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© 2007 American Society for Nutrition J. Nutr. 137:2279-2284, October 2007

Nutrition and Disease

Inflammatory Markers of Atherosclerosis Are Decreased after Moderate Consumption of Cava (Sparkling Wine) in Men with Low Cardiovascular Risk1,2

Mónica Vázquez-Agell3,4, Emilio Sacanella3–5,*, Ester Tobias3, María Monagas3,4, Emilia Antúnez3–5,, Raúl Zamora-Ros6, Cristina Andrés-Lacueva6, Rosa Ma Lamuela-Raventós6, Joaquim Fernández-Solá3–5,, José Ma Nicolás3–5, and Ramon Estruch3–5,

3 Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona 08036, Spain; 4 CIBER 06/03: Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid 28029, Spain; 5 Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona 08036, Spain; and 6 Department of Nutrition and Food Science-XaRTA, Pharmacy School, University of Barcelona, Barcelona 08007, Spain

* To whom correspondence should be addressed. E-mail: esacane{at}clinic.ub.es.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Participants and Methods
 Results
 Discussion
 LITERATURE CITED
 
Atherosclerosis is considered a low-grade inflammatory disease. Polyphenol-rich alcoholic beverages (red wine) have shown a more pronounced antiinflammatory effect than polyphenol-free alcoholic beverages (gin). However, no studies to our knowledge have evaluated the antiinflammatory effects of alcoholic beverages with medium-level polyphenol content such as cava (sparkling wine). We enrolled 20 healthy men (aged 34 ± 9 y) in a randomized crossover study to receive 30 g ethanol/d as cava or gin for 28 d. Before both interventions, subjects abstained from alcohol for 2 wk. Inflammatory biomarkers of atherosclerosis and expression of adhesion molecules on peripheral leukocytes were measured before and after each intervention. Likewise, dietary intake and exercise were also evaluated. Expression of lymphocyte function-associated antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), Sialyl-Lewisx (SLex), and CD40 on monocytes decreased after cava intake (all P < 0.05), whereas only SLex was reduced after gin intake (P = 0.036). Circulating markers of atherosclerosis including vascular cell adhesion molecule-1, E-selectin, and P-selectin decreased after both interventions (all P < 0.05). High-sensitivity C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), IL-6, monocyte chemoattractant protein-1 (MCP-1), and CD40L were diminished only after cava intake (all P < 0.05). The effects of cava on circulating CD40L, ICAM-1, and MCP-1, and monocyte surface expression of CD40, LFA-1, and VLA-4 were greater than those of gin (all P < 0.05). In conclusion, both cava and gin showed antiinflammatory properties; however, cava had a greater protective effect, probably due its polyphenol content.


   Introduction
TOP
 ABSTRACT
 Introduction
Participants and Methods
 Results
 Discussion
 LITERATURE CITED
 
Many epidemiological studies involving subjects of different gender, race, and age have shown that moderate alcohol consumption is associated with a reduced risk of cardiovascular disease (1–4). Because part of the atheroprotective effects associated with moderate alcohol intake has been attributed to changes in serum lipoproteins, coagulation, and platelet aggregation, other alternative mechanisms have been proposed (5–7).

Up to the 1980s, atherosclerosis was considered to be the result of lipid accumulation in the arterial wall. Nonetheless, better knowledge of the atheroma plaque formation has led to the conclusion that atherosclerosis is, indeed, a chronic low-grade inflammatory disease of the arterial wall (8). Large epidemiologic studies have reported a significant association between moderate alcohol consumption and lower levels of inflammatory biomarkers related to atherosclerosis (9–14), suggesting that antiinflammatory effects of alcoholic beverages may play a role in their protective effect against cardiovascular disease (15). Because this effect was independent of the type of alcoholic beverage (liquor, beer, and wine), some researches attributed this action to ethanol itself (16). However, other epidemiologic studies have found significant differences in the effects of wine and other alcoholic beverages on global mortality, cardiovascular mortality, and incidence of cancer, in favor of wine (17,18). The heterogeneity in the results obtained in these epidemiologic studies may be due to the fact that it is very difficult to adequately monitor diet and physical activity in such studies. Because almost all alcoholic beverages (some spirits, beer, and wine) contain ethanol and nonalcoholic compounds (mainly polyphenols), it seems difficult to differentiate the effects of both compounds in epidemiologic studies.

Other types of evidence may be obtained regarding the biologic plausibility of this hypothesis. Clinical trials measuring the effects of moderate alcoholic beverage intake in surrogate markers of atherosclerosis in humans may be used to explain the mechanisms by which alcoholic beverages could exert their positive effects. In this sense, previous studies have concluded that polyphenol-rich alcoholic beverages, such as red wine, exert a higher antiinflammatory effect than ethanol itself (19). However, up to now, no clinical trials to our knowledge have analyzed the effects of medium-level polyphenol-content beverages, such as cava (sparking wine) compared with those observed after the administration of a polyphenol-free alcoholic beverage, such as gin. We embarked, therefore, upon a prospective, randomized crossover clinical trial to evaluate the effects of moderate intake of cava vs. gin on adhesion molecules, chemokines, and other inflammatory biomarkers related to the early stages of atherosclerosis.


   Participants and Methods
TOP
 ABSTRACT
 Introduction
 Participants and Methods
Results
 Discussion
 LITERATURE CITED
 
    Participants and study design. We selected 30 healthy men, between 25 and 50 y, who were working in the Department of Internal Medicine of our institution and reported a daily ethanol intake ranging from 10 to 30 g over the last 5 y. Five declined participation, 3 did not meet lipid criteria, and 2 suffered from hypertension. Thus, we finally included 20 volunteers who gave informed consent to a protocol approved by the Institutional Review Board of the Hospital Clinic. None reported any of the following exclusion criteria: diabetes mellitus, tobacco smoking, hypertension, LDL cholesterol levels > 4.14 mmol/L, HDL cholesterol levels < 1.04 mmol/L, coronary heart disease (CHD),7 family history of premature CHD, cerebrovascular disease, peripheral vascular disease, HIV infection, alcoholic liver disease, malnutrition, or neoplastic or acute infection disease. In addition, no subjects were receiving any medication or taking any vitamin supplements. Participants received free cava and gin but no monetary compensation.

The study was an open, prospective, randomized, crossover, and single-blinded clinical trial in which subjects received 30 g ethanol/d as cava (0.3 L/d) or gin (0.1 L/d) for 28 d in a random order. Before both interventions, the subjects abstained from alcohol for 2 wk (washout periods 1 and 2). We followed the dietary intake and physical activity of the participants throughout the study. Before and after each intervention period, we withdrew blood samples after overnight fasting and coded them with random numbers to perform biochemical tests and immunological studies. Finally, at the end of each intervention, a clinician assessed any adverse effects from the interventions by administering a checklist of symptoms, including bloating, fullness or indigestion, altered bowel habit, dizziness, and other symptoms possibly associated with alcoholic beverage intake.

    Alcoholic beverages. We used a monovarietal cava made from white grapes of Vitis vinifera cv. Chardonnay (12% alcoholic strength) and gin (40% alcoholic strength) in this study. We selected these beverages on the basis of their polyphenolic content (medium level for the cava and negligible for the gin). Total phenolic compounds were determined by the Folin-Ciocalteu reagent (20). In addition, individualized phenolic compounds were determined by HPLC as previously described (21) (Table 1).


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  		TABLE 1 Total phenolic and individual phenolic compound concentrations of Chardonnay cava

 
    Diet and exercise monitoring. The participants in the study followed an isocaloric Mediterranean-type diet, which was designed according to their personal preferences. Participants were not allowed to consume onions, virgin olive oil, and green and black tea, which are rich in polyphenols and antioxidants. Other foods with high polyphenol content, ascorbic acid, {alpha}-tocopherol, and/or ß-carotene, such as cocoa, chocolate, orange and tomato juices, nuts, some fruits (oranges, lemons, strawberries, grapes, melon, apples, and apricots), some vegetables (spinach, turnips, carrots, parsley, peppers, garlic, and tomatoes), and soybean products were restricted, providing a similar antioxidant content for all the participants throughout the study. Before and after each intervention, we used a 3-d food recall questionnaire, validated in our population (22), to assess the dietary intake and converted this information into nutritional data using the Professional Diet Balancer software (Cardinal Health Systems). We monitored physical activity with the Minnesota Leisure Time Physical Activity Questionnaire (23).

    Laboratory analysis. At the end of each 4-wk period (run-in, intervention 1, wash-out, and intervention 2), we obtained blood samples from fasting and a spot urine specimen. Immunophenotyping of peripheral blood mononuclear cells (PBMC) were performed. Serum and EDTA-plasma samples were stored at –80°C for analysis of inflammatory molecules at the end of the study. Analyses determined in frozen samples of plasma as was homocysteine by fluorescence polarization immunoassay (Siemens Medical Solutions Diagnostics) or whole serum as appropriate were: high-sensitivity C-reactive protein (hsCRP) by particle-enhanced immunonephelometry; soluble adhesion molecules [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin), monocyte chemoattractant protein-1 (MCP-1), and CD40L by standard ELISA (Bender MedSystems). We used high sensitivity immunoassays for IL-6 and TNF{alpha} to detect low serum concentrations of these molecules (80 pg/L and 310 pg/L, respectively). Intra- and inter-assay variation coefficients for hsCRP, ICAM-1, VCAM-1, E-selectin, P-selectin, CD40L, MCP-1, TNF{alpha}, and IL-6 ranged from 1.8 to 5.4% and from 0.9 to 9.9%, respectively.

We performed all analyses in duplicate. As a measure of intervention compliance, we measured urinary resveratrol metabolites by HPLC-MS/MS before and after each intervention, as previously reported (24).

    PBMC immunophenotyping. PBMC were isolated from whole blood by density gradient centrifugation over Ficoll-Hypaque (Pharmacia) (25). We analyzed the expression of adhesion molecules on PBMC surface via double direct immunofluorescence using commercial monoclonal antibodies. Cell counting and fluorescence analysis were performed in a FACScan Clinical Cytometer (Becton-Dickinson) using the CellQuest software. The adhesion molecules studied were: very late activation antigen-4 (VLA-4) (Cytogmos), lymphocyte function-associated antigen-1 (LFA-1) (Bender MedSystems), Mac-1 (Bender MedSystems), and Sialyl-Lewisx (SLex) (Beckman Coulter). CD40 (Caltag Laboratories), another related molecule, was also measured. We identified monocytes and T-lymphocytes separately using anti-CD14 and anti-CD2 (Caltag Laboratories) monoclonal antibodies, respectively.

    Statistical analysis. We performed statistical analysis using the SPSS Statistical Analysis system 11.0. Values in the text are expressed as means ± SD, unless otherwise indicated. Values with a skewed distribution (hsCRP, VCAM-1, ICAM-1, and IL-6) were transformed to their natural logarithm for analyses. We compared changes in outcome variables in response to each intervention treatment with the 2-tailed paired t test. To exclude the presence of a carryover effect for the 2 interventions, we compared the outcome variables observed before the cava and gin treatments and did not observe differences in any of the variables analyzed (see above). Within- and between-group differences are expressed as mean percent difference (95% CI). Differences were considered significant at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Participants and Methods
 Results
Discussion
 LITERATURE CITED
 
    Baseline characteristics, intervention compliance, diet, exercise monitoring, and side effects. Of 30 eligible subjects, we excluded 10 from the study for the reasons explained above. Thus, we included the remaining 20 healthy men (34 ± 9 y, range 25–50 y) in the study and randomly assigned them to 1 of the 2 interventions (cava or gin). All subjects completed both phases of the study. Prior to participating in the study, they reported a daily ethanol intake of 16.8 ± 12.6 g during a period of 17 ± 10 y. We evaluated the compliance of intervention by analyzing participants' reports and recounts of empty bottles returned. In addition, as an objective measure of intervention compliance, we determined resveratrol metabolites in urine. The urine concentration of total resveratrol metabolites increased by 72.4 nmol/g (95% CI = 48.5–96.2 nmol/g; P = 0.005) after the cava intervention compared with the corresponding wash-out period, whereas we did not find any significant changes after the gin intervention. Based on these data, all participants were compliant. Self-reported diets were close to the planned diets and none of the subjects consumed a significant quantity of polyphenol-rich foods during the study, so the nutritional intake including total energy, carbohydrates, fat, protein, and vitamins was similar before and after each intervention period in all the subjects. Only 1 participant reported a 1-d violation (onion) 17 d before assessment. In addition, we did not find any significant differences in physical activity throughout the study (Table 2). None of the participants reported any side effects during the both phases of the study.


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  		TABLE 2 Dietary intake, body weight, and exercise energy output in men before and after cava and gin interventions1

 
    Expression of cell adhesion molecules on leukocyte cell surface. Expression of cell adhesion molecules on leukocyte cell surface before and after each intervention is reported in Table 3. Adhesion molecule expression did not differ before cava and gin intervention. Changes in T-lymphocyte surface molecules were minimal. We detected a reduction in LFA-1 expression after cava intake by 16% (P = 0.001) and an upregulation of LFA-1 expression after gin intake by 19% (P = 0.034); however, the rest of molecules did not differ on T-lymphocytes. Changes were more prominent on monocyte surface. After cava intake, there were reductions of 11–21% in LFA-1 (P = 0.048), VLA-4 (P = 0.015), SLex (P = 0.01), and CD40 (P = 0.033) expression. On the other hand, after the gin intake period, only SLex declined (P = 0.036). The following molecules were significantly downregulated more by cava than by gin: LFA-1 in T-lymphocytes (P = 0.001) and monocytes (P = 0.021), VLA-4 in monocytes (P = 0.008), and CD40 in monocytes (P = 0.029).


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  		TABLE 3 Expression of inflammatory molecules on leukocyte cell surfaces of men before and after cava and gin interventions1

 
    Changes in homocysteine and circulating inflammatory markers. Plasma homocysteine concentrations were similar before and after cava (10.9 ± 2.7 µmol/L to 11.5 ± 3.6 µmol/L) or gin (10.5 ± 2.6 µmol/L to 11.2 ± 2.9 µmol/L) intervention periods. Serum adhesion molecule concentrations did not differ before both the interventions. Some circulating adhesion molecules and other inflammatory biomarkers changed after each intervention (Fig. 1). After the cava period, concentrations of CD40L (P = 0.015), VCAM-1 (P = 0.001), hsCRP (P = 0.049), IL-6 (P = 0.008), P-selectin (P = 0.01), E-selectin (P = 0.02), ICAM-1 (P = 0.013), and MCP-1 (P = 0.01) diminished from 11 to 27%. After gin consumption, we observed reductions of 13–18% in serum E-selectin (P = 0.012), P-selectin (P = 0.028), and VCAM-1 (P = 0.034) concentrations and 21% higher MCP-1 levels (P = 0.026). The effect of cava was greater than that of gin for CD40L (P = 0.030), ICAM-1 (P = 0.015), and MCP-1 (P = 0.001).


Figure 1
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  		FIGURE 1  Percent changes from baseline in circulating adhesion molecules and other inflammatory biomarkers in healthy men after cava and gin consumption. Values are means and 95% CI, n = 20. Asterisks indicate different from baseline: *P < 0.05; **P < 0.01. #Different from gin, P < 0.05.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Participants and Methods
 Results
 Discussion
LITERATURE CITED
 
In this 3-mo feeding intervention trial, consumption of 30 g ethanol/d as cava was associated with a downregulation of the expression of LFA-1, VLA-4, SLex, and CD40 in monocytes and of LFA-1 in T-lymphocytes. In addition, serum concentrations of hsCRP, VCAM-1, ICAM-1, E-selectin, P-selectin, IL-6, MCP-1, and CD40L also decreased after cava intake. Gin intake also exerted an antiinflammatory effect, because serum concentrations of VCAM-1, E-selectin, and P-selectin decreased and, also, SLex was downregulated in monocyte surface. However, the effects of cava on inflammatory biomarkers of atherosclerosis were significantly greater than those of gin.

The epidemiological association between moderate alcohol consumption and lower prevalence of atherosclerosis may have several pitfalls, because even in prospective cohort studies it is difficult to assess the type and amount of ethanol intake exactly and to control the effects of the diet consumed and physical activity performed on the variables studied (26). In fact, some investigators have suggested that the lower risk of CHD in moderate drinkers may be also related to their characteristic lifestyle or the consumption of a healthier diet (27). It should be taken into account that fruits and vegetables contain large amounts of polyphenolic compounds, such as flavonoids, and some studies have suggested that flavonoid intake may explain the low mortality rates from CHD reported in Western countries (28,29). On the other hand, physical activity increases HDL cholesterol serum concentrations (30) and may reduce cardiovascular mortality by itself. Thus, the issue of nutrition and exercise may be solved in only well-designed clinical trials in which the intervention could be monitored by biochemical analysis. To avoid this problem, in this trial, we monitored nutritional intake and exercise performed throughout the study by means of validated scales, but we did not detect any differences in these variables between the periods of the study. We also assessed protocol compliance by personnel interviews, counting empty bottles, and measuring concentrations of resveratrol metabolites in urine after each intervention (24). After analyzing all these data, we concluded that protocol compliance was nearly 100% in all the subjects. Therefore, the changes observed in inflammatory variables analyzed in the study should be attributed to the consumption of cava or gin.

The mechanisms by which moderate alcohol consumption may prevent atherosclerosis are not completely known. Beyond changes in lipid profile, coagulation, and fibrinolitic system observed in alcohol drinkers, the involvement of other alternative mechanisms may completely explain the protective effect of alcoholic beverages (7,13,31). Thus, the possible antiinflammatory effects of alcoholic beverages in the arterial wall have become a matter of research (15).

Epidemiological studies suggest that moderate alcohol intake is associated with reduced levels of circulating inflammatory predictive markers of atherosclerosis (9,14,32). In this sense, a reduction in C-reactive protein, {alpha}1-globulins, {alpha}2-globulins, IL-6, sTNF-R1, sTNF-R2, and fibrinogen have been observed in moderate drinkers compared with nondrinking subjects. Likewise, moderate amounts of red wine inhibit the expression of MCP-1 and neointimal hyperplasia after a balloon injury in cholesterol-fed rabbits (33), whereas in vitro studies show that ethanol inhibits MCP-1 expression in IL-1ß-activated human endothelial cells (34). Previous clinical trials performed by our group revealed that moderate consumption of red wine exerted greater antiinflammatory effects than ethanol itself (gin). In addition, red wine prevented nuclear factor-{kappa}B activation in PBMC, a process that activates genes involved in immune and inflammatory responses (35,36). These antiinflammatory effects have been attributed to the high polyphenol content of red wines. The results of this study also confirm that moderate consumption of cava, a medium-level polyphenol content beverage, is able to reduce the expression of adhesion molecules that participate in the passage of monocytes and T-lymphocytes into the arterial wall.

The interaction of T-lymphocytes and monocytes with endothelium through adhesion molecules is the first event in atheroma plaque formation. This process may involve several steps such as rolling, tethering, firm adhesion, and transmigration of circulating mononuclear cells in which different adhesion molecules participate (8). Selectins and SLex exert their function during the rolling phase, whereas integrins, ICAM-1, and VCAM act during firm adhesion and transmigration (37). Our results suggest that moderate consumption of cava and gin may have an effect in the initial phases of the atherosclerosis process. Until now, no studies to our knowledge have reported the antiinflammatory effect of cava consumption in human beings. These effects may contribute, with others previously reported (such as reduction of LDL oxidation in vitro or decrease of aortic fatty streak formation in hamsters) (38,39), to the overall beneficial effect of wine against atherosclerosis.

In summary, our study suggests that alcoholic beverages with medium-level polyphenol content such as cava induce greater reductions of inflammatory markers of atherosclerosis (adhesion molecules, cytokines, and CD40/CD40L system) compared with alcoholic beverages with negligible levels of polyphenols, such as gin. Therefore, these data suggest that some of the atheroprotective effect of alcoholic beverages could be partially mediated by their antiinflammatory activity in the vascular wall.


   FOOTNOTES
 
1 Supported by the Spanish Ministries of Education and Science and Health (PI020611, PI041837, PI051519, G03/140, CB06/03, ALI/AGL 2006-14228-C03-02/01, and 2005-0559). Back

2 Author disclosures: M. Vázquez-Agell, E. Sacanella, E. Tobias, M. Monagas, E. Antúnez, R. Zamora-Ros, C. Andrés-Lacueva, R. M. Lamuela-Raventós, J. Fernández-Solá, J. M. Nicolás and R. Estruch, no conflicts of interest. Back

7 Abbreviations used: CHD, coronary heart disease; hsCRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte function-associated antigen-1; MCP-1, monocyte chemoattractant protein-1; PBMC, peripheral blood mononuclear cell; SLex, Sialyl-Lewisx ; VCAM-1, vascular cell adhesion molecule-1; VLA-4, very late activation antigen-4. Back

Manuscript received 12 June 2007. Initial review completed 26 June 2007. Revision accepted 20 July 2007.


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 Introduction
 Participants and Methods
 Results
 Discussion
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