Red Wine Research Paper

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ABSTRACT

The objective of this article is to review the existing literature concerning the effects and mechanisms of action of red wine consumption vs. other alcoholic beverages on the risk of cardiovascular disease (CVD). Of particular interest is the form and quantity of alcohol consumed. This relationship between alcohol consumption and mortality is well supported by epidemiologic studies, which have suggested that different forms of alcohol alter the relative risk values for mortality from CVD. Although not without exception, current evidence from epidemiologic and experimental studies suggests a protective effect against the development of CVD with moderate consumption of red wine. The exact nature of the protective effect remains to be established. However, mechanisms including LDL oxidation and alterations in hemostatic variables are being increasingly recognized as contributory. Key components of red wine thought to be responsible for the protective effects include phenolic compounds and alcohol content. Despite the research presented, some questions relating to the current recommendations regarding moderate alcohol consumption and cardiovascular health remain. However, collectively, the literature aids in understanding some of the ways in which alcoholic beverages and their components affect the health of our population.

cardiovascular disease, phenolic compounds, red wine, alcohol

Growing evidence suggests the existence of a negative correlation between alcoholic beverage consumption of 1–2 drinks/d and the incidence of cardiovascular disease (CVD)3, (1, 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.

Epidemiologic research seeks to uncover trends established within large populations that identify current health phenomena of interest to the scientific community. Through the identification and characterization of such events, researchers can focus their efforts on explaining the observed population trends. Grønbæk et al. (11) 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).

Protective Roles of Ancillary Compounds.

Many researchers believe that it is unlikely that ethanol content is solely responsible for the postulated effects; therefore, they have focused their attention on other constituents of alcoholic beverages, which may be the agents responsible (6, 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.

TABLE 1

Comparison of red and white wine, red wine polyphenols and an alcoholic drink on plasma and LDL-associated antioxidant effects1

Supplement Plasma polyphenols Plasma lipid peroxides LDL polyphenols LDL peroxidation lag time LDL conjugated-diene formation LDL lipid peroxides LDL peroxidation lag time 
Red wine ↑38% ↓32% ↑26% ↑31% ↓15% ↓22% ↑31% 
White wine No change ↑23% Not reported Not reported ↑14% Not reported Not reported 
White wine plus polyphenol powder ↑27% ↓29% ↑62% ↑21% ↓11% ↓23% ↑21% 
Polyphenol powder capsules ↑28% ↓28% ↑29% ↑27% ↓12% ↓25% ↑27% 
Alcoholic drink No oxidative or antioxidative effects were observed after the control drink 
Supplement Plasma polyphenols Plasma lipid peroxides LDL polyphenols LDL peroxidation lag time LDL conjugated-diene formation LDL lipid peroxides LDL peroxidation lag time 
Red wine ↑38% ↓32% ↑26% ↑31% ↓15% ↓22% ↑31% 
White wine No change ↑23% Not reported Not reported ↑14% Not reported Not reported 
White wine plus polyphenol powder ↑27% ↓29% ↑62% ↑21% ↓11% ↓23% ↑21% 
Polyphenol powder capsules ↑28% ↓28% ↑29% ↑27% ↓12% ↓25% ↑27% 
Alcoholic drink No oxidative or antioxidative effects were observed after the control drink 

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A recent study by Caccetta et al. (9) 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.

FIGURE 1

Schematic representation of the effects of alcohol on risk factors for cardiovascular disease (CVD).

FIGURE 1

Schematic representation of the effects of alcohol on risk factors for cardiovascular disease (CVD).

Obviously, consumption of red wine alone will not inhibit the development of CVD, and the prescription for doing so should be examined on an individual basis. Currently, the evidence presented is not sufficient to warrant widespread general public acceptance of the benefits of red wine consumption on decreased risk of CVD because the mechanism of action and all possible side effects are not agreed upon within the scientific community. There exists also the dilemma of the population adopting the attitude that “if some alcohol is good, then more is better.” The health implications of such trends should not be ignored.

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