Original article

Clinical Nutrition University. The place of nutrition in the prevention

of cardiovascular diseases (CVDs)
Y.A. Carpentier
a
, R.S. Komsa-Penkova
b,
*
a
Free University of Brussels, Brussels, Belgium
b
Medical University-Pleven, Pleven, Bulgaria
a r t i c l e i n f o
Article history:
Received 14 July 2011
Accepted 31 October 2011
Keywords:
CVD
Prevention
Risk factors
Lifestyle
Nutrition
s u m m a r y
CVDs, including coronary heart disease (CHD) and stroke, currently represent the major causes of
mortality and morbidity all over the world. In Europe, CVDs are responsible for 43% of deaths in men and
55% in women and for 30% of all deaths before the age of 65 years. CVD burden could be substantially
reduced by early diagnosis and appropriate measures, since atherosclerotic lesions may be substantially
improved in response to measures taken.
CVD results from a combination of genetic and environmental factors; some factors vary between
different ethnic groups. Plasma lipid prole is an important, but certainly not the only, risk factor for CVD.
Prevention includes healthy lifestyle: no smoking, weight control, physical activity, and healthy dietary
intake; control of blood pressure, plasma glucose, and inammation is important.
The Mediterranean diet is a good example of healthy dietary pattern. Components of the Mediterra-
nean diet may be adapted to nutritional habits of different countries, taking into account differences of
taste and culture. The benets of a healthy lifestyle exceed, but are additive to, those of medical
treatment.
2011 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights
reserved.
Learning objectives
To demonstrate the importance of cardiovascular diseases
(CVD) in morbidity and mortality in the world.
To review the major risk factors for CVD.
To give an overviewon the importance of lifestyle components,
particularly diet, in the modication of different risk factors,
and in the prevention of CVD.
To review the mechanisms through which nutrition may affect
CVD.
To provide global and specic recommendations on healthy
diets.
1. Rationale for prevention of CVD
CVDs, including coronary heart disease (CHD) and stroke,
currently represent the major causes of mortality and morbidity all
over the world. In Europe, CVDs are responsible for 43% of deaths in
men and 55% in women and for 30% of all deaths before the age of
65 years.
1
In 2000, CVDs also accounted for 22% of all disability adjusted
life years (DALYs) lost in Europe.
Eighty percent of CV accidents could probably be avoided by
lifestyle adjustment (weight control, smoking abstinence, phys-
ical activity, and a healthy diet), together with proper manage-
ment of clinical and biological risk factors. Fig. 1 (data taken from
European statistics
2,3
) represents the evolution of cardiovascular
mortality in several European countries. In developed countries,
there is clearly a decreasing trend as a reection of appropriate
measures. However, in countries with a more recent access to
a Westernized way of life, the tendency is towards an increase.
This corresponds to the trend observed all over the world. In
developing countries, there is a sharp contrast between a high
CVD incidence in cities in relation to urbanisation, and a lower CV
mortality rate in the rural areas.
4
Most of the current research
efforts have been aiming to identify and treat individual-level risk
factors of CVD. Despite important achievements, the inequalities
continue to persist.
The projection for the major causes of deaths all over the world
in 2020 suggests a further rise in CVD mortality and morbidity,
mainly in developing countries.
5
In addition, the epidemics of
obesity and the frequently associated metabolic syndrome raise
* Corresponding author. Tel.: 359 887365357.
E-mail address: rkomsa@gmail.com (R.S. Komsa-Penkova).
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1751-4991/$36.00 2011 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.eclnm.2011.10.002
e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 6 (2011) e272ee282
major concerns for the immediate and mid-term future, even in
developed countries.
6,7
2. The atherosclerotic lesion
The major typical feature of CVDis the atherosclerotic plaque, an
inammatory lesion which develops insidiously around cholesterol
depots in the intima of the arterial wall over many (20e30)
years.
8e10
This is due to the fact that particles carrying cholesterol
in plasma may cross the endothelium (inner unicellular layer of the
vessel) and enter the intimal space of the arterial wall
11
; while low-
density lipoproteins (LDL) may in some conditions be endocytosed
by intimal macrophages and deposit cholesterol in the intima. This
is associated with further recruitment, in the intima, of macro-
phages and lymphocytes, and increased production of inamma-
tory mediators. Another important factor in the initial phase of the
process is a dysfunction of the endotheliuminduced by atherogenic
lipoproteins and hypertension; the endothelium loses its capacity
to produce nitric oxide (which induces vasodilatation, but also
protects against arterial remodelling and platelet aggregation) and
secretes free radicals and inammatory mediators. The inamma-
tion may thicken the arterial wall locally and reduce the lumen
(creating a stenosis), but may also erode the lesion; interaction
between blood platelets, lipids, and different mediators quickly
induce thrombus formation at the site of erosion. In fact, coronary
artery occlusion is much more often caused by a thrombus after
rupture of a fragile lesion than by progressive stenosis.
Cholesterol deposition and development of inammatory
lesions are prevented by high-density lipoproteins (HDL) which
ensure a reverse cholesterol transport to the liver (and glands
producing steroid-derived hormones) and reduce inammatory
and peroxidative reactions.
It is important to understand that endothelial dysfunction and
inammatory reactions may be corrected by appropriate lifestyle
and therapeutic measures, causing the atherosclerotic lesion to be
reversed, modied or stabilised. As a corollary, the vast majority of
CVD accidents can and should be prevented.
3. Risk factors for cardiovascular disease events
Plasma cholesterol concentration has long been considered as
the major (if not the sole) risk factor for CVDs. Indeed, Fig. 2 (adapted
from
12
) is often used to conrm the strong correlation between
total cholesterol concentration and coronary heart disease.
However, one should also consider the huge differences in the
rate of CVD mortality between countries with similar average
cholesterol levels (e.g. w220 to 230 mg/dl or 5.5e5.6 mmol/l). This
supports the role of other factors. Indeed, the initiation and
development of the atherosclerotic lesion are related to a combi-
nation of several independent risk factors.
Some factors (genetic background, familial and personal history,
gender) may not be modiable while others may be corrected or
improved (Table 1).
3.1. Serum lipids
Since cholesterol deposition in the arterial wall is a key and early
step in the initiation of the atherosclerotic process,
13,14
decreasing
the number of LDL particles (and/or avoiding their retention in the
intimal space) has been a primary target (Table 2).
15
This is achieved by improving the number and activity of LDL
receptors largelylocated inthe liver; drugs suchas statins efciently
stimulate LDL removal, but nutrition may also activate or impede
receptor activity. Also, evidence that some LDL, modied by per-
oxidation, glycation, addition of adducts, or presence of additional
apoprotein(a) have a markedly increased atherogenic potential
16,17
has drawn attention to the role of LDL size and composition, as well
as to the impact of associated pathologies such as diabetes mellitus,
chronic renal failure, chronic inammatory diseases.
18
Tobacco
smoking is a major risk factor and air pollution has also been
implicated; again, nutrition may affect LDL atherogenicity.
Attention is currently paid not only to decreasing LDL-
cholesterol, but also to increasing the number of HDL particles;
this can be achieved by lifestyle adjustments: weight
19
control,
physical activity, non-smoking and proper nutrition.
20,21
A high
concentration of plasma triglycerides is recognised as a direct risk
factor (increased coagulation, impaired endothelial function, etc)
22
but may also have indirect effects by decreasing HDL level and
increasing LDL atherogenicity via formation of atherogenic small
dense (sd) LDL.
3.2. Hypertension
Hypertension increases the entry of LDL particles into the intima
and impedes their return into the circulation; it also raises perox-
idative damage, inducing endothelial dysfunction and LDL modi-
cations; dietary manipulation may help reducing blood pressure,
e.g. by reducing weight and salt intake.
3.3. Inammatory processes
In different organs and at distant sites from atherosclerotic
lesions, inammation is now recognised as an aggravating factor, Fig. 1. Mortality from CVD in Europe (1980e1995) (data taken from refs.
2,3
).
Fig. 2. Relationship between coronary death rates and mean serum cholesterol in 19
European countries and Japan.
12
Y.A. Carpentier, R.S. Komsa-Penkova / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 6 (2011) e272ee282 e273
since it increases free radical production, induces LDL modications
and increases LDL retention in the intima, but also causes macro-
phage activation and stimulation of LDL uptake into the intima;
again, adequate nutrition may help to modulate inammation.
23
3.4. High homocystein concentration
A high homocystein level in plasma is another risk factor, via
a toxic effect on the endothelium and induction of peroxidative
damage. Apart from pathological conditions (e.g., chronic renal
failure), a low folic acid status is often present in subjects with
impaired homocystein metabolism
24
; this is generally related to
genetic polymorphisms of enzymes involved in homocystein
metabolism. Supplementationwith folic acid, sometimes combined
with supplementation of vitamin B6 (pyridoxine) and vitamin B12
may lower homocystein levels
25
; however, the efcacy of these
supplementation on clinical outcome has not been demonstrated.
3.5. Obesity
Obesity is associated with an increased risk of coronary heart
disease and stroke.
26
The distribution of fat in different areas of the
body is important since accumulation of fat within the abdominal
cavity (as observed in truncal or android obesity) represents
a much more severe cardiovascular risk than accumulation in
subcutaneous adipose tissues (i.e. gynoid obesity). This explains
why waist circumference measurements, and to some extent waist-
to-hip ratio, is a more relevant index of coronary disease risk than
BMI values.
27
The relation between obesity and cardiovascular risk
is via an effect on lipid and lipoproteinprole, on blood pressure, on
insulin-resistance, on inammation, on endothelial function, and
on thrombus formation. This, together with epidemiological
observations, has led to the concept of the metabolic syndrome.
28
The metabolic syndrome represents the clustering of anthro-
pometric, clinical, and biological cardiovascular risk factors. It is
dened as the simultaneous presence of (at least) three among the
following risk factors: high waist circumference (>94 cm in men
and 80 cm in women), high blood pressure (>135/85 Hg cm), high
plasma triglycerides (>150 mg/dL or 1.69 mmol/L), low plasma
HDL-cholesterol (<40 mg/dL or 1 mmol/L in men and 50 mg/dL or
1.25 mmol/L in women), and high plasma glucose concentration
(>100 mg/dL).
29,30
It should be noted that cut off values for
parameters of the metabolic syndrome may vary between guide-
lines from different associations. However, a common concern is
that the worldwide epidemic of obesity may stop or reverse the
decline of cardiovascular disease burden in Western countries and
raise it in developing countries.
Importantly, lifestyle and dietary patterns have a strong inu-
ence on most components of the metabolic syndrome.
3.6. Smoking
There is overwhelming evidence for an adverse effect of
smoking on health.
31
In long-term smokers, smoking is considered
to be responsible for 50% of all avoidable deaths, half of which are
a consequence of cardiovascular disease.
32,33
Although only 20%
of US inhabitants are smokers, cigarettes account for 435,000
deaths every year (13). Tobacco smoking increases the risk of
atherosclerotic disease via several mechanisms (some of which are
not fully understood yet): smoking increases peroxidative damage,
alters endothelial functions, inuences homocysteine levels,
34
enhances both the development of atherosclerosis, the occur-
rence of thrombosis and activates platelets and leukocytes. The
impact of smoking on atherosclerosis progression is greater for
subjects with diabetes and hypertension.
3.7. Air pollution
It has become evident that air pollution may severely increase
cardiovascular burden. Recent studies suggest that, within a given
city, the rate of cardiovascular events may be doubled in some
areas, with a direct relationship to trafc, particularly diesel
exhaust fumes. Among the different components of air pollution,
long- and short-term exposures to ne particulate matter <2.5 mm
(PM 2.5) are generally considered to be responsible for increased
cardiovascular morbidity and mortality,
35
as well as for inducing
deep vein thrombosis. However, accumulation of ultrane particles
may also play a role in favouring cardiac events. Air pollution
appears to increase risks particularly in non-smokers and in
Table 2
Serum lipid fractions (adapted from ref.
36
).
LDL-cholesterol Total cholesterol >5.0 mmol/L and LDL-cholesterol
>3.0 mmol/L are related to CVD risk and are the
primary focus of management. Reduction of total
and LDL-cholesterol unequivocally diminishes CVD
risk, including stroke.
Triglycerides
(triacylglycerols)
Moderately raised triglycerides (>1.7 mmol/l,
w150 mg/dl) are related to risk; associations with
abdominal obesity and blood sugar inverse associ-
ation with HDL-cholesterol
HDL-cholesterol HDL-cholesterol relates inversely to CVD risk.
HDL-cholesterol concentration <1 mmol/l
(w40 mg/dl) in men and <1.2 mmol/l (w45 mg/dl)
in women indicates increased risk.
HDL is involved in reverse cholesterol transport; it is
antiatherogenic, anti-inammatory and anti-
thrombotic particle.
Total cholesterol/HDL ratio Total cholesterol/HDL ratio relates to risk but better
risk estimation may be possible if they are consid-
ered separately.
Apo B/A1 ratio Apo B/A1 ratio relates strongly to risk but it is not
known if it should be a treatment goal.
Lp(a) Lp(a) relates to risk, is genetically determined, but
resistant to modication.
Table 1
Risk factors for cardiovascular disease.
Modiable factors Non-modiable factors
Lifestyle Clinical parameters Biological parameters
Western diet
Tobacco smoking
Weight gain/ obesity
Sedentary life
Psychological stress
Air pollution
High blood pressure
High waist circumference
Insulin-resistance diabetes
Metabolic syndrome
Renal insufciency
High plasma cholesterol conc.
High LDL-cholesterol conc.
Low HDL-cholesterol conc.
High triglyceride conc.
Markers of chronic inammation
Thrombogenic factors
Markers of lipid peroxidation
Markers of endothelial dysfunction
Age
Gender
Family history of premature CVD
Personal history of CVD
Genetically predisposed ethnic groups
Y.A. Carpentier, R.S. Komsa-Penkova / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 6 (2011) e272ee282 e274
subjects with the metabolic syndrome. Exposure to PM increase
cardiovascular problems (myocardial ischaemia and infarction,
heart failure, hypertension, arrhythmias, strokes) via different
pathways: systemic inammation and oxidative stress, alterations
in autonomic balance, and direct action of PM constituents on
vasculature with endothelial dysfunction.
3.8. Combination of risk factors
The combination of several factors, e.g. hypertension plus high
cholesterol and smoking markedly enhances the risk of CV acci-
dents (Fig. 3). In order to better assess the risk for development of
CVD, different multifactorial risk models have been proposed.
The Guidelines of the European Society of Cardiology recom-
mend a new model for total risk estimation based on the SCORE
(Systematic COronary Risk Evaluation) system.
36
The risk is dened
on the basis of age, gender, systolic blood pressure, total cholesterol
and smoking status and is expressed in terms of absolute 10 year
probabilityof developinga fatal cardiovascular event for populations
living either in low risk regions (Belgium, France, Greece, Italy,
Luxemburg, Spain, Switzerland and Portugal) and in high-risk
regions of Europe.
A previous event, the presence of diabetes or a familial history of
severe cardiovascular accidents at an early age markedly raise risks.
Thus, the aetiology of CVDs is multifactorial and most of the
time involves a combination of genetic and behavioural factors.
37
4. Genetic factors: polymorphisms and epigenetic
As indicated above, a family history of CVD in a rst degree
relative aged <55 (men) or 65 (women) years carries an indepen-
dent relative risk of 1.5e1.7.
38,39
Genetic background is involved in the presence of different risk
factors. Among these, abnormal lipid phenotypes are associated
with 40e60% heritability, and even of >90% in the case of lipo-
protein or Lp(a).
40
The prevalence of familial hypercholesterolaemia
(FH) is very low (1/10
6
) for the homozygotous form, but not
uncommon (1/500) for the heterozygotous form. Of note, at similar
concentrations of cholesterol and LDL-cholesterol, FH is associated
with a more severe disease than non-FH.
More recently, the presence of a high proportion of small dense
(sd) LDL or B phenotype in subjects with excess weight gain and
a sedentary life style is largely associated with a dominant geno-
type. The heritability of diabetes is also well known.
Multiple polymorphisms with small but cumulative effects on
risk are under investigation, genetic polymorphism in fatty acid
desaturase.
41,42
The information on genetic factors is important for identifying
patients at high risk of developing CHD,
43e45
in order to provide an
opportunity, at an earlier stage, for aggressive therapeutic inter-
vention together with lifestyle and dietary guidance.
It is also important to understand how genetic polymorphisms
may affect the response to a given diet or to specic supplemen-
tation (nutrigenetic) and how much specic nutrients may modify
the expression of a number of genes (epigenenetic), some of these
modications being transmitted to the next generation.
5. Relationship between nutrition and CVD risk
5.1. Impact of dietary habits on CVD burden
As indicated in Fig. 2, CVD burden may vary substantially
between different countries and areas of the world. While many
Western countries appear to be at high risk, original observations of
a very lowprevalence of CVDs disease were made in countries such
as Japan and Crete.
That such differences in CVD burden are not primarily due to
different genetic background is conrmed by observations that
Japanese migrants moving to Hawaii and the USA show increased
CVD rates, in relation to their adoption of Western dietary habits
and the related rise in serum cholesterol concentrations. Similarly,
African populations, living according to original primitive habits,
appear protected from CVD while their counterparts in contact
with Western civilization develop atherosclerotic lesions. Of
interest, marked differences of CVD prevalence may exist between
different areas within a given country, as shown by a much lower
CVD incidence in Southern vs. Northern part of France. In Europe,
populations surrounding the Mediterranean sea appear particu-
larly protected, which led to the concept of a Mediterranean diet
with its potential to prevent chronic diseases, such as CVD diabetes,
and cancer.
5.2. The Mediterranean diet
The Mediterranean diet may vary substantially from one region
to another. As presented on Fig. 4
46
it is mainly based on:
a high consumption of fruits, vegetables, whole bread and
other cereals, beans, nuts and seeds;
a large consumption of olive oil which represents an important
source of monounsaturated fats;
the regular consumption of sh and poultry, and of selected
dairy products (cheese and yogurt);
a low consumption of red meat;
consumption of wine in low to moderate amounts.
In a recent survey,
47
dietary pattern was determined in a large
sample of 22043 adults, aged from 20 to 86 years of the Greek
population, which was then followed up for 44 months. Those who
continued to adhere strictly to the Mediterranean diet showed
a 50% lower mortality rate than those who switched to a western-
ized diet; this observation held true for both genders (Fig. 5).
This study conrms the potential for nutrition in disease
prevention and highlights the concept of feeding patterns i.e.
preferential intake of groups of foods; indeed, with the notable Fig. 3. The multiplicative effect of risk factors (adapted from ref.
36
).
Y.A. Carpentier, R.S. Komsa-Penkova / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 6 (2011) e272ee282 e275
exception of oily sh, no single protective nutrient could be
identied in the Mediterranean diet.
Of interest, the Mediterranean diet concept is not limited to
a small number of foods, but can be enlarged and adapted to other
areas and to populations with very different tastes and cultural
habits.
48
This was highlighted by a study of secondary CVD
prevention conducted in Lyon, France.
49
After a myocardial infarct,
605 patients were randomly assigned to receive a regular (step 1
American Heart Association) prudent diet together with standard
care and encouragement to take regular physical exercise (control
group), or to similar measures plus an experimental translation of
the Cretan diet (Fig. 6).
As shown from the survival rates in Fig 5, adding an adapted
type of Mediterranean diet was associated with improved outcome
(with lower rates of morbidity and mortality) which was evident
from the very rst months and persisted throughout the 5 year
follow up.
5.3. Evidence that lifestyle and proper nutrition may reduce CVD
burden
Several models of healthy diets may be considered, allowing
greater acceptability among people of differing nationality and
cultural traditions. When other protective aspects of lifestyle (no
smoking, weight control, and regular physical exercise) are also
integrated, the reduction in CVD mortality may reach w50%, and to
this may be added the benet provided by pharmacological treat-
ment of hyperlipidaemia and arterial hypertension.
The effects of a dietary portfolio of cholesterol-lowering foods
vs. lovastatin on serum lipids and C-Reactive Protein were inves-
tigated by D.J.A. Jenkins et al. (Table 3).
50
The study included 46 volunteers e healthy adults with mild
hyperlipidaemia undergoing 4-week dietary intervention vs. drug
on the basis of a prudent diet. This study showed that a dietary
manipulation over 4 weeks, combining several nutrients with
a (weak) hypolipidaemic effect, can reduce LDL-C and CRP as ef-
ciently as a rst generation statin (Fig. 7). The remaining challenge
is to design attractive menus with palatabl nutrients and similar
properties.
Another study, showing the importance of Mediterranean diet,
was conducted in Sweden on women with mild hyperlipidaemia
and a metabolic syndrome.
51
The Mediterranean diet showed the
potential to reduce not only serum TG (by 17%) but also total
cholesterol (by 13%) and LDL-cholesterol (by 23%) as well as apo B
(by 17%) in otherwise healthy Swedish subjects with metabolic
syndrome; in contrast, omega-3 supplementation only affects
plasma TG (Fig. 8).
There are, therefore, several possible ways of achieving a healthy
diet, allowing cultural factors and personal taste to be taken into
account.
6. Inuence of nutrition on CVD risk factors: dietary fats?
While this paragraph provides evidence for a protective effect of
diet on CVD risk, it must be emphasised that the evolution of die-
tary habits in most areas of the world, particularly developing
countries, is going in the opposite direction with a switch from an
Fig. 4. The Mediterranean diet (adapted from ref.
46
).
Fig. 5. Adherence to a Mediterranean diet and survival in a Greek Population (adapted
from ref.
47
).
Fig. 6. Mediterranean diet, traditional risk factors, and the rate of cardiovascular
complications after myocardial infarction (MI) (adapted from ref.
49
).
Y.A. Carpentier, R.S. Komsa-Penkova / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 6 (2011) e272ee282 e276
originally healthy diet to a more Western pattern. The resulting rise
in CVD burden is a cause for concern.
As mentioned above, dietary habits may have a potent effect on
CVDrisk (Fig. 9); this is not achieved via the regulation of one single
risk factor (e.g. lowering plasma cholesterol level), but via the
modulation of several parameters eg cell signalling and metabo-
lism, and on intercellular communication.
6.1. Dietary fats
Although the primary focus of the Lyon Heart Study was to
provide an adaptation of the Mediterranean diet, a special effort
was made to increase the intake of n3 fatty acids, namely a-
Linolenic acid (ALA). A parallel can be made with previous obser-
vations of a low incidence of CVD mortality in Greenland Eskimos.
(by comparison with the Danish population living in the conti-
nental part of the country) to studies using supplementation of sh
oils or n3 long-chain fatty acids frommarine sources, as discussed
later.
Dietary fat induces changes in cholesterol and lipid metabolism,
and modulates insulin effects/cellular response.
52
These changes
indirectly affect (Fig. 10) membrane composition, formation of
eicosanoid derivatives and activation of sterol regulatory element-
binding protein (SREBP).
Among the nutrients present in various foods, fat and choles-
terol have received a lot of attention from health professionals and
the media. In addition to their effect on plasma total and LDL-
cholesterol, dietary fatty acids have an important impact on the
fatty acid composition of cell membrane phospholipids, and
therefore on cell metabolism.
For a number of years, the high fat intake prevailing in most
Western countries has been considered as the enemy responsible
for the high rate of CVDs. This is particularly due to the high content
of saturated fats in the typical Western diet.
53
Indeed, different fatty acids may variably affect plasma choles-
terol and its distribution in lipoproteins (Fig. 11). Equations have
been proposed to predict the effect of dietary saturated and
unsaturated fatty acids on plasma total and LDL-cholesterol (LDL-
C).
54
However, these equations were developed for Western pop-
ulations and it is likely they do not apply to all ethnic groups.
6.2. Saturated fatty acids
Saturated fats with no double bonds (Fig. 12) raise total serum
cholesterol levels and LDL-C levels.
55
These fatty acids (FAs) also
increase the rigidity of cell membranes and alter the function of LDL
receptors, and possibly raise cholesterol production in the liver.
Specic fatty acids, i.e. myristic (C14:0) and lauric (C12:0) acids
present in butterfat and in tropical (coconut and palm kernel) oils,
increase plasma cholesterol more than palmitic acid (C16:0), the
most prevalent fatty acid in the food supply
56
; in contrast, stearic
acid (C18:0), also very common in foods, is rapidly converted to
oleic acid (C18:1 n9), and does not elevate blood cholesterol. Of
interest, saturated fatty acids may also raise CVDrisk by stimulating
platelet aggregability and activating some coagulation factors; this
may explain why many CV accidents occur during during the
postprandial phase.
The major food sources of saturated fats are animal fats such as
red meats and whole milk dairy products but also some vegetable
oils such as palm oil which is increasingly used in many products
and preparations; the labelling as vegetable oil may be particularly
misleading to the public. In contrast, meat fromchicken and turkey
contain less saturated fat, especially if skinless. Despite the pre-
sencs of saturated fatty acid in the composition of dairy products,
some benecial association between the intake of dairy products
and body weight, body fat plasma cholesterol and blood pressure
were observed. Along with medium chain fatty acids, whey
proteins, fermented products, minerals may contribute to the
benecial effect of dairy products.
57,58
With a notable exception of conjugated linoleic acids present in
milk, most natural unsaturated FAs have a cis conguration, which
induces an angle in the chain at the site of the double bond. A
higher number of double bonds are related to lower freezing
temperatures typical of oils rich in polyunsaturated FAs.
Table 3
Effects of a dietary portfolio of cholesterol-lowering foods vs. lovastatin on serum
lipids and C-reactive protein (adapted from ref.
50
).
Forty-six healthy hyperlipidaemic adults: 25 M; 21 F; 59 1 y; BMI 27.6 0.5
Intervention: randomly assigned to
A: diet very low in sat fats & rich in whole cereals
B: same diet Lovastatin 20 mg
C: diet high in plant sterols (1.0 g/1000 kcal)
Soy proteins (21.4 g/1000 kcal)
Viscous bres (9.8 g/1000 kcal)
Almonds (14 g/1000 kcal)
Fig. 7. Changes from baseline in LDL-C, LDL-C-HDL-C ratio, and C-Reactive protein, reecting. Effects of a dietary portfolio cholesterol-lowering foods vs. lovastatin on serum lipids
and C-Reactive Protein (adapted from ref.
50
).
Y.A. Carpentier, R.S. Komsa-Penkova / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 6 (2011) e272ee282 e277
6.3. Trans fatty acids
These are geometrical isomers of cis-unsaturated fatty acids
with a saturated e like conguration; they are generally produced
by industry to increase fusion temperature and give a more solid
texture to vegetable oils. Frying food may also increase trans FA
content and consumption. However, these trans FAs have a very
negative impact on plasma lipid prole, increasing of LDL-C,
decreasing HDL-C levels, and raising lipoprotein concentrations.
They are considered more atherogenic than saturated fats
59
and
may also increase CVD risk.
60
This property is not shared by natural
trans fatty acids present in dairy fats.
There is a consensus to recommend a sharp decline in the
consumptionof trans fattyacids producedby hydrogenation. However,
they are too often replaced by semi-solid fractions of palm oil.
6.4. Monounsaturated fatty acids (MUFAs)
The major food sources of monounsaturated fats (a single
double bond) are vegetable and nuts oils: from 72% in almond and
olive oils, avocado, to peanut (51%) oils. The only nutritionally
important MUFA is oleic. Replacement of saturated and trans FAs
with monounsaturated or polyunsaturated fats of vegetable origins
in decreases of LDL-cholesterol
61
increases in HDL-cholesterol,
further reductions in the ratio of total to HDL-cholesterol and
reductions in C-reactive protein.
62
6.5. Polyunsaturated fatty acids (PUFAs)
Polyunsaturated FAs have different chemical composition
providing two main groups: n6 and n3 PUFAs. Linoleic acid is
the main representative of the n6 group, made up of 18 carbon
atoms and two double bonds (Fig. 12). The n6 group fatty acids
mainly originate from walnut, soyabean, and maize oils.
a-Linolenic acid (ALA) is the precursor in the n3 group (18
carbon atoms and three double bonds). ALA is an essential fatty
acid. The main food sources are certain vegetable oils: soybean,
sunower and linen oils.
62,63
In prospective epidemiological
studies, a high intake of ALA is associated with a reduction in fatal
cardiovascular events.
64,65
Eicosapentaenoic acid (EPA) and doco-
sahexaenoic acid (DHA) are two important representatives of the
n3 group, derived mainly from sh oils and fats.
The consumption of PUFAs instead of saturated FAs or trans FAs
is inversely correlated to risk of CVD
66,67
as shown in prospective
epidemiological investigations.
61,68
The intake of PUFAs reduces
plasma LDL-cholesterol and, to a lesser extent, HDL-cholesterol as
compared to saturated FAs. This was shown by several randomised
clinical trials in which saturated fats were replaced by vegetable
oils (rich in n6 PUFAs).
PUFAs and to a lesser extent MUFAs may slightly reduce HDL-
cholesterol, but the ratio of total to HDL-cholesterol remains
markedly improved. It is recognised that the consumption of n6
fatty acids has become excessive, raising inammatory reactions.
Therefore, the emphasis is on increasing intake of n3 PUFAs.
69
Fig. 8. Healthy Swedish women with mild hyperlipidaemia and a metabolic syndrome adjunctive effect of a Mediterranean (vs. Swedish) diet plus physical exercise (adapted from
ref.
51
).
Fig. 9. Mechanisms through which nutrition inuences CVD risk (adapted from ref.
52
). Fig. 10. Dietary fat inuences (adapted from
22
).
Y.A. Carpentier, R.S. Komsa-Penkova / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 6 (2011) e272ee282 e278
Systematic review of randomised studies of high monounsaturated
or high polyunsaturated diets suggests no signicant differences in
total, LDL or HDL-cholesterol with these two types of fat. Triglyc-
eride levels were reduced by 0.14 (95% CI 0.00e0.29) mmol/l on the
diets high in PUFAs especially by omega-3 FAs. There is much
evidence suggesting that consumption of EPA and DHA are bene-
cial for triglycerides, blood pressure, haemostatic balance and
heart rhythm
70,71
(Table 4).
Of interest n3 PUFAs have only a mild effect on raising HDL-
cholesterol levels, but no effect on LDL-cholesterol.
However, at high dose, they may markedly reduce plasma
triglycerides and free fatty acids, both in fasting and postprandial
conditions.
Of potential importance, high dietary intake of PUFAs may
increase the sensitivity of LDL particles to oxidative damage, which
in turn may profoundly raise their atherogenicity. In contrast, oleic
acid (probably with other components of olive oil) reduces LDL
susceptibility to oxidation. In addition, high dietary intake of n6
PUFAs appears to stimulate the development of inammatory
reactions, an effect which is largely inhibited by n3 PUFAs. In
general, the evidence for the benets of sh oil is stronger in
secondary than in primary prevention.
72
The supplementation of the diet with 850 mg of EPA/DHA (sh
oil) in subjects who had heart attacks, was found by GISSI
study
73e75
to be associated with 21% reduction in total mortality,
a 30% reduction in CV death and a 45% decrease in sudden death
during the 3.5 year follow-up period [RR for total mortality 0.59
(95% CI 0.36e0.97), n 11,323] (Fig. 13).
Mode of action of n3 PUFAs varies:
Components of cell membranes
Formation of eicosanoids
Formation of second messengers involved in cell signalling
pathways
Gene regulation
n3 PUFAs affect cell responses by regulation of gene expression
and subsequent downstream events. n3 PUFAs control transcrip-
tion factors such as peroxisome proliferator-activated receptors
(PPARs) and sterol regulatory element-binding proteins.
76
FAs effects on cellular responses vary from changes in surface
adhesion molecule expression to altered cytokine production.
n3 PUFAs posses an important effect on transcriptional activity
of certain genes:
Decrease inammation: [ PPARs YNFkB
76
Decrease fat synthesis (TG>chol): Y SREBP
77
Increase fat oxidation: [ PPARs
78
Improve i.c. antioxidant defences: YNFkB
Decrease cachexia: YNFkB
Efforts at reducing total fat intake have led to increasing
carbohydrate calories. However, if high carbohydrate diets effec-
tively reduce LDL-cholesterol, they also markedly raise plasma
triglycerides (in genetically predisposed individuals), the fraction of
atherogenic small dense LDL, and reduce the fraction of protective e
HDL particles.
In that respect, while views on the role of polyunsaturated fats
have evolved over the past 30 years, a strict limitation in the intake
of saturated fats (<8e10% of calorie intake) remains a strong and
consensual recommendation.
Thus, instead of advising high or low carbohydrate diets, it
would be meaningful to mention the type of carbohydrates and fats
included.
Such healthy diets reduce CVD risk via several mechanisms
including their effects on lipids, weight reduction, lowering of
blood pressure, oxidative stress, control of glucose and endothelial
function, reduction of inammatory and thrombotic reactions.
Fig. 11. Predicted changes in serum lipids and plasma lipoproteins (adapted from
ref.
54
).
Fig. 12. Structure and naming of selected 18-carbon fatty acids (adapted from ref.
77
).
Table 4
Inuence of n3 fatty acids on lipid metabolism, serum lipids and lipoproteins.
n3 Fatty acids and
lipid metabolism
n3 Fatty acids and
plasma lipoproteins
Inhibition of FA release
from fat stores
Inhibition of hepatic lipogenesis
Inhibition of TAG synthesis
Inhibition of apo B net production
[ Fat oxidation
Y Ectopic fat storage
Y Hepatic production of VLDL
[ VLDL /LDL conversion
Y Plasma triglycerides
Y Plasma VLDL-TG and
VLDL-Cholesterol
[ Or /HDL-cholesterol,
but / apo A-1
[ LDL-cholesterol
(generally slight)
Y Fraction of small dense LDL
(phenotype B subjects)
Fig. 13. GISSI-prevenzione trial: secondary endpoint results: early effect of omega-3
PUFAs on all-cause mortality (adapted from ref.
75
).
Y.A. Carpentier, R.S. Komsa-Penkova / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 6 (2011) e272ee282 e279
6.6. Dietary cholesterol intake
The response to lowcholesterol diet is extremely heterogeneous
among subjects and individual susceptibilities, suggesting that
some patients might benet substantially from low cholesterol
diet.
79
Generally reduction of cholesterol intake has relatively small
effects on serum lipids: reduction of 100 mg dietary cholesterol per
day appears to reduce total serum cholesterol by only 0.06 or
0.07 mmol/l (roughly 1%).
80,81
Indeed, certain subjects may need
professional advice on food and food choices to select a diet asso-
ciated with a reduction of CVD risk.
82
Recent progress in the understanding of cholesterol absorption
by the intestine and the nding of genetic polymorphisms leading
to increased absorption of cholesterol
83
suggest that a high dietary
cholesterol intake impacts on plasma cholesterol in w20% of the
population referred to as high absorbers. Of note, these subjects
also absorb a signicant proportion of plant sterols; since plant
sterols may be found in atherosclerotic lesions, caution may be
advised regarding the use of plant sterol preparations to lower
plasma cholesterol.
It is perhaps naive to expect any single nutrient to have a major
effect in preventing CVD.
84
In the past decade nutrition research
has moved from the study of micronutrients and macronutrients
cardioprotective properties to focus on evaluating food-based
approaches to prevent cardiovascular diseases.
85
In observational
studies, specic dietary patterns have been identied that are
associated with increased or decreased incidence of cardiovascular
events.
7. Recommendations for management of risk in clinical
practice
The new European guidelines on cardiovascular disease
prevention in clinical practice
36
have been prepared to manage the
risk of CVD in clinical practice and contain strategies for preventing
CVD.
The new European guidelines were developed in cooperation
with a number of other European medical and clinical organisa-
tions: ESC, represented by its European Association of Prevention
and Rehabilitation and Working Group on Cardiovascular Nursing;
European Society of Atherosclerosis; European Society of Hyper-
tension (ESH); European Heart Network; Family Practice (World
Organization of National Colleges, Academies and Academic Asso-
ciations of General Practitioners/Family Physicians e WONCA);
International Society of Behavioral Medicine; European Association
for the Study of Diabetes (EASD)/International Diabetes Federation
Europe; and European Stroke Initiative.
7.1. Strategies for promoting CVD prevention
7.1.1. Multimodal interventions
86
The primary prevention strategy is promotion of a healthy
lifestyle including a proper low-calorie nutrition combined with
increased physical activity. Most studies demonstrate that physi-
cally active people have signicantly lower mortality from cardio-
vascular disease, compared with sedentary people. There is a clear
relationship between physical activity and lipid prole, indicating
a reduction in plasma triglycerides and an increase in HDL-
cholesterol in individuals who exercise regularly.
87,88
Change and management of behavioural risk factors are as
follows.
Dietary changes;
prevention and management of smoking;
management of physical activity;
control of arterial hypertension;
management of dyslipidemia;
prevention of risk of CVD in diabetes; and
prevention in subjects with the metabolic syndrome.
The subjects at low risk for CVD should be helped to maintain
this state lifelong,
89
and those at increased CVD risk should be
helped to reduce their risk.
90,91
Nutrition is an integral part of this
strategy. Patients with cardiovascular disease and individuals at
high risk should be given recommendations on their food and
dietary options combined with increased physical activity.
No smoking;
healthy food choices (5 portions of fruit and vegetables per
day);
physical activity: walk 3 km daily, or 30 min of any moderate
activity;
BMI <25 kg/m
2
and avoidance of central obesity;
blood pressure <140 mm Hg systolic blood pressure (SBP);
total cholesterol <5 mmol/L (w190 mg/dL);
low-density lipoprotein (LDL) cholesterol <2.5 mmol/L
(w100 mg/dL); and
blood glucose <6 mmol/L (w110 mg/dL).
The guidelines appropriately give highest priority to the highest
risk subjects because these people gain most from risk modica-
tion. This includes patients with established atherosclerotic CVD,
asymptomatic individuals who have multiple risk factors, Type 2 or
type 1 diabetics with microalbuminuria, those with markedly
increased single risk factors, or close relatives of subjects with
premature atherosclerotic CVD.
The goals of CVDprevention in these high-risk individuals are as
follows.
Blood pressure <130/80 mmHg if feasible;
total cholesterol <4.5 mmol/L (w175 mg/dL) with an option
of <4 mmol/L (w155 mg/dL) if feasible;
LDL-cholesterol <2.5 mmol/L (w100 mg/dL) with an option
of <2 mmol/L (w80 mg/dL) if feasible; and
fasting blood glucose <5 mmol/L (w80 mg/dL) and glycated
haemoglobin (HbA1c) <6.5% if feasible.
The prevention paradox is that high risk individuals gain most
from preventive measures- but most CVD deaths come from
apparently low risk subjects because they are so numerous.
The three strategies aimed at (1) the general population, (2)
primary prevention in high risk individuals, and (3) secondary
prevention in those with established CVD, should be complemen-
tary, but not competitive.
Conict of interest
None declared.
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