EDITORIAL: Is the Beneficial Effect of Mediterranean Diet on Cardiovascular Risk Partly Mediated through Better Blood Pressure Control?
Authors: Anagnostis Panagiotis , Sfikas George , Gotsis Efthimios , Karras Spyridon , Athyros Vasilios G. 
Published: November 2013

A few days ago, in August 2013, a Cochrane Database
Systemic Review reported that the existing limited evidence
to date on the effect of Mediterranean diet (MD) on primary
prevention of cardiovascular disease (CVD), suggests some
favorable effects on risk factors; however, the reduction of
CVD event rates was not mentioned [1]. The review included
11 trials (15 papers, 52,044 participants); 7 trials described
the intervention as a MD. Clinical events were reported
in only one trial [Women's Health Initiative (WHI)
48,835 postmenopausal women with an intervention not described
as a MD but increased fruit and vegetable and cereal
intake], where no statistically significant effects of the intervention
were seen on fatal and non-fatal endpoints during the
8 years of its duration [1]. Since the WHI study was huge
and had a great weight in the analysis, it eliminated any other
beneficial effect on CVD incidence from other studies.
Moreover, in this study the diet used as an intervention was
not MD.

On April 2013 the results of the Prevención con Dieta
Mediterránea (PREDIMED), a multicenter trial from Spain,
were published in New England Journal of Medicine [2].
The study included a total of 7,447 persons (aged 55-80
years) with no CVD at baseline. These were randomized to 1
of 3 diets: a MD supplemented with extra-virgin olive oil, a
MD supplemented with mixed nuts or a control diet (advice
to reduce dietary fat) [2]. An interim analysis terminated the
trial prematurely at 4.8 years. The primary endpoint was the
rate of major CVD (myocardial infarction, stroke, or CVD
death). The multivariable-adjusted hazard ratios were 0.70
(95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95%
CI, 0.54 to 0.96) for the group assigned to a MD with extravirgin
olive oil and the group assigned to a MD with nuts, respectively, vs. the control group [2]. No diet-related adverse
effects were reported [2]. Moreover, a post hoc analysis
of PREDIMED that will be published in September 2013,
in the American Journal of Clinical Nutrition, suggests that
one of the mechanisms by which MD, particularly if supplemented
with virgin olive oil, can exert health benefits is
through changes in the transcriptomic response of genes related
to CVD risk [3]. These results of the PREDIMED trial
confirm that changes in diet can have beneficial effects on
CVD risk. However, the study was criticized for mainly 3
reasons. One is that in MD the dietary pattern as an entity is
rather more important than the inclusion or avoidance of
specific nutrients [4]. Second there were low (in absolute
terms) primary composite CVD outcome rates (3.8% and
3.4% in the intervention groups vs. 4.4% in the control
group) and a minor absolute risk difference (range 0.6 to
1%), thus limiting the importance of the study findings [5].
Furthermore there were statistically significant differences in
baseline characteristics between the groups: men (+5.7%),
obese persons (+4.7%), diuretic use (+3.5%), and oral hypoglycaemic
use (+3.2%) in the control group than in the intervention
group [5]. And third there was a complete lack of
policy implications [6]. The PREDIMED trial was neither a
pure test of a Mediterranean-style diet nor a pure test of extra-
virgin olive oil or nuts. All the above make the interpretation
of the PREDIMED trial similarly difficult to that of the
Lyon Diet Heart Study [7], which tested provision of a margarine
rich in alpha-linolenic acid on top of brief advice to
consume a MD in high CVD risk patients with astonishing
results [7].

Policymakers [8] and Great Scientific Organizations, like
Mayo Clinic [9], already recommend consumption of a
Mediterranean-style diet on the basis of a body of evidence
from observational and interventional studies, in antithesis to
the findings of the Cochrane Database Systemic Review [1].
On the other hand, the policy implications of the PREDIMED
trial related primarily to the supplemental foods [2]
and not MD itself, thus, we probably have to go both back
and elsewhere to find evidence base for the benefits of MD and if these are related in any degree to blood pressure (BP)
reduction.

The Seven Countries Study showed that the risk and rates
of heart attack and stroke both at the population and at the
individual level were directly and independently related to
the level of serum total cholesterol (TC). It demonstrated that
the association between TC level and coronary heart disease
(CHD) risk from 5 to 40 years follow-up is found consistently
across different cultures [10,11]. The Seven Countries
Study started in 1958 in former Yugoslavia. In total, 12,763
men, 40–59 years of age, were enrolled as 16 cohorts, in 7
countries, in 4 regions of the world (United States, Northern
Europe, Southern Europe, Japan); 1 cohort is in the United
States, 2 cohorts in Finland, 1 in the Netherlands, 3 in Italy,
5 in the former Yugoslavia (two in Croatia, and three in Serbia),
2 in Greece (1 in Crete and 1 in Corfu), and 2 in Japan
[10]. The Seven Countries Study has continued, with high
levels of participation, for more than 50 years.􀀁The initial and
objective data on CVD health in relation to the MD originated
from the Seven Countries Study [10]. CHD deaths in
the United States and Northern Europe greatly exceeded
those in Southern Europe, even when controlled for age, TC
and BP levels, smoking, physical activity, and weight [12].
After further investigation, the importance of the eating pattern
characterized as the MD became clear [12,13]. What
exactly is meant by "Mediterranean diet" today, and its benefits,
is detailed by other researches during the last 20 years
[14,15]. During the 90's, for the first time, the concept of a
food pyramid and the need for an adherence to MD score
were born [14-16]. As a result of the Seven Countries Study,
the MD has been popularized as a "healthy" diet. Nevertheless,
it has not replaced the "prudent" diet commonly prescribed
to coronary patients [17]. The Crete cohort of the
Seven Countries Study had the lowest rates of deaths from
CVD [10]; even the 25 year mortality was lower than others
(for example vs. the Italian cohort) [18]. This was attributed
to the entire lifestyle of Cretans including a variation of MD,
the Cretan-type MD. Many investigators during the last 20
years would rather refer to the Cretan-type MD rather than
plain MD, which is a rather abstract definition [19-22].

The 40 years’ CVD mortality in the Corfu cohort showed
that participants also benefited from the long-term adoption
of a nutritional pattern (close to the Cretan-type) of MD, the
presence of physical activity, optimism, and a positive psychological
profile [23]. During the last 15 years, and before
the economic crisis, Greeks adopted a more western way of
life. Nevertheless, several aspects of the traditional Greek
way of life and diet, suggest that a relatively high consumption
of vegetables and fruits or olive oil and bread, remained
well-established among large segments of the Greek population,
and may explain why a population with a few healthy
habits still enjoys one of the longer life expectancies among
the 16 cohorts of the Seven Country Study 40 years after its
initiation [23].

The Working Group on Epidemiology and Prevention of
the European Society of Cardiology (ESC) coordinated in
2003 information from 12 European cohort studies, including
205,000 persons, and assessed the 10-year CVD mortality
rates. This gave birth to the SCORE (Systematic Coronary
Risk Estimation) project [24]. The European Society of Cardiology encouraged the creation of local SCORES for
each country, based on the original SCORE and local data.
Indeed the HellenicSCORE (equations and charts) present
the calibration of the risk by age group and sex, based on
mortality data, as reported by the National Statistical Services
of Greece and prevalence data regarding smoking, TC
and BP levels, as reported by the ATTICA study [25]. This
was very successfully tested in the ATTEMPT Study [26].
The predicated rates of CVD were verified in a survival
study with a nearly 4-year follow-up in patients with metabolic
syndrome and randomization to intensive versus moderate
risk factor treatment [27]. In the meantime the MD
score (MedDietScore) was developed, according to the adherence
to MD [28].􀀁The weekly consumption of the following
9 food groups: non-refined cereals(whole grain bread
and pasta, brown rice, etc.), fruits, vegetables, legumes, potatoes,
fish, meat and meat products, poultry, full
fat dairy products (like cheese, yoghurt, milk), as well
asolibe oil and alcohol intake, were included [28]. The inclusion
of dietary evaluation (MedDietScore), as well as
other sociodemographic and anthropometric characteristics,
increases the accuracy and reduces estimating bias of CVD
risk prediction models [29]. Thus, we have a country adjusted
integrated system that can predict CVD risk. It was
clear, during the use of HellenicSCORE and MedDietScore,
that a better adherence to MD was related to a lower CVD
risk. On the contrary, aging, central fat, hypertension (HTN),
diabetes, inflammation, low social status and abstinence
from a MD seem to predict CVD events within a 5-year period;
actual data from the ATTICA study [30]. All these put
the adoption of MD at a high position among CVD risk factors,
for good and for bad, according to the degree of adoption
(MedDietScore).

However, does MD affect the level of BP? Is HTN one of
the factors to increase CVD risk if the adherence to MD
(MedDietScore) is low? There is some evidence on this issue.

It has been suggested by a review on the dietary influences
on BP that there is more than enough evidence from
observational and clinical studies that diets low in saturated
fats and sodium and rich in fruits, vegetables, and fiber, with
adequate amounts of potassium, calcium, and magnesium,
are effective in the prevention and treatment of HTN alone
or as an adjunct to pharmacologic therapy [31]. Such dietary
combinations are provided by the MD [31]. The association
of adherence to the MD with the incidence of HTN was
evaluated among 9,408 men and women enrolled in a dynamic
Spanish prospective cohort (SUN) study during 1999-
2005 [32]. The adherence to MD was associated with reduced
mean values of systolic BP [moderate adherence, -2.4
mm Hg (95% CI: -4.0, -0.8); high adherence, -3.1 mm Hg
(95% CI: -5.4, -0.8)] and diastolic BP [moderate adherence, -
1.3 mm Hg (95% CI: -2.5, -0.1); high adherence, -1.9 mm
Hg (95% CI: -3.6, -0.1)] after 6 years of follow-up [32].
These results suggest that adhering to a Mediterranean-type
diet could contribute to the prevention of age-related increase
in BP [32]. In the ATTICA Study the mean value of
the MedDiet Score was 25.5 (±3) for men and 27 (±3) for
women (p<0.001). The prevalence of HTN was 36.6% in
men and 23.7% in women (p<0.001) [33]. Diet score was
23.5±6.4 in hypertensive and 26.8±6.6 in normotensive individuals (p<0.001). The sensitivity of defining people with
HTN was higher than for any other CVD risk factor, suggesting
that the adoption of MD reduces the risk for HTN
[33]. In an elderly population of Cyprus, another Mediterranean
Country, 60% of men and 58% of women have HTN,
along with other classical CVD risk factors [34]. A 10-unit
increase in the MedDietScore was associated with 21%
lower odds of having one additional risk factor, including
HTN, in women (p< 0.001) and with 14% lower odds in men
(p=0.05) [34]. The results of the CARDIO2000 study [35]
point out that the adoption of MD by physically active subjects
seems to significantly reduce the coronary heart disease
(CHD) events and prevent, just about, the one-third of acute
CHD syndromes, in controlled subjects with HTN [35]. This
supports the idea that MD combined with physical activity
provides substantial protection from acute coronary events in
patients with HTN [35]. Other data from the SUN Study also
[36] suggest that there is an inverse relationship between
fruit and vegetable consumption and the prevalence of nonpreviously
diagnosed HTN in a Mediterranean population
with a very high intake of both fat (paradoxically) and plantderived
foods [36]. There was a 77 % reduction in the prevalence
of HTN for those with the higher consumption of both
fruit and vegetables compared with those at the lower quintiles
of both food groups [36]. This inverse relationship was
also evident when considering BP as a continuous variable,
with a mean systolic BP and diastolic BP of 2.2 mmHg
lower for those with the highest consumption of fruit and
vegetables compared with those with the lowest intake [36].
The study concludes that in a Mediterranean population,
with an elevated fat consumption, a high fruit and vegetable
intake is inversely associated with BP levels [36]. From the
same (SUN) study it was reported that there is an inverse
association between fiber or fruit/vegetable consumption and
weight gain, thus emphasizing the importance of replacing
some dietary compounds by such foods and fiber-rich products,
which may help to avoid weight gain [37]. This brinks
about the issue of MD and obesity, mainly central, which is
the key clinical manifestation of metabolic syndrome
(MetS); this includes HTN.

Data suggest that the prevalence of MetS has dramatically
increased during the recent years, especially in Western
Countries and South East Asia [38]. More than one third (35
%) of adults in the U.S. could be characterized as having the
MetS, which translates to nearly 84 million U.S. adults affected
by MetS [38]. Unfortunately the prevalence of MetS
in Mediterranean Countries is high (one forth of the adult
population), although definitely lower than that in U.S.
[39,40]. It has been shown by prospective cohort studies,
cross-sectional studies and clinical trials that adherence to
the MD was associated with reduced risk of the MetS and its
individual components also, in particular waist circumference,
triglycerides levels, low density lipoprotein cholesterol
(HDL-C), BP levels and glucose metabolism [38,41]. These
effects of MD increase life expectancy in patients with MetS
[42].

On the other hand, Mediterranean countries, such as
Greece, have experienced a rapid social-economic change in
the last 15 years and recently an economic crisis; both having
negative impacts on healthy eating. These community
changes affect nutritional habits and there is a tendency to abandon the traditional healthy MD [43]. However, if we
continue to try at the elementary school level, things might
be better than they look. A study aiming to examine the
long-term effects of the "Cretan Health and Nutrition Education
Program" on BP, examined several parameters: BP, dietary,
anthropometrical and physical activity data nearly 10
years after the original study (at baseline year 1992-1993,
and follow-up examination at year 2001-2002) [44]. The
findings of the study revealed that the increase over the 10-
year period in systolic BP and diastolic BP was higher in the
control group than in the MD intervention group (P=0.003
and P<0.001 respectively). These facts are encouraging, indicating
favorable changes in BP, micronutrients intake,
body mass index (BMI) and physical activity over a 10-year
period and 4 years after program's cessation [44]. We just
have to keep trying to establish MD at an early age.

In brief, MD reduces CVD risk and this action could be
at least in part attributed to the reduction of BP and MetS.
Given that the complete adoption of MD is practically impossible,
a high degree of adherence is desirable. This could
substantially reduce adverse CVD events as well as the incidence
of acute coronary syndromes, by one third, If combined
with a high level of physical activity. A high adherence
to MD also reduces the prevalence of MetS, a part of
which is HTN, and diminishes its clinical consequences,
improving life expectancy. It is more effective if MD is
adopted early in life.