Epidemiologic evidence for the cardioprotective effects associated with consumption of alcoholic beverages

Transcription

1 Pathophysiology 10 (2004) Review Epidemiologic evidence for the cardioprotective effects associated with consumption of alcoholic beverages Morten Grønbæk Centre for Alcohol Research, National Institute of Public Health, Svanemøllevej 25, DK-2100 Copenhagen, Denmark Received 3 October 2003; accepted 3 October 2003 Abstract The impact of alcohol intake on mortality from all causes has been described in a large number of prospective population studies from many countries. Most have shown a J-shaped relation between alcohol intake and subsequent mortality, indicating that there are both beneficial and harmful effects of ethanol on health. The risk of death from ischemic heart disease is seen to be significantly increased, and highest among abstainers, but not significantly increased among heavy drinkers. Some studies have found plausible mechanisms for the beneficial effect of light to moderate drinking. Subjects with a moderate alcohol intake have a higher level of high density lipoprotein than abstainers. Further, moderate drinkers are seen to have a lower low density lipoprotein. Also, alcohol has a beneficial effect on platelet aggregation, and thrombin level in blood is higher among drinkers than among non-drinkers. In the other end of the range of intake, the ascending leg of the U-shaped curve has been explained by the increased risk of cirrhosis, pancreatitis, and development oropharynx, oesophagus, and breast cancer. In exploring the French paradox, it has been suggested that wine may have beneficial effects additional to that of ethanol. Recently, several prospective population studies have supported this idea. It is, however, also likely that the apparent additional beneficial effect of wine on health in addition to the effect of ethanol itself is a consequence of confounding Elsevier Ireland Ltd. All rights reserved. Keywords: Cardioprotective effects; Alcoholic beverages; Drinking pattern 1. Introduction During the last decades, a large number of prospective population studies from many countries have described the impact of alcohol intake on mortality as J-shaped, indicating that there is a beneficial effect of a light to moderate alcohol intake as well as a detrimental effect of a high alcohol intake [1 19]. This J-shape has by some authors been explained as an artefact due to misclassification or confounding. Prevailing beliefs among these is that abstainers comprise a mixture of former heavy drinkers, underreporting drinkers, ill persons who have stopped drinking, and persons with a specially unhealthy lifestyle apart from abstaining [11,20,21]. However, most researchers attribute the J to a combination of beneficial and harmful effects of ethanol itself. This is based on findings from population studies of alcohol-related morbidity and cause-specific mortality, showing a decreased Tel.: address: mg@niph.dk (M. Grønbæk). relative risk of cardiovascular disease, and an increased risk of certain cancers and cirrhosis, with increased alcohol intake [19] (Fig. 1). In this review the arguments for a positive effect of a light to moderate alcohol itself, subsequent different types of alcoholic beverages, on cardiovascular disease will be weighted. The association between alcohol intake (ethanol) and cardiovascular disease has received quite some attention the last decades. Both case control and cohort studies have consistently shown that light to moderate drinkers are at lower risk of cardiovascular disease and death than non-drinkers [19,22 31]. Most agree that this declining risk curve can be interpreted as a causal relation, although the strength of the apparently protective effect is still disputed. However, many studies report a decline in risk of cardiovascular disease in the range of 25 30% [32]. Several plausible mechanisms for the apparently cardioprotective effect of a light to moderate intake of alcohol have been suggested. Subjects who drink alcohol have higher serum levels of high density lipoprotein and lower of low density lipoprotein than abstainers. Thus, high density lipoprotein has been suggested to be a mediator of 40 60% of the effect of alcohol /$ see front matter 2003 Elsevier Ireland Ltd. All rights reserved. doi: /j.pathophys

2 84 M. Grønbæk / Pathophysiology 10 (2004) Mortality from all causes 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0 < Alcohol, drinks per day Fig. 1. The relationship between alcohol and all-cause mortality. on ischemic heart disease [33 40]. Also, alcohol has a beneficial effect on platelet aggregation, and thrombin level in blood is higher among drinkers than among non-drinkers [41 43]. A few small-scale intervention studies have further indicated that alcohol has a beneficial effect on fibronolytic factors [44]. Although it seems well established from the large number of prospective population studies that there are cardioprotective effect of alcohol, is quite evident that there are several factors which may influence the strength of this effect. It has hence been suggested that the cardioprotective effect of alcohol depends on the drinkers age and sex, and on the way the alcohol is ingested; steady or binge. The type of alcoholic beverage may be another of these factors. The largest of the prospective studies have shown that the effect of alcohol and cardiovascular disease may be modified by sex and age. Hence, two American studies have shown that the apparent cardioprotective effect seems stronger among the elderly [19,22]. A recent meta-analysis of 28 cohort studies papers by Corrao et al found a 20% decreased risk for coronary heart disease among light to moderate drinkers, and that risk increased among heavy increased. They further found that the apparent cardioprotective effect of alcohol is different among men and women. They further concluded that the degree of protection from moderate doses of alcohol should be reconsidered [45]. In a recent study from the American Cancer Society, the different mortality risk functions for different age intervals was emphasised [22]. In consistency with this, one of the few studies not showing a U-shaped relation is one of young (Swedish) men [10]. The potential differences in effect of alcohol in different age groups can be explained by the fact that incidence of different causes of deaths differs from age group to age group. For example, the proportion of death from breast cancer decreases after middle-age, while the relative frequency of death from cardiovascular disease increases dramatically. If alcohol has a carcinogenic effect on the breast and an antiatherogenic effect on the heart, this may explain the different shapes of the curve of the younger and the older populations. 3. The influence of drinking pattern One of the mechanisms by which alcohol is assumed to exert its beneficial effect on coronary heart disease, is by lowering high density lipoprotein [35,37 40,46]. Studies in rats have shown that a steady small intake of alcohol implies an increase in high density lipoprotein level, while a peak intake of the same average amount of alcohol does not [47,48]. In a recent study of 11,511 cases of acute myocardial infarction or fatal coronary heart disease and 6077 controls in New South Wales, Australia, it was shown that individuals who had a steady small intake of alcohol had lower odds for fatal coronary heart disease, while those who had the same average intake, but consumed their alcohol once or twice per week, had not [49]. Apart from this, the important question of a relation between frequency and amount of drinking has not been examined in observational epidemiologic studies. A recent study of Americans showed that light to moderate drinkers who had occasions of heavy drinking had a significant higher mortality compared to those who had the same average intake [50]. In conclusion, these findings suggest that drinking pattern steady versus binge drinking may play a role in the apparent cardioprotective effect of alcohol. 2. The influence of age and sex 4. The influence of type of alcohol While there is an increasing body of evidence that alcohol (ethanol) itself has cardioprotective properties, the question whether there are different risks and benefits associated with the different types of alcoholic beverages; beer, wine and spirits, is still unresolved. However, during the last years both epidemiological and experimental studies have brought support to the hypothesis that substances in wine has cardioprotective effects in addition to those of ethanol [51] Cross-sectional studies In ecological studies, in which the units of analyses typically are entire countries or regions, it has been shown that

3 M. Grønbæk / Pathophysiology 10 (2004) France has a low rate of cardiovascular disease despite the high smoking rates and typical high fat diet in France. This so-called French paradox has been explained by the fact that the French drink more wine than for instance Americans and Finns, who have higher rates of cardiovascular disease. Ecological studies have several limitations. The results are often inconclusive since a few individuals can conceivably be responsible for a large proportion of the alcohol consumption. Also, no correction can be made for confounders, and the possibility exists and the populations studied may be very heterogeneous. Nevertheless, these studies gave start to the hypotheses of an additional effect of wine with regard to cardioprotection Case control and cohort studies A number of recent cohort studies have addressed the question whether there are differences in the effect of drinking wine, beer and spirits. Most of those having been able to address the question in populations with a variation in intake of all three types of beverages have found wine drinkers to be at lower risk of all-cause mortality and in some instances also of mortality from cardiovascular disease [51 54]. A larger number of studies of the effect of alcohol on cardiovascular disease have superficially addressed the question of different effects of the different types of beverages [19,23 26,55 57]. These case control studies and prospective studies have in common that they mention their finding; no significant difference, a trend towards a stronger effect of beer, etc. in a few sentences in papers devoted to the analysis of effect of total alcohol on incidence or mortality from coronary heart disease. It is, therefore, quite difficult to extract from most of the papers, the distribution of intake of the different beverages, and how the authors reached their conclusions. Some of these studies are further impaired by a narrow intake of total alcohol [58]. Despite these methodological difficulties, several of these studies were included in a review by Rimm et al, who concluded that ethanol itself is responsible for the decreased risk among light to moderate alcohol drinkers [59]. The question of effects of the different types of alcoholic drinks on cardiovascular disease mortality can be approached in two different ways; is it alcohol or another substance or is it alcohol and another substance which, in low doses, implies the beneficial effect. Rimm et al. used the first approach. In their review it was shown that the U-shaped relation between alcohol intake and cardiovascular disease mortality persisted in populations with very different drinking patterns, such as wine drinkers in Italy and beer drinkers on Hawaii [12,57,59]. Hence, the lower risk of morbidity and mortality from cardiovascular disease among drinkers of a small dose of ethanol is a consistent finding. However, in order to answer the question whether substances in one of the beverages have an additional beneficial effect on coronary heart disease a significant intake of all three types of beverages in the particular population examined, is needed [60]. As mentioned above, only a few papers have more profoundly addressed the question of different effects of beer, wine and spirits on mortality from coronary disease. Klatsky and Armstrong reported a trend towards a lower mortality from coronary heart disease among those who preferred wine, than among those who preferred spirits or beer [61]. This division into preferers of types of alcohol has advantages with regard to interpretation of the results, given most subjects solely prefer one type. The latter is the case in the Kaiser Permanente Study (personal communication). But it may also lead to loss of information as well as misclassification, if many of the subjects drink two or all three types of beverages. The method of categorisation into preference of a given type of alcohol further hinders comparison with the group of abstainers from one specific type of beverage. In a recent paper from the same study, it was suggested that male beer drinkers and female wine drinkers are at lower risk of hospitalisation from cardiovascular events (than male wine and spirits drinkers, and female beer and spirits drinkers, respectively) [62]. However, in this paper, a log-linear relationship between increasing intake of (type of) alcohol and risk of cardiovascular events is assumed, in spite of previous suggestions of a U- or J- or even L-shaped relation between alcohol intake and cardiovascular disease. An analysis which estimates a conglomerate of a decreased risk, no risk difference, and an increased risk for stepwise increasing alcohol intake, is most likely to dilute the positive and negative effects of the different types of alcohol on coronary artery disease. The subsequent control for total alcohol intake does not weaken the potential impact of the mistake in making this assumption. Further, this control for total alcohol introduces the problem of co-variation which is introduced by the inclusion of both alcohol intake and beer, wine and spirits in the same model [63]. The latter problem has not yet been solved. In the analyses from the Copenhagen City Heart Study, beer, wine and spirits were introduced separately (together) into the Poisson models. The reference group (relative risk = 1.0) therefore differed from type to type. Even though patients taking disulfiram and dipsomaniac patients were excluded from the analysis, these differences may affect the interpretation of the results. Further, one would expect that the recognised effect of ethanol itself on mortality would imply an effect modification of drinking one type of alcohol on drinking the other. On the other hand, the influence of type of beverage on mortality was, in the range of intake from never to 3 5 drinks per day, statistically independent, and persisted throughout the 12 years of follow-up [51]. In a recent larger study from Copenhagen, we studied the effect of percentage wine intake of total alcohol intake at a given alcohol intake level (Fig. 2). With regard to all-cause mortality, we found large significant beverage-specific differences, in favour for wine. However, the results with regard to cardiovascular disease (here death from coronary heart disease) were a non-significant and only very little deceased in risk among wine drinkers (Fig. 3) [54]. A recent meta-analysis suggested that wine

4 86 M. Grønbæk / Pathophysiology 10 (2004) ,6 1,4 Mortality from All Causes 1,2 1 0,8 0,6 0, > 3 5 Alcohol Consumption, drinks/wk Fig. 2. Effect of percentage wine intake of total alcohol intake at a given alcohol intake level on all-cause mortality : no wine; : Wine; : 1 30% wine; : >30% wine is warranted. conferred a larger protective effect than other types of beverages [64] but the methods the inclusion of studies controlled and not controlled for different confounders were questioned [65]. Until now, the question of an association between different types of alcohol and morbidity from cerebrovascular disease has been sparsely studied. The findings by Truelsen et al., that wine drinkers are at lower risk of ischemic stroke than non-drinkers, are consistent with previous findings from the same cohort [51]. The fact that the findings are from the previously described cohort, may weaken the scientific impact of the results with regard to consistency (redundancy), even though it had a certain public impact [66]. Hence, while several authors argue that the biological mechanisms of substances in wine shown in in vitro studies is not supported by epidemiological findings mine is that the latter, the epidemiological studies, can be questioned with regard to the ability to show these properties. 1,6 1,4 Mortality from CHD 1,2 1 0,8 0,6 0, > 21 Alcohol Consumption, drinks/wk Fig. 3. Effect of percentage wine intake of total alcohol intake at a given alcohol intake level on mortality from coronary heart disease : No wine; : Wine is warranted.

5 M. Grønbæk / Pathophysiology 10 (2004) Plausible biological mechanisms Substances in wine have been shown to have the platelet aggregation inhibiting effect also found to pertain to ethanol [67 70]. Further, an inhibiting effect on low density lipoprotein oxidation of unknown factors in wine was shown [71] Also other mechanisms related to not specified factors in wine, have been suggested to play a role in the prevention of cardiovascular disease [72 77]. Apart from the effect on platelet and low density lipoprotein oxidation, a vasodilating effect has been proposed [78], perhaps due to an effect of wine on the endothelium [79]. The suggestions from the experimental studies have only been sparsely reproduced in population studies. Thus, one of the first studies on flavonoid intake in humans, found a lower risk of coronary heart disease among subjects who had a high dietary intake of flavonoids [80], while recent data from the Nurses Health Study did not support the findings [75]. Further, several other antioxidant effects which may inhibit carcinogenesis but also may have an effect on cardiovascular disease have been proposed [67,81 89]. Several of these antioxidants are present in both fruits and vegetables, as well as in wine [73,76,90,91]. In the case of the existence of one or several plausible biological mechanisms by which an association can be explained, the more likely a causal explanation is to the relation. On the other hand, the likelihood of a positive (e.g. Medline-) search for supportive studies, increases with the increase in number of journals. It should also be kept in mind, that in the case of any beneficial effect of wine, vast economic interests are involved, most of which are in favour of positive studies. Thereby, the risk of publication bias is enhanced Bias In the type of studies included in this review emphasis being laid on prospective population studies one obvious source of bias is misclassification of subjects according to their self-reported alcohol intake. Studies of the validity of self-reported total alcohol intake [104] have mainly concentrated on validating total alcohol intake in suspected alcoholics [105,106], while intake validity among low-consumers in the general population is poorly studied [107]. Until now no reference of alcohol intake (sales reports, collateral information, biological markers, etc.) has been identified. Some biochemical markers of alcohol intake have been suggested, as for example -glutamyl transferase, high dentity lipoproteine and carbohydrate-deficient transferrin, the latter being one of the most promising [108]. However, in a study from Copenhagen, it was shown that carbohydrate-deficient transferrin was an invalid marker of a self-reported alcohol intake in a general population [109]. With regard to information on alcohol intake from the general population, the need for any such marker can further be questioned. First of all, participants in prospective cohort studies sampled from the general population have less reason to underreport, or deny, their alcohol intake than alcoholics or insurance populations [61]. Secondly, in a study on alcoholic cirrhosis, we found that self-reported alcohol intake in the questionnaire used in most of the studies included in this review, is a reliable measure of true alcohol intake, since self-reported alcohol intake is a valid predictor of this outcome [110]. Thirdly, self-reported alcohol intake is the only measure, which is of clinical relevans, due to the practical and ethical issues, which prevent use of other measures. The issue of consequences of random and non-random misclassification has been discussed more thoroughly earlier [111] Beverage-specific reporting bias Differential beverage-specific reporting bias by high or low consumers by the frequency questionnaire could, to some extent, explain the apparent lower mortality among wine than among beer and spirits drinkers. Alcohol intake in general assessed from simple frequency questionnaires has been validated in several studies [104] but the possible reporting bias of wine, beer and spirits from the simple frequency questionnaires, often used in population studies, has not been examined. In a study from Copenhagen, the answers to intake of beer, wine, and spirits from a frequency questionnaire were compared with those given to a dietician to the same questions [112]. The correlation between total alcohol consumption reported by questionnaire and interview was 0.8. There were no differences between frequency questionnaire and interview information between subgroups of total alcohol intake among men (P = 0.4), while heavy drinking women reported a higher total alcohol intake (23 drinks versus 18 drinks per week) on the questionnaire than in the interview (P <0.001) [112]. With regard to type of beverage, which will be dealt with in the following, there was an overall agreement between frequency questionnaire and dietary interview. Thus, most subjects pertaining to one consumption category of any type of beverage according to the frequency questionnaire, also responded to this category in the interview. Mean differences between intake of all three types of beverages were very small or zero, and there were no systematic differences at different levels of average intakes of any of the types of beverages. This is not a true validation study, as none of the two methods can be considered as reference or gold standard. Thus, alcohol intake may have been underreported, and subjects may have reported intake of the three types of beverages differentially. Nevertheless, the close agreement seen for most individuals suggests that in the range of a small to moderate intake of different types of beverages, the more simple questionnaire approach is not disadvantageous to the expensive and time consuming personal interview. In conclusion, differential reporting bias of these types of drinks does not seem to be an explanation of the apparent lower mortality among wine drinkers than among beer and spirits drinkers.

6 88 M. Grønbæk / Pathophysiology 10 (2004) Potential confounders of the relation between wine and mortality When reviewing the different epidemiological papers on type of beverage and cardiovascular disease, the question still remains whether it is the drink or the drinker? As mentioned above, several biological mechanisms from substances present in wine but in beer and spirits may explain the epidemiological findings. However, recently a few studies have shown that other factors, differently distributed among wine drinkers and non-wine drinkers may confound the above mentioned relations. Another factor which may be of importance drinking pattern. As mentioned above, a study from US have shown that binge drinkers have a higher mortality from all-causes than steady drinkers [50]. With regard to coronary heart disease, a study from Australia shows that only those who were steady drinkers had an apparently beneficial effect of drinking light to moderately [49]. Hence, if wine drinkers were steady drinkers and beer drinkers more likely binge drinkers, this may itself explain the above mentioned differences. However, a recent study from Denmark showed that this does not seem to, since wine drinkers were more likely to binge than beer drinkers [103]. In conclusion most epidemiological studies support the clinical and the experimental suggestions of an effect of wine in addition to a light to moderate alcohol intake on cardiovascular disease, although the differences to a large extend may be due to confounding. The interpretation of the results from the studies included in this review is a decreased mortality from cardiovascular disease among wine drinkers. Several important potential confounding factors were already included in most of the analyses included in this review [18,51,110, ]. Smoking is known to confound the estimates of the effect of alcohol intake on mortality, and was therefore controlled for. Intake of alcohol, in particular beer and spirits, was associated with smoking, and the associations between intake of beer and spirits and relative risk of both upper digestive tract cancer and lung cancer were attenuated by adjustment for smoking. Since smoking is such a strong risk factor for both cancers, the remaining risk associated with intake of beer and spirits may be caused by residual confounding and the results must be interpreted with caution. Wine intake was positively correlated with social class variables in the Copenhagen City Heart Study [118], but the apparent protective effect of wine, with regard to mortality, was not significantly weakened when controlling for this factor [109]. Sex, age, body mass index, and physical activity did not confound our results either. Of course, it cannot be excluded that there is residual confounding by some of the included variables, or that other, possibly unknown, confounders are involved Subjective health Self-reported subjective health has in several studies been shown to be a strong predictor of both coronary heart disease and all-cause mortality [100]. Further, a recent study from Finland showed a J-shaped relation between total alcohol intake and subjective health, which suggests that the U-shaped relation between alcohol intake and mortality may be confounded by this factor [102]. In the Copenhagen Healthy City Survey these results was reproduced. Further, it was shown that, when broken down into wine, beer and spirits, the J-shaped relation persisted only among wine drinkers (Table 4) [101]. The analyses of the cross-sectional data further revealed that the relation between type of alcohol and self-reported subjective health remained after stratification on sex, smoking, and chronic disease. An additional analysis of preference of different types showed that beer drinkers had an odds ratio of 1.5 ( ) of having suboptimal health compared to preferrers of wine [101]. Hence, even though the temporal link is not fully enlightened, it is suggested that subjective health may play a role in the interpretation of the relation between wine intake and mortality Diet A high intake of fruit, vegetables and fish and a low intake of saturated fat has been suggested to reduce risk of coronary heart disease morbidity as well as mortality [91 93]. The so-called Mediterranean diet which includes fruits and vegetables, has in six out of ten cohort studies been found to have a weak protective effect on coronary heart disease [91,92,94]. A review concluded that there is a protective effect of vegetable intake on cancer [119]. Therefore, diet may play a role in the interpretation of the relation between alcoholic beverage type and both coronary heart disease mortality and cancer morbidity. However, very little attention has been paid to the relation between alcohol beverage choice and diet. In the Danish Diet Cancer and Health Study, preference of wine was associated with a higher intake of fruit, fish, vegetables, salad and a higher frequency of use of olive oil for cooking compared with preference of beer or spirits in both men and women (Table 5) [95]. The association between type of beverage and dietary habits was further illustrated by the odds for a healthy diet by categories of increasing intake of wine. For most of the dietary habits examined, there was a dose-dependent increase in odds ratios with increasing wine intake. Drinkers of one to three glasses of wine per day, though, were seen to have the highest adjusted odds ratios with regard to most of the specific dietary components. The strongest associations for both men and women were seen for the use of olive oil for cooking. In men drinking four glasses of wine or more a day, an odds ratio of 4.6 ( ) for using olive oil was observed [95]. Ina recent study from US, this was confirmed [96] However, the confounding effect of dietary factors should be very strong to explain the above mentioned findings [97]. Further, recent studies from Italy and France suggest that diet is not a strong confounder in these countries, where wine has also been found to have additional effect compared to beer and spirits [98,99].

7 M. Grønbæk / Pathophysiology 10 (2004) The finding that wine is associated with a presumably healthy diet, was suggested in an editorial recently [120], but only little data has been published on this topic. One Finnish study has found that female wine drinkers had a significantly higher intake of carotenoids and that male wine drinkers had a high intake of Vitamin C [89]. Klatsky et al. suggested that traits of persons who preferred wine in general were more favourable to health compared to beer and spirits drinkers. Thus, wine preferers smoked the least and had more years of formal education and the lowest body mass index [121]. It has recently been suggested that these beverage-specific dietary habits are not a Danish phenomenon only [122]. It is likely that drinking habits and dietary habits have developed contemporarily during adulthood among the individuals examined. This means that one of the factors in this cross-sectional study may confound the seemingly important effect of the other and thereby, that diet may confound the findings in the other studies [51, ]. However, the mentioned dietary studies were not controlled for wine intake [91,92,94,119]. Therefore, the question still remains; which factor is the real confounder diet or wine. 5. Conclusions The U-shaped relation between alcohol intake and all-cause mortality is influenced by several factors. Among these components are: age, since the U-shape seems to persist among the elderly, while not among young subjects, sex, since the ascending leg of the curve seems to be steeper among women than men, drinking pattern, since a small daily intake seems to imply a decreased mortality from cardiovascular disease, while binge drinking does not, and type of alcohol, since wine drinkers in some studies seem to be at lower risk than beer and spirits drinkers. The latter was explored in detail in the present review. The findings that wine drinkers are at a decreased risk of mortality from cardiovascular disease and decreased risk of incidence of ischemic stroke than non-wine drinkers, suggest (as opposed to proves) that substances present in wine, but not in beer and spirits, may be responsible for a beneficial effect on the outcome, in addition to that from a light intake of ethanol. Differential reporting bias of the three types of beverages is not a problem in studies such as most population studies, since there are no differences between reported intake of beer, wine and spirits in the thorough dietary interview and a simple food-frequency questionnaire. Self-reported subjective health may to some extend explain the findings of a lower mortality among wine drinkers than among beer and spirits drinkers, since only wine drinkers in Copenhagen were at lower odds for suboptimal health. This factor has not been taken into account in previous analyses. Further, the finding that Danish wine drinkers more frequently than beer and spirits drinkers have an intake of indicators of a healthy diet, may affect the interpretations from the prospective studies. The problem may be serious and it may be insignificant until now there is no clear evidence that there is a very large protective effect of any dietary items, and the studies suggesting any such effect have not controlled their results for intake of wine Public health impact In most western societies, these well-established beneficial effects of a light to moderate alcohol intake will have no consequences neither for doctor-patient advice, nor for more general public health messages. First of all, the potential message is, due to the several effect modifiers reviewed above (age, sex, drinking pattern and type of alcohol) very complex. Second, the target group for a message of a beneficial effect of alcohol is extremely small in most countries, since abstinence is seldom. References [1] A.R. Dyer, J. Stamler, O. Paul, M. Lepper, Alcohol consumption, cardiovascular risk factors, and mortality in two Chicago epidemiologic studies, Circulation 56 (1977) [2] W.C. Blackwelder, K. Yano, G.G. Rhoads, A. Kagan, T. Gordon, J.S. Palfrey, Alcohol and mortality: The Honolulu Heart Study, Am. J. Med. 68 (1980) [3] A.R. Dyer, J. Stamler, O. Paul, M. Lepper, Alcohol consumption and 17-year mortality in the Chicago Western Electric Company Study, Prevent. Med. 9 (1980) [4] D. Kozararevic, D. McGee, N. Vojvodic, Z. Racic, T. Dawber, T. Gordon, W. Zukel, Frequency of alcohol consumption and morbidity and mortality: The Yugoslavia Cardiovascular Disease Study, Lancet 22 (March) (1980) [5] A.L. Klatsky, G.D. Friedman, A.B. Siegelaub, A 10-year Kaiser-permanente experience, Ann. Intern. Med. 95 (1981) [6] M.G. Marmot, G. Rose, M.J. Shipley, B.J. Thomas, Alcohol and mortality: a U-shaped curve, Lancet 14 (March) (1981) [7] S. Kono, M. Ikeda, S. Tokudome, M. Nishizumi, M. Kuratsune, Alcohol and mortality: a cohort study of male Japanese physicians, Int. J. Epidemiol. 15 (1986) [8] T.C. Camacho, G.A. Kaplan, R.D. Cohen, Alcohol consumption and mortality in Alameda county, J. Chron. Dis. 40 (3) (1987) [9] T. Gordon, J.T. Doyle, Drinking and mortality. The Albany Study, Am. J. Epidemiol. 125 (1987) [10] S. Andreasson, P. Allebeck, A. Romelsjö, Alcohol and mortality among young men: Longitudinal study of Swedish conscripts, BMJ 296 (1988) [11] A.G. Shaper, G. Wannamethee, M. Walker, Alcohol and mortality in british men: explaining the U-shaped curve, Lancet 2 (1988) [12] G. Farchi, F. Fidanza, S. Mariotti, A. Menotti, Alcohol and mortality in the Italian rural cohorts of the seven countries study, Int. J. Epidemiol. 21 (1992) [13] A.L. Klatsky, M.A. Armstrong, G.D. Friedman, Alcohol and mortality, Ann. Intern. Med. 117 (1992) [14] L.O. De Labry, R.J. Glynn, M.R. Levenson, J.A. Hermos, J.S. LoCastro, P.S. Vokonas, Alcohol consumption and mortality in an American male population: recovering the U-shaped curve findings from the Normative Aging Study, J. Stud. Alcohol 53 (1992) [15] K.J. Cullen, M.W. Knuiman, N.J. Ward, Alcohol and mortality in Busselton, western Australia, Am. J. Epidemiol. 137 (1993)

8 90 M. Grønbæk / Pathophysiology 10 (2004) [16] J. Rehm, M.M. Richter, M. Elton, Effects on mortality of alcohol consumption, smoking, physical activity, and close personal relationships, Addiction 88 (1993) [17] R. Doll, R. Peto, E. Hall, K. Wheatley, R. Gray, Mortality in relation to consumption of alcohol: 13 years observations on male British doctors, BMJ 309 (1994) [18] M. Grønbæk, A. Deis, T.I.A. Sørensen, U. Becker, K. Borch-Johnsen, C. Müller, P. Schnohr, G. Jensen, Influence of sex, age, body mass index, and smoking on alcohol and mortality, BMJ 308 (1994) [19] C.S. Fuchs, M.J. Stampfer, G.A. Colditz, E.L. Giovannucci, J.E. Manson, I. Kawachi, D.J. Hunter, S.E. Hankinson, C.H. Hennekens, B. Rosner, F.E. Speizer, W.C. Willett, Alcohol consumption and mortality among women, N. Engl. J. Med. 332 (1995) [20] A.G. Shaper, Alcohol and mortality: a review of prospective studies, Br. J. Addict. 85 (1990) [21] S. Andréasson, P. Allebeck, A. Romelsjö, L.T. Kozlowski, R.G. Ferrence, A.G. Eadie, A.G. Shaper, Alcohol and ill health: the continuing debate, Br. J. Addict. 86 (1991) [22] M.J. Thun, R. Peto, A.D. Lopez, J.H. Monaco, S.J. Henley, C.W. Heath Jr., R. Doll, Alcohol consumption and mortality among middle-aged and elderly U.S. adults, N. Engl. J. Med. 337 (1997) [23] E.B. Rimm, E.L. Giovannucci, W.C. Willett, G.A. Colditz, A. Ascherio, B. Rosner, M.J. Stampfer, Prospective study of alcohol consumption and risk of coronary disease in men, Lancet 338 (1991) [24] S.J. Kittner, M.R. Garcia-Palmieri, R. Costas Jr., M. Cruz-Vidal, R.D. Abbott, R.J. Havlik, Alcohol and coronary heart disease in Puerto Rico, Am. J. Epidemiol. 117 (1983) [25] L. Rosenberg, D. Slone, S. Shapiro, D.W. Kaufman, O.S. Miettinen, P.D. Stolley, Alcoholic beverages and myocardial infarction in young women, Am. J. Pub. Health 71 (1981) [26] C.H. Hennekens, W. Willett, B. Rosner, D.S. Cole, S.L. Mayrent, Effects of beer, wine, and liquor in coronary deaths, JAMA 242 (18) (1979) [27] M.G. Marmot, Alcohol and coronary heart disease, Int. J. Epidemiol. 13 (2) (1984) [28] R.D. Moore, T.A. Pearson, Moderate alcohol consumption and coronary artery disease, Medicine 65 (1986) [29] S. Zakhari, M. Wassef, Alcohol and the cardiovascular system, in: M.D. Bethesta (Ed.), Research Monograph-31, National Institute on Alcohol Abuse and Alcoholism, [30] A.L. Klatsky, M.A. Armstrong, G.D. Friedman, Risk of cardiovascular mortality in alcohol drinkers, ex-drinkers and nondrinkers, Am. J. Cardiol. 66 (1990) [31] R.D. Lindeman, L.J. Romero, A.S. Allen, H.C. Liang, R.N. Baumgartner, K.M. Koehler, P.J. Garry, Alcohol consumption is negatively associated with the prevalence of coronary heart disease in the New Mexico Elder Health Survey, J. Am. Geriatr. Soc. 47 (1999) [32] M. Maclure, Demonstration of deductive meta-analysis: ethanol intake and risk of myocardial infarction, Epidemiol. Rev. 15 (1993) [33] W.S. Dai, R.E. LaPorte, D.L. Hom, L.H. Kuller, J.A. D Antonio, J.P. Gutai, M. Wozniczak, B. Wohlfahrt, Alcohol consumption and high density lipoprotein cholesterol concentration among alcoholics, Am. J. Epidemiol. 122 (1985) [34] A. van Tol, M.G. van der Gaag, L.M. Scheek, T. van Gent, H.F. Hendriks, Changes in postprandial lipoproteins of low and high density caused by moderate alcohol consumption with dinner, Atherosclerosis 141 (1998) S101 S103. [35] M.H. Criqui, L.D. Cowan, H.A. Tyroler, S. Bangdiwala, G. Heiss, R.B. Wallace, R. Cohn, Lipoproteins as mediators for the effects of alcohol consumption and cigarette smoking on cardiovascular mortality: results from the lipid research clinics follow-up study, Am. J. Epidemiol. 126 (1987) [36] P. Puchois, N. Ghalim, G. Zylberberg, P. Fievet, C. Demarquilly, J.-C. Fruchart, Effect of alcohol intake on human apolipoprotein A I-containing lipoprotein subfractions, Arch. Intern. Med. 150 (1990) [37] M.J. Stampfer, F.M. Sacks, S. Salvini, W.C. Willette, C.H. Hennekens, A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction, N. Engl. J. Med. 325 (1991) [38] I. Suh, J. Shaten, J.A. Cutler, L.H. Kuller, Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol, Ann. Intern. Med. 116 (1992) [39] J.M. Gaziano, J. Buring, J.L. Breslow, S.Z. Goldhaber, B. Rosner, M. VanDenburgh, W. Willett, C.H. Hennekens, Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction, N. Engl. J. Med. 329 (1993) [40] L.M. Srivastava, S. Vasisht, D.P. Agarwal, H.W. Goedde, Relation between alcohol intake, lipoproteins and coronary heart disease: the interest continues, Alcohol Alcohol. 29 (1994) [41] T.W. Meade, M.V. Vickers, S.G. Thompson, Y. Sterling, A.P. Haines, G.J. Miller, Epidemiological characteristics of platelet aggregability, BMJ 290 (1985) [42] M. Hillbom, M. Kangasaho, M. Kaste, H. Numminen, H. Vapaatalo, Acute ethanol ingestion increases platelet reactivity: is there a relationship to stroke? Stroke 16 (1985) [43] S. Renaud, M. de Lorgeril, Wine, alcohol, platelets, and the French paradox for coronary heart disease, Lancet 339 (1992) [44] H.F.J. Hendriks, J. Veenstra, E.J.M. Velthuis-te Wierik, G. Schaafsma, C. Kluft, Effect of moderate dose of alcohol with evening meal on fibronolytic factors, BMJ 308 (1994) [45] G. Corrao, L. Rubbiati, V. Bagnardi, A. Zambon, K. Poikolainen, Alcohol and coronary heart disease: a meta-analysis, Addiction 95 (2000) [46] M. Paunio, O.P. Heinonen, J. Virtamo, M.J. Klag, V. Manninen, D. Albanes, G.W. Comstock, HDL cholesterol and mortality in Finnish men with special reference to alcohol intake, Circulation 90 (6) (1994) [47] M.R. Lakshman, S.J. Chirtel, L.C. Chambers, B.S. Campbell, Hepatic synthesis of apoproteins of very low density and high density lipoproteins in perfused rat liver: influence of chronic heavy and moderate doses of ethanol, Alcohol. Clin. Exp. Res. 13 (1989) [48] R.C. Lin, B.A. Miller, Effect of chronic alcohol ingestion on the binding of high density lipoproteins to rat hepatic membranes: involvement of apolipoprotein E, Alcohol. Clin. Exp. Res. 16 (1992) [49] P. McElduff, A.J. Dobson, How much alcohol and how often? Population based case control study of alcohol consumption and risk of a major coronary event, BMJ 314 (1997) [50] J. Rehm, T.K. Greenfield, J.D. Rogers, Average volume of alcohol consumption, patterns of drinking, and all-cause mortality: results from the US National Alcohol Survey, Am. J. Epidemiol. 153 (2001) [51] M. Grønbæk, A. Deis, T.I.A. Sørensen, U. Becker, P. Schnohr, G. Jensen, Mortality associated with moderate intake of wine, beer, or spirits, BMJ 310 (1995) [52] S.G. Wannamethee, A.G. Shaper, Type of alcoholic drink and risk of major coronary heart disease events and all-cause mortality, Am. J. Pub. Health 89 (1999) [53] H. Theobald, L.O. Bygren, J. Carstensen, P. Engfeldt, A moderate intake of wine is associated with reduced total mortality and reduces mortality from cardiovascular disease, J. Stud. Alcohol 61 (2001) [54] M. Grønbæk, U. Becker, D. Johansen, A. Gottschau, P. Schnohr, H.O. Hein, G. Jensen, T.I.A. Sørensen, Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer, Ann. Intern. Med. 133 (2000)

9 M. Grønbæk / Pathophysiology 10 (2004) [55] C.A. Camargo, C.H. Hennekens, J.M. Gaziano, J.R. Glynn, J.E. Manson, M.J. Stampfer, Prospective study of moderate alcohol consumption and mortality in US male physicians, Arch. Intern. Med. 157 (1997) [56] M.J. Stampfer, G.A. Golditz, W.C. Willett, F.E. Speizer, C.H. Hennekens, A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women, N. Engl. J. Med. 319 (1988) [57] K. Yano, G.G. Rhoads, A. Kagan, Coffee, alcohol and risk of coronary heart disease among Japanese men living in Hawaii, N. Engl. J. Med. 297 (1977) [58] M. Grønbæk, Wine and mortality, Biofactors 6 (1997) [59] E.B. Rimm, A. Klatsky, D. Grobbee, M.J. Stampfer, Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine or spirits? BMJ 312 (1996) [60] M. Grønbæk, T.I.A. Sørensen, Alcohol consumption and risk of coronary heart disease (Letter), BMJ 313 (1996) 365. [61] A.L. Klatsky, M.A. Armstrong, Alcoholic beverage choice and risk of coronary artery disease mortality: do red wine drinkers fare best? Am. J. Cardiol. 71 (1993) [62] A.L. Klatsky, M.A. Armstrong, G.D. Friedman, Red wine, white wine, liquor, beer, and risk for coronary artery disease hospitalization, Am. J. Cardiol. 80 (1997) [63] M. Grønbæk, Alcohol and coronary artery disease (Letter), Am. J. Cardiol. 4 (1998) 530. [64] A. di Castelnuovo, S. Rotondo, L. Iacoviello, M.B. Donati, G. de Gaetano, Meta-analysis of wine and beer consumption in relation to vascular risk, Circulation 105 (2002) [65] E.B. Rimm, M.J. Stampfer, Wine, beer, and spirits: are they really horses of a different color? Circulation 105 (2002) [66] L. Schiavone, Study Links Moderate Wine Drinking, Lower Stroke Risk, no , CNN, CNN Television. [67] M.L. Bierenbaum, M.L. Struck, A.C. Tomeo, J. Halley, T.R. Watkins, Effect of red and white wine on serum lipids, platelet aggregation, oxidation products and antioxidants, Clin. Res. 42 (1994) 157A. [68] C.R. Pace-Asciak, S. Hahn, E.P. Diamandis, G. Soleas, D.M. Goldberg, The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease, Clin. Chim. Acta 235 (1995) [69] C.R. Pace-Asciak, O. Rounova, S.E. Hahn, E.P. Diamandis, D.M. Goldberg, Wines and grape juices as modulators of platelet aggregation in healthy human subjects, Clin. Chim. Acta 246 (1996) [70] S.C. Renaud, J.C. Ruf, Effects of alcohol on platelet functions, Clin. Chim. Acta 246 (1996) [71] E.N. Frankel, J. Kanner, J.B. German, E. Parks, J.E. Kinsella, Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine, Lancet 341 (1993) [72] M.G.L. Hertog, D. Kromhout, C. Aravanis, H. Blackburn, R. Buzina, F. Fidanza, A. Jansen, A. Menotti, S. Nedeljkovic, M. Pekkarinen, B.S. Simic, H. Toshima, E.J.M. Feskens, P.C.H. Hollman, M.B. Katan, Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study, Arch. Intern. Med. 155 (1995) [73] M.G.L. Hertog, P.C.H. Hollman, Potential health effects of the dietary flavonol quercetin, Eur. J. Clin. Nutr. 50 (1996) [74] P. Knekt, R. Järvinen, A. Reunanen, J. Maatela, Flavonoid intake and coronary mortality in Finland: a cohort study, Brit. Med. J. 312 (1996) [75] E.B. Rimm, M.B. Katan, A. Ascherio, M.J. Stampfer, W.C. Willett, Relation between intake of flavonoids and risk for coronary heart disease in male health professionals, Ann. Intern. Med. 125 (1996) [76] T. Nakagami, N. Nanaumi-Tamura, K. Toyomura, T. Nakamura, T. Shigehisa, Dietary flavonoids as potential natural biological response modifiers affecting the autoimmune system, J. Food Sci. 60 (4) (1995) [77] J.-C. Ruf, J.L. Berger, S. Renaud, Platelet rebound effect of alcohol withdrawal and wine drinking in rats relation to tannins and lipid peroxidation, Arterioscler. Thromb. Vasc. Biol. 15 (1995) [78] M. Flesch, A. Schwarz, M. Bohm, Effects of red and white wine on endothelium-dependent vasorelaxation of rat aorta and human coronary arteries, Am. J. Physiol. 275 (H1) (1998) [79] U.R. Pendurthi, J.T. Williams, R.S. Rao, Resveratrol, a polyphenolic compound forund in wine, inhibits tissue factor expression in vascular cells: a possible mechanism for the cardiovascular benefits associated with moderate condumption of wine, Arterioscler. Thromb. Vasc. Biol. 19 (1999) [80] M.G.L. Hertog, E.J.M. Feskens, P.C.H. Hollman, M.K. Katan, D. Kromhout, Dietary antioxidant flavonoids and risk of coronary heart disease: The Zutphen Elderly Study, Lancet 342 (1993) [81] M.N. Diaz, B. Frei, J.A. Vita, J.F. Keaney Jr., Antioxidants and atherosclerotic heart disease, New Engl. J. Med. 337 (6) (1997) [82] R.M. Hoffman, H.S. Garewal, Antioxidants and the prevention of coronary heart disease, Arch. Intern. Med. 155 (1995) [83] Y.B. de Rijke, N.M. Demacker, N.A. Assen, L.M. Sloots, M.B. Katan, A.F.H. Stalenhoef, Red wine consumption does not affect oxidizability of low-density lipoproteins in volunteers, Am. J. Clin. Nutr. 63 (1996) [84] J.A. Vinson, B.A. Hontz, Phenol antioxidant index: comparative antioxidant effectiveness of red and white wines, J. Agric. Food Chem. 43 (2) (1995) [85] E.R. Greenberg, J.A. Baron, T.D. Tosteson, D.H. Freeman Jr., G.J. Beck, J.H. Bond, T.A. Colacchio, J.A. Coller, H.D. Frankl, R.W. Haile, J.S. Mandel, D.W. Nierenberg, R. Rothstein, D.C. Snover, M.M. Stevens, R.W. Summers, R.U. van Stolk, A clinical trial of antioxidant vitamins to prevent colorectal adenoma, New Engl. J. Med. 331 (3) (1994) [86] M. Serafini, A. Ghiselli, A. Ferroluzzi, Red wine, tea, and antioxidants, Lancet 344 (1994) 626. [87] B. Halliwell, G.P. Walsh, Antioxidants in wine (Letter), Lancet 341 (1993) [88] R.J. Ward, T.J. Peters, The antioxidant status of patients with either alcohol-induced liver damage or myopathy, Alcohol Alcohol. 27 (1992) [89] P. Knekt, R. Järvinen, R. Seppänen, A. Rissanen, A. Aromaa, O.P. Heinonen, D. Albanes, M. Heinonen, E. Pukkala, L. Teppo, Dietary antioxidants and the risk of lung cancer, Am. J. Epidemiol. 134 (1991) [90] G. Cao, R.M. Russel, N. Lischner, R.L. Prior, Serum antioxidant capacity is increased by consumption of strawberries, spinach, red wine or Vitamin C in elderly women, J. Nutr. 128 (1998) [91] J.D. Potter, K. Steinmetz, Vegetables, Fruit and Phytoestrogens as Preventive Agents, IARC Science Publication 61 90, [92] A.R. Ness, J.W. Powles, Fruit and vegetables, and cardiovascular disease: a review, Int. J. Epidemiol. 26 (1997) [93] M.R. Law, J.K. Morris, By how much does fruit and vegetable consumption reduce the risk of ischaemic heart disease? Eur. J. Clin. Nutr. 52 (1998) [94] M.K. Serdula, T. Byers, A.H. Mokdad, E. Simoes, J.M. Mendlein, R.J. Coates, The association between fruit and vegetable intake and chronic disease risk factors, Epidemiology 7 (1996) [95] A. Tjønneland, M. Grønbæk, C. Stripp, K. Overvad, Wine intake and diet in a random sample of Danish men and women, Am. J. Clin. Nutr. 69 (1999) [96] J.C. Barefoot, M. Gronbaek, J.R. Feaganes, R.S. McPherson, R.B. Williams, I.C. Siegler, Alcoholic beverage preference, diet, and health habits in the UNC Alumni Heart Study, Am. J. Clin. Nutr. 76 (2002) [97] M. Grønbæk, T.I.A. Sørensen, Is the effect of wine on health confounded by diet? (Letter), Epidemiology 13 (2002) 236.