Alcohol and Alcoholism Advance Access originally published online on January 10, 2005
Alcohol and Alcoholism 2005 40(2):102-105; doi:10.1093/alcalc/agh132
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Alcohol & Alcoholism Vol. 40, No. 2 © Medical Council on Alcohol 2005; all rights reserved
A DAILY GLASS OF RED WINE: DOES IT AFFECT MARKERS OF INFLAMMATION?
1 Department of Medical Genetics, 2 Department of Clinical Chemistry, 3 Center of Preventive Medicine and 4 Research Center, Ullevål University Hospital, 0407 Oslo, Norway
* Author to whom correspondence should be addressed at: Department of Medical Genetics, Ullevål University Hospital, 0407 Oslo, Norway. Tel.: +47 22119860; Fax: +47 22119899; E-mail: l.j.retterstol{at}ioks.uio.no
(Received 13 September 2004; first review notified 1 October 2004; in revised form 2 November 2004; accepted 25 November 2004)
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Aims: Epidemiological studies have shown that moderate consumption of alcohol is associated with a decreased risk of developing cardiovascular disease, but the causal mechanisms are only partly understood. As inflammation is an important process in the progression of atherosclerosis, we hypothesized that the protective effect of red wine is partly mediated through a reduction in inflammation. Methods: We conducted a randomized controlled crossover trial to study the effect of red wine on the levels of the inflammatory markers serum C-reactive protein (CRP) and plasma fibrinogen in healthy, non-smoking individuals. The subjects were randomized to drink one glass of red wine (150 ml, 15 g alcohol) every day (‘wine period’) or to undergo a period of total abstention from alcohol (‘abstention period’). After 3 weeks they switched intervention group. Eighty-seven volunteers completed the study (mean age 50 years). Results: Red wine did not reduce CRP levels and only marginally reduced fibrinogen levels compared with a similar period without alcohol. Conclusions: Consumption of 150 ml of red wine slightly reduced fibrinogen levels but did not reduce CRP levels.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Observational studies have suggested that a moderate intake of alcohol is associated with a lower risk of developing cardiovascular disease (Doll et al., 1994
; Di Castelnuovo et al., 2002; Corrao et al., 2004), but this apparent protective effect of alcohol is not fully understood. Since atherosclerosis is regarded as an inflammatory process (Ross, 1999), we hypothesized that alcohol consumption affects inflammation. High levels of fibrinogen and C-reactive protein (CRP), both markers of inflammation, are associated with a risk of developing cardiovascular disease (Meade et al., 1986; Humphries et al., 1987; Ridker et al., 1997, 1998). Observational studies have shown an association between alcohol consumption and the levels of inflammatory markers (Ernst and Resch, 1993; Imhof et al., 2001; Albert et al., 2003). If moderate consumption of alcohol reduces the degree of inflammation, this may partly explain the beneficial effect of alcohol on the cardiovascular system.
A recent meta-analysis pointed out that an alcohol intake of 20 g/day is associated with the lowest risk of developing coronary heart disease (Corrao et al., 2004). We wanted to investigate whether consumption of alcohol at this level reduced the levels of markers of inflammation. Since there are indications that wine (Grønbæk et al., 1995; Renaud et al., 1999), and perhaps red wine in particular (Goldberg et al., 2001), confers special cardioprotective effects, we chose red wine as the source of alcohol in this study. We performed a crossover study to observe the effects of moderate intake of alcohol on CRP and fibrinogen levels.
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SUBJECTS AND METHODS |
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The participants were recruited through an advertisement placed in a large newspaper in Oslo. According to the protocol, all the participants were 35–70 years old, healthy individuals who had not smoked tobacco daily for at least 3 months. On entering the trial, they completed a questionnaire relating to the exclusion criteria and alcohol consumption, under the guidance of a physician. The exclusion criteria included clinically recognized chronic diseases (such as diabetes, cardiovascular disease, cancer, inflammatory bowel disease, liver and renal disorders, chronic autoimmune disease and chronic infections) and treatment with statin or aspirin (and, for females, oral hormone replacement therapy or a desire to become pregnant). Only participants who reported that they did not drink alcohol every day on a regular basis were recruited. The subjects were randomized to start with a period of drinking one glass of red wine (150 ml of Cabernet Sauvignon, 15 g alcohol) every day (‘wine period’) or to undergo a period of total abstention from alcohol (‘abstention period’). After 3 weeks, the participants switched intervention group with no wash-out period.
No restrictions were placed on how and when the participants should drink their wine. The study was approved by the regional ethics committee and all the participants gave their written, informed consent.
Measurements of CRP levels were analysed in the same run after the study was completed, using a high-sensitivity method (range 0.1–20 mg/l, intra-assay coefficient of variation <2% at 0.5 mg/l; Roche Diagnostics, Mannheim, Germany). Fibrinogen was consecutively measured using Clauss' method on fresh samples (Clauss, 1957). The procedure was executed blindly. The levels of lipids and liver enzymes were measured from freshly drawn blood using routine methods.
Since the distribution of CRP and fibrinogen levels is highly skewed, non-parametric methods were applied to test for differences and correlations (Mann–Whitney U-test, Spearman's correlation coefficient and Kruskal–Wallis test). Multivariate linear regression analyses were performed to identify variables that were independently associated with CRP and fibrinogen levels, after ln-transformation of the variables with skewed distribution. We calculated that 90 individuals would be sufficient to obtain 80% test power to detect a difference of at least 10% of the levels of CRP and fibrinogen in this study.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Out of the 92 participants, 87 (95%) completed the study. The mean age was 50 years (SD 9.6), and 57 out of the 87 subjects were females (Table 1). Details regarding the drinking habits of the subjects before the study are given in Table 2. Table 3 shows the correlation factors between different variables and the CRP and fibrinogen levels, respectively. As indicated in Table 4, the wine-drinkers appeared to have the lowest CRP values before intervention, and the beer-drinkers appeared to have the lowest fibrinogen levels, compared with those who drank other types of alcohol or who were abstainers. The levels of CRP and fibrinogen correlated significantly to each other. A significant correlation was also observed between CRP levels and body mass index (BMI), non-fasting glucose, high density lipoprotein (HDL), triglycerides and gamma-glutamyl transferase (GGT) levels, whereas fibrinogen levels only correlated weakly to non-fasting glucose levels. Only BMI was independently associated with the ln CRP and ln fibrinogen levels in a linear multiple regression model (P = 0.04 in both cases).
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We observed no effect on CRP levels and only a 3% reduction in fibrinogen levels (Table 5) when the abstention period was compared with the wine period. Subanalyses excluding those who had a CRP value of >5 mg/l, or those who had differences of >3 mg/l during the study (trying to avoid changes not caused by alcohol intake, but rather by intercurrent infections or trauma) gave essentially the same results. We also performed subanalyses according to gender. In men, CRP levels were increased after the wine period compared with the abstention period [median value 1.17 (interquartile range 0.83–2.18) vs 0.91 (0.80–1.60), P = 0.08]. In women, the median CRP level was slightly lower after the wine period: 0.77 (0.35–1.83) compared with 0.91 (0.48–2.01) in the abstention period (P = 0.99). Fibrinogen levels were lower after the wine period than in the abstention period in both sexes, but this was statistically significant only for women [for men: 2.90 (2.80–3.20) vs 3.00 (2.70–3.50), P = 0.99; for women: 3.10 (2.70–3.30) vs 3.30 (2.88–3.62), P = 0.02]. Levels of serum total cholesterol were slightly reduced whereas no effect was observed on the levels of HDL cholesterol. A small reduction in GGT levels was also observed after the abstention period (Table 5).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The intake of red wine in the present study was modest (150 ml, 15 g alcohol), and this intake of red wine had no clinically relevant effect on the inflammatory markers. Our study does not support the hypothesis that moderate intake of wine reduces inflammation. These findings are apparently at variance with observational studies indicating that moderate intake of alcohol has a beneficial effect on cardiovascular diseases through an effect on inflammation (Imhof et al., 2001
; Albert et al., 2003), which found a J-shaped correlation curve between CRP levels and alcohol intake, indicating lower CRP values in subjects who drank at least one alcoholic drink per day. Neither of these studies reported any association between the levels of CRP and the type of alcoholic beverage. However, such cross-sectional studies cannot prove causality. A previous study of 19 subjects observed that consumption of beer (for men: four beers, equivalent to 40 g of alcohol, per day; for women: three beers, equivalent to 30 g of alcohol, per day) reduced CRP levels by >30% and fibrinogen levels by 
10% (Sierksma et al., 2002). No carry-over effect was observed in that study. In another study of 40 men, CRP levels were reduced by >20% after drinking red wine (30 g alcohol), and fibrinogen levels were reduced by 10% (Estruch et al., 2004). Interestingly, red wine had a greater effect on markers of inflammation than gin in the latter study. Both studies had duration and crossover designs similar to those of the present study. However, there were also several important differences that might explain the discrepancies between this study and the previous studies.
First, the amounts of alcohol were at least twice as high in the two previous studies. Observational studies suggest that intakes of 20–40 g (Imhof et al., 2001) or one unit (Albert et al., 2003) of alcohol every day were associated with the lowest levels of inflammatory markers. Furthermore, a meta-analysis has shown that an alcohol consumption of 20 g/day was associated with the lowest risk of developing coronary heart disease (Corrao et al., 2004). The amount of alcohol consumed in the present study was lower (15 g), but still close to these levels. Therefore, one might expect that a glass of red wine a day would reduce both CRP and fibrinogen levels, but this was not the case in this study. Perhaps there is a threshold effect of alcohol on the levels of inflammatory markers above the amount consumed in this study. If the red wine intake had been two or three glasses, we might have observed a greater effect on the levels of inflammatory markers. In addition, the effects may differ when alcohol is consumed along with food, as in the two previous studies (Sierksma et al., 2002; Estruch et al., 2004). The participants in the latter study generally reported a higher daily intake of alcohol than in the present study and also included current smokers. Furthermore, different habits of alimentation between different countries such as Spain and Norway may influence the effects of wine.
Second, the baseline levels of CRP and fibrinogen were higher in both these trials compared with our study. The effect of alcohol may be less significant for lower than for higher levels of CRP and fibrinogen.
Third, small studies could differ by chance. Although this was not a large study, the sample size in this trial was two (Estruch et al., 2004) or three times (Sierksma et al., 2002) larger than in the previous trials.
Finally, two-thirds of the participants in this trial were women, whereas the study by Estruch et al. (2004) included only men. However, we did not observe a significant reduction in CRP values after the wine period for men; on the contrary, the opposite trend was observed, although it was not statistically significant.
Fibrinogen levels were slightly reduced during the wine period in this study. One could speculate that red wine acts more on the fibrinolytic system and thereby decreases coagulation, which could reduce cardiovascular risk. However, we believe that a difference in the variance between the CRP and fibrinogen measurements is a more plausible explanation of why fibrinogen and not CRP levels showed a statistically significant result.
The observed reduction in total cholesterol levels, but not HDL, in the red wine period was surprising. One could speculate that red wine affects diet by lowering the intake of saturated fatty acids and thereby lowering total cholesterol. However, as indicated in Table 5, there was also a slight reduction in total cholesterol levels between inclusion and the abstention period, which may suggest that the subjects were on a slightly healthier diet while the study was being conducted, perhaps due to increased attention to their diet in general. We have no data to explore these speculations further.
The highly significant correlation between the two acute-phase reactants CRP and fibrinogen is not surprising, and is in line with our previous reports (Retterstol et al., 2002, 2003). Similarly, CRP levels have been shown to correlate with BMI and HDL levels in previous studies (Retterstol et al., 2003). The correlations to non-fasting triglycerides and glucose need to be confirmed in future studies, while a small effect on GGT was also observed in the study by Sierksma et al. (2002).
From samples obtained at inclusion, one might get the impression that wine-drinkers have lower CRP levels, while beer-drinkers have lower fibrinogen levels. These findings should be interpreted with caution, as these data were obtained from questionnaires and combinations of different alcoholic beverages were frequently reported. Randomized prospective studies comparing wine and beer (or other types of alcohol) should be used to address this question. In addition, data related to smoking and use of medication or other substances were also obtained from the same questionnaires. Theoretically, some participants may have given incorrect information. However, we tried to correct for any uncertainties when the physician interviewed the participants at inclusion.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Consumption of 150 ml of red wine a day had no significant effect on CRP levels in healthy individuals, and reduced fibrinogen concentrations only slightly at this power level. Comparisons of different types of alcohol at different intakes should be made in future studies. Finally, as several observational studies consistently seem to indicate that moderate alcohol intake may have a beneficial effect on the cardiovascular system, randomized prospective studies focusing on hard end-points are warranted to refute or confirm this effect. However, there could be several difficulties and ethical problems in carrying out such a study.
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ACKNOWLEDGEMENTS |
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Red wine for this study was provided by Arcus A.S. We thank the Sigurd K. Thoresen Foundation for financial support.
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REFERENCES |
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