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School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada
2To whom correspondence should be addressed. E-mail: jonesp{at}macdonald.mcgill.ca.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONProtective Roles of Ethanol.Protective Roles of Ancillary...REFERENCES |
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KEY WORDS: • cardiovascular disease • phenolic compounds • red wine • alcohol
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONProtective Roles of Ethanol.Protective Roles of Ancillary...REFERENCES |
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2
3
4)
. This J- or U-shaped association was described
by Kiechl et al. (5)
, with light drinkers facing a lower
risk of CVD compared with heavy drinkers or abstainers. According to
other authors (6
7
8
9
10)
, the benefits from alcohol
consumption arise from the consumption of wine, especially red wine.
Further epidemiologic studies (11
12
13)
have also supported
the view that the protective effect of alcohol is specific to red wine.
Such effects of red wine have been the basis for the French Paradox,
which suggests that despite an increased intake of saturated fat within
France, the French population exhibits a low incidence of CVD mortality
(14)
. This paradox too, is thought to be related to the
high prevalence of red wine consumption (15
,16)
. The main
objective of this review is to critically define the plausible health
benefits of red wine consumption and assess possible mechanisms of
action by which they manifest themselves with regard to CVD risk. |
Protective Roles of Ethanol. |
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TOPABSTRACTINTRODUCTIONProtective Roles of Ethanol.Protective Roles of Ancillary...REFERENCES |
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examined the association between intake of different
types of alcoholic drinks and mortality in a population of 13,000 men
and women between the ages of 30 and 79 y. In this population, the
relative risk of death from CVD was reduced from 1.00 in nondrinkers to
0.4 for those who drank 3–5 glasses of wine/d. With respect to the
intake of beer, 3–5 bottles/d conveyed a reduction in risk of 0.72
compared with not drinking beer. Conversely, the results related to the
intake of distilled alcohol products exhibited different trends, mainly
that weekly or daily consumption actually increased the relative risk
of CVD to 1.08 and 1.35, respectively.
From these results, Grønbæk et al. (11)
surmised
that the J- or U-shaped relation between alcohol intake and
mortality, historically related to the beneficial and harmful effects
of ethanol, might be a result of a combination of the individual
attributes of wine, beer and spirits. Further, in that study,
individuals consuming 3–5 glasses of wine/d possessed half the risk of
dying as those who never drank wine. In contrast, consumption of 3–5
drinks of spirits/d was associated with increased mortality. Moreover,
these researchers concluded that light and moderate wine drinking is
associated with a dose-dependent decrease in all-cause
mortality that is attributed to a decrease in
cardiovascular-related disease.
Truelson et al. (13)
utilized a cohort study to
examine the influence of alcohol intake and the different types of
alcohol on risk of first-ever stroke in a large Danish population.
After adjusting for confounding factors, subjects who drank wine weekly
were found to have a significantly lower risk of stroke. Meanwhile, the
difference was marginally significant for subjects reporting daily
consumption of wine. The intake of neither beer nor spirits was
associated with a change in risk. From the data outlined, Truelson et
al. (13)
concluded that the moderate intake of wine is
associated with a lower risk of stroke.
Renaud et al. (12)
evaluated the effect on mortality
of wine drinking in Eastern France. The analysis was conducted among
34,014 men aged 40–60 y, between 1978 and 1983. After adjustment for
confounders, the authors established that a decreased risk of 27–39%
for both CVD and coronary heart disease (CHD) was evident at all levels
of alcohol intake >22 g/d, 
2 glasses of wine. The authors concluded
that moderate intake of alcohol, mainly in the form of wine, appears to
protect from death due to CVD and CHD, in addition to other causes.
In examining the results and conclusions of these epidemiologic
studies, the magnitude of the sample size must not cloud limitations,
which are inherently present. The point at which analysis of the
robustness of these studies becomes difficult concerns the method of
obtaining information from the respondents. The use of broad-based
questionnaire systems is open to scrutiny because of the increased risk
of respondent bias; thus data interpretation becomes uncertain
(17)
. This style of research is beneficial for noting
trends within a large population, but it is difficult to establish
whether in fact observed trends are representative of what occurs
within the population.
The ability to judge whether an association exists between a type
of alcoholic drink and CVD requires observational data in which
individual intake can be linked directly to CVD (3
,18)
.
These types of data have not been presented within the limits of the
epidemiologic studies examined. The cohort studies examined identify a
strong inverse association between alcohol intake and CVD
(11
12
13)
. Using the results presented, the authors implied
that a single type of alcoholic beverage, in this case red wine,
provides the most benefit of all to CVD. A major difficulty with these
studies is the possible different drinking patterns and aspects of
lifestyle correlated with choice of drink within particular
populations. In these studies in which wine intake was significantly
associated with a reduced risk of CVD, wine was normally consumed by
much of the population within a healthy range, usually 1–2 drinks/d.
Another consideration is whether beverages were consumed during meal
time, or more irregularly throughout the day. Such differences in
consumption patterns may also affect the observed health benefits
(3
,5
,13
,16
,17)
.
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Protective Roles of Ancillary Compounds. |
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TOPABSTRACTINTRODUCTIONProtective Roles of Ethanol.Protective Roles of Ancillary...REFERENCES |
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7
8
9
10
,19
20
21)
. The
protective effects of red wine have been proposed on the basis that in
addition to its alcohol content, it contains more phenolic compounds
than do other alcoholic beverages (6
7
8
9
10
,19
20
21)
. These
authors examined the differential actions of beer, spirits, grape juice
and both red and white wine to better understand the effects of such
beverages on CVD.
Understanding the mechanisms that explain how the constituents of
red wine influence living systems can be examined only through
observations and trials contained within experimental studies. Several
studies have been conducted with the purpose of helping to identify
some possible explanations for the trends seen within the epidemiologic
research. Pellegrini et al. (19)
conducted a randomized
crossover study to evaluate the effect of moderate consumption of red
wine on platelet aggregation and hemostatic variables. Their goal was
to discriminate between effects of alcohol vs. those due to
nonalcoholic components.
Significant differences in bleeding time were not found among the
treatments. In addition, platelet aggregation induced by collagen was
significantly decreased by alcohol, whereas nonalcoholic components had
no effect. ADP-induced platelet aggregation, however, was not
influenced by either alcohol or nonalcohol components. A significant
decrease was observed in fibrinogen due to alcohol, whereas
nonalcoholic components caused a small and nonsignificant rise in this
value. The results suggested that the beneficial effects measured were
due to the alcohol content of the treatment and were unrelated to the
nonalcoholic components. On the basis of their findings, the authors
claimed that moderate intake of alcohol may reduce fibrinogen level and
therefore at least one major risk factor of CVD. The validity of these
conclusions is compromised in part by the researchers’ disregard for
confounders including diet and environment, which may have influenced
the results. In addition, lack of information regarding subject
selection and criteria, including a definition of habitual alcohol
intake, raises questions regarding the representativeness of the
subject population. In contrast, work by Keevil et al.
(20)
established substantial inhibition of platelet
activity in healthy humans after drinking 2 cups of purple grape
juice for 1 wk. Their study of platelet aggregation using
whole-blood aggregometry with collagen, ADP or thrombin agonists is
thought to be more sensitive than platelet-rich plasma aggregation
using the same agonists. This methodological difference may explain why
other groups failed to see any effects from nonalcohol beverage
components (19)
.
Wollny et al. (6)
conducted an in vivo experiment
with rats to establish whether ethyl alcohol and red or white wine
exert comparable effects on hemostasis and thrombosis. Further, these
workers examined whether the removal of the alcohol from wine would
decrease its potential effects on these variables. The authors
concluded that red wine modified hemostatic parameters and prevented
experimental thrombosis, regardless of its alcohol content. White wine
was ineffective, whereas alcohol-free red wine was as effective as
the original wine, suggesting that red wine components other than
alcohol were responsible for the observed effects. Ethyl alcohol did
not affect hemostatic parameters, but experimental thrombosis was
decreased. This finding confirms that chronic or long-term alcohol
consumption has antithrombotic properties, suggesting the existence of
a different mechanism from that of nonalcoholic red wine components.
Study limitations described included difficulty in analyzing all
components of wine, differences in wine based on type of grape,
variations in methods of cultivation and production, and the possible
negative effects on wine components of lyophilization done to obtain
alcohol-free red wine. The characteristics of the red and white
wines were examined using a series of analytical procedures including
HPLC. Using this approach, levels of total phenols, flavonoids,
anthocyanins and tannins were determined. HPLC methodology has been
noted as superior for analyzing polyphenols by Nigdikar et al.
(8)
. In summary, the results lend experimental support and
biological plausibility to the observed epidemiologic protection from
CVD associated with red wine consumption.
Frankel et al. (7)
examined whether red wine
inhibited copper-catalyzed oxidation of LDL in humans. Natural
flavonoids found in wine were found to donate hydrogen or react with
superoxide anions, hydroxyl radicals and lipid peroxyl radicals, all of
which may cause lipid peroxidation in vivo. Two possible mechanisms for
this action were advanced, i.e., that phenolic compounds complex with
Cu++ to reduce it to Cu+, which may in turn
reduce hydroperoxides, and that during the LDL peroxidation, phenols in
wine may act as self-regenerating reducing components. Therefore,
these authors concluded that with regular ingestion of these
antioxidant phenols via red wine consumption, a collective reduction in
the oxidation of lipoproteins may occur and thus contribute to the
improvement of atherosclerosis and morbidity and mortality from CVD.
Conclusions drawn from this study were specific as to the effects
of wine consumption on the improvement of LDL oxidation and thrombotic
phenomena, yet they were not generally supported by available data. Use
of a sample size of two limited the robustness of the conclusions. In
addition, this study did not take into account all possible confounders
including age difference between subjects, diet, physical activity or
environmental conditions that may have seriously affected LDL
properties. None of the resultant values presented within the
paper are supported by any mention of significant difference. Hence, it
is natural to question the validity of the results and conclusions
stated. Despite these limitations, Miyagi et al.(10)
conducted a similar study to confirm the inhibition of human LDL
oxidation by flavonoids. The authors compared the effects of flavonoids
from red wine and grape juice. Their results confirmed that both red
wine and grape juice inhibited the Cu2+-catalyzed human LDL
oxidation in vitro. However, Miyagi et al. (10)
reported
that only red wine consumption resulted in LDL resistance to oxidation
in vivo. From this observation, it was postulated that the potential
for intestinal absorption of flavonoids is increased due to the alcohol
content of the red wine. Carbonneau et al. (22)
and
Serafini et al. (4)
noted that alcohol is a natural
stabilizing agent for polyphenolic compounds in red wine. Carbonneau et
al. (22)
criticized the findings of such in vitro
experiments (7)
because of the inability to determine what
concentrations of phenolic components are in fact present in the plasma
after consumption.
Further in vivo investigations concerning the effects of purple
grape juice on endothelial function and LDL oxidation were conducted by
Stein et al. (21)
. Fifteen humans with an average age of
62 y, suffering from angiographically documented coronary artery
disease (CAD), were supplemented with 7.7 mL/(kg · d) of purple
grape juice for 14 d. The authors found that short-term
ingestion of purple grape juice significantly improved endothelial
function and reduced the susceptibility of LDL to copper-induced
oxidation in these CAD patients. These benefits were observed despite
the subjects’ use of antioxidant vitamins and lipid-lowering
medications. Endothelial function was measured by performing
high-resolution brachial artery ultrasonography, which was used to
calculate flow-mediated vasodilation. Despite the small number of
subjects involved, this measure of endothelial function is considered
very sensitive, and reproducible (21)
. Such evidence led
the authors to propose that the flavonoids in purple grape products
independently of alcohol content may prevent cardiovascular events
through the mechanisms outlined above.
Nigdikar et al. (8)
compared red and white wines,
red wine polyphenols and a control alcoholic drink on LDL oxidation in
humans. Analyses of the results (Table 1
) showed no significant differences among any of the groups treated with
the various red wine polyphenol forms. There was, however, a
significant difference observed between the groups treated with white
wine and the control drink vs. those treated with the various red wine
polyphenol forms. These results led Nigdikar et al. (8)
to
conclude that red wine consumption increases plasma and LDL
polyphenols, in addition to enhancing the antioxidant activity that was
shown by decreased plasma total peroxides, increased lag time and
decreased lipid peroxides in the copper-catalyzed peroxidation of
LDL-conjugated dienes. It can therefore be extrapolated that
decreasing LDL oxidation through the consumption of red wine may
prevent the development of CVD.
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was designed
to determine whether specific phenolic acids could be detected in blood
circulation after red wine consumption and whether their presence had
any acute effect on serum and LDL oxidation. The presence of alcohol in
red wine had no significant effect on the absorption of phenolic acids
into circulation over the first 4 h after consumption. In
addition, the consumption of red wine or dealcoholized red wine had no
significant effect on ex vivo serum or LDL oxidation when measured over
4 h. The results are inconsistent with other research findings in
which the consumption of red wine decreased LDL oxidation in humans
(7
,8
,10)
. Such differences reflect the complexity of
potential mechanisms exhibited by polyphenolic compounds in vivo.
Caccetta et al. (9)
provided an alternative hypothesis
regarding the benefits seen from consumption of different beverages,
stating that evidence exists that alcohol consumption can induce
oxidative stress through free radical formation, which interferes with
antioxidant defense mechanisms, or by interfering with enzymes involved
in the antioxidation process. These authors suggest that the overall
effect of alcoholic beverages on LDL oxidation may be a balance between
two forces, namely, the prooxidant and antioxidant components of the
beverages consumed. The authors concluded that although the consumption
of both regular and dealcoholized red wine significantly increased the
plasma concentrations of phenolic acids, there was no effect on LDL
oxidation over the 4-h time period studied (9)
. Obviously,
the question arises whether a 4-h time period is adequate for measuring
LDL oxidation effects. Longer-term controlled studies are required
to better understand the effects and mechanisms of wine polyphenolic
compounds.
Despite a variety of possible mechanisms for the observed effects
of red wine consumption on CVD that have been described, the field is
not unequivocal (6
7
8
9
,19
20
21)
. These mechanisms form a
biological basis for a causal relation between red wine consumption and
lower rates of CVD. However, the mechanisms observed may differ as a
result of the acute vs. chronic effects of alcohol consumption.
Furthermore, it becomes difficult to establish what should be termed
chronic intake because various researchers view chronic as representing
different time periods (6
,8
,19)
or make no mention of
chronic habits at all (7)
. This discrepancy is difficult
to resolve because conducting chronic experiments on human subjects
raises issues of ethical conduct with regard to chronic exposure and
its possible negative effects.
Only one study amid the literature reviewed mentioned possible
differences arising among wine varieties such as wines made from
different types of grapes, grown in different regions or cultivated in
different ways (6)
. These differences may lead to varying
concentrations of the polyphenolic compounds; hence, their
pharmacologic properties may differ. It is possible that such
differences may influence conclusions drawn from correlations between
total consumption of red wine in a population and mortality from CVD
(14)
.
In summary, questions raised by the existing literature
establish a clear understanding that some benefits exist from both the
phenolic compounds of red wine and alcohol itself (Fig. 1
). However, due to the multifactorial nature of the issues discussed,
the results outlined are difficult to assimilate to obtain a concise
conclusion. The health benefits and mechanisms observed might be
heavily influenced by social, genetic and environmental factors, which
have not been addressed specifically in this literature. The
epidemiologic literature has established a decreased relative risk of
CVD with regular intake of alcohol. The authors’ data collection and
analyses have shown that the type of alcoholic beverage favored to gain
such effects appears to be red wine. However, the limitations of such
work must not be discounted. The experimental data describe many
effects of red wine and establish some that are attributed to the
alcohol content and others effected by supplementary compounds within
wine or simply grape juice. The alcohol appears to provide effects at
the hemostatic level, whereas the phenolic compounds found in red wine
and grape juice are postulated to be involved primarily with LDL
oxidation.
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FOOTNOTES |
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3 Abbreviations used: CAD, coronary artery disease; CHD, coronary heart disease; CVD, cardiovascular disease.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONProtective Roles of Ethanol.Protective Roles of Ancillary...REFERENCES |
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