1744–52.

10. Willett WC. The Mediterranean diet: science and practice. PublicHealth Nutr. 2006;9(1A):105–10.

11. Nordmann AJ, Suter-Zimmermann K, Bucher HC, et al. Meta-analysis comparing Mediterranean to low-fat diets for modificationof cardiovascular risk factors. Am J Med. 2011;124(9):841–51. e2.

12. Martinez-Gonzalez MA, de la Fuente-Arrillaga C, Lopez-Del-Burgo C, et al. Low consumption of fruit and vegetables and riskof chronic disease: a review of the epidemiological evidence andtemporal trends among Spanish graduates. Public Health Nutr.2011;14(12A):2309–15.

13. Sofi F. The Mediterranean diet revisited: evidence of its effective-ness grows. Curr Opin Cardiol. 2009;24(5):442–6.

14. Estruch R, Martinez-Gonzalez MA, Corella D, et al. Effects ofdietary fibre intake on risk factors for cardiovascular disease insubjects at high risk. J Epidemiol Community Health. 2009;63(7):582–8.

15. Nordmann A. Mediterranean or low-fat diets to reduce cardiovas-cular risk? Praxis (Bern 1994). 2011;100(21):1283–8.

16.• Grosso G, Mistretta A, Frigiola A, et al. Mediterranean diet andcardiovascular risk factors: a systematic review. Crit Rev Food SciNutr. 2014;54(5):593–610. This reference by Grosso et al. is impor-tant in assessing the epidemiological evidence for the role of theMedDiet in CV disease prevention.

17. Serra-Majem L, Roman B, Estruch R. Scientific evidence of inter-ventions using the Mediterranean diet: a systematic review. NutrRev. 2006;64(2 Pt 2):S27–47.

18. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence onbenefits of adherence to the Mediterranean diet on health: anupdated systematic review and meta-analysis. Am J Clin Nutr.2010;92(5):1189–96.

19. Fernandez LC, Serra JD, Alvarez JR, et al. Dietary fats and cardio-vascular health. Aten Primaria. 2011;43(3):157 e1–16.

20. Benito M, Oria R, Sanchez-Gimeno AC. Characterization of theolive oil from three potentially interesting varieties from Aragon(Spain). Food Sci Technol Res. 2010;16(6):523–30.

21. Van Horn L, McCoin M, Kris-Etherton PM, et al. The evidence fordietary prevention and treatment of cardiovascular disease. J AmDiet Assoc. 2008;108(2):287–331.

22. Babio N, Bullo M, Salas-Salvado J. Mediterranean diet and meta-bolic syndrome: the evidence. Public Health Nutr. 2009;12(9A):1607–17.

23. Kastorini CM, Milionis HJ, Goudevenos JA, Panagiotakos DB.Mediterranean diet and coronary heart disease: is obesity a link? -A systematic review. Nutr Metab Cardiovasc Dis. 2010;20(7):536–51.

24. Richard C, Couture P, Ooi EM, et al. Effect of mediterranean dietwith and without weight loss on apolipoprotein b100metabolism inmen with metabolic syndrome. Arterioscler Thromb Vasc Biol.2014;34(2):433–8.

25. Kastorini CM, Milionis HJ, Esposito K, et al. The effect ofMediterranean diet on metabolic syndrome and its components: ameta-analysis of 50 studies and 534,906 individuals. J Am CollCardiol. 2011;57(11):1299–313.

26. Champagne CM. The usefulness of a Mediterranean-based diet inindividuals with type 2 diabetes. Curr Diab Rep. 2009;9(5):389–95.

27. Esposito K, Maiorino MI, Ceriello A, Giugliano D. Prevention andcontrol of type 2 diabetes by Mediterranean diet: a systematicreview. Diabetes Res Clin Pract. 2010;89(2):97–102.

28. Ajala O, English P, Pinkney J. Systematic review and meta-analysisof different dietary approaches to the management of type 2 diabe-tes. Am J Clin Nutr. 2013;97(3):505–16.

29. Lasa A, Miranda J, Bullo M, et al. Comparative effect of twoMediterranean diets versus a low-fat diet on glycaemic control inindividuals with type 2 diabetes. Eur J Clin Nutr 2014. doi:10.1038/ejcn.2014.1.

30. Darmon N, Khlat M. An overview of the health status of migrantsin France, in relation to their dietary practices. Public Health Nutr.2001;4(2):163–72.

31. Mead A, Atkinson G, Albin D, et al. Dietetic guidelines on food andnutrition in the secondary prevention of cardiovascular disease -evidence from systematic reviews of randomized controlled trials(second update, January 2006). J HumNutr Diet. 2006;19(6):401–19.

32. Hooper L. Primary prevention of CVD: diet and weight loss. ClinEvid (Online). 2007;2007:0219.

33. Badimon L, Vilahur G, Padro T. Nutraceuticals and atherosclerosis:human trials. Cardiovasc Ther. 2010;28(4):202–15.

34. Von Schacky C. Coronary artery disease. Dtsch Med Wochenschr.2002;127(46):2429–31.

35. Saulle R, Semyonov L, La Torre G. Cost and cost-effectiveness ofthe Mediterranean diet: results of a systematic review. Nutrients.2013;5(11):4566–86.

36. Perez-Jimenez F, AlvarezdeCienfuegos G, Badimon L, et al.International conference on the healthy effect of virgin olive oil.Eur J Clin Investig. 2005;35(7):421–4.

37. Faine LA, Rodrigues HG, Galhardi CM, et al. Effects of olive oiland its minor constituents on serum lipids, oxidative stress, andenergy metabolism in cardiac muscle. Can J Physiol Pharmacol.2006;84(2):239–45.

38. Brzosko S, De Curtis A,Murzilli S, et al. Effect of extra virgin oliveoil on experimental thrombosis and primary hemostasis in rats. NutrMetab Cardiovasc Dis. 2002;12(6):337–42.

39. Tyrovolas S, Panagiotakos DB. The role of Mediterranean type ofdiet on the development of cancer and cardiovascular disease, in theelderly: a systematic review. Maturitas. 2010;65(2):122–30.

40. Proietti AR, del Balzo V, Dernini S, et al. Mediterranean diet andprevention of non-communicable diseases: scientific evidences.Ann Ig. 2009;21(3):197–210.

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