Critique 066: Is it the alcohol or the polyphenols in red wine (or both) that decrease cardiovascular disease in wine drinkers? — 16 January 2012

Chiva-Blanch G, Urpi-Sarda M, Llorach R, Rotches-Ribalta M, Guillèn M, Casas R, Arranz S, Valderas-Martinez P, Portoles O, Corella D, Tinahones F, Lamuela-Raventos RM, Andres-Lacueva C, Estruch R. 

Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: a randomized clinical trial.  Am J Clin Nutr 2012. doi: 10.3945/ajcn.111.022889.

Authors’ Abstract

Background: Few clinical studies have focused on the alcohol- independent cardiovascular effects of the phenolic compounds of red wine (RW).

Objective: We aimed to evaluate the effects of ethanol and phenolic compounds of RW on the expression of inflammatory biomarkers related to atherosclerosis in subjects at high risk of cardiovascular disease.

Design: Sixty-seven high-risk, male volunteers were included in a randomized, crossover consumption trial. After a washout period, all subjects received RW (30 g alcohol/d), the equivalent amount of dealcoholized red wine (DRW), or gin (30 g alcohol/d) for 4 wk. Before and after each intervention period, 7 cellular and 18 serum inflammatory biomarkers were evaluated.

Results: Alcohol increased IL-10 and decreased macrophage-derived chemokine concentrations, whereas the phenolic compounds of RW decreased serum concentrations of intercellular adhesion molecule-1, E-selectin, and IL-6 and inhibited the expression of lymphocyte function-associated antigen 1 in T lymphocytes and macrophage-1 receptor, Sialil-Lewis X, and C-C chemokine receptor type 2 expression in monocytes. Both ethanol and phenolic compounds of RW downregulated serum concentrations of CD40 antigen, CD40 ligand, IL-16, monocyte chemotactic protein-1, and vascular cell adhesion molecule-1.

Conclusion: The results suggest that the phenolic content of RW may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of RW may modulate soluble inflammatory mediators in high-risk patients.

Forum Comments

Background:  Observational epidemiologic studies relating wine and alcohol to health all suffer from the fact that they, of necessity, compare people who prefer certain beverages, but not the beverages themselves.  While there have been many intervention trials in animals, randomized trials in humans are less common.  Randomized cross-over trials, in which each subject receives all interventions in sequence, can be especially important as they tend to avoid baseline differences among subjects and can detect effects of different interventions with smaller numbers of subjects. 

Brief synthesis of the present study:  This study included 67 male volunteers in Spain who were considered to be at “high-risk” of cardiovascular disease on the basis of increased BMI, smoking, diabetes, hypertension, or other risk factors.  About one half of the individuals were taking ACE inhibitors, statins, aspirin, and/or oral hypoglycemic drugs, so the results of this study may be especially relevant for patients in the real world. 

The subjects agreed to not consume any alcohol for a baseline period, then for three one-month periods consumed 30 g/day of alcohol as red wine or as gin, or an equivalent amount of phenolics from dealcoholized red wine.  The polyphenol contents of the RW and the DRW interventions were the same.  A very high degree of compliance of the subjects with the assigned interventions is evidenced by results of counting numbers of empty bottles of the intervention beverage returned, dietary records, urinary metabolites, etc.  Further, there is good evidence that there were no important changes between periods in diet or exercise habits.  The effects of each intervention on a large number of adhesion molecules and chemokines that affect inflammation and relate to the development of vascular disease were evaluated. 

The key results of the study were that both ethanol and nonalcoholic compounds in red wine have potentially protective effects that may reduce the risk of vascular disease.  Specifically, the authors conclude that “the phenolic content of red wine may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of red wine may modulate soluble inflammatory mediators in patients at high risk of cardiovascular disease.” 

Specific comments on the study:  Most reviewers considered this to be a well-done, comprehensive study.  As one reviewer commented: “This is an excellent paper. The results strongly indicate an effect of wine polyphenols on inflammation (in broad and modern terms) and this is just what we expect from the biochemistry and nutritional effects of fruits and vegetables.  The effect of ethanol, on the other hand, likely fits a hormetic mechanism, where low doses regularly supplied are protective while high doses in a single shot are worsening the progression of disease.”  Another reviewer added: “We need more information on separating the effects of beer, wine, and various types of spirits.  Some spirits like brandy and whisky can have useful antioxidant effects, so distinguishing effects among different types of beverages may be informative.”

Another Forum reviewer commented: “This is a very interesting paper that goes a way towards answering the question whether it is the alcohol or polyphenols in red wine that confer the health benefits.  The trial was well conducted and controlled, with very detailed analyses.  It would have been interesting to analyse any changes in conventional risk factors after the interventions.  It would also have been interesting in the study to determine the effects on vascular function by, for example, brachial artery activity (flow mediated dilatation).” 

Given that the effects of both alcohol and polyphenols on physiologic factors (e.g., platelet function, fibrinolysis) are transient, generally lasting for no more than 24 hours, it was appropriate that the subjects in this study were instructed to consume the intervention substance (RW, gin, DRW) on a daily basis.  When drinking is moderate, there is no evidence that having “alcohol-free days” is beneficial to health.  Indeed, most epidemiologic studies show better health effects from daily consumption rather than from drinking on only several days per week.

Still another Forum reviewer considered this to be “a good paper with interesting, and not unexpected findings.  The results strengthen the view that red wine has advantages over other alcoholic beverages concerning health benefits because it contains both ethanol and many polyphenols.”  Another reviewer agreed: “Although clinical observations and then epidemiological studies have suggested beverage-specific differences, studies like this one help illuminate the path of effect; we need more of them.” 

Concerns about the present study:  One Forum reviewer stated: “This appears to be a carefully designed and well executed study, but I have four concerns: (1) The study has been undertaken in high-risk individuals, more than half of whom are hypertensive, a quarter dyslipidaemic, and a quarter diabetic.  It is not described what happened to the conventional risk factors during the interventions.  (For example, any improvement in inflammatory markers may have come at the cost of higher blood pressure with the alcohol interventions.)  (2) Was there any weight change that could have confounded any of the outcomes?  (3) Both polyphenol and alcohol biomarkers were measured – did the change in these biomarkers correlate with the changes in any of the inflammatory markers; i.e., any suggestion of a dose response relationship?  (4) Even though at least 30 outcome variables were assessed, the authors do not describe any correction for multiple comparisons.”

Another Forum reviewer:  “This is a well conducted study, and adds to our understanding of the potential cardiovascular benefits of alcohol and the non-alcoholic compounds of alcoholic beverages.  However, in this study more than one-half of the high-risk subjects consumed drugs with known anti-inflammatory effects, which could be a confounding factor.  The anti-inflammatory effects of these pharmaceuticals may be responsible for the beneficial results, and may not be related to the RW, DRW and gin interventions.”  However, others think that this concern is unlikely to be important since this was a cross-over study, and there were no changes in lifestyle or medication use between the intervention periods.

Taking genetic factors into consideration:  While not evaluated in the present study, it is well known that physiologic responses to polyphenols and to alcohol are strongly affected by underlying genetic factors.  As a reviewer stated: “In the present study, we do not know whether or not these participants had certain genetic polymorphisms that put them into a high-risk category.  People with the metabolic syndrome tend to have adverse genetic profiles, and alcohol intake may have detrimental effects in certain individuals due to their genetic make up.  Therefore, testing for relatively common gene mutations involved in dyslipidaemia may be useful in identifying individuals who may, or may not, benefit from alcohol drinking.”

One reviewer commented that “It would have been interesting if this study was done on healthy individuals on no medication, and without specific genetic risk factors for cardiovascular disease.”  In contrast, other reviewers considered the selection of subjects to be particularly useful in that it reflected the typical patients seen in clinical practice, for whom advice regarding alcohol use must be provided.  Given that subjects did not modify their diet, other lifestyle factors, or medications between intervention periods, the differences in effect can be attributed to the interventions themselves.

Forum Summary

Human randomized intervention trials of wine and alcohol are not common.  This randomized, cross-over study was based on 67 male volunteers in Spain who were considered to be at “high-risk” of cardiovascular disease.  The subjects agreed to not consume any alcohol for a baseline period, then for three one-month periods consumed 30 g/day of alcohol as red wine or as gin, or an equivalent amount of phenolics from dealcoholized red wine.  The effects of each intervention on a large number of adhesion molecules and chemokines that affect inflammation and relate to the development of vascular disease were evaluated. 

The key results of the study were that both ethanol and nonalcoholic compounds in red wine have potentially protective effects that may reduce the risk of vascular disease.  Specifically, the authors conclude that “the phenolic content of red wine may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of red wine may modulate soluble inflammatory mediators in patients at high risk of cardiovascular disease.” Thus, this study provides important new mechanistic evidence that the reduced risk of cardiovascular disease among red wine drinkers observed in most epidemiologic studies may result from a combination of both the alcohol and the polyphenols in the wine.

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Comments on this paper were provided by the following members of the International Scientific Forum on Alcohol Research:

Dee Blackhurst, PhD, Lipid Laboratory, University of Cape Town Health Sciences Faculty, Cape Town, South Africa

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Ian Puddey, MD, Dean, Faculty of Medicine, Dentistry & Health Sciences, University of Western Australia, Nedlands, Australia

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA