This is the first controlled study on the effects of patterns of alcohol consumption on atherosclerotic plaque development. While epidemiological studies support an association between alcohol and cardiovascular disease there is lack of evidence-based data, free of artifacts or confounding variables often found in human population studies and where the validity of self-reported data is an area of concern. We report here, for the first time, a differential effect of daily-moderate vs. weekend-binge alcohol consumption on atherosclerotic plaque development. Animal models are essential for testing hypotheses in a controlled manner and mouse models in particular have proved useful to study atherosclerotic lesion development. We established a low-flow hypercholesterolemic model of atherosclerosis using partial carotid artery ligation in the apolipoprotein E knockout (apoE KO) mouse (recently described by Nam, et al. 12
), in which the left external and internal carotid arterial branches are isolated and ligated, reducing left carotid blood flow to flow via the patent occipital artery () 10
. This model exhibits several key pathological characteristics similar to those seen in humans, in particular a large number of infiltrated monocytes/macrophages, increased MMP-9 expression and cholesterol deposits 13
The blood alcohol levels observed in these mice over time followed a similar pattern to that observed in humans following moderate and binge alcohol consumption 14
. Alcohol delivery by gavage allowed us to unequivocally ensure that each animal received the desired amount over a short period of time as opposed to ad libitum in drinking water. Coupled with blood alcohol measurement this ensured that the levels reached were those associated with moderate and binge alcohol consumption, and therefore allowed us to accurately replicate these drinking patterns in the mouse.
The majority of studies of alcohol and body weight have generally only examined average volumes of alcohol consumption. In the present study, greater increases in body weight were observed in the binge-drinking group when compared to the moderate group, despite the fact that both groups consumed the same total weekly volume of alcohol. These effects of different patterns of alcohol consumption on body weight are in agreement with a study demonstrating that persons who consumed the smallest quantity of alcohol the most frequently were leanest, and those who consumed the greatest quantity of alcohol the least frequently were heaviest 15
. Our results support the idea that alcohol may contribute to excess body weight among certain drinkers, especially those in the binge group.
The mechanisms by which moderate alcohol consumption decreases coronary artery disease are likely complex and multiple. A major beneficial effect of alcohol on atherosclerosis is explained by its action on plasma lipids. Plasma HDL and LDL levels are increased and decreased, respectively, by moderate alcohol consumption 16
. In the current study, both patterns of alcohol consumption increased plasma HDL levels, with a more pronounced effect observed in the binge-drinking group than in the moderate group. These findings are in agreement with studies that have reported an association between alcohol intake and serum lipid levels, most notably an increase in HDL cholesterol 16
. Despite both patterns having a favorable effect on plasma HDL levels, it was observed that while daily-moderate alcohol consumption lowered LDL levels by 40%, weekend-binge alcohol consumption elevated LDL levels by 20%, compared to control mice. LDL is pro-atherogenic increasing the risk of heart disease, whereas HDL is anti-atherogenic and decrease the risk of disease 17
. A comprehensive review of previous studies indicates that LDL levels are increased by heavy drinking episodes 18
and a recent study in rats has shown that heavy ethanol ingestion caused increased LDL-C levels 19
. Our results highlight the importance of drinking pattern on plasma lipid levels. It is well documented that a 10% increase in plasma LDL levels results in a 20% increase in atherosclerosis risk 17
. Our data indicate that daily-moderate drinking favorably changes the plasma lipid profile ie., increasing HDL-C and decreasing LDL-C plasma levels. On the other hand, weekend-binge drinking resulted in elevated plasma HDL-C levels but also elevated plasma LDL-C levels, the latter an established risk factor for atherosclerosis.
The inhibitory effect of daily-moderate alcohol on plaque development shown here is in agreement with meta-analysis of the relationship between alcohol consumption and coronary heart disease; ie., compared with abstinence from alcohol, low-to-moderate daily consumption of alcohol is associated with the lowest risk for coronary heart disease incidence 4
. Ours is the first controlled study demonstrating a differential effect of daily-moderate versus weekend-binge alcohol consumption on atherosclerotic plaque development and it highlights the importance of considering patterns of alcohol consumption, as opposed to total amount consumed, in relation to the cardiovascular effects of alcohol. Our findings are also in agreement with a recent prospective cohort study which demonstrated that regular and moderate alcohol intake throughout the week, the typical pattern in middle aged men in France, is associated with a low risk of ischemic heart disease, whereas a binge drinking pattern more prevalent in Belfast confers a higher risk 20
In addition to exerting favorable effects on plasma lipoproteins it has also been suggested that moderate alcohol consumption may exhibit anti-inflammatory properties 21, 22
. Our data suggest that the two patterns of alcohol consumption compared differentially affect the inflammatory component (i.e., infiltrated monocytes) and this may explain the differences in plaque development that were observed between the two groups. We have previously reported that ethanol in a range spanning both moderate and binge levels (10 - 100 mM) inhibits interleukin-1β-stimulated vascular endothelial cell MCP-1 secretion and subsequent monocyte adhesion in a dose-dependent manner 21
. However, it must be noted that in those in vitro
experiments with endothelial cells there is no significant metabolism of ethanol occurring. More recently we have demonstrated that in contrast to ethanol, incubation with its metabolite acetaldehyde, increases monocyte adhesion and the expression of endothelial cell inflammatory mediators 21, 23
. Co-incubation of endothelial cells with ethanol, 10 mM and 25 mM, completely reversed acetaldehyde-mediated monocyte adhesion 23
. Taken together, the results from our in vitro
studies suggest that following alcohol consumption there may be a delicate interplay between ethanol and acetaldehyde on monocyte recruitment within the vasculature. If the quantity of alcohol consumed is great enough to result in acetaldehyde levels that remain elevated after ethanol levels have been diminished, it is likely that the acetaldehyde present may have detrimental effects on the vasculature by promoting monocyte recruitment. These differential effects of alcohol and its primary metabolite, acetaldehyde, observed on vascular cells in vitro
may underlie the contrasting effects of daily-moderate and weekend-binge alcohol consumption on atherosclerotic plaque development in vivo
Alcohol has many effects on the cardiovascular system. Although most vascular research has focused on the cardioprotective effects of moderate alcohol consumption, some effects are unfavorable and may explain the increase in cardiovascular events following episodes of binge drinking. The Behavioral Risk Factor Surveillance System shows the binge drinking rate among all adults to be 14.8% 24
. This type of drinker may take longer for a health care professional to become concerned about enough to consider an intervention. One study 25
has shown that a positive response to the question “On any single occasion during the past 3 months, have you had more than 5 drinks containing alcohol?” accurately identifies patients who meet either NIAAA’s criteria for at-risk drinking or the criteria for alcohol abuse or dependence specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM–IV) 26
. It has recently been reported that alcohol screening and counseling is one of the highest ranked preventative services among 25 effective services that were evaluated 27
. However, the current levels of delivery for alcohol screening and counseling were the lowest of comparably ranked services. In a national survey of problem drinkers, only 8.7% reported having been asked and counseled about their alcohol use in the last 12 months 28
. Health psychologists argue that motivating people to change their drinking behavior depends upon belief surrounding issues such as their vulnerability to harm as a result of their behavior, the benefits of change, and whether people believe they can implement strategies for change 29
. Researchers point to the ‘lack of longitudinal studies to determine the relationship between patterns of alcohol consumption and the development of diseases’ 30
. Individuals have yet to be convinced of the dangers of binge drinking as opposed to long-term alcohol misuse.
Our findings demonstrate a differential effect of daily-moderate vs. weekend-binge alcohol consumption on atherosclerotic plaque development, and highlight the importance of considering patterns of alcohol consumption, in addition to total amount consumed, in relation to the cardiovascular effects of alcohol. The results obtained in the present study provide strong evidence to support a health message discouraging binge drinking. Providing scientific evidence to healthcare professionals that binge drinking can accelerate atherosclerosis, may encourage them to perform brief interventions for individuals with at-risk drinking behavior.