Critique 057: Differences in effects on atherosclerosis of regular moderate drinking and binge drinking. An experimental study in mice – 20 September 2011
Liu W, Redmond EM, Morrow D, Cullen JP. Differential effects of daily-moderate versus weekend-binge alcohol consumption on atherosclerotic plaque development in mice. Atherosclerosis 2010, doi:10.1016/j.atherosclerosis.2011.08.034
Objectives: We examined the effect of daily-moderate (2 drinks/day, 7 days/week) and weekend-binge (7 drinks/day, 2 days/week) patterns of alcohol consumption on plasma lipid levels and physiological parameters of atherosclerotic plaque development. Methods: ApoE k/o mouse were fed (1) ‘daily-moderate’ (blood alcohol content: 0.07%) or (2) ‘weekend-binge’ (blood alcohol content: 0.23%), or (3) an isocaloric cornstarch mix. Then, to induce atherosclerotic plaque formation, all groups underwent partial carotid artery ligation, started on an atherogenic diet and continued on the alcohol feeding regimen. After 2 weeks plasma lipid levels and atherosclerotic plaque formation were assessed.
Results: While there was an increase in HDL-C levels in both binge and moderate groups, LDL-C levels were significantly decreased in the daily-moderate drinking mice and significantly elevated in the weekend-binge drinking mice. In the daily-moderate alcohol group there was a decrease in atherosclerotic plaque volume, concomitant with an increase in lumen volume and decreased macrophage accumulation, when compared to no alcohol mice. In contrast, after 4 weeks of weekend-binge alcohol there was an increase in plaque volume, concomitant with a decrease in lumen volume and increased deposition of macrophages.
Conclusion: These findings demonstrate for the first time a differential effect of daily-moderate vs. weekend-binge alcohol consumption on atherosclerotic plaque development and highlight the importance of patterns of alcohol consumption, as opposed to total amount consumed, in relation to the cardiovascular effects of alcohol.
Background. Epidemiologic studies are increasingly showing that regular moderate consumption of alcohol has considerable beneficial effects on the risk of cardiovascular disease and on the risk of many other chronic diseases of ageing. On the other hand, the consumption of even similar amounts of alcohol but on only one or two days per week (a binge-drinking pattern), is not associated with benefits and is often associated with adverse effects on health. Some have argued that these differences according to drinking pattern are not due to the frequency of drinking, but are associated with differences in type of beverage or other lifestyle habits among drinkers (i.e., regular moderate drinkers tend to smoke less, exercise more, eat a healthier diet, etc., while binge drinkers do not have these characteristics). The present study is important as it demonstrates similar results as seen in humans when comparing different drinking patterns among experimental animals.
There have been previous studies of effects of alcohol in ApoE k/o mice, and not all have found such dramatic effects as reported in the present study. For example, Bentzon et al1 concluded that “neither ethanol nor red wine polyphenols reduced mature atherosclerosis or changed the content of collagen in plaques in apolipoprotein E–deficient mice.” However, the Bentzon et al study was not comparing different drinking patterns. Further, that study added alcohol to the drinking water of the animals, so the specific amounts consumed by each animal varied, and only a minority of animals in the alcohol group showed detectable alcohol in the blood.
Other studies have shown beneficial effects on atherosclerosis in such mice from red wine polyhenolics. Stocker and Halloran2 reported that “Dealcoholized red wine contains polyphenolic compounds capable of synergizing with vitamin E, and long-term moderate consumption can decrease atherosclerosis in apolipoprotein E gene deficient mice.” Also, Waddington et al3 found that “lipid deposition is independent of lipid oxidation and that the protective action of red wine polyphenols is independent of any antioxidant action of these compounds.” It would be of interest to determine if the beneficial effects of alcohol (shown in the present study) and of polyphenols from wine are similar, and if they are perhaps additive in their effects on the development of atherosclerosis.
Comments on the present study: Forum reviewers were impressed with the implementation and results of this study; in fact, some thought the results were “too good.” For example, such a big difference in LDL-cholesterol among the two groups of animals was “almost incredible” and is hardly reproducible in humans. It is hoped that these dramatic effects can be duplicated in further studies. The authors’ discussion focuses on the implications of this experiment for human studies, but provides a limited amount of comparison with previous studies of alcohol/wine effects in ApoE k/o mice.
In the present study, animals were given ethanol by oral gavage, so there is little question about the amount of alcohol ingested in each animal. It is not possible to determine whether results would have been different between the administration of different types of alcoholic beverage: beer, wine, or spirits, as only ethanol was given. Also, the timing of the administration of alcohol to food ingestion is not given; in humans, blood alcohol levels are much reduced when alcohol is administered in close proximity to the ingestion of food. While very detailed information on effects on lipids were presented, it would have been useful if the investigators also reported the effects of the different alcohol patterns on CRP or other markers of inflammation, as well as on liver enzymes. We are still far from understanding the mechanism of action, although inflammation may contribute to the effect, as denoted by the presence of macrophages in this study.
One Forum reviewer stated: “This is a very nice study, confirming in an animal model the biphasic nature of the effect of alcohol on progression of atherosclerosis. We are still far from tempting to suggest realistic mechanisms. On the other hand, the evidence perfectly fits the usual hormetic mechanism, where low doses regularly supplied are protective while high doses in a single shot are worsening the progression of disease.” Another reviewer stated: “By controlled experiment it gives crisp and clear-cut results that are useful and intuitive when considering what we thought we knew, and what we may indeed do know. Cheers to the brave mice!” Still another Forum reviewer thought that it is good to have confirmation in a controlled experiment of what has been shown in epidemiologic studies. “It is nice to not have to agonize over smoking and other lifestyle factors that may confound results in human observational studies — none of the mice were smokers.”
1. Bentzon JF; Skovenborg E, Hansen C, Møller J, Saint-Cricq de Gaulejac N, Proch J, Falk E. Red wine does not reduce mature atherosclerosis in Apolipoprotein E-deficient mice. Circulation 2001;103:1681-1687.
2. Stocker R, O’Halloran RA. Dealcoholized red wine decreases atherosclerosis in apolipoprotein E gene-deficient mice independently of inhibition of lipid peroxidation in the artery wall. Am J Clin Nutr 2004;79:123–130.
3. Waddington E, Puddey IB, Croft KD. Red wine polyphenolic compounds inhibit atherosclerosis in apolipoprotein E-deficient mice independently of effects on lipid peroxidation. Am J Clin Nutr 2004;79:54–61.
An excellent study among experimental animals has reported very dramatic differences between the effects of alcohol administered in moderation on a daily basis and the same total weekly amount of alcohol administered on only two days of the week: binge drinking. The mice used in the study that were given regular moderate amounts of alcohol showed no weight gain, improved lipid values, and much less development of atherosclerosis than did control animals. However, those given alcohol in a binge-drinking pattern showed worse outcomes than control animals, and much worse outcomes than those given regular moderate alcohol.
This experimental study provides strong support for the frequent finding among humans in epidemiologic studies: benefits from regular moderate drinking, adverse effects from binge drinking. It is especially important since, being an experimental study, the potential confounding effects of other lifestyle habits are not an issue, as is always the case for observational studies among humans.
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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:
David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Creina Stockley, clinical pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA