Some epidemiological studies found a lower risk of cardiovascular disease among wine drinkers than among drinkers of other types of ethanol. This difference might be due to an effect of nonalcohol compounds in wine on important cardiovascular risk factors. The objective of this study was to compare the effect of red wine, nonalcohol compounds of red wine and placebo on established cardiovascular risk factors.
A parallel, four-armed intervention study.
A total of 69 healthy 38–74-y-old men and women.
Subjects were randomised to either 1: red wine (males: 300 ml/day, 38.3 g alcohol/day, female subjects: 200 ml/day, 25.5 g alcohol/day), 2: water+red grape extract tablets (wine-equivalent dose), 3: water+red grape extract tablets (half dose), or 4: water+placebo tablets for a period of 4 weeks. No other sources of alcohol or anthocyanin were allowed. Plasma high-density lipoprotein (HDL)-cholesterol (HDL-C), low-density lipoprotein (LDL)-cholesterol (LDL-C), HDL-C/LDL-C-ratio, very-low-density lipoprotein (VLDL)-triacylglycerol, total cholesterol, fibrinogen, factor VII coagulant activity (FVIIc), blood pressure, and body weight were determined before and after intervention.
Wine consumption was associated with a significant 11–16% increase in fasting HDL-C and 8–15% decrease in fasting fibrinogen relative to not drinking wine. There were no significant treatment effects on fasting LDL-C, HDL-C/LDL-C-ratio, VLDL-triacylglycerol, total cholesterol, FVIIc, or blood pressure. Drinking wine was associated with relative body weight increments closely corresponding to the energy contributed by the alcohol component.
Moderate red wine consumption for 4 weeks is associated with desirable changes in HDL-C and fibrinogen compared with drinking water with or without red grape extract. The impact of wine on the measured cardiovascular risk factors thus seems primarily explained by an alcohol effect. Our finding suggests that the putative difference in cardiac risk associated with wine vs other alcoholic beverages might be rather explained by other life-style confounders than by red wine contents of nonalcohol components.
This study was supported by Chr. Hansen A/S, Denmark.
Correlational studies have suggested that the relation between alcohol intake and cardiovascular disease (CVD) may be influenced by the type of alcohol drunk (Leger et al, 1979; Renaud & de Lorgeril, 1992; Criqui & Ringel, 1994). A number of recent prospective cohort studies have suggested that wine drinkers are at lower risk of death from all causes of CVD (Klatsky & Armstrong, 1993; Grønbæk et al, 1995; Wannamethee & Shaper, 1999; Theobald et al, 2000) and maybe even death from both CVD and cancer (Grønbæk et al, 2000) than users of other alcoholic beverages. However, the apparent benefit of wine drinking may be confounded by wine drinkers having better traits and lifestyle habits, including diet, than beer and spirits drinkers. (Rimm et al, 1996; Tjønneland et al, 1999).
Besides alcohol, red wine contains several types of antioxidant polyphenols, including anthocyanins, which might affect the risk of CVD (Frankel et al, 1993; de Rijke et al, 1996; Carbonneau et al, 1997; Day et al, 1997; Miyagi et al, 1997; Caccetta et al, 2000; Young et al, 2000). Previous intervention trials on the effect of red wine or red wine polyphenols on established cardiovascular risk factors are few and the studies were mostly small and low-powered (Goldberg et al, 1996; Hayek et al, 1997; Leighton et al, 1999; Stein et al, 1999; Van der Gaag et al, 2000; Mezzano et al, 2001). In the present trial, we aimed at comparing the effect of red wine, red fermented grape extract (ie red wine minus alcohol), and placebo on selected cardiovascular risk factors.
Subjects and methods
Subjects were recruited through posting in supermarkets and workplaces, through advertisement in local newspapers, and through written applications to randomly selected persons from Frederiksberg, Denmark. The eligible individuals were healthy and aged 38–75 y. Exclusion criteria were: regular use of lipid lowering drugs, antihypertensives, and antioxidant supplements, uncommon dietary habits (eg vegetarianism), and alcoholism. Major weight changes (>3 kg) during intervention, elevated plasma concentrations (>10 mg/l) of C-reactive protein (an indicator of inflammation) in study samples (Wilkins et al, 1998), and noncompliance with the study protocol were also predefined as exclusion criteria. A total of 74 subjects were included in the study. One female subject dropped out due to digestion problems unrelated to the study. Furthermore, four subjects were excluded (one male did not show up for blood sampling, one male was noncompliant with respect to alcohol rules, one female subject had elevated C-reactive protein in plasma at baseline, and one female took vitamin C for 3 days during intervention). Data from the remaining 69 completers were used for the present paper. Their baseline characteristics are shown in Table 1. The study was approved by the Municipal Ethical Committee of Copenhagen and Frederiksberg. All participants gave their written consent for participation after having received oral and written information about the experimental procedure. After the study, all completers received a gift (four bottles of wine in a trolley) sponsored by Chr. Hansen A/S.
The study was designed as a parallel four-armed placebo-controlled intervention study. The subjects were randomly divided into four groups of similar size after stratification for gender. Participants consumed daily during 4 weeks either red wine (males: 300 ml, female subjects: 200 ml), water and red grape extract (wine-equivalent dose of total polyphenol, total anthocyanin, delphinidin-3-glucoside, and malvidin-3-glucoside or half dose), or water and placebo tablets as shown in Table 2. The red wine used was a Domaine de Malepère, 1999 based on Merlot and Cabernet-Sauvignon and with an alcohol content of 12.75%. The daily alcohol intake in the red wine group thus was 38.3 g for male and 25.5 g for female subjects. This dosage corresponds to the upper limit of recommended intakes in DK and UK and is associated with the lowest CVD risk in epidemiological studies (Royal College of Physicians, 1987; Grønbæk et al, 1997). The red grape extract was made the same year by the same producer and based on several different types of red grapes. After maceration and alcoholic fermentation, the grapes were drained and pressed and the polyphenols purified. The total polyphenol, anthocyanin, delphinidin-3-glucoside, and malvidin-3-glucoside content of the full-dose red grape extract was matched with the red wine. On basis of the information from the producer, four and six tablets of red grape extract were estimated to match 200 and 300 ml of red wine, respectively. The content of specific anthocyanins was analysed (Table 2). The placebo and red grape extract tablets were equal with the exception of the content of polyphenols, which in the placebo tablets were replaced by 346.1 mg of microcrystalline cellulose. The intervention was double-blinded with regard to consumption of extract and placebo tablets. The subjects collected wine, extract, or placebo tablets three times during the intervention. All subjects were given a measuring cup to measure out red wine or water. The subjects were instructed to open either a plastic bag with the exact amount of tablets or a new bottle of wine containing 375 ml every day. Wine, tablets, and water had to be consumed along with the evening meal. A week before and during the 4-week intervention no other sources of alcohol or anthocyanin were allowed. The subjects were given a list over 32 different foods (Table 2) containing anthocyanins that they had to avoid during the intervention, but otherwise participants were asked not to change their dietary and physical exercise habits. Samples were taken immediately before (Table 1) and after the intervention period.
Anthocyanin content of wine and tablets
The standard curves for anthocyanin analyses were prepared in five concentration levels in 10% aqueous formic acid containing 10% acetonitrile (pH=1.7) (Fisher Scientific International Company, Loughborough, UK). Three repetitions of each concentration level were prepared from separate weighings of the standards. The standard curve for malvidin-3-glucoside was prepared in the range 0–0.1 mg/ml and the standard curve for delphinidin-3-glucoside was prepared in the range 0–0.01 mg/ml. The standard curves were linear within these ranges. Delphinidin-3-glucoside, malvidin-3-glucoside, and cyanidin-3,5-diglucoside of HPLC purity were obtained from Polyphenols (Sandnes, Norway). Aliquots of 250 μl of each standard were analysed in doublet by LC-MS.
The anthocyanin content of one day's intake of tablets (women: four tablets, men: six tablets; see Table 3) was analysed in duplicate. To each tablet was added 40 μg cyanidin-3,5-diglucoside in 40 μl 10% aqueous formic acid (Merck, Darmstadt, Germany), 10% acetonitril as an internal standard and then left to dry. The tablets were crushed and extracted with 55 ml 13% ethanol (99.9%, ph. eur. from De Danske Spritfabrikker, Aalborg, Denmark), 9% formic acid in water for 1 h at room temperature. Aliquots of 125 μl of the extracts were added with 125 μl formic acid and injected on the LC-MS system. As a 100% control of the internal standard, to 40 μg cyanidin-3,5-diglucoside dissolved in 40 μl, 10% aqueous formic acid and 10% acetonitril were added 55 ml of the extraction mixture. This mixture (125 μl) was diluted 1:1 with formic acid and analysed in triplicate. The wine was diluted 1:1 in formic acid and two aliquots of 250 μl were injected directly onto the LC-MS system. Purified Milli-Q water with resistivity >18 Ω/cm (Millipore, Bedford, MA, USA) was used throughout.
HPLC/MS-analysis was carried out on a HP 1100 HPLC-APCI-MS system from Agilent Technologies (Waldbronn, Germany) with diode array detector. The system was equipped with a 250 μl injection loop and a Zorbax SB-C18 column (4.6 × 150 mm, 5 μm) with a guard cartridge (C-18, 4 × 4 mm, 5 μm), both from Agilent Technologies. The column was maintained at 40°C using a thermostatically controlled compartment. The UV/Vis spectra, which were used for quantification, were recorded on-line during analysis. Signals were obtained at 520, 350 and 290 nm simultaneously. A peak scan was carried out between 230 and 700 nm with 2 nm steps. Identification and quantification were performed by APCI-MS in positive mode. Identification of anthocyanins was performed in scan mode and quantification in selected ion monitoring for the identified compounds with masses 465 m/z (delphinidin-3-glucoside) and 493 m/z (malvidin-3-glucoside). The following optimal conditions were used: fragmentor voltage, 70 V; APCI capillary voltage, 1000 V; corona current, 4.0 μA; vaporiser temperature, 500°C; nebulizer pressure, 60 psig, and drying gas temperature, 300°C. The flow rate was 1 ml/min using the mobile phases: A: 0.5% HCOOH in H2O and B: ACN. The elution profile was a linear gradient from 1% B in A (v/v) to 100% B in A (v/v) followed by a column wash with 100% B in A (v/v).
Venous blood samples were drawn in the morning after minimum 12 h fasting and supine resting for 10 min. Subjects abstained from tobacco smoking during fasting. Subjects were instructed to avoid heavy physical activity 36 h prior to blood sampling. Blood was collected in EDTA tubes and stored on ice until isolation of plasma by centrifugation (3000 × g for 15 min at 4°C). Plasma used for analyses of total cholesterol and high-density lipoprotein (HDL)-cholesterol (HDL-C) was stored at −20°C. Very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) fractions were isolated from fresh plasma by single density gradient ultracentrifugation in a Beckman L7 ultracentrifuge using a 50.4 Ti rotor and 4 ml open top tubes as described in Baumstark et al (1991) and stored at −80°C. Cholesterol, triacylglycerol, and HDL-C were determined on a Cobas Mira Plus (Roche, Basel, Switzerland) using commercially available kits (Boehringer Mannheim, Germany). Analytical variations (CV) were less than 1.5%.
Blood for factor VII coagulant activity (FVIIc) and fibrinogen analyses was collected in tubes containing citrate. Within 1.5 h, plasma was isolated by centrifugation (3000 × g for 15 min at 20°C) and stored at −80°C until analysis. FVIIc was determined with a one-stage clotting assay using human FVII deficient plasma (Biopool, Dandiag, Denmark) and human placenta tissue factor (Thromborel S, Beringwerke AG, Germany). For determination of fibrinogen, an IL Test Fibrinogen-C (IL Test TM, ILS Laboratories Scandinavia, Denmark) and Hemostasis Reference Control (Biopool, Dandiag, Denmark) were used. FVIIc and fibrinogen were analysed on an ACL 300 (Automated Coagulation Laboratory, Instrumentation Laboratory, Italy). CV% were 3.2 and 1.7 for FVIIc and fibrinogen, respectively.
Blood for C-reactive protein analysis was collected in dry tubes and serum isolated by centrifugation (3000 × g for 15 min at 20°C) and stored at −20°C until analysis. For determination of C-reactive protein, the immunoturbidimetry principle was used with antibodies (DAKO®, Denmark) containing rabbit antihuman C-reactive protein. C-reactive protein was analysed on a Cobas Mira Plus (Roche, Basel, Switzerland, with a CV % of 2.2 and a lower detection limit of 5 mg/l).
Antropometric and physiological measurements
Before and after intervention blood pressure and body weight were measured in the morning after 12 h of fasting. The subjects rested in supine position for 10 min before blood pressure were measured. Blood pressure was measured using an automatically inflating cuff (Omron, model HEM-705CP, R&D, Japan). For body weight the same digital scale was used each time (Lindeltronic 8000 C, Frederiksberg, Denmark). Body mass index was calculated as body weight (kg) divided by height2 (m2).
Habitual alcohol intake
At prestudy screening, subjects were interviewed about amount, frequency, and type of alcohol consumed during the last month. On basis of this information, units of habitual alcohol consumtion were estimated (Table 1).
All results are given as means +/−standard error of mean (s.e.m). Data were analysed and presented as changes from initial fasting levels. Differences between the groups were tested by parametric analysis of variance (ANOVA). In case of significant group difference (ANOVA), individual group differences were tested with unpaired t-tests with Bonferroni correction. The χ2 test was used for comparing groups regarding to sex, menopausal status, and smoking. We used SPSS 10.0 for Windows 1999 (SPSS inc., Illinois, USA) for all tests. To examine whether alcohol consumption caused body weight changes, the wine group was compared to the three tablet groups combined. The significance level was set at 0.05.
A total of 69 subjects completed the study. There were no significant differences between groups at baseline (Table 1).
HDL-C changes varied highly significantly between groups. Red wine caused a 6% increase, while 5–10% decreases were seen in the other three groups. Taken together, these figures indicate a red wine-attributable 11–16% increase in HDL-C. There were no significant difference in HDL-C changes between the extract and placebo groups. No other significant lipid effects were observed (Table 4).
Fibrinogen changes varied significantly between groups. Red wine was associated with a 5% decrease, while full-dose extract caused a 10% increase (group comparison, P<0.05). The data in Table 3 indicate a red wine-attributable 8–15% fall in plasma fibrinogen. FVIIc was not significantly affected in any group (Table 4).
Antropometric and physiologic variables
Body weight changes did not differ between groups according to ANOVA. However, the red wine group experienced less weight loss than the other three groups combined at borderline significance (−0.11 vs −0.56 kg, P=0.054). Blood pressure was not influenced differently between groups (Table 4).
The present parallel four-armed intervention study shows that drinking red wine in moderation increases HDL-C by 11–16% and decreases fibrinogen by 8–15% compared with drinking water with or without red fermented grape extract. Our finding strongly suggests that it is the alcohol component of red wine that is causing these putative beneficial effects. According to epidemiological studies, HDL-C and fibrinogen changes of this magnitude (around 10%) may lower CVD risk by 10–25%, respectively (Rimm et al, 1999). It should be noted that baseline HDL-C and fibrinogen levels differed between groups (insignificantly) with the red wine group having the lowest HDL-C and highest fibrinogen values. Our findings therefore should be interpreted with some caution. Regression towards the mean may have contributed to them. However, Rimm et al (1999) estimated comparable effects of alcohol on HDL-C in their recent meta-analysis of 25 intervention trials. They concluded that 30 g of alcohol daily raises HDL-C by 8.3%. In our study, female subjects consumed 25.5 g and male subjects 38.3 g of alcohol daily. We observed no differences between intake of red wine, red grape extract, and placebo regarding the effect on VLDL-triacylglycerol. In Rimm's meta-analysis, 30 g of alcohol daily was associated with a plasma triglyceride increase of 5.69 mg/dl (0.065 mmol/l) (Rimm et al, 1999). Our study did not have sufficient power to detect VLDL-triglyceride changes of that magnitude and therefore we cannot exclude a minor triglyceride-raising effect of alcohol at the tested dosage.
According to Rimm et al (1999) a moderate consumption of alcohol does not affect plasma FVIIc, but may lower fibrinogen. In a cross-sectional study of 4967 men and women, Mennen et al found a U-shaped association between fibrinogen concentrations and both alcohol and wine consumption. The fibrinogen concentration was lowest in those drinking 40–59 g of alcohol per day (Mennen et al, 1999). Estruch et al (2004) found reduced fibrinogen leves after consumption of both wine and gin. Neither Burr et al (1986) nor Pikaar et al (1987) found changes in fibrinogen levels after consumption of alcohol. Pellegrini et al performed a randomised crossover study with 11 male subjects participating. Red wine consumption lowered fibrinogen and it was suggested that the effect was due to alcohol and not to the nonalcoholic fraction present in red wine. (Pellegrini et al, 1996) Our findings support that alcohol consumption is associated with a clinically relevant reduction in fibrinogen whereas FVIIc levels are unaffected.
The red wine group had a mean weight loss of 0.11 kg which differed at borderline significance from the average 0.56 kg weight loss seen in the other three groups combined. The difference in weight loss between the red wine and the ‘tablet’ groups corresponds closely to the energy contributed by alcohol during intervention. Alcohol consumption thus seems to lead to a net increase in energy intake and therefore may contribute to hypercaloric diets and obesity in the general population. Studies have shown that body weight loss causes increased HDL-C (Williams, 2004) and decreased fibrinogen (Hankey et al, 2002). In our study, the increase in HDL-C and decrease in fibrinogen in the red wine group were significant different from the other three groups combined in defiance of the weight loss in the three groups.
Alcohol intake is assumed to be associated with an increase in blood pressure (Langer et al, 1992), but in the present study we found no effect of red wine on systolic or diastolic blood pressure. Furthermore, we found no differences between red wine or red grape extract on blood pressure: however, it should be observed that our study had no statistical power to detect limited blood pressure effects. On the other hand, our findings are in agreement with those of Klatsky et al (1977) who found no association between an alcohol intake of 1–2 units a day and increased blood pressure in an epidemiologic study.
Our study had several limitations. Of major relevance is the question whether our grape extract was a valid representative of the nonalcoholic compounds present in red wine. We cannot exclude that the polyphenol profile and bioavailability of the tablets differed from that of wine. Certainly, some differences are very likely to exist. However, the analyses of contents of two major anthocyanins indicated that there was good resemblance between wine and tablets. Furthermore, earlier trials showed that alcohol has no influence on anthocyanin and flavonoid bioavailability, suggesting that the polyphenol bioavailability of wine and tablets was similar (Bell et al, 2000; Frank et al, 2003). We asked all participants to avoid certain foods rich in polyphenols during the study, but made no estimations of their actual dietary intakes before and during intervention. However, it also appears almost impossible to make valid assessments of polyphenol intakes from dietary records knowing the large variation in contents not only between varieties of fruits and vegetables but also within specific varieties depending on ripeness. CVD is also determined by other risk factors not assessed in our study. A risk factor such as endothelial dysfunction may be improved by consumption of red wine and polyphenols.
In conclusion, the daily intake of 2–300 ml red wine increased the HDL-C and lowered the fibrinogen relative to drinking water with or without red fermented grape extract. The effect of red wine on HDL-C and fibrinogen thus seems to be caused by the alcohol component. We did not observe any triacylglycerol-raising effect of alcohol at the tested moderate dosing. However, body weight tended to differ between groups as predicted from the energy content of red wine indicating that alcohol consumption is associated with a net increase in total energy intake. We conclude that moderate alcohol consumption in the form of red wine and other beverages is associated with beneficial changes in blood lipids and fibrinogen that may help to reduce the CV risk factors, but that the body weight may increase. The polyphenols of red wine seem to have virtually no effect on the investigated traditional risk factors for CVD.
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Guarantors: P Marckmann and M Grønbæk.
Contributors: ASH, PM and MG initiated the formulation of the primary study hypothesis, discussed the core ideas, designed the protocol and wrote the paper. ASH collected and analysed all data. LOD, I-LFN and SEN discussed the core ideas, performed the biochemical analysis and edited the paper.
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Cite this article
Hansen, A., Marckmann, P., Dragsted, L. et al. Effect of red wine and red grape extract on blood lipids, haemostatic factors, and other risk factors for cardiovascular disease. Eur J Clin Nutr 59, 449–455 (2005). https://doi.org/10.1038/sj.ejcn.1602107
- intervention trial
- red wine
- high-density lipoprotein
- cardiovascular disease
- factor VII coagulant activity
- body weight
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