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COLLECTIVE REVIEWS

Olive Oil, the Mediterranean Diet, andCardiovascular Health

Christina L Huang, BA, Bauer E Sumpio, MD, PhD, FACS

The Mediterranean Diet

Inhabitants of Southern European and North African re-gions surrounding the Mediterranean Sea have a longer lifeexpectancy and lower risk of chronic diseases than in otherregions of the world.1 It is believed that thediet and lifestyleof these Mediterranean populations have led to decreasedrates of cancer, diabetes, andheart disease.The 1968 SevenCountries Study concluded that coronary heart disease wasnot a major indicator of mortality in men who inhabitedthe Greek island of Crete.2 The occurrence of myocardialinfarction, fatal and nonfatal, was 26 in 10,000 Cretans, in

contrast to the Northern Finland cohort, where the ratewas 1,074 in 10,000.3 Although the Mediterranean dietvaries somewhat regionally, its nutritional model of wholegrains, vegetables, fruits, red wine, and olive oil is believedto contribute to decreased rates of coronary heartdisease. Arecent survey in the region of Girona, Spain, of 3,179 sub-

jects found that adherence to the traditional Mediterraneandiet was inversely associated with body mass index andobesity, major risk factors forheart disease.4 Health benefitsof the Mediterranean diet have precipitated studies on theeffects of its various components, specifically extra virginolive oil (EVOO).

Mediterranean countries have maximized their use ofolive oil, becoming the largest consumers, producers, andexporters of both olives and olive oil. Together they man-ufacture approximately 90% of the total olive oilproduced.Because of olive oils role as the primary source of fat in-take, the Mediterranean diet is high in monounsaturatedfatty acids (MUFA), specifically oleic acid, and low in sat-urated fatty acids (SFA).5 Studies affirm that dietarycis-MUFA have a greater antiatherosclerotic effect than SFAand are comparable with the effects of polyunsaturatedfatty acids (PUFA) on cardiovascular risk factors.6,7

Worldwide, the Japanese and Cretan populations havethe lowest SFA intake, 3% to 8% and 8% of total fatconsumption, respectively. The Japanese and Cretan co-

horts in the Seven Countries Study hadthe lowest ischemicheart disease (IHD) mortality rates.8 Cretans exhibited alow rate of IHD and low plasma cholesterol levels despitetheir high fat diet (33% to 40% of caloric intake).9 ForCretans, olive oil provides approximately 29% of the totaldietary energy and this accounts for the islands unusuallyhigh MUFA-to-SFA ratio.10 Conversely, Finland, with the

worlds highest SFA intake at 20% of their diet, has thehighest rates of IHD mortality, with a rate of 132.2 IHDdeaths per 100,000 deaths, and Japan and Greece have arate of 28.6 and 64.7, respectively11 (Fig. 1A, 1B). Per

capita olive oil consumption can be loosely correlated torates of IHD mortality, with the exception of France and

Japan.Although a variety of factors play a role in heart disease

mortality rates, including differing regional diets, healthcare quality, and socioeconomic status, it is generally estab-lished that the Finnish diet of fatty red meats, butter, andbread is highly conducive to heart disease when compared

with the Mediterranean diet. Fat- and calorie-dense foodssupport the physicallydemanding Finnish lifestyle of livingand laboring in cold, wet conditions. Other factors, includ-ing genetic differences, stress levels, and Finlands arduous

work environments, can contribute to these observedhealth disparities. In contrast, whole grains, fresh vegeta-bles, red wine, and olive oil are sufficient in the temperateMediterranean basin and, as research now shows, this di-etary complex might contribute to a decreased risk of car-diovascular disease. Epidemiologic and biologic evidencealso suggest that moderate consumption of red wine has animportant role in low rates of IHD because of the antioxi-dative nature of its resveratrol component. It should benoted also, that although diet does influence cardiovascularhealth, a host of confounding variables, such as lifestyle,exercise, stress level, environment, and genetics, play a rolein the health of those in the Mediterranean region.

The Japanese and Mediterranean diets and lifestyle areremarkably similar, and both emphasize physical activity.The core components of the Japanese and Mediterraneandiets are cereals; vegetables such as beansand nuts; and leanmeat, such as fish (Fig. 2A, 2B). Although the Japanesepopulation only hasa per capita consumption of oliveoilof0.24 kg peryear, vegetables andvegetableoils are integral tothe diet.

In the United States, the US Department of Agriculture,

Disclosure Information: Nothing to disclose.

Received December 14, 2007; Revised January 31, 2008; Accepted February11, 2008.From the Department of Surgery, Yale University School of Medicine, NewHaven, CT.Correspondence address: Bauer Sumpio, MD, PhD, Department of Surgery,

Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520.email:[email protected]

407 2008 by the American College of Surgeons ISSN 1072-7515/08/$34.00

Published by Elsevier Inc. doi:10.1016/j.jamcollsurg.2008.02.018
mailto:[email protected]:[email protected]:[email protected]


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approved a new pyramid incorporating elements of theJapanese and Mediterranean diets (Fig. 2C). The previous1992 Food Pyramid was revised to emphasize regular mod-erate consumption of olive oil and red wine, encourages

daily exercise, anddistinguishes between good andbad fats,and whole and processed grains. This article intends toreview the data that links olive oil to decreased rates of heartdisease risk factors, including arteriosclerosis, high bloodpressure, and hypercholesterolemia.

From olive to oil

The Mediterranean region is positioned at the convergenceof the hot Saharan and the cool Atlantic climates. Thisresults in dry summers and mild winters, which provide afavorable extended growing season for vegetables andfruits.12 The regions substantial sun exposure has been cor-related to the high antioxidant content in plants. Vegeta-tion native to the area has augmented its production ofantioxidants to defend against reactive oxygen species pro-duced during photosynthesis. Recent epidemiologic stud-ies have established an inverse relationship between intakeof fruit and vegetablebased antioxidants and mortalityrates from chronic diseases.13

Themostwidespread species ofolive is the Olea europaeaand its genus includes 35 species of evergreen shrubs andtrees.14 Olive trees have an unusual ability to develop rootsfrom temporary buds at the lower end of their trunks, areresistant to severe weather conditions, and are able to growin infertile soil. Olive fruit maturation spans severalmonths and its taste and chemical composition is depen-dent on growing conditions, including latitude, wateravailability, and temperature. The maturation, harvesting,and developing process of olives and olive oil is heavilydependent on regional techniques.

Olive oil extraction is conducted through pressure, cen-trifugation, and percolation. Nonedible olive oil undergoesa refining process and is blended with edible oils to obtainregular olive oil.14 Virgin olive oil is obtained under me-

chanical conditions that do not alter its composition and itis not mixed with other oils. EVOO is the highest quality

olive oil and accounts for only 10% of oil produced. It hasa free acidity, expressed as oleic acid, of not0.8%. Experts

judge it for taste, mouth feel, and aroma; the oil tends to bemost delicate in flavor. Refined olive oil has a free acidity of0.3%. Regular olive oil, a blend of refined and virgin oliveoils has a free acidity of 0.1%.14

Themajor components ofoliveoilareknown as thesapon-ifiable or glyceride fraction. Glycerols represent 98% oftotal oil weight and are composed mainly of triacylglycerols(Table 1). Oleic acid makes up 70% to 80% of the fatty acidsin olive oil. Minor components are present in about 2% ofoil

weight and include230chemicalcompounds.These minor

components are present almost exclusively in virgin olive oilbecausetherefiningprocessexpunges these compounds.Con-siderable research has centered on extra virgin andvirgin oliveoil with the belief that these minor components contain im-portant cardiovascular protective effects.

Several components of olive oil have beneficial healtheffects on the atherosclerotic and thrombotic pathways,

which include lipid oxidation, hemostasis, platelet aggre-gation, coagulation, and fibrinolysis. Oleic acid, a majorcomponent, and the polyphenolstocopherol,hydroxyty-

Figure 1. (A) Per capita consumption of olive oil in selected coun-

tries (Olive Oil Council Data). (B) Rates of coronary heart disease

mortality according to the World Health Organization standard (Car-

diovascular Disease Infobase).

Abbreviations and Acronyms

CM chylomicronsEVOO extra virgin olive oilICAM-1 intercellular adhesion molecule-1IHD ischemic heart disease

IMT intima-media thicknessMUFA monounsaturated fatty acidsNO nitric oxidePAI-1 plasminogen activator inhibitor-1PUFA polyunsaturated fatty acidsSFA saturated fatty acidsVCAM-1 vascular cell-adhesion molecule-1

408 Huang and Sumpio Mediterranean Diet and Cardiovascular Health J Am Coll Surg


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rosol, and oleuropeinexert the most substantial antiath-erosclerotic effects.

Oleic acid and heart disease

LDL, HDL, oxidation, and chylomicrons

Oleic acid is preventive in the development of atheromasand subsequent thrombi through their establishment oflarger MUFA-to-PUFA and MUFA-to-SFA ratios, in-creased resistance to oxidation, and induction of largerhydrolysable chylomicrons (CM). Increased levels ofLDL are important factors in arteriosclerosis, as theyfacilitate transport of cholesterol to arteries . LDL, whichcarries about two-thirds of plasma cholesterol, can infil-trate the arterial wall and attract macrophages, smoothmuscle cells, and endothelial cells. Once embedded inthe intima, LDL undergoes oxidation to oxLDL, con-tributing to foam-cell formation. Circulating oxLDLinduces transcription of adhesion factors and is chemo-tactic for monocytes and leukocytes, thereby inhibitingegression of macrophages from plaques.15 Conversely,HDL are antiatherogenic. Unlike their larger counter-part, HDL primarily deliver cholesterol to the liver to bemetabolized and excreted or reused. It is also hypothe-sized that HDL are able to dislodge cholesterol mole-cules from atheromas in arterial walls.

LDLare less susceptible to free radical oxidation in a dietenriched by MUFA. MUFA are more stable than PUFAand more resistant to oxidation.16A supplemental diet of

EVOO was found to decrease LDL oxidation in rabbitswith experimentally induced arteriosclerosis.17 It also led tolower atherosclerotic lesions in all aortic fragments isolatedfrom the rabbits.18 In addition, MUFA consumption, spe-cifically that of oleic and linoleic acids, has been linked to adecrease in human plasma levels of LDL and an increase inserum HDL.19 In one trial, 24 human subjects diagnosed

with peripheral vascular disease were fed EVOO or refinedolive oil for 3 months. It was found that LDL susceptibilityto oxidation was considerably lower after the EVOOperiod.20

Additional studies suggest that in a meal enriched with

MUFA, larger, more beneficial CM are secreted and rapidlycleared. CM transport dietary cholesterol and fats to theliver and periphery and are strongly atherogenic. They canpenetrate the artery wall and facilitate foam-cell formation.One trial found statistically significant differences betweenolive oils ability to increase the entry of CMs after inges-tion of a meal more so than fish, safflower, and palm oils.21

Oleic acid sustained a large CM size for the longest post-prandial period of time in comparison with sunflower oil,mixed oil, and beef tallow.22

Figure 2. (A) Mediterranean Diet Food Pyramid (neac.eat-online.ne).

(B) Asian Diet Food Pyramid (http://www.neac.eat-online.net).

(C) United States 2005 US Department of Agricultureapproved

Food Pyramid (http://www.mypyramid.gov).

409Vol. 207, No. 3, September 2008 Huang and Sumpio Mediterranean Diet and Cardiovascular Health
http://www.neac.eat-online.net/http://www.neac.eat-online.net/http://www.neac.eat-online.net/http://www.mypyramid.gov/http://www.mypyramid.gov/http://www.mypyramid.gov/http://www.neac.eat-online.net/


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Hemostasis, platelet aggregation, and fibrinolysis

Oleic acid consumption decreases platelet sensitivity andaggregation, lowers levels of the coagulation factor VII(FVII), and increases fibrinolysis.23A full mechanistic ex-planation of the ability of dietary MUFA to decrease plate-let aggregation has yet to be determined. Studies suggestthatchanges in membrane lipid fluidity and long-chainn-3fatty acid from oleic acid can reduce platelet sensitivity tocollagen and other coagulatory factors, induce a hypersen-

sitivity to aggregation antagonist, ADP, and inhibit throm-boxane and prostaglandin synthesis.24,25

Fifty-one healthy adults participated in a 4-month trialwith diets of high and moderate MUFA intake (18% and15% of caloric intake, respectively) and a diet high in sat-urated fats (16% intake). At 8 weeks, those on the high andmoderate MUFA diets demonstrated a decrease in plateletaggregation when exposed to platelet agonists, ADP, ara-chidonic acid, and collagen. The reduction in aggregatory

Table 1. The Major Glyceride Fraction and Minor Nonglyceride Fraction of Olive Oil

Extra virgin Virgin Refined*

Glyceride fraction

Fatty acids (g/100 g)

16:0 Palmitic 6.6 8.6 9.1

16:1n-7 Palmitoleic 0.4 1.1 0.6

18:0 Stearic 2.8 1.9 3.4

18:1n-9 Oleic 83.1 78.7 78.6

18:2n-6 Linoleic 5.1 8.3 6.2

18:3n-3 -Linoleic 0.6 0.4

18:3n- -Linoleic 0.4 0.5

Nonglyceride fraction*

Component (mg/kg)

Aliphatic alcohols

C18C30 alcohols 200 200 200

Triterpene alcohols 5003,000 5003,000 5003,000

Total sterols 1,260.8 687.4 1,366.6

Cholesterol 1.9 2.8 2.0

5-Avenasterol 91.5 35.1 82.7

-Sitosterol 1,124.4 640.9 1,268.8

Sitostanol 7.3 2.3 1.1

Stigmasterol 8.2 6.4 12.0

Proteins (g/kg) 1.76 1.76 1.26

Nonglyceride esters 100250 100250 100250

Waxes 250 250 350

Hydrocarbons

Squalene 4,277 ND 2,598

-carotene 0.334.0 ND ND

Polyphenols

Lipophilic

-tocopherols 300 ND 200

Tocotrienols ND ND None

Hydrophilic 401,000 401,000 None

Hydroxytyrosol-Tyrosol

Considered to be the major constituents of polyphenols, although data is inconsistentin quantifying the total concentrations, which depend on irrigation and harvestingtechniques.

*All data from Olive Oil and Health10 unless otherwise noted.Phenols are removed completely during the refining process and so are not present in refined oil. Currently there is no standard measurement for quantificationof phenols in olive oil and present values cannot be compared with total polyphenol content or that of individual compounds.Squalene can make up to 40% of the weight of minor components.-tocopherols make up to 95% of total tocopherols.ND, No data.



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response to ADP and arachidonic acid was sustained in thehigh-MUFA group for the entire 16-week trial.26

Several animal studies confirmed olive oils correlationto a reduction in thrombogenic factors. Rats fed anEVOO-enriched diet hada lower rate of thrombotic occlu-

sion in an aortic loop model, a lower incidence of venousthrombosis, and an extended bleeding time relative to acontrol group on a normal diet.27 Hypercholesterolemicrabbits fed a virgin olive oil diet compared with those on aSFA diet hada substantial decrease in platelet hyperactivity,subendothelial thrombogenicity, and platelet lipid perox-ide production. In addition to marked changes in choles-terol, triglycerides, and HDL, the olive oil supplementstimulated endothelial synthesis of prostacyclin, and low-ered thromboxane B2 plasma levels.28

Human trials found that 3 weeks of a MUFA-enricheddiet resulted in a substantial reduction in von Willebrand

Factor levels. von Willebrand Factor induces irreversiblebinding of platelets to the subendothelial collagen layer.29

In a study of 25 people on low-fat, high-MUFA, or high-SFA diets, the MUFA diet induced a statistically significantdecrease in von Willebrand Factor activity, 71.8% com-pared with 78.6% for the SFA diet.5

In the case of plaque rupture, tissue factor and FVIIproteins are released as a component in the coagulationcascade. High FVII levels increase the risk of fatal coronaryheart disease because of coronary thrombosis.30 Tissue-factor complexes with FVII to activate the fibrin cascade.Research has found varying results on the effects of oleic

acid on tissue factor and its inhibitor, tissue factor pathwayinhibitor. A high MUFA diet has been linked to decreasedlevels of FVII.31A recent study with an isocaloric replace-ment of a MUFA-enriched Mediterranean diet found areduction in plasma tissue factor pathway inhibitor. Al-though this can be seen as detrimental, it has been sug-gested that low tissue factor pathway inhibitor levels indi-cate the presence of the protease in theendothelium, whichhas a regulatory effect on thrombogenesis.5

Human trials have examined the effect of MUFA, oleicacid, and other vegetable oils on tissue plasminogen activa-tor and plasminogen activator inhibitor-1 (PAI-1). When

21 young healthy males were given two low-fat diets andtwo oleic acidenriched diets from virgin olive oil with thesame dietary cholesterol as the low-fat diet, there was adecrease in PAI-1 plasma levels with both oleicacidenriched diets. Substantial decreases in insulin levelsand PAI-1 activity were observed, suggesting an improve-ment in insulin sensitivity during high-MUFA olive oildiets.32Another intervention compared the isocaloric sub-stitution of a palmitic acid diet for a low-fat or a MUFAdiet in 25 healthy male subjects. Both diets decreased

PAI-1 plasma levels with a higher reductive effect with theMediterranean diet.5

A study involving urban and rural populations in West-ern Sicily found that conversion from an urban diet to aMediterranean diet for8 weeks substantially reduced FVIIcand PAI-1 activity. Conversely, a rural Mediterranean dietpopulation that switched to an urban diet developed sub-stantial increases in FVIIc, t-PA antigen, PAI-1 activity,and fibrinogen.33 In a study with 15 volunteers ingestingeither an SFA-rich diet or an MUFA-rich diet, the diet withMUFA from high oleic acid sunflower oil resulted in alower concentration of FVIIc, LDL cholesterol, and trig-lycerides.34A study was comprised of 69 students in a con-trolled feeding environment, where they were fed sun-flower, rapeseed, or olive oil. The sunflower oil decreasedFXIIa,FXIIc, andFIXc after 4 weeks.Rapeseed oil inducedzero change. The olive oil diet induced a decrease in FVIIc,

FXIIc, FXIIa, and FXc.35

Polyphenols and heart disease

The minor constituents of olive oil also have substantialvascular and cardioprotectiveeffects.The unsaponifiable ornonglyceride fraction of EVOO is rich in hydrocarbons,nonglyceride esters, tocopherols, flavonoids, sterols, andphenolic constituents (Table 2). The proportions of theseminor compounds depend on the manufacturingprocessesof oil. Because these processes vary by oil mill, it is difficultto quantify the dietary intake of these components; andMediterranean countries tend to consume EVOO, which

is much richer in phenolic compounds than refined oils.The main antioxidants in olives are carotenoids and

polyphenolic compounds. The primary polyphenols areoleuroepein, hydroxytyrosol, and -tocopherol. Oleuro-pein, the major polyphenol, consists of up to 14% of thetotal net weight.36 Hydroxytyrosol is a byproduct of oleu-ropein.37 -tocopherol, also known as an active form ofvitamin E, is highly resistant to oxidative degradation.38

Although it exists in relatively low concentrations in oliveoil, its daily consumption augments the overall antioxidantcontent in the human body and protects against free radi-cals and lipid peroxidation in humans.39

Polyphenols interfere with the chain of reactions initi-ated and supported by free radicals.40 This prevents DNAdamage, lipid hydroperoxide formation, and lipid peroxida-tion.41 In addition, exogenous antioxidants increase the con-centration of antioxidants present in the body and protectagainstdegenerative diseases.42 Flavonoids contribute by spar-ing the basal levels of-carotene, urate,andvitamins C andEactivity.15 The phenolic compounds decrease the presence ofcell-adhesion molecules, increase nitric oxide (NO) dispos-ability, suppress platelet aggregation, and boost total phenolic



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content of LDL to delay arteriosclerosis, reduce inflamma-tion, and inhibit oxygen use in neutrophils.43

LDL and oxidation

Free radicals are responsible for oxidation of plasma LDLinto atherogenic oxLDL. They have deleterious effects oncellular membranes and internal structures, which canbring about the onset of cardiovascular disease.15 Theorthodiphenolic structure of hydroxytyrosol and oleuro-pein confers an especially strong antioxidant property.44 Itis believed that these polyphenols exert their antioxidantactivity by chelating free metal ions, such as copper andiron, and also by scavenging free radicals.45

The effects of polyphenols on LDL susceptibility to

copper-mediated oxidation in rabbits with normalized lev-els of vitamin E was reported. Rabbits were fed diets ofrefined olive oil, EVOO, and high oleic sunflower oil. TheEVOO rabbits demonstrated no change in cholesterol or

vitamin E levels after 6 weeks. They had a 30% longer lagphasebefore oxidation compared with therefined oliveoilandsunfloweroilgroup.46 Rats fed dietsofoliveoil hada decreasedconcentration of lipoproteins and thiobarbituric acidreactive substances, end products of lipid peroxidation.47

The Attica epidemiologic study conducted in the pri-marily urban Greek province of Attica examined the corre-lation between Mediterranean diet adherence and levels ofantioxidants and oxLDL. Those with the highest Mediter-ranean diet score, on average, had11% higher levels of total

Table 2. Composite Results from Research on Oleic Acid and Polyphenol Effects on Cardiovascular Function

Oleic acid effects Polyphenol effects

Lipoproteins 1 Serum HDL16

2 Plasma LDL2Oxidation of LDL17, 19

1 Lag phase before oxidation46

Maintain vitamin E basal levels40

2Oxidation of LDL40

1 Inhibition of thiobarbituric acid reactive substances49

1 Phenolic concentrationChylomicrons 1 CM secretion

1 CM size22

Platelets 2 Collagen sensitivity2 Platelet aggregation

2 Collagen-induced thromboxane production by 94%57

High-MUFA diet2 vWF25

2 Venous thrombosis2Thrombotic occlusion1 Bleeding time27

2 C-reactive protein and interleukins, markers of inflammation60

2 Platelet hyperactivity28

2 Platelet aggregation1 Prostacyclin

2 Inhibited platelet aggregation and camp-PDE58

2 Sensitivity to ADP and arachidonic acid2 FVIIc response26 2Aggregation when exposed to APD and collagen agonists57

Coagulation 2 FVII31 2 Postprandial increase in FVIIa53

2 FVIIc34

2 LDL cholesterol, triglycerides

2 FXIIc, FXIIa, FXc35

Fibrinolysis 2 Plasma PAI-11 t-PA5

2 PAI-1 plasma concentration and activity53

1 Insulin sensitivity32

Vasodilation 1 Postprandial vasodilation1 Final products of NOReversal of cholesterol-induced vasoconstriction53

1 LDL oxidation resistance50

1Nitric oxide2 Lipoperoxides53

Adhesion molecules 2 VCAM-1 and E-selection expression5 2Monocyte cell adhesion to endothelium2 VCAM-1 levels62

2Monocyte chemotaxis and cell adhesion 2 Cell surface expression of ICAM-1 and VCAM-161

CM, chylomicrons; ICAM, intercellular adhesion molecule; MUFA, monounsaturated fatty acids; PAI-1, plasminogen activator inhibitor-1; PDE, phospho-diesterase; t-PA, tissue plasminogen activator; VCAM, vascular cell-adhesion molecule; vWF, von Willebrand Factor.



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antioxidant capacity than those in the lowest tertile. Inaddition, the study found that those with the strongestadherence to the Mediterranean diet, on average, had 19%lower oxLDL-cholesterol levels than those with the lowestdietary score.48

A multicenter study, part of the Prevencin con DietaMediterrnea Studies (PREDIMED), conducted a ran-domized controlled trial of asymptomatic subjects at highrisk for cardiovascular disease.Three-hundredand seventy-two participants from 10 Spanish Primary Care Centers

were placed on a low-fat diet or a traditional Mediterraneandiet supplemented with either nuts or virgin olive oil. A3-month followup found substantial decreases in oxLDLlevels in both Mediterranean diet groups.49

NO activity and endothelial dysfunction

In hypercholesterolemia, the production of superoxide an-ions andother free radicalspecies is increasedin endothelialcells, smooth muscle cells, and monocytes when compared

with that of normocholesterolemic controls.50 These spe-cies degrade NO and a damaged endothelium cannot pro-duce sufficient NO, which can lead to monocyte recruit-ment, platelet aggregation, and thrombosis. DiminishedNO bioactivity can cause constriction of coronary arteriesduring exercise and vascular inflammation leading to li-poprotein oxidation and foam-cell formation.51

On the other hand, other studies have found that ox-LDL stimulates NO synthase transcription and synthesisin bovine aortic cells.52 Studies also demonstrated increasedexpression of NO and NO synthase in atherosclerotic rab-bit aorta tissue and human atherosclerotic plaques. It ispostulated that this overproduction accompanies rapid ox-idative inactivation or conversion of the NO to toxic nitro-gen oxides because of accumulation of superoxide anionsand free radicals.51

Studies suggest that vascular dysfunction can be reversedthrough intake of agents able to scavenge these radicals.39

Consumption of a meal with high phenolic EVOO im-proved endothelium-dependent microvascular vasodila-tion during the first 4 hours of the postprandial period inhypercholesterolemic volunteers. Subjects fed the phenol-rich meal displayed a higher concentration of NO andlower lipoperoxide levels than those fed a low-phenol meal.This improvement is linked with a decrease in oxidativestress and increase in the final products of NO.53 In addi-tion, oleuropein stimulated NO production in mouse mac-rophages and activated the inducible form of NOsynthase.54

Rabbits with cholesterol-induced impaired endothelialdilation were given a supplement of -tocopherol or-carotene. The -tocopherol led to complete reversal ofvasoconstriction. Additionally, increased concentrations of

-tocopherol were detected in the plasma, aorta, andLDL.The -tocopherol was able to increase the resistance toLDL ex vivo oxidation after exposure to copper.50

A survey of 20,343 subjects, as part of the Greek cohortof the EPIC (EuropeanProspective Investigation into Can-cer and Nutrition) study, found that adherence to the Med-iterranean diet was inversely related to systolic and diastolicblood pressure. Olive oil, vegetables, and fruits were theprincipal factors responsible for the overall effect of theMediterranean diet on arterial blood pressure. Interest-ingly, cereals, generally considered to be beneficial tohealth, were correlated to increases in arterial bloodpressure.55

The PREDIMED study investigated the effect of thelow fat and two Mediterranean diet diets on 772 adults

with high risk for cardiovascular disease. The Mediterra-nean diet participants with hypertension showed statisti-cally significant reductions from baseline values in systolicbloodpressure, andthe low-fat groupshowed a mean increasein blood pressure. The Mediterranean diet participants dem-onstrated improved lipid profiles, decreased insulin resistance,and reducedconcentrations of inflammatory molecules com-pared with the low-fat group.56

Platelet aggregation

An in vitro study examined the effects of hydroxytyrosoland oleuropein on platelet aggregation. Hydroxytyrosolcompletely inhibited ADP (2M) and collagen (2g/mL)induced platelet aggregation in platelet-rich plasma.57 Theaggregation inhibition potency of hydroxytyrosol wasfound to be equivalent to that of aspirin. In the same study,hydroxytyrosol was also found to inhibit collagen andthrombin-induced thromboxane B2 production. In hu-man volunteers, it was also reported that the pure olive leafextract with 5.40 mg/mL polyphenol oleuropein, was ca-pable of inhibiting in vitro platelet activation in healthy,nonsmoking male individuals.58

DellAgli and colleagues59 examined the effects of oilextracts of high and low phenol content and single phenolson platelet aggregation to prove that cAMP and cGMP-phosphodiesterases might be a biologic target of plateletaggregation inhibition. Of the polyphenols examinedoleuropein, hydroxytyrosol, tyrosol, and the flavonoidsquercetin, luteolin, and apigeninoleuropein had themost substantial effect on platelet aggregation inhibitionfollowed by luteolin.The oil extracts and the single phenolsexhibited inhibition in a concentration-dependent manneron aggregation and on cAMP-phosphodiesterases.

In a randomized controlled trial in Naples, Italy, 180subjects witha metabolic disorder were instructed to followa Mediterranean-style diet supplemented with olive oil.

After 2 years, there was marked improvement in endothe-



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lial function, withstatisticallysignificant decreases in bloodpressure, cholesterol, insulin and glucose levels and plateletaggregation response to L-arginine. There were substantialreductions in markers of systemic vascular inflammation,including C-reactive protein and interleukins. Sixty of 90participants in the intervention group experienced reduc-tions in risk factors, such that they were no longer classifiedas having metabolic syndrome.60 It is still unclear through

what exact pathway polyphenols inhibit platelet aggrega-tion. It is hypothesized to be mediated by a phenol-induceddecrease in eicosanoid production or through the degrada-tion of cAMP in conjunction with inhibition of the arachi-donic acid cascade.59

Endothelial adhesion molecules

The inflammatory response during atherogenesis includesadhesion of leukocytes, monocytes, and lymphocytes to the

endothelium. Adhesion of these molecules is facilitated byintercellular adhesion molecule-1 (ICAM-1), vascular celladhesion molecule-1 (VCAM-1) and E-selection.61 Onestudy reported thatphysiologically relevant dosages of phe-nolic extract from EVOO reduced cell surface expression ofICAM-1 and VCAM-1.62A mixture of olive oil polyphe-nols, including oleuropein, hydroxytyrosol, and tyrosol,also induced a decrease in VCAM-1 mRNA levels andpromoter activity and ICAM-1 and E-selection expres-sion.62 The PREDIMED study on human subjects foundthat the Mediterranean diet supplemented with olive oilresulted in statistically significant reductions in inflamma-

tory markers including C-reactive protein, interleukin-6,ICAM-1, and VCAM-1 when compared with a low-fatdiet.56

Lastly, little research hasexamined the effect of the Med-iterranean diet on the vascular wall. The PEDIMED studyexamined the effect of olive oil on morphologic changes inthe vascular wall. Measurements of carotid intima-mediathickness (IMT) have been used as surrogate markers toevaluate the severity of atherosclerotic disease. An increaseof 0.2 mm in IMT has been reported to imply a 28% and31% increase in risk for stroke and myocardial infarction,respectively.63 Data collected on 190 participants found

that those who consumed the least amount of olive oilhavethe highest IMT. The study found a statistically significantdifference in IMT between those who consumed 6 to 34 gand 35 to 74 g of olive oil per day.64

SUMMARY

In recent years, the Mediterranean diet has become in-creasingly popular, gaining widespread attention amongthe nutrition and research communities. Increasingawareness of the role of fats, sugars, and processed foods

in obesity, cardiovascular disease, diabetes, and cancer isgenerating modifications in dietary habits. Many ofthose interested in weight loss, cardiovascular diseaseprevention, and other health issues are largely inclinedto adopt the Mediterranean diet. The Mediterraneandiet encourages a balanced intake of a broad range offoods and does not require exclusive adherence to a sin-gle nutrient or type of food. The popularity of pizza,pasta, and beans, elements of the Mediterranean diet,suggests that it can satisfy many dietary preferences.Ultimately, it is pivotal that Mediterranean diet foodsare prepared without SFA, and regularly incorporate ol-ive oil, fresh vegetables, and lean meats.

Olive oil is a type of food that can easily replace com-monly used animal oils, lard, andbutters that are detrimen-tal to ones health. Research has demonstrated the advan-tageous effects of olive oil on health on the epidemiologic

and cellular levels. Much more research needs to be con-ducted especially at the cellular level, to more fully under-stand the pathways by which oleic acid and the polyphe-nols in olive oil help to reduce cardiovascular disease riskfactors. In addition, clinical studies, prospective or ran-domized, with hard outcomes such as death or myocardialinfarction, are still lacking and difficult to conduct. Never-theless, current evidence suggests that the components

within EVOO exert a beneficial effect on cardiovascularhealth. As such, it seems that integrating olive oil as a dress-ing, condiment, and cooking lubricant would be a positivehealth benefit in light of increasing rates of cardiovascular

disease andobesity rates within the United States, the Med-iterranean regions, and worldwide.

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