European Heart Journal Supplements (2001) 3 (Supplement D), D33–D36
‘Protective nutrients’ and up-to-date dietary
recommendations
D. Kromhout
Division of Public Health Research, National Institute of Public Health and the Environment, BA Bilthoven,
The Netherlands
In the past, dietary recommendations were focused on
reductions in the consumption of foods and nutrients
deemed bad for health, such as saturated fat, dietary
cholesterol and salt. In more recent years, an increased
consumption of foods and nutrients deemed good for
health has also been emphasized, e.g., increased consumption of vegetables, fruits, legumes, fish, dietary fibre and
polyunsaturated fatty acids. Another major development
has been the change from dietary recommendations for
specific diseases, such as coronary heart disease and diabetes, to integrated, comprehensive dietary recommendations for chronic diseases and health in general. A
healthy diet forms an important component of a healthy
lifestyle. This also includes advice not to smoke and to be
physically active for at least 30 min each day. Such a
lifestyle prevents coronary heart disease and is important
for both primary and secondary prevention.
Observational studies and clinical trials on n-3 polyunsaturated fatty acids suggest that besides a diet low
in saturated and trans fatty acids and in cholesterol, a
healthy diet also needs to contain adequate amounts of
alpha-linolenic acid (2 g . day "1) and EPA and DHA
(200 mg . day "1).
Introduction
In the past, dietary recommendations were focused on
reducing the consumption of foods and nutrients
deemed bad for health, e.g. saturated fat, dietary
cholesterol and salt. In more recent years, increasing
emphasis has been given to encouraging the consumption of foods and nutrients deemed good for
health, e.g. vegetables, fruits, legumes, fish, dietary
fibre and polyunsaturated fatty acids. Another major
development has been the change from dietary recommendations for specific diseases such as coronary heart
disease and diabetes, to integrated, comprehensive
Correspondence: D. Kromhout, Division of Public Health
Research, National Institute of Public Health and the
Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
1520-765X/01/0D0033+04 $35.00/0
Evidence that a diet rich in fruits and vegetables may
protect against coronary heart disease is increasing. Fruits
and vegetables are plentiful sources of antioxidants. Until
recently, most research in this area was focused on the
so-called nutritive antioxidants, vitamins with antioxidant
properties such as tocopherol (vitamin E), carotenoids and
vitamin C. Recently, there is an increasing interest in the
so-called non-nutritive antioxidants. These are polyphenols present in plant foods and have strong antioxidant
properties.
Clinical trials with vitamin E supplements were mainly
negative. High-dose, pharmacological supplementation
of diet with so-called ‘protective’ nutrients, however,
do not relate to the nutritional domain. In future trials
a dose corresponding to a multiple of the recommended dietary allowance of 10 mg . day "1 should be
used rather than the high, pharmacological doses used so
far.
(Eur Heart J Supplements 2001; 3 (Suppl D): D33–D36)
? 2001 The European Society of Cardiology
Key Words: Healthy diet, fatty acids, antioxidants, n-3
polyunsaturated fatty acids, vitamin E.
dietary recommendations for chronic diseases and
health in general. An example is the report on ‘Diet,
nutrition and the prevention of chronic diseases’ prepared by an expert group of WHO[1]. The recommendations of this report were adapted for coronary heart
disease by an expert group of the European Society of
Cardiology (ESC) and included in the Task Force
Report on Prevention of Coronary Heart Disease in
Clinical Practice[2].
Diet is an important risk determinant of coronary
heart disease. A major risk factor for coronary
heart disease is total or low-density lipoprotein (LDL)
cholesterol. Experimental research has shown that oxidized LDL rather than native LDL is the culprit in the
development of atherosclerosis and its clinical complications, such as coronary heart disease[3]. The concentration of oxidized LDL is determined by environmental
? 2001 The European Society of Cardiology
D34 D. Kromhout
Table 1 Population goals for nutrients and foods
Limits for
population:
average intake
Nutrient or food
Saturated (and trans) fatty acids (% energy)
Polyunsaturated fatty acids (% energy)
Dietary fibre (g . day "1)
Fruits and vegetables (g . day "1)
Legumes, nuts, seeds (g . day "1)
Cholesterol (mg . day "1)
Fish (g . day "1)
Salt (g . day "1)
<10
3–7
27–40
>400
>30
<300
>20
<6
Adapted from Diet, nutrition and the prevention of chronic
diseases, report of a WHO Study Group 1990[1].
factors. Different fatty acids have LDL cholesterolelevating or LDL cholesterol-lowering effects. Oxidation of LDL is influenced by the balance between
pro-oxidants through, for instance, smoking and the
presence of antioxidants in the diet.
The role of diet on coronary heart disease is not
limited to the effect of diet on lipoproteins. It has also
been shown, for instance, that fatty acids influence
haemostatic factors[4]. Recently evidence was obtained
that polyunsaturated fatty acids may prevent ventricular
fibrillation and arrhythmias[5]. These results make
clear that diet is an important determinant of coronary
heart disease. There are several pathways through which
diet exerts its influence on the occurrence of coronary
heart disease. This short overview will focus on the effect
of dietary fatty acids and antioxidants in relation
to coronary heart disease with an emphasis on n-3
polyunsaturated fatty acids and alpha-tocopherol
(vitamin E).
Fatty acids
The recommendations for a healthy diet by the ESC
Task Force on Prevention of Coronary Heart Disease
are summarized in Table 1. Such a diet should be low in
saturated and trans fatty acids (<10% of energy) and
dietary cholesterol (<300 mg . day "1). The average
intake of trans fatty acids in Western European
countries is 0·5–2·0% of total energy intake (1·6–
5·4 g . day "1), being lowest in Mediterranean countries[6].
Currently, the optimal diet for lipoprotein levels is
controversial[7]. Should it be a diet low in saturated fat
and high in unsaturated fat or a low saturated fat diet
that is rich in complex carbohydrates? The first will
provide the best lipoprotein levels; an example is the
traditional Mediterranean diet. An example of the
second diet, low in saturated fat and high in carbohydrates, is the traditional Japanese diet. Both of these
diets are associated with the best life-expectancy in the
world. For primary and secondary coronary heart disease prevention in Europe the best advice is to use a diet
low in saturated fatty acids by replacing them in part
Eur Heart J Supplements, Vol. 3 (Suppl D) June 2001
with monounsaturated and polyunsaturated fatty acids,
as well as with complex carbohydrates.
Polyunsaturated fatty acids can be divided into n-6
and n-3 polyunsaturated fatty acids. Linoleic acid, a
fatty acid with 18 carbon atoms and two double bonds,
is the best-known representative of the n-6 polyunsaturated fatty acid family. This fatty acid is present
in margarines rich in polyunsaturated fatty acids. In
most Western European countries the intake of linoleic
acid is adequate. In countries characterized by a low
linoleic acid intake in the past, for example Finland and
Scotland, a low intake of this fatty acid (<4% of energy)
was associated with an increased risk of coronary heart
disease[8,9]. At an average population intake of 6% of
energy in linoleic acid there is no association with
coronary risk.
Alpha-linolenic acid is the parent compound of the
polyunsaturated fatty acids of the n-3 family and has 18
carbon atoms and three double bonds. This fatty acid is
present in certain oils, e.g. soybean oil and canola
(rapeseed) oil, and also in wholemeal bread, fruits and
vegetables. A protective effect of alpha-linolenic acid
intake on coronary heart disease was found in prospective cohort studies[10,11]. In a controlled clinical trial, 600
post-myocardial infarction patients were randomized
to either a Mediterranean diet enriched with alphalinolenic acid, or to a usual prudent post-infarction
diet[12]. After an average follow-up period of 27 months
total mortality in the experimental group was reduced
by as much as 70%, and cardiac mortality by 76%. The
investigators ascribe this effect to alpha-linolenic acid.
However, the diet of the two groups differed also in
fruits and vegetables. This dramatic effect on mortality
observed in this trial may be due to the healthy diet
in general and not only to an increased intake of
alpha-linolenic acid.
Observational research has shown that the consumption of fish once or twice a week compared with no fish
protects against coronary heart disease mortality[13].
This effect is strongest for fatty fish. The results of
studies carried out in The Netherlands and in the
context of the Seven Countries Study played a major
role in this area[14–16]. Studies from the U.S.A. showed
that the strongest association was observed for the
hardest end-point. In a prospective study an inverse
association was observed with sudden death[17], and in a
case-control study with cardiac arrest[18]. In the latter
study also a dose–response relation was observed
between both fish consumption and the concentration
of n-3 polyunsaturated fatty acids in red blood cell
membranes in relation to cardiac arrest.
Fatty fish consumption was also related to coronary
heart disease mortality in the DART trial[19]. This trial
was carried out among 2000 cardiac patients for 24
months. Patients who consumed fatty fish two or three
times per week had a 29% reduction in all-cause mortality, and a 33% reduction in cardiac mortality. These
results indicate the possibility that fatty fish protects
against coronary and all-cause mortality, possibly
through its content of n-3 polyunsaturated fatty acids.
Protective nutrients D35
The hypothesis was tested in the GISSI–Prevention
trial[20]. This trial, which included over 11 000 patients,
tested the effect of supplementation of about
850 mg . day "1 of the n-3 polyunsaturated fatty acids
eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA). Compliance was about 70%, so that the
actual additional intake of these fatty acids was about
600 mg . day "1. This was associated with a reduction of
20–35% in coronary heart disease mortality and 14–20%
in all-cause mortality. These results suggest that a diet
low in saturated and trans fatty acids and in dietary
cholesterol is not the only factor of importance. It is also
necessary that a healthy diet contains adequate amounts
of alpha-linolenic acid and EPA and DHA. As an expert
group concluded, probably an intake of 2 g . day "1 of
alpha-linolenic acid and 200 mg . day "1 of very long
chain n-3 polyunsaturated fatty acids (EPA and DHA)
is adequate[21].
Antioxidants
Evidence that a diet rich in fruits and vegetables may
protect against coronary heart disease is increasing[22,23].
Fruits and vegetables are rich sources of antioxidants.
Until recently most research in this area was focused on
so-called nutritive antioxidants, vitamins with antioxidant properties such as tocopherol (vitamin E), carotenoids and vitamin C. Recently there has been an
increasing interest in the so-called non-nutritive antioxidants. These are polyphenols present in plant foods
with strong antioxidant properties. An example of these
compounds are flavonols that are present in tea, red
wine, apples and onions. In a cohort study it was shown
that flavonols are protective against coronary heart
disease[24].
Great emphasis is given in research on antioxidants
and coronary heart disease to vitamin E. In three
case-control studies no association was observed
between vitamin E levels in blood and cardiovascular
disease[25]. A weak inverse relationship between plasma
vitamin E and angina pectoris was found in a casecontrol study carried out in Scotland[26]. Finally, no
association was noted between alpha-tocopherol concentration in adipose tissue and myocardial infarction in
the multicentre EURAMIC case-control study[27].
Inverse associations were observed between vitamin E
intake and coronary heart disease risk in five prospective
studies[28–32]. However, in three of the studies the association was noted for supplement users[28–30], and in two
studies for the vitamin E content of the diet[31,32]. This
means that the results of these cohort studies suggest a
protective effect of vitamin E on CHD risk. However, it
is unclear what level of intake provides protection.
In the CHAOS trial the hypothesis was tested whether
vitamin E supplementation among cardiac patients
could prevent the risk for reinfarction and mortality[33].
There was a reduction in non-fatal myocardial infarction in patients supplemented with vitamin E. However,
no association was observed with respect to hard endpoints, cardiovascular and all-cause mortality. Similar
results in relation to hard end-points were observed in
the ATBC trial carried out in Finland among 30 000
smokers, in the GISSI–Prevention trial on 11 000 cardiac patients in Italy and in the HOPE trial on 9500
cardiac and diabetic patients in Canada[20,34,35]. These
results show that vitamin E supplementation is not
effective in preventing cardiovascular and all-cause
mortality.
The average intake of vitamin E in European
populations varies between 10 and 30 mg . day "1[36].
In the different trials the supplementation of
vitamin E amounted to 50 mg . day "1[33] and 270–
540 mg . day "1[20,33,35]. This means that in most supplementation trials the dose used was at least 10 times
higher than average intake. It can be questioned whether
such a high dose is needed. These high doses belong to
the pharmacological domain and do not relate to the
nutritional domain. It may be more useful to adopt in
trials a dosage corresponding to a multiple of the
recommended dietary allowance of 10 mg . day "1,
rather than doses of 270–540 mg . day "1. We have also
observed a similar development in relation to n-3 polyunsaturated fatty acids supplementation trials. In the
first generation trials, 5–10 g of n-3 polyunsaturated
fatty acids per day were used. It is now recommended
less than 1 g . day "1 be used because observational
epidemiological studies and intervention trials already
observe preventive effects of about 200 mg . day "1 of
n-3 polyunsaturated fatty acids.
A healthy diet for primary and
secondary prevention of coronary
heart disease
The protective effect in coronary patients of a healthy
diet, low in saturated and trans fatty acids and with a
large amount of fruits and vegetables, was shown in a
trial conducted in India[37]. About 400 patients were
randomized either to a healthy diet rich in plant foods or
to a control diet. Coronary patients who followed the
healthy diet had a 42% reduction in cardiac mortality
and a 45% reduction in all-cause mortality. The results
from this trial are supported by the results from
observational studies. Men in Finland, Italy and the
Netherlands who complied best with a healthy diet score
based on the WHO recommendation for prevention of
chronic diseases[1] showed an 18% reduction in cardiovascular disease mortality and a 13% reduction in
all-cause mortality compared with men who had the
worst diet score[38]. Similar results were obtained in a
cohort study from Greece. All-cause mortality was
lowest among the elderly following a traditional
Mediterranean diet[39].
A healthy diet forms an important component of a
healthy lifestyle. This also includes advice not to smoke
and to be physically active for at least 30 min each day.
Such a lifestyle prevents coronary heart disease and is
important for both primary and secondary prevention.
Eur Heart J Supplements, Vol. 3 (Suppl D) June 2001
D36 D. Kromhout
The relative risks associated to coronary heart disease
risk factors including dietary factors are similar in
cardiac patients and healthy persons. The absolute risk
is substantially higher in cardiac patients. Therefore
there is no real difference in applying preventive
measures, including dietary recommendations, to cardiac patients and healthy persons.
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