The Mediterranean Diet: Its Effect on Cardiovascular Disease

The Mediterranean Diet:

Its Effect on Cardiovascular Disease

Neal A. Scott, M.D., Ph.D.

Peninsula Cardiovascular, Inc.

2490 Hospital Drive, Suite 212

Mountain View, CA 94040

650-962-4460

Key Words:

Mediterranean Diet

Cardiovascular Mortality

Myocardial Infarction

Coronary Heart Disease

Metabolic Syndrome

Running Title: Mediterranean Diet and Cardiovascular Disease

Scott, NA The Mediterranean Diet and Cardiovascular Disease

ABSTRACT

What is now commonly known as the Mediterranean Diet has its origins in

the foods consumed and the lifestyle of the people who lived in the

Mediterranean region during the middle of the twentieth century. The

lifestyle consisted of a diet rich in vegetables, whole grains, fruit, olive oil,

nuts and fish, with a paucity of red meat and other sources of saturated fat.

In addition, daily exercise and wine were also important components of this

lifestyle. The benefits in terms of a significant decrease in cardiovascular

mortality and morbidity have been proven repeatedly in clinical trials. The

mechanism of the decrease in cardiac events appears to be due to

improvement in function of the vascular endothelium. This review

summarizes a number of the trials that examined the hypothesis that the

Mediterranean Diet can significantly decrease the incidence of myocardial

infarction and cardiac mortality.

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The health benefits of foods indigenous to the Mediterranean region have

been advocated since the Renaissance, when Giacomo Castelvetro, an

Italian exile living in England, wrote a book in an attempt to convince the

English of the many ways an Italian diet could improve health (Castelvetro &

Riley 1990). Unfortunately, these efforts were unsuccessful and the classical

Northern European dietary fare flourished and spread to the American

colonies. The traditional American diet has since changed considerably,

mainly due to the supply of foodstuffs and the efforts of individuals and

businesses to influence what people in this country eat. Although claims

have been made for the therapeutic powers and vivacity of a multitude

medicinal diets over the past several centuries, until relatively recently there

has been a paucity of scientific evidence that convincingly demonstrates that

a particular diet can increase lifespan and decrease susceptibility to the

major cause of death in industrialized countries: heart disease. The interest

in what is now known as the Mediterranean Diet comes from the

observations made in the 1960s that people from the area surrounding the

Mediterranean Sea had some of the lowest rates of death from coronary

disease in the world (Helsing 1995). In 1961, overall life expectancy was

higher in the Greek population than any other national group tracked by the

World Health Organization (World Health Organization 1993). Throughout

the 1960s, most industrialized countries, especially those in Northern and

Western Europe, experienced what appeared at that time to be inexplicable

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increases in the number of deaths from cardiovascular diseases, while the

rates in most Mediterranean countries, especially Greece, remained at a low

level (Helsing 1995). Based on his knowledge of the differences in dietary

intake between Northern Europe and the Mediterranean area, Ancel Keys, a

noted nutritional scientist, who also developed K-rations for the United

States military, theorized that the differences were related to dietary factors.

Keyes and his colleagues published the results of their observations in the

early 1950’s. These studies found that typical Italian diets were remarkably

low in fat (20% of total calories), or just half the proportion observed in the

diets of comparable American groups (Keys et al. 1954). By that time, long

before such ideas became commonplace, Keys had associated the typical

American diet, rich in meats and dairy fats, with an increased risk of

coronary heart disease (Nestle 1995). In 1959, Ancel Keys and his wife

wrote a cookbook based on the Mediterranean diet that was designed to help

the general public reduce risks of developing coronary artery disease (Keys

& Keys 1959). In a forward to this book, Dr. Paul Dudley White, widely

viewed as the founder of American cardiology (Hurst 1991), extolled both

the health benefits and the taste of the recipes in this book.

For the purposes of this discussion, the Mediterranean diet can be defined as

the dietary pattern found in the olive-growing areas of the Mediterranean

region in the late 1950s and early 1960s (Trichopoulou & Lagiou 1997). The

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Mediterranean Sea borders 21 countries and the diets vary from country to

country. For example, the Italian Mediterranean diet is moderate in olive oil

and high in cereals, the Greek diet uses much more olive oil and fruits, while

in Spain olive oil and fish are popular foods. Although there are many

variants of the Mediterranean diet, some common components can be

identified: low saturated fat, high mono-unsaturated fat (olive oil); moderate

intake of alcohol, mainly in the form of wine with meals; high consumption

of vegetables, fruits, legumes, and cereals; moderate consumption of fish,

milk and dairy products, mostly in the form of cheese; and low consumption

of meat and meat products.

The pivotal study which proved that diet could influence life expectancy was

initiated by Keys in the late 1950’s and known as the ‘Seven Countries

Study’. This study closely examined the diet and activities of men from

seven countries (US, Japan, Finland, Italy, former Yugoslavia, Greece, The

Netherlands). There were a total of 11,579 men who were divided into 15

groups, about two groups per country. Each subject who entered was

between the ages of 40 - 59 and had no prior history of heart disease or

cancer. Careful dietary histories were obtained and, in most cases, the

subjects’ food intake was closely monitored in their home for a week by a

nutritionist. In addition, during that week many subjects were asked to

have duplicate meals prepared which were then given to the investigators

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for a detailed chemical analysis. Also, the physical activity associated with

the occupation of each participant was carefully assessed.

After 15 years, there was a marked difference in death rates between the

groups. For example, the death rate from coronary disease in the group of

men from East Finland was 1202 deaths per 10,000 men while the death

rate from coronary disease in the group of men from Crete (Greece) was

only 38 deaths per 10,000 men (Figure 1). The investigators then set out to

determine why there was such a large difference in death rates between the

groups. When they looked at differences in known risk factors for coronary

disease such as age, smoking habits, blood pressure, body mass index, and

serum cholesterol, these factors only explained 46% of the discrepancy in

the coronary death rates.

Seven Countries Study:

• 15 cohorts of 11,579 men aged 40 – 59 from 7 countries with no

known medical problems were followed for 15 years.

• 2,288 died in 15 yrs

• Death rates varied between groups

• Differences in age, smoking habits, blood pressure and serum

cholesterol explained only 46% of the cardiovascular deaths

(Insert Figure 1 here)

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The investigators then examined the diets of the groups. As expected, there

were major differences between the groups in what they ate. The groups

who lived near the Mediterranean Sea ate much more fish, vegetables, olive

oil (which is rich in mono-unsaturated fat), whole grains, nuts, and fruit

while the groups from Northern Europe and the United States had a diet that

placed greater emphasis on meat, saturated fat and products using refined

sugar. The investigators then accounted for this difference in diet by

factoring in the amount of saturated fat and mono-unsaturated fat in the

diets. They constructed a ratio of the mono-unsaturated fat (mainly olive

oil) over saturated fat (meat, butter, etc) in the diet. When the

investigators incorporated this component into their calculations, 96% of the

difference between death rates from coronary disease was then explained.

This study not only demonstrated an important link between diet and death

from coronary disease, it also proved that the amount of saturated fat in the

diet was a major influence on mortality (Keys et al. 1986).

Seven Countries Study:

• The groups differed in average diets

• The higher the mono-unsaturated / saturated fat in the diet, the lower

the death rate from coronary artery disease

• Inclusion of that ratio with age, blood pressure, smoking habits, and

serum cholesterol explained 96% of the deaths from coronary disease.

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This study proved that the “Mediterranean Diet” was associated with low

rates of death from heart disease. In addition, there were also fewer deaths

from cancer in the groups from around the Mediterranean. Although the

diets varied between countries, on the whole, the diet of the Mediterranean

groups consisted of relatively large amounts of whole grains, non-refined

cereals, brown rice, vegetables, legumes, fresh fruits, olive oil, nuts, low-fat

dairy products and fish. Less commonly seen were poultry, refined sweets

and potatoes. Red meat was eaten rarely, usually once a week, and then in

small portions. In addition, red wine was used moderately on a daily basis.

Daily vigorous exercise was also a common finding. Of note, the mortality

differences from coronary artery disease between groups remained large

after twenty five years of follow-up (Menotti et al. 1999).

(Place Figure 2 here)

The Mediterranean diet is probably the most extensively studied diet in the

world. When we think of a diet, usually the concept of weight loss comes to

mind. Unlike the more commonly known weight loss diet that were designed

by an individual, the Mediterranean diet was not designed as a weight-loss

diet but rather was an observation of the life-prolonging effect of an

established diet from a geographic region.

Therefore, what is referred to as a Mediterranean diet is actually a

lifestyle that not only includes important dietary components but

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also incorporates daily exercise and moderate intake of alcohol,

mostly as red wine. The major aspect of this diet/lifestyle is its ability to

prolong life in people who follow its guidelines. A key concept is that the

Mediterranean diet is based on the dietary habits of relatively poor people

who lived in the Mediterranean region in the 1960’s. Most of these people

had little or no exposure to fast food, red meat, or processed foods. In

addition, since many were farmers working their own land, they had high

levels of daily physical activity. Obviously, we cannot turn back the clock

and transport ourselves to a different part of the world. However, what we

have from the Seven Countries Study is detailed information on what was

contained in the diets of all of the subjects.

Mediterranean Diet Score

The degree of adherence of any other diet can be standardized to the

Mediterranean diet with a “score” that provides an index of how close a

particular diet is to the Mediterranean diet. Several scores have been

described in the literature. Although the units of each Mediterranean dietary

score vary, the higher the score, the closer a particular diet is to the

Mediterranean diet. A lower the score means less adherence with the

Mediterranean diet.

(Insert Table 1 here)

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Mediterranean Diet and Mortality

Several studies conducted in a number of countries have demonstrated an

association between a high Mediterranean diet score and enhanced survival.

Greece

A study involved 22,043 healthy adults between ages 20 and 86 who were

followed for 44 months. Adherence to the traditional Mediterranean diet was

assessed by a 10-point Mediterranean-diet score that incorporated the

salient characteristics of this diet (range of scores, 0 to 9, with higher scores

indicating greater adherence). A two-point higher Mediterranean diet score

was associated with a 25% reduction in total mortality, with a significant

decrease in deaths due to coronary disease and cancer (Trichopoulou et al.

2003).

Europe

In an attempt to determine if the Mediterranean dietary recommendations

could be applied to non-Mediterranean populations (where intake from

mono-unsaturated fats such as olive oil is limited), Trichopuolou et al.

devised a modified Mediterranean diet score (10 points, higher scores

correlated with greater adherence) that substituted mono-unsaturated fats

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(mainly olive oil) with the sum of mono-unsaturated fats and

polyunsaturated fats (olive oil + vegetable oil) in the numerator of the fat

ratio. They followed 74,607 European men and women over age 60 without

a history of heart disease, stroke or cancer at the time of enrollment for a

mean follow-up period of 89 months. They obtained complete information

about dietary history and potentially confounding variables (blood pressure,

cholesterol, smoking status, etc). The extent of adherence to the

Mediterranean diet was then scored on a 10-point scale. The investigators

found that the Mediterranean diet, when modified to apply throughout

Europe, was associated with increased survival. A two unit increase in

Mediterranean diet score was associated with a 7% increase in survival

(Trichopoulou et al. 2005).

United States

A key question is whether the Mediterranean dietary pattern could also

decrease mortality in a population of US residents. Mitrou et al. published a

study where they followed 214,284 men and 166,012 women for five years.

The study participants were part of a National Institutes of Health and

American Association of Retired Persons diet and health study. They were

between the ages of 50 and 71 and resided in six states (California, New

Jersey, Florida, Louisiana, North Carolina, and Pennsylvania) and two

metropolitan areas (Atlanta and Detroit). The participants had no prior

history of heart disease, cancer, diabetes, stroke, emphysema or end-stage

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renal disease at the time of entry into the study. Information about

demographics, smoking and physical activity was also obtained. Careful

dietary histories were taken and conformity with the Mediterranean dietary

pattern was assessed with a 10 point Mediterranean diet score. The mean

follow-up time was 10 years. The Mediterranean dietary pattern was

associated with reduced all-cause and cause-specific mortality. There was a

very significant relationship between adherence to the Mediterranean dietary

pattern (a high Mediterranean Diet Score) and freedom from death from

cardiovascular disease (Figure 3), cancer (Figure 4) and all causes (Mitrou et

al. 2007).

(Place Figures 3 and 4 here)

These results provide strong evidence for a beneficial effect of higher

conformity with the Mediterranean dietary pattern on risk of death from all

causes, including deaths due to cardiovascular disease and cancer, in a US

population.

Australia

Harriss et al. noted that migrants to the Australian continent from the

Mediterranean area have a lower mortality than native-born Australians.

They prospectively examined the relationship between dietary patterns and

mortality from cardiovascular and ischemic heart disease in an ethnically

diverse population of 40,653 adult volunteers aged 40 - 69, 24% of whom

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were Mediterranean born. After adjusting for established risk factors, the

investigators found that Mediterranean foods were inversely associated with

cardiovascular disease and ischemic heart disease mortality in models

adjusting for a prior history of cardiovascular disease, diabetes, waist-to-hip

ratio, body-mass index, and hypertension. The authors concluded that

frequent consumption of traditional Mediterranean foods is associated with

reduced cardiovascular mortality after controlling for important risk factors

and country of birth (Harriss et al. 2007). In a prospective cohort study

involving 141 Anglo-Celts and 189 Greek-Australians aged 70 or more that

was performed in Melbourne, Australia, Kouris-Blazos et al. examined

whether adherence to the Mediterranean diet affects survival of elderly

people in a developed, non-Mediterranean country. A one unit increase in a

10-unit Mediterranean diet score was associated with a 17% reduction in

overall mortality. The decrease in mortality was at least as evident among

Anglo-Celts as among Greek-Australians (Kouris-Blazos et al. 1999).

Elderly

Knoops et al. followed elderly 1507 men and 832 women between 70 and 90

years of age at entry who had no prior history of heart disease or cancer.

After following these patients for 10 years, the investigators found that

adherence to the Mediterranean diet, regular exercise and non-smoking

status was associated with a 50% decrease in mortality (Knoops et al.

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2004). Osler and Schroll studied the diets of 202 patients between ages 75

and 80 from a community in Denmark for a mean of 6 years. A diet score,

with seven dietary characteristics of the Mediterranean diet, was used to

assess its relationship to overall mortality. A one unit increase in the dietary

score predicted a 21% reduction in mortality (Osler & Schroll 1997).

In summary, these studies prove that in subjects with no prior history of

heart disease, adherence to a Mediterranean diet can significantly increase

survival, mainly through a decrease in cardiac events. Some studies have

also shown that cancer mortality rates can also be diminished.

The Mediterranean Diet in Patients with Coronary Artery Disease

Patients with a history of coronary heart disease have a very significant

survival benefit when they adopt the Mediterranean diet. The most

convincing study was a randomized trial conducted in Lyon, France. All 605

patients who entered the study had experienced a recent myocardial

infarction. They were randomly assigned to one of two groups; one group

was told to follow a prudent low-fat diet as instructed by the hospital

nutritionist and the patient’s physician, while the other group was placed on

the Mediterranean diet and received dietary counseling. After two years, the

study was terminated early because of the large decrease in cardiac events

(cardiac death, repeat myocardial infarction) in the Mediterranean diet group

(Renaud et al. 1995). After the study was stopped, most of the patients

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assigned to the Mediterranean Diet chose to remain on that diet. Both

groups were then followed for a total of 46 months. The investigators found

that the rate (per 100 patients per year) of cardiac death or non-fatal

myocardial infarction was 4.07 in the prudent low-fat diet group and 1.24 in

the Mediterranean diet group (de Lorgeril et al. 1999) (Table 2).


This study has been widely quoted in the literature but concern has been

raised about the design of the study since there was a difference in dietary

counseling between the two groups. A study by Tuttle et al. randomized

survivors of their first myocardial infarction to two dietary intervention

groups of approximately 50 patients each: a low-fat diet (American Heart

Association Step II diet) or a Mediterranean-style diet. Both groups received

dietary counseling sessions for the two year duration of the study. In

addition, a ‘usual-care’ group of similar patients was matched to the study

patients in a case-control design. There was no significant difference in

primary outcome-free survival (a composite of all-cause and cardiac deaths,

myocardial infarction, hospital admissions for heart failure, unstable angina

pectoris or stroke) between the Mediterranean-style diet and the Low-fat

diet groups over a median follow-up period of 46 months. However, the

patients receiving dietary intervention had a significantly better primary

outcome-free survival than the usual-care controls (Tuttle et al. 2008).

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Trichopoulou et al. (Trichopoulou et al. 2007) studied 2671 individuals, living

in 9 European countries, who, at enrolment, were 60 years of age or older,

and had reported that they had been diagnosed as having had a prior

myocardial infarction but no cancer or stroke. These patients were

prospectively followed for a mean period of 6.7 years. Increased adherence

to the modified Mediterranean diet by two units on a 10-point Mediterranean

diet score among persons with a history of myocardial infarction at

enrollment was associated with an 18% reduction of mortality.

In another study, Panagiotakos et al. examined almost all of the survivors of

myocardial infarctions in 6 hospitals in urban and rural Greece between

October 2003 and September 2004. They enrolled a total of 2172 patients

(76% men, 24% women), recorded careful dietary histories and assessed

adherence to the Mediterranean diet with a dietary score. They also

examined the biochemical indices of cardiac damage (cardiac enzymes)

measured at the time of their myocardial infarction. They found that the

higher the Mediterranean diet score, the lower the values of the cardiac

enzymes (troponin, creatine phosphokinase-MB fraction), which, in other

words, means the smaller the myocardial infarction (Knoops, de Groot,

Kromhout, Perrin, Moreiras-Varela, Menotti, & van Staveren 2004).

Trichopuolou et al. examined 1302 men and women with a diagnosis of

coronary artery disease who were followed for a mean of 3.78 years. They

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examined their dietary intake and determined the adherence to the

Mediterranean diet with a 10-point Mediterranean diet score. They found

that those patients who had higher adherence to the Mediterranean diet by 2

points had a 27% lower overall mortality and a 31% lower cardiac mortality

(Brunner et al. 2008).

Iestra et al. followed 426 men and women who were over age 70, all of

whom had a prior myocardial infarction. They followed the patients for 10

years and found that those patients who had at least 3 of the following: non-

smoking status, frequent physical activity, moderate alcohol consumption,

Mediterranean diet, had a 40% lower mortality than those without 3 of these

factors (Brunner, Mosdol, Witte, Martikainen, Stafford, Shipley, & Marmot

2008).

In order to ascertain whether simple dietary advice to increase the

consumption of Mediterranean foods, given in a clinical setting, leads to

reduced mortality after a myocardial infarction. Barzi et al. monitored the

intakes of 11,323 patients who sustained a myocardial infarction. All

subjects received advice to increase their consumption of fish, fruit, raw and

cooked vegetables and olive oil. Associations of food intakes, a combined

dietary score, and the risk of death over 6.5 years were estimated. They

found that subjects generally improved their diet according to the advice

given. All Mediterranean foods were associated with a significant reduction

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in risk of death. Compared with people in the worst dietary score quartile,

the odds ratio for those in the best score quartile was 0.51. In other words,

the odds of a cardiac event in the quartile with the best diet scores was

about half that of the group with the worst diet scores. A good diet score

had a protective effect in sub-groups defined by age, gender, smoking, and

concomitant drug therapy. This study showed that patients who have had a

myocardial infarction can respond positively to simple dietary advice, and

that this advice can be expected to lead to a substantial reduction in the risk

of early death (Barzi et al. 2003).

These studies and a number of others, firmly support the concept that the

Mediterranean diet can have a major influence on decreasing the incidence

of repeat coronary events and increasing the survival of patients with

coronary artery disease.

Can the Mediterranean Diet Prevent a Myocardial Infarction?

Akesson et al. followed 24,444 post-menopausal women who were free from

cardiovascular disease, cancer and diabetes at baseline. They collected

careful dietary histories and quantified the activity level of each of the

participants. After a 6 year follow-up period, they found that the

combination of the Mediterranean diet, moderate alcohol consumption, not

smoking, regular exercise and having a waist-hip ratio less than 0.85 could

prevent 77% of the heart attacks in the study population (Akesson et al.

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2007). In a case-control study that included 171 patients and 171 matched

control patients, Martinez-Gonzalez et al. quantified the risk reduction of the

incidence of a first myocardial infarction provided by a Mediterranean diet.

The investigators reported that the higher the Mediterranean diet score, the

lower the odds of myocardial infarction. Moreover, a significant inverse

trend between the diet score and the risk of myocardial infarction was

observed after adjustment for the main cardiovascular risk factors (Martinez-

Gonzalez et al. 2002). These data support the hypothesis that the

Mediterranean diet is an effective independent means of reducing the risk of

myocardial infarction. From these studies it is obvious that a lifestyle that

stresses vegetables, fruit, whole grains, fish, with sparse consumption of

animal meat, regular (daily) exercise and wine in moderation is associated

with a very low probability of developing symptomatic coronary artery

disease.

Comparisons of the Mediterranean Diet with a Low-Fat Diet

For the past several decades, the dietary dogma in the United States has

been that diets that are low in fat are optimal for cardiovascular health.

Unfortunately, the data linking a low fat diet to a marked decrease in

mortality are less than impressive. Hooper et al. performed a meta-analysis

that examined the effect of 26 randomized trials that examined the effect of

a low-fat diet on total mortality and cardiovascular mortality (Hooper et al.

2001). They found that a low-fat diet had little effect on total mortality and

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only a modest effect on cardiovascular mortality (6% decrease). There was

a 16% decrease in total cardiovascular events. Since that study was

published, Howard et al randomized 48,835 post-menopausal women to two

groups. One group received intensive behavior modification in group and

individual sessions designed to reduce total fat intake to 20% of calories

and increase the intake of vegetables/fruits to 5 servings/day and grains to

at least 6 servings/day. No formal intervention regarding saturated fat or

trans-fat was provided. The comparison group received diet-related

education materials. Over a mean follow-up period of 8.1 years, the dietary

intervention that reduced total fat intake and increased intakes of

vegetables, fruits, and grains did not significantly reduce the risk of coronary

disease, stroke, or cardiovascular disease. These data suggest that

intensive behavior modification to achieve the goals of a “low-fat” diet does

not provide any benefit over just being handed a sheet of paper with dietary

guidelines (Howard et al. 2006).

These and other studies highlight the importance of the type of fat as

opposed to the amount of fat. The Mediterranean diet is low in saturated fat

but high in mono-unsaturated and poly-unsaturated fat. Several studies

have demonstrated that enriching diets with poly-unsaturated fatty acids

provides cardiovascular benefit. The Finnish Mental Hospital Study

(Turpeinen et al. 1979), Health Professionals Follow-up Study (Mozaffarian

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et al. 2005), Oslo Diet-Heart Study (Leren 1970), and British Medical

Research Council Soybean Oil Trial (British Medical Research Council 1968)

have all shown that polyunsaturated fatty acid-enriched diets can decrease

coronary event rates by 12% to 44% over a 5- to 8-year period. Notably,

these studies did not use low-fat diets; in fact, 35% to 46% of the total

calories in the experimental diets were allocated to fat.

The effects of a Mediterranean diet or a low-fat diet on cardiovascular

disease risk factors which were defined as: body-mass index, total and

triacylglycerol-rich lipoprotein cholesterol, triacylglycerols, apolipoproteins A-

I and B, insulinemia, glycemia, and a homeostasis model assessment score.

The study was performed on 212 patients who were assigned to either a

Mediterranean diet or a low-fat diet for 3 months. The investigators found a

9% reduction in cardiovascular disease risk with the low-fat diet and a 15%

reduction with the Mediterranean diet. Although the difference between the

two diets was not significant, it is possible that the duration of the study was

too short to allow for any observable benefit between the two diets. Also,

the prior studies focused on mortality and/or well-defined cardiac events, as

opposed to the compounds measured in this study (Vincent-Baudry et al.

2005).

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In summary, these studies demonstrate that, in patients without clinical

heart disease, the cardiovascular mortality benefits from following a low-fat

diet are, at best, relatively small. In contrast, diets rich in mono-

unsaturated and poly-unsaturated fat lead to a marked decrease in

myocardial infarction and cardiovascular mortality.

The Effect of the Mediterranean Diet on the Vascular Endothelium

The single layer of cells that function as the boundary between the blood and

the artery wall play a pivotal role in the initiation and progression of

atherosclerosis. The early process of inflammation is thought to stem from

dysfunction of these endothelial cells, which enables an inflammatory

response with the attraction and penetration of inflammatory cells into the

intimal and medial layers of the blood vessel wall. Inflammatory cells are

also thought to mediate the rupture of an atherosclerotic plaque, which is

thought to be an important cause of myocardial infarction (Libby 2006).

The initiation of an atherosclerotic plaque is believed to be triggered by

common risk factors for atherosclerosis: a diet high in saturated fat,

tobacco, hypertension, hyperglycemia, obesity or inactivity. The endothelial

cell expression of adhesion molecules (e.g., VCAM-1) that bind monocytes

and T-lymphocytes is one of the initial processes in plaque formation. These

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monocytes then migrate into the artery wall and ingest lipids to form lipid-

rich macrophages known as foam cells, an important component of an

atherosclerotic plaque. Expression of VCAM-1 can be stimulated by an

atherogenic diet, which causes the accumulation of modified lipoprotein

particles in the intimal artery layer. An important modified lipoprotein is

oxidized low-density lipoprotein, which not only stimulates adhesion

molecule expression but also triggers the release of cytokines such as

interleukin-6 (IL-6). There is accumulating evidence that circulating levels

of oxidized low-density lipoprotein are predictors of acute coronary events

such as myocardial infarction in patients with established coronary disease

and in the general population (Holvoet et al. 2001), (Meisinger et al. 2005).

Studies have shown that certain dietary components, many of which are

present in the Mediterranean diet, can cause reductions in levels of these

and other biomarkers of inflammation (Basu, Devaraj, & Jialal 2006).

Pitasavos et al. studied the effect of the Mediterranean diet on total

antioxidant capacity in 3042 participants who had no clinical evidence of

cardiovascular disease. Adherence to the Mediterranean diet was assessed

on the basis of a diet score that incorporated the inherent characteristics of

this diet. The investigators measured total anti-oxidant concentration and

found that it was positively correlated with diet score. The participants in

the highest tertile of the diet score had, on average, 11% higher total anti-

oxidant concentration levels than did the participants in the lowest tertile,

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even after adjustment for relevant confounders. On the other hand, the

participants in the highest tertile of the diet score had, on average, 19%

lower oxidized LDL-cholesterol concentrations than did the participants in the

lowest tertile. An additional analysis showed that total anti-oxidant

concentration was positively correlated with the consumption of olive oil and

of fruit and vegetables, whereas it was inversely associated with the

consumption of red meat (Pitsavos et al. 2005).

Fito et al. designed a study to assess the effect of the Mediterranean diet on

lipoprotein oxidation. They examined 372 subjects (210 women, 162 men;

age range: 55-80 years) who were at high cardiovascular risk. They were

randomly assigned to either a low-fat diet, a Mediterranean diet

supplemented with free olive oil or a Mediterranean diet supplemented with

free nuts. After the 3-months, mean oxidized low-density lipoprotein (LDL)

levels decreased in the Mediterranean diet - virgin olive oil and

Mediterranean diet - nuts groups, without changes in the low-fat diet group.

Changes in oxidized LDL levels in the Mediterranean diet - virgin olive oil

group reached significance when compared with that of the low-fat group.

The authors concluded that individuals at high cardiovascular risk who

improved their diet toward a Mediterranean dietary pattern showed

significant reductions in cellular lipid levels and LDL oxidation (Fito et al.

2007).

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Lapointe et al. examined the effect of a nutritional intervention promoting

the Mediterranean diet under free-living conditions on circulating oxidized

LDL in a group of 71 healthy women from the Quebec City metropolitan

area. Their 12-wk nutritional intervention consisted of 2 courses on nutrition

and 7 individual sessions with a dietitian. A score based on the 11

components of the Mediterranean pyramid was established to determine the

adherence to the Mediterranean diet. Plasma oxidized LDL concentrations

decreased by 11.3% after 12 wk of nutritional intervention despite a lack of

change in plasma LDL cholesterol. Also, an increase in the Mediterranean

dietary score was significantly correlated with a decrease in the oxidized LDL

concentrations. More specifically, increases in servings of fruits and

vegetables were associated with decreases in oxidized LDL concentrations

(Lapointe et al. 2005).

Endothelial Function

In a study designed to determine the effect of diet on endothelial function,

lipid concentrations and P-selectin levels, 22 hypercholesterolemic men on a

baseline saturated fat diet were assigned in a crossover design to the U.S.

National Cholesterol Education Program (NCEP) stage 1 diet (a low-fat diet)

or a Mediterranean diet. Each dietary period lasted 28 days. Compared with

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the baseline saturated fat diet, flow-mediated vasodilatation (an index of

normal vascular function) increased during the Mediterranean diet but not

during the NCEP-1 diet. In addition, levels of plasma cholesterol, low-

density lipoprotein cholesterol, apo-lipoprotein B, and P-selectin decreased

during both the NCEP-1 and Mediterranean diets. The authors concluded

that in hypercholesterolemic men, diets low in fat (especially saturated fat)

and diets rich in mono-unsaturated fats improve endothelial function

(Fuentes et al. 2001).

C-Reactive Protein

C-reactive protein (CRP) is a downstream acute phase reactive protein that

is commonly used as a marker of vascular inflammation. Elevated levels of

CRP have been linked with increases in cardiac events (myocardial

infarctions, sudden cardiac death) in patients with symptomatic coronary

artery disease (Dibra et al. 2003), (Keshavamurthy et al. 2000), (Tommasi

et al. 1999). In an effort to determine if dietary changes could influence

CRP levels, Fung et al. compared the associations between diet scores and

biomarkers of inflammation (plasma concentrations of C-reactive protein,

interleukin 6, E-selectin, soluble intercellular cell adhesion molecule 1, and

soluble vascular cell adhesion molecule 1) in 690 women (ages 43-69) with

no prior history of heart disease or diabetes, who were enrolled in the

26


Nurses’ Health Study. They found that diets with high intakes of fruits,

vegetables, grains, nuts and fish, moderate in alcohol and a high ratio of

mono-unsaturated to saturated fat (such as the Mediterranean diet) had

strong inverse associations with biomarkers of inflammation and endothelial

dysfunction (Fung et al. 2005). Pitsavos et al. evaluated the association of

physical activity and diet with C-reactive protein levels in 1337 men and

women (ages 18-89) with abdominal obesity. Adherence to the

Mediterranean diet was assessed with a dietary score (0-55). Compared

with those with low CRP levels, subjects with high CRP levels were physically

inactive, were less likely to adopt the Mediterranean diet, had higher blood

glucose levels, a higher prevalence of hypertension, a lower high-density

lipoprotein cholesterol level and had higher anthropomorphic indices.

Moreover, adoption of the Mediterranean diet in combination with medium

physical activity seems to reduce the likelihood of having high CRP levels by

72%, irrespective of cigarette smoking and various other clinical and

biological characteristics (Pitsavos et al. 2007).

When 3042 healthy men and women ages 18-89 were grouped into thirds

based on a Mediterranean dietary score, the subjects with the highest

adherence to the Mediterranean diet had 20% lower CRP levels, 17% lower

IL-6 levels, 14% lower white blood cell count levels and 6% lower fibrinogen

levels than those in the lowest third (Chrysohoou et al. 2004). In an effort

27


to determine whether the association between the reduction in inflammation

seen with the Mediterranean diet is due to genetic or other familial factors,

Dai et al. determined the adherence to the Mediterranean diet in 345 sets of

middle-aged twins and examined plasma levels of C-reactive protein, IL-6

and known cardiovascular risk factors. Adherence to the Mediterranean diet

was associated with reduced levels of interleukin-6 but not C-reactive

protein after adjustment for total energy intake, other nutritional factors,

known cardiovascular risk factors, and use of supplements and medications.

When the overall association of adherence to the diet with interleukin-6

levels was partitioned into between- and within-pair effects, the between-

pair effect was not significant and the within-pair effect was highly

significant (P<0.0001). A 1-unit within-pair absolute difference in the diet

score was associated with a 9% lower interleukin-6 level. These results

suggest that shared environmental and genetic factors are unlikely to play a

major role in the association between adherence to the Mediterranean diet

and the decrease in systemic inflammation. In addition, these results also

support the hypothesis that reduced inflammation is an important

mechanism linking the Mediterranean diet to reduced cardiovascular risk

(Dai et al. 2008).

Estruch et al. randomized 772 asymptomatic patients who were judged at

high risk for cardiovascular disease to a low-fat diet, or one of two

28


Mediterranean diets. Those allocated to the Mediterranean diets received

nutritional education and either free olive oil or free nuts. After 3 months

the Mediterranean diet groups displayed lower values for fasting plasma

glucose levels, systolic blood pressure and the cholesterol/high-density

lipoprotein ratio and C-reactive protein levels (Estruch et al. 2006).

In contrast to the above studies, Michalsen et al. were unable to

demonstrate a benefit of the Mediterranean diet in 48 patients who had

documented coronary artery disease and received 100 hours of education

when they were compared to 53 patients with coronary disease who

received written advice only. Both groups were followed for one year.

Median levels of CRP, fibrinogen, fasting insulin, serum cholesterols and

triglycerides were unchanged in both groups (Michalsen et al. 2006). In a

more recent study, 872 patients judged to be at high risk for cardiovascular

disease because of the presence of diabetes or at least three classical risk

factors for cardiovascular disease had their dietary adherence to the

Mediterranean diet assessed by a food-frequency questionnaire. Those with

highest consumption of nuts and virgin olive oil showed the lowest

concentrations of C-reactive protein, VCAM-1, ICAM-1 and IL-6. However,

patients with higher adherence values to the Mediterranean diet did not

show significantly lower concentrations for the inflammatory markers VCAM-

1 and ICAM-1 (Salas-Salvado et al. 2008).

29


When all of the above studies are examined, the preponderance of data

suggest that the Mediterranean diet probably decreases cardiac events

through a mechanism that involves endothelial function. The exact factors

that are most critical for this effect have not yet been identified.

Mediterranean Diet and Metabolic Syndrome

The Metabolic Syndrome is characterized by a group of metabolic risk factors

in of metabolic origin that appear to directly promote the development of

atherosclerotic cardiovascular disease. Although the specific criteria vary, in

general this syndrome is characterized by obesity, insulin resistance (or

diabetes), hypertriglyceridemia, low high-density lipoprotein levels, and

systemic arterial hypertension (Grundy et al. 2005). The Metabolic

Syndrome has a prevalence of approximately 22% of American society, with

the percentage increasing to over 40% for people over age 60 (Ford, Giles,

& Dietz 2002). Patients with Metabolic Syndrome have a significantly higher

risk for the development of symptomatic coronary artery disease (Solymoss

et al. 2003), (Anuurad et al. 2007) and mortality from cardiovascular

disease (Ford 2004). In addition, the coronary atherosclerosis in these

patients appears to be more severe and is associated with more clinical

events than those without the syndrome (Butler et al. 2008), (Wassink et al.

2008), (Hong et al. 2007). There is a growing body of evidence that a major

30


contributor to the increase in cardiovascular risk is an elevation of the level

of vascular inflammation (Ford 2003), (Ford et al. 2003) that may be due to

an elevated intake of carbohydrates and saturated fat, as seen in a typical

American diet (Giugliano, Ceriello, & Esposito 2006), (Panagiotakos &

Polychronopoulos 2005). Lutsey et al. followed 9514 study participants for 9

years and identified 3782 cases of Metabolic Syndrome. They determined

that a Western dietary pattern was associated with the Metabolic Syndrome.

Of note, the intake of fried foods, meat, and diet soda were independent

predictors (Lutsey, Steffen, & Stevens 2008).

In order to determine if a Mediterranean diet could prevent the onset of the

Metabolic Syndrome, Tortosa et al. followed 2563 subjects who were initially

free of Metabolic Syndrome or diabetes, hypertension, hypercholesterolemia

or hypertriglyceridemia for 6 years. Adherence to the Mediterranean diet

was assessed with a 10-point score. Those with the highest adherence to

the Mediterranean diet had the lowest incidence of Metabolic Syndrome

(Tortosa et al. 2007). When 578 residents of the Canary Islands were

examined, 24% had the Metabolic Syndrome. After detailed assessment of

their diet, adherence to the Mediterranean diet was not related to the

prevalence of the Metabolic Syndrome, however, some individual

components of the Mediterranean diet showed a protective effect on the

31


Metabolic Syndrome and its components (Alvarez Leon, Henriquez, & Serra-

Majem 2006).

In a trial to determine if a dietary intervention could decrease the incidence

and vascular abnormalities associated with the Metabolic Syndrome, Pitsavos

et al. randomized 180 patients with the Metabolic Syndrome to two groups.

Patients in the intervention group (n=90) were instructed to follow a

Mediterranean-style diet and received detailed advice about how to increase

daily consumption of whole grains, fruits, vegetables, nuts, and olive oil

while patients in the control group (n=90) followed a prudent diet

(carbohydrates, 50%-60%; proteins, 15%-20%; total fat, <30%). Nutrient

intake; endothelial function score as a measure of blood pressure and

platelet aggregation response to L-arginine; lipid and glucose parameters;

insulin sensitivity; and circulating levels of high-sensitivity C-reactive protein

and interleukins 6 (IL-6), 7 (IL-7), and 18 (IL-18). After 2 years, the

patients following the Mediterranean-style diet consumed more foods rich in

monounsaturated fat, polyunsaturated fat, and fiber and had a lower ratio of

omega-6 to omega-3 fatty acids. Total fruit, vegetable, and nuts intake,

whole grain intake, and olive oil consumption were also significantly higher

in the intervention group. The level of physical activity increased in both

groups by approximately 60%, without a difference between groups. Mean

body weight decreased more in patients in the intervention group than in

32


those in the control group. Compared with patients consuming the control

diet, patients consuming the intervention diet had significantly reduced

serum concentrations of C-reactive protein, IL-7, and IL-18, as well as

decreased insulin resistance. Endothelial function score improved in the

intervention group but remained stable in the control group. At 2 years of

follow-up, 40 patients in the intervention group still had features of the

metabolic syndrome, compared with 78 patients in the control group

(Esposito et al. 2004). In addition to the effects on markers of

inflammation, adoption of the Mediterranean Diet is associated with a

significant reduction in coronary risk in patients with the Metabolic Syndrome

(Pitsavos et al. 2003). Overall, these data suggest that the Mediterranean

diet may decrease the incidence of and improve the vascular dysfunction of

individuals with the Metabolic Syndrome.

Diabetes

Diabetes is commonly regarded as the most dangerous risk factor for

cardiovascular disease. Diabetes has been associated with obesity and the

incidence of diabetes increases proportionally with body-mass index.

Lifestyle changes have been shown to prevent the onset of diabetes in high-

risk individuals (Tuomilehto et al. 2001), (Knowler et al. 2002). Toobert et

al. demonstrated that an intervention program that incorporated a

Mediterranean-style diet, in addition to exercise, smoking cessation, stress

management training and group support could decrease the incidence of

33


diabetes in post-menopausal women (Toobert et al. 2003). Brunner et al.

compared the diets of 7731 men and women over age 50 who were followed

for 15 years. Those patients with a Mediterranean-like diet had a

significantly lower risk of developing diabetes than the group with the

‘unhealthy’ dietary pattern (white bread, processed meat, fries, full-cream

milk, sweets, white bread, biscuits, cakes, processed meat, and high-fat

dairy products) (Brunner, Mosdol, Witte, Martikainen, Stafford, Shipley, &

Marmot 2008). Martinez-Gonzalez et al. followed 13,380 university

graduates without diabetes for 4.4 years (ages 33 – 43). They found that

the subjects who adhered closely to the Mediterranean diet had a lower risk

of diabetes (Table 3). A two point increase in a ten point Mediterranean

Dietary Score was associated with a 35% relative reduction in the risk of

diabetes (Martinez-Gonzalez et al. 2008).


Summary

In conclusion, the Mediterranean diet is associated with significant

reductions in the incidence of mortality from coronary disease in most

patient sub-groups, including subjects with no prior history of cardiac

disease, but especially in those with prior myocardial infarction. In general,

the benefits obtained from the Mediterranean diet appear to be proportional

to the amount of adherence to the diet. The mechanism of the protective

34


effect appears to be related to improved function of the vascular endothelial

cells and a decrease in markers of systemic inflammation and oxidation of

low-density lipoprotein. There are data that demonstrate that the

Mediterranean diet may also decrease the incidence of conditions that are

associated with increased risk for the development of coronary disease, such

as metabolic syndrome and diabetes.

35


Figure 1. Coronary heart disease death rates after 15 years between the groups in East Finland, with the highest coronary mortality and Crete (Greece), the group with the lowest coronary death rate.

36


Figure 2. The Mediterranean Dietary Pyramid.

37


Figure 3. Cardiovascular mortality rates in 380,376 Americans in relation to their Mediterranean Diet Score.

38


0

100

200

300

400

500

600

700

800

Score 0 - 3 Score 4 - 5 Score 6 - 9

Death Rate per 100,000 person -yrs


Cancer Mortality

Men

Women


Figure 4. Cancer mortality rates in 380,376 Americans in relation to their Mediterranean Diet Score.

39


Table 1. A 55 point (maximum) Mediterranean Diet Score (Panagiotakos et al. 2007).How often do you consume: Frequency of consumption (servings/week or otherwise stated)

Non-refined cereals Never 1–6 7–12 13–18 19–31 >32

(whole grain bread, pasta, rice, etc) 0 1 2 3 4 5

Potatoes Neve

r 1–4 5–8 9–12 13–18 >18

0 1 2 3 4 5

Fruits Neve

r 1–4 5–8 9–15 16–21 >22

0 1 2 3 4 5

Vegetables Neve

r 1–6 7–12 13–20 21–32 >33

0 1 2 3 4 5

Legumes Neve

r <1 1–2 3–4 5–6 >6

0 1 2 3 4 5

Fish Neve

r <1 1–2 3–4 5–6 >6

0 1 2 3 4 5

Red meat and meat products ≤1 2–3 4–5 6–7 8–10 >10

5 4 3 2 1 0

Poultry ≤3 4–5 5–6 7–8 9–10 >10

0 1 2 3 4 5

Dairy products (cheese, yoghurt, milk) ≤10 11–15 16–20 21–28 29–30 >30

0 1 2 3 4 5

Use of olive oil in cooking (times/week)Neve

r Rare <1 1–3 3–5 Daily

0 1 2 3 4 5

Alcoholic beverages <300 300 400 500 600 >700 or 0

40


(ml/day, 100 ml=12 g ethanol) 0 1 2 3 4 5

Table 2. The Effect of the Mediterranean Diet on Cardiac Events in the Lyon Heart Study (de Lorgeril, Salen, Martin, Monjaud, Delaye, & Mamelle 1999).

Composite Outcome Mediterranean Diet (n=302)

Number of Events

Low-Fat Diet (n=303)

Number of Events

p Value

Cardiac Death + MI 14 44 0.0001

Cardiac Death + MI+ Secondary Endpoints*

27 90 0.0001

Cardiac Death + MI+ Secondary Endpoints*

+ Hospitalization for Minor Events

95 180 0.0002

MI = Myocardial Infarction

* = Unstable Angina, Stroke, Heart Failure, Pulmonary or Peripheral Embolism

Table 3. Incidence and Relative Risk of Type-2 Diabetes During Follow-up According to Adherence to a Mediterranean Diet Score at Baseline (Martinez-Gonzalez, Fuente-Arrillaga, Nunez-Cordoba, Basterra-Gortari, Beunza, Vazquez, Benito, Tortosa, & Bes-Rastrollo 2008).

Med Diet Score n Unadjusted Cumulative Incidence of

Multivariate

adjusted incidence

41


Type II Diabetes (%)

Rate Ratio

(95% CI)Low (0-2) 2253 0.40 1 (reference)Intermediate (3-6) 9604 0.23 0.40 (0.18-0.90)High (7-9) 1523 0.13 0.17 (0.04-0.72)

References

Akesson, A., Weismayer, C., Newby, P. K., & Wolk, A. 2007, "Combined effect of low-risk dietary and lifestyle behaviors in primary prevention of myocardial infarction in women", Arch.Intern.Med., vol. 167, no. 19, pp. 2122-2127.

Alvarez Leon, E. E., Henriquez, P., & Serra-Majem, L. 2006, "Mediterranean diet and metabolic syndrome: a cross-sectional study in the Canary Islands", Public Health Nutr., vol. 9, no. 8A, pp. 1089-1098.

Anuurad, E., Chiem, A., Pearson, T. A., & Berglund, L. 2007, "Metabolic syndrome components in african-americans and European-american patients and its relation to coronary artery disease", Am.J.Cardiol., vol. 100, no. 5, pp. 830-834.

Barzi, F., Woodward, M., Marfisi, R. M., Tavazzi, L., Valagussa, F., & Marchioli, R. 2003, "Mediterranean diet and all-causes mortality after myocardial infarction: results from the GISSI-Prevenzione trial", Eur.J.Clin.Nutr., vol. 57, no. 4, pp. 604-611.

Basu, A., Devaraj, S., & Jialal, I. 2006, "Dietary factors that promote or retard inflammation", Arterioscler.Thromb.Vasc.Biol., vol. 26, no. 5, pp. 995-1001.

British Medical Research Council 1968, "Controlled trial of soya-bean oil in myocardial infarction", Lancet, vol. 2, no. 7570, pp. 693-699.

Brunner, E. J., Mosdol, A., Witte, D. R., Martikainen, P., Stafford, M., Shipley, M. J., & Marmot, M. G. 2008, "Dietary patterns and 15-y risks of major coronary events, diabetes, and mortality", Am.J.Clin.Nutr., vol. 87, no. 5, pp. 1414-1421.

Butler, J., Mooyaart, E. A., Dannemann, N., Bamberg, F., Shapiro, M. D., Ferencik, M., Brady, T. J., & Hoffmann, U. 2008, "Relation of the metabolic syndrome to quantity of coronary atherosclerotic plaque", Am.J.Cardiol., vol. 101, no. 8, pp. 1127-1130.

Castelvetro, G. & Riley, G. t. 1990, The Fruit, Herbs and Vegetables of Italy Viking, London.

42


Chrysohoou, C., Panagiotakos, D. B., Pitsavos, C., Das, U. N., & Stefanadis, C. 2004, "Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study", J.Am.Coll.Cardiol., vol. 44, no. 1, pp. 152-158.

Dai, J., Miller, A. H., Bremner, J. D., Goldberg, J., Jones, L., Shallenberger, L., Buckham, R., Murrah, N. V., Veledar, E., Wilson, P. W., & Vaccarino, V. 2008, "Adherence to the mediterranean diet is inversely associated with circulating interleukin-6 among middle-aged men: a twin study", Circulation, vol. 117, no. 2, pp. 169-175.

de Lorgeril, M., Salen, P., Martin, J. L., Monjaud, I., Delaye, J., & Mamelle, N. 1999, "Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study", Circulation, vol. 99, no. 6, pp. 779-785.

Dibra, A., Mehilli, J., Braun, S., Hadamitzky, M., Baum, H., Dirschinger, J., Schuhlen, H., Schomig, A., & Kastrati, A. 2003, "Association between C-reactive protein levels and subsequent cardiac events among patients with stable angina treated with coronary artery stenting", Am.J.Med, vol. 114, no. 9, pp. 715-722.

Esposito, K., Marfella, R., Ciotola, M., Di Palo, C., Giugliano, F., Giugliano, G., D'Armiento, M., D'Andrea, F., & Giugliano, D. 2004, "Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial", JAMA: The Journal of the American Medical Association, vol. 292, no. 12, pp. 1440-1446.

Estruch, R., Martinez-Gonzalez, M. A., Corella, D., Salas-Salvado, J., Ruiz-Gutierrez, V., Covas, M. I., Fiol, M., Gomez-Gracia, E., Lopez-Sabater, M. C., Vinyoles, E., Aros, F., Conde, M., Lahoz, C., Lapetra, J., Saez, G., & Ros, E. 2006, "Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial", Ann.Intern Med, vol. 145, no. 1, pp. 1-11.

Fito, M., Guxens, M., Corella, D., Saez, G., Estruch, R., de la, T. R., Frances, F., Cabezas, C., Lopez-Sabater, M. C., Marrugat, J., Garcia-Arellano, A., Aros, F., Ruiz-Gutierrez, V., Ros, E., Salas-Salvado, J., Fiol, M., Sola, R., & Covas, M. I. 2007, "Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial", Arch Intern Med, vol. 167, no. 11, pp. 1195-1203.

Ford, E. S. 2003, "The metabolic syndrome and C-reactive protein, fibrinogen, and leukocyte count: findings from the Third National Health and Nutrition Examination Survey", Atherosclerosis, vol. 168, no. 2, pp. 351-358.

Ford, E. S. 2004, "The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the National Health and Nutrition Examination Survey II Mortality Study", Atherosclerosis, vol. 173, no. 2, pp. 309-314.

43


Ford, E. S., Giles, W. H., & Dietz, W. H. 2002, "Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey", JAMA: The Journal of the American Medical Association, vol. 287, no. 3, pp. 356-359.

Ford, E. S., Mokdad, A. H., Giles, W. H., & Brown, D. W. 2003, "The metabolic syndrome and antioxidant concentrations: findings from the Third National Health and Nutrition Examination Survey", Diabetes, vol. 52, no. 9, pp. 2346-2352.

Fuentes, F., Lopez-Miranda, J., Sanchez, E., Sanchez, F., Paez, J., Paz-Rojas, E., Marin, C., Gomez, P., Jimenez-Pereperez, J., Ordovas, J. M., & Perez-Jimenez, F. 2001, "Mediterranean and low-fat diets improve endothelial function in hypercholesterolemic men", Ann.Intern Med, vol. 134, no. 12, pp. 1115-1119.

Fung, T. T., McCullough, M. L., Newby, P. K., Manson, J. E., Meigs, J. B., Rifai, N., Willett, W. C., & Hu, F. B. 2005, "Diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction", Am.J.Clin.Nutr., vol. 82, no. 1, pp. 163-173.

Giugliano, D., Ceriello, A., & Esposito, K. 2006, "The effects of diet on inflammation: emphasis on the metabolic syndrome", J.Am.Coll.Cardiol., vol. 48, no. 4, pp. 677-685.

Grundy, S. M., Cleeman, J. I., Daniels, S. R., Donato, K. A., Eckel, R. H., Franklin, B. A., Gordon, D. J., Krauss, R. M., Savage, P. J., Smith, S. C., Jr., Spertus, J. A., & Costa, F. 2005, "Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement", Circulation, vol. 112, no. 17, pp. 2735-2752.

Harriss, L. R., English, D. R., Powles, J., Giles, G. G., Tonkin, A. M., Hodge, A. M., Brazionis, L., & O'Dea, K. 2007, "Dietary patterns and cardiovascular mortality in the Melbourne Collaborative Cohort Study", Am.J.Clin.Nutr., vol. 86, no. 1, pp. 221-229.

Helsing, E. 1995, "Traditional diets and disease patterns of the Mediterranean, circa 1960", Am.J.Clin.Nutr., vol. 61, no. 6 Suppl, pp. 1329S-1337S.

Holvoet, P., Mertens, A., Verhamme, P., Bogaerts, K., Beyens, G., Verhaeghe, R., Collen, D., Muls, E., & Van de, W. F. 2001, "Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease", Arterioscler.Thromb.Vasc.Biol., vol. 21, no. 5, pp. 844-848.

Hong, Y., Jin, X., Mo, J., Lin, H. M., Duan, Y., Pu, M., Wolbrette, D. L., & Liao, D. 2007, "Metabolic syndrome, its preeminent clusters, incident coronary heart disease and all-cause mortality--results of prospective analysis for the Atherosclerosis Risk in Communities study", J.Intern Med, vol. 262, no. 1, pp. 113-122.

Hooper, L., Summerbell, C. D., Higgins, J. P., Thompson, R. L., Capps, N. E., Smith, G. D., Riemersma, R. A., & Ebrahim, S. 2001, "Dietary fat intake and prevention of cardiovascular disease: systematic review", BMJ, vol. 322, no. 7289, pp. 757-763.

44


Howard, B. V., Van Horn, L., Hsia, J., Manson, J. E., Stefanick, M. L., Wassertheil-Smoller, S., Kuller, L. H., LaCroix, A. Z., Langer, R. D., Lasser, N. L., Lewis, C. E., Limacher, M. C., Margolis, K. L., Mysiw, W. J., Ockene, J. K., Parker, L. M., Perri, M. G., Phillips, L., Prentice, R. L., Robbins, J., Rossouw, J. E., Sarto, G. E., Schatz, I. J., Snetselaar, L. G., Stevens, V. J., Tinker, L. F., Trevisan, M., Vitolins, M. Z., Anderson, G. L., Assaf, A. R., Bassford, T., Beresford, S. A., Black, H. R., Brunner, R. L., Brzyski, R. G., Caan, B., Chlebowski, R. T., Gass, M., Granek, I., Greenland, P., Hays, J., Heber, D., Heiss, G., Hendrix, S. L., Hubbell, F. A., Johnson, K. C., & Kotchen, J. M. 2006, "Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial", JAMA: The Journal of the American Medical Association, vol. 295, no. 6, pp. 655-666.

Hurst, J. W. 1991, "Paul Dudley White: the father of American cardiology", Clin.Cardiol., vol. 14, no. 7, pp. 622-626.

Keshavamurthy, C. B., Kane, G. R., Magdum, A. P., & Sahoo, P. K. 2000, "Serum fibrinogen and C-reactive protein levels predict major adverse cardiac events in unstable angina", Indian Heart J., vol. 52, no. 1, pp. 36-39.

Keys, A., Fidanza, F., SCARDI, V., Bergami, G., Keys, M. H., & DI LORENZO, F. 1954, "Studies on serum cholesterol and other characteristics of clinically healthy men in Naples", Arch Intern Med, vol. 93, no. 3, pp. 328-336.

Keys, A. & Keys, M. 1959, Eat Well and Stay Well Doubleday & Co..

Keys, A., Menotti, A., Karvonen, M. J., Aravanis, C., Blackburn, H., Buzina, R., Djordjevic, B. S., Dontas, A. S., Fidanza, F., Keys, M. H., & . 1986, "The diet and 15-year death rate in the seven countries study", Am.J.Epidemiol., vol. 124, no. 6, pp. 903-915.

Knoops, K. T., de Groot, L. C., Kromhout, D., Perrin, A. E., Moreiras-Varela, O., Menotti, A., & van Staveren, W. A. 2004, "Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project", JAMA: The Journal of the American Medical Association, vol. 292, no. 12, pp. 1433-1439.

Knowler, W. C., Barrett-Connor, E., Fowler, S. E., Hamman, R. F., Lachin, J. M., Walker, E. A., & Nathan, D. M. 2002, "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin", N.Engl.J.Med, vol. 346, no. 6, pp. 393-403.

Kouris-Blazos, A., Gnardellis, C., Wahlqvist, M. L., Trichopoulos, D., Lukito, W., & Trichopoulou, A. 1999, "Are the advantages of the Mediterranean diet transferable to other populations? A cohort study in Melbourne, Australia", Br.J.Nutr., vol. 82, no. 1, pp. 57-61.

Lapointe, A., Goulet, J., Couillard, C., Lamarche, B., & Lemieux, S. 2005, "A nutritional intervention promoting the Mediterranean food pattern is associated with a decrease in circulating oxidized LDL particles in healthy women from the Quebec City metropolitan area", J.Nutr., vol. 135, no. 3, pp. 410-415.

45


Leren, P. 1970, "The Oslo diet-heart study. Eleven-year report", Circulation, vol. 42, no. 5, pp. 935-942.

Libby, P. 2006, "Inflammation and cardiovascular disease mechanisms", Am.J.Clin.Nutr., vol. 83, no. 2, pp. 456S-460S.

Lutsey, P. L., Steffen, L. M., & Stevens, J. 2008, "Dietary intake and the development of the metabolic syndrome: the Atherosclerosis Risk in Communities study", Circulation, vol. 117, no. 6, pp. 754-761.

Martinez-Gonzalez, M. A., Fernandez-Jarne, E., Serrano-Martinez, M., Marti, A., Martinez, J. A., & Martin-Moreno, J. M. 2002, "Mediterranean diet and reduction in the risk of a first acute myocardial infarction: an operational healthy dietary score", Eur.J.Nutr., vol. 41, no. 4, pp. 153-160.

Martinez-Gonzalez, M. A., Fuente-Arrillaga, C., Nunez-Cordoba, J. M., Basterra-Gortari, F. J., Beunza, J. J., Vazquez, Z., Benito, S., Tortosa, A., & Bes-Rastrollo, M. 2008, "Adherence to Mediterranean diet and risk of developing diabetes: prospective cohort study", BMJ, vol. 336, no. 7657, pp. 1348-1351.

Meisinger, C., Baumert, J., Khuseyinova, N., Loewel, H., & Koenig, W. 2005, "Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population", Circulation, vol. 112, no. 5, pp. 651-657.

Menotti, A., Kromhout, D., Blackburn, H., Fidanza, F., Buzina, R., & Nissinen, A. 1999, "Food intake patterns and 25-year mortality from coronary heart disease: cross-cultural correlations in the Seven Countries Study. The Seven Countries Study Research Group", Eur.J.Epidemiol., vol. 15, no. 6, pp. 507-515.

Michalsen, A., Lehmann, N., Pithan, C., Knoblauch, N. T., Moebus, S., Kannenberg, F., Binder, L., Budde, T., & Dobos, G. J. 2006, "Mediterranean diet has no effect on markers of inflammation and metabolic risk factors in patients with coronary artery disease", Eur.J.Clin.Nutr., vol. 60, no. 4, pp. 478-485.

Mitrou, P. N., Kipnis, V., Thiebaut, A. C., Reedy, J., Subar, A. F., Wirfalt, E., Flood, A., Mouw, T., Hollenbeck, A. R., Leitzmann, M. F., & Schatzkin, A. 2007, "Mediterranean dietary pattern and prediction of all-cause mortality in a US population: results from the NIH-AARP Diet and Health Study", Arch.Intern.Med., vol. 167, no. 22, pp. 2461-2468.

Mozaffarian, D., Ascherio, A., Hu, F. B., Stampfer, M. J., Willett, W. C., Siscovick, D. S., & Rimm, E. B. 2005, "Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men", Circulation, vol. 111, no. 2, pp. 157-164.

Nestle, M. 1995, "Mediterranean diets: historical and research overview", Am.J.Clin.Nutr., vol. 61, no. 6 Suppl, pp. 1313S-1320S.

46


Osler, M. & Schroll, M. 1997, "Diet and mortality in a cohort of elderly people in a north European community", Int.J.Epidemiol., vol. 26, no. 1, pp. 155-159.

Panagiotakos, D. B., Pitsavos, C., Arvaniti, F., & Stefanadis, C. 2007, "Adherence to the Mediterranean food pattern predicts the prevalence of hypertension, hypercholesterolemia, diabetes and obesity, among healthy adults; the accuracy of the MedDietScore", Prev.Med, vol. 44, no. 4, pp. 335-340.

Panagiotakos, D. B. & Polychronopoulos, E. 2005, "The role of Mediterranean diet in the epidemiology of metabolic syndrome; converting epidemiology to clinical practice", Lipids Health Dis., vol. 4, no. 1, p. 7.

Pitsavos, C., Panagiotakos, D. B., Chrysohoou, C., Papaioannou, I., Papadimitriou, L., Tousoulis, D., Stefanadis, C., & Toutouzas, P. 2003, "The adoption of Mediterranean diet attenuates the development of acute coronary syndromes in people with the metabolic syndrome", Nutr.J., vol. 2, p. 1.

Pitsavos, C., Panagiotakos, D. B., Tzima, N., Chrysohoou, C., Economou, M., Zampelas, A., & Stefanadis, C. 2005, "Adherence to the Mediterranean diet is associated with total antioxidant capacity in healthy adults: the ATTICA study", Am.J.Clin.Nutr., vol. 82, no. 3, pp. 694-699.

Pitsavos, C., Panagiotakos, D. B., Tzima, N., Lentzas, Y., Chrysohoou, C., Das, U. N., & Stefanadis, C. 2007, "Diet, exercise, and C-reactive protein levels in people with abdominal obesity: the ATTICA epidemiological study", Angiology, vol. 58, no. 2, pp. 225-233.

Renaud, S., de Lorgeril, M., Delaye, J., Guidollet, J., Jacquard, F., Mamelle, N., Martin, J. L., Monjaud, I., Salen, P., & Toubol, P. 1995, "Cretan Mediterranean diet for prevention of coronary heart disease", Am.J.Clin.Nutr., vol. 61, no. 6 Suppl, pp. 1360S-1367S.

Salas-Salvado, J., Garcia-Arellano, A., Estruch, R., Marquez-Sandoval, F., Corella, D., Fiol, M., Gomez-Gracia, E., Vinoles, E., Aros, F., Herrera, C., Lahoz, C., Lapetra, J., Perona, J. S., Munoz-Aguado, D., Martinez-Gonzalez, M. A., & Ros, E. 2008, "Components of the mediterranean-type food pattern and serum inflammatory markers among patients at high risk for cardiovascular disease", Eur.J.Clin.Nutr., vol. 62, no. 5, pp. 651-659.

Solymoss, B. C., Bourassa, M. G., Lesperance, J., Levesque, S., Marcil, M., Varga, S., & Campeau, L. 2003, "Incidence and clinical characteristics of the metabolic syndrome in patients with coronary artery disease", Coron.Artery Dis., vol. 14, no. 3, pp. 207-212.

Tommasi, S., Carluccio, E., Bentivoglio, M., Buccolieri, M., Mariotti, M., Politano, M., & Corea, L. 1999, "C-reactive protein as a marker for cardiac ischemic events in the year after a first, uncomplicated myocardial infarction", Am.J.Cardiol., vol. 83, no. 12, pp. 1595-1599.

Toobert, D. J., Glasgow, R. E., Strycker, L. A., Barrera, M., Jr., Radcliffe, J. L., Wander, R. C., & Bagdade, J. D. 2003, "Biologic and quality-of-life outcomes from the Mediterranean Lifestyle Program: a randomized clinical trial", Diabetes Care, vol. 26, no. 8, pp. 2288-2293.

47


Tortosa, A., Bes-Rastrollo, M., Sanchez-Villegas, A., Basterra-Gortari, F. J., Nunez-Cordoba, J. M., & Martinez-Gonzalez, M. A. 2007, "Mediterranean diet inversely associated with the incidence of metabolic syndrome: the SUN prospective cohort", Diabetes Care, vol. 30, no. 11, pp. 2957-2959.

Trichopoulou, A., Bamia, C., Norat, T., Overvad, K., Schmidt, E. B., Tjonneland, A., Halkjaer, J., Clavel-Chapelon, F., Vercambre, M. N., Boutron-Ruault, M. C., Linseisen, J., Rohrmann, S., Boeing, H., Weikert, C., Benetou, V., Psaltopoulou, T., Orfanos, P., Boffetta, P., Masala, G., Pala, V., Panico, S., Tumino, R., Sacerdote, C., Bueno-de-Mesquita, H. B., Ocke, M. C., Peeters, P. H., van der Schouw, Y. T., Gonzalez, C., Sanchez, M. J., Chirlaque, M. D., Moreno, C., Larranaga, N., Van Guelpen, B., Jansson, J. H., Bingham, S., Khaw, K. T., Spencer, E. A., Key, T., Riboli, E., & Trichopoulos, D. 2007, "Modified Mediterranean diet and survival after myocardial infarction: the EPIC-Elderly study", Eur.J.Epidemiol., vol. 22, no. 12, pp. 871-881.

Trichopoulou, A., Costacou, T., Bamia, C., & Trichopoulos, D. 2003, "Adherence to a Mediterranean diet and survival in a Greek population", N.Engl.J.Med., vol. 348, no. 26, pp. 2599-2608.

Trichopoulou, A. & Lagiou, P. 1997, "Healthy traditional Mediterranean diet: an expression of culture, history, and lifestyle", Nutr.Rev., vol. 55, no. 11 Pt 1, pp. 383-389.

Trichopoulou, A., Orfanos, P., Norat, T., Bueno-de-Mesquita, B., Ocke, M. C., Peeters, P. H., van der Schouw, Y. T., Boeing, H., Hoffmann, K., Boffetta, P., Nagel, G., Masala, G., Krogh, V., Panico, S., Tumino, R., Vineis, P., Bamia, C., Naska, A., Benetou, V., Ferrari, P., Slimani, N., Pera, G., Martinez-Garcia, C., Navarro, C., Rodriguez-Barranco, M., Dorronsoro, M., Spencer, E. A., Key, T. J., Bingham, S., Khaw, K. T., Kesse, E., Clavel-Chapelon, F., Boutron-Ruault, M. C., Berglund, G., Wirfalt, E., Hallmans, G., Johansson, I., Tjonneland, A., Olsen, A., Overvad, K., Hundborg, H. H., Riboli, E., & Trichopoulos, D. 2005, "Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study", BMJ, vol. 330, no. 7498, p. 991.

Tuomilehto, J., Lindstrom, J., Eriksson, J. G., Valle, T. T., Hamalainen, H., Ilanne-Parikka, P., Keinanen-Kiukaanniemi, S., Laakso, M., Louheranta, A., Rastas, M., Salminen, V., & Uusitupa, M. 2001, "Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance", N.Engl.J.Med, vol. 344, no. 18, pp. 1343-1350.

Turpeinen, O., Karvonen, M. J., Pekkarinen, M., Miettinen, M., Elosuo, R., & Paavilainen, E. 1979, "Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study", Int.J.Epidemiol., vol. 8, no. 2, pp. 99-118.

Tuttle, K. R., Shuler, L. A., Packard, D. P., Milton, J. E., Daratha, K. B., Bibus, D. M., & Short, R. A. 2008, "Comparison of Low-Fat Versus Mediterranean-Style Dietary Intervention After First Myocardial Infarction (from The Heart Institute of Spokane Diet Intervention and Evaluation Trial)", Am.J.Cardiol., vol. 101, no. 11, pp. 1523-1530.

48


Vincent-Baudry, S., Defoort, C., Gerber, M., Bernard, M. C., Verger, P., Helal, O., Portugal, H., Planells, R., Grolier, P., Amiot-Carlin, M. J., Vague, P., & Lairon, D. 2005, "The Medi-RIVAGE study: reduction of cardiovascular disease risk factors after a 3-mo intervention with a Mediterranean-type diet or a low-fat diet", Am.J.Clin.Nutr., vol. 82, no. 5, pp. 964-971.

Wassink, A. M., van der, G. Y., Olijhoek, J. K., & Visseren, F. L. 2008, "Metabolic syndrome and the risk of new vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm", Eur.Heart J., vol. 29, no. 2, pp. 213-223.

World Health Organization, U. N. Food and health indicators in Europe: nutrition and health 1961-1990. 1993. Copenhagen, World Health Organization Regional Office for Europe. Ref Type: Computer Program

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Health & Medicine

The Mediterranean Diet: Its Effect on Cardiovascular Disease