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

800
700
600
500
400
300
200
100
0
Cancer Mortality
Score 0 - 3 Score 4 - 5 Score 6 - 9
Death Rate per 10,0 person - yrs
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
27 90 0.0001
+ Secondary Endpoints*
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)
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Ref Type: Computer Program
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