Complications of atherosclerosis remain the leading cause of morbidity and mortality in industrialized countries. Epidemiological studies have repeatedly demonstrated that moderate alcohol intake has a beneficial effect on cardiovascular disease. The purpose of this review is to examine the epidemiological and biological evidence supporting the intake of red wine as a means of reducing atherosclerosis. On the basis of epidemiological studies, moderate intake of alcoholic beverages, including red wine, reduces the risk of cardiovascular, cerebrovascular, and peripheral vascular disease in populations. In addition to the favorable biological effects of alcohol on the lipid profile, on hemostatic factors, and in reducing insulin resistance, the phenolic compounds in red wine appear to interfere with the molecular processes underlying the initiation, progression, and rupture of atherosclerotic plaques. Whether red wine is more beneficial than other types of alcohol remains unclear. Definitive data from a large-scale, randomized clinical end-point trial of red wine intake would be required before physicians can advise patients to use wine as part of preventative or medical therapies.
- alcoholic intake
- French Paradox
- phenolic compounds
numerous epidemiological studies have concluded that a moderate intake of alcohol is associated with a reduced risk of morbidity and mortality secondary to atherosclerotic complications. Ethanol intake from any type of alcoholic beverage appears beneficial (82), but red wine seems to confer additional health benefits (44). The regular drinking of red wine has been suggested as the explanation for the “French Paradox,” the relatively low incidence of coronary atherosclerosis in France compared with other Western countries, despite the high intake of saturated fat (75). The combination of ethanol and phenolic compounds in red wine is thought to be responsible for the apparent protective effects (115). Despite numerous epidemiological and biological studies, insufficient information exists to definitively recommend wine intake as a therapeutic intervention to prevent or treat atherosclerotic disease. This review of red wine and atherosclerosis will examine the epidemiology of atherosclerotic disease and alcohol, particularly wine consumption, the beneficial biological effects on atherosclerosis derived from red wine compounds, and the current medical recommendations regarding alcohol intake.
Moderate alcohol consumption, defined as 1 to 2 drinks a day, has been suggested to increase overall survival in a number of different population groups (12, 37, 43, 49, 97, 114). One standard drink is generally considered to be 1.5 oz of liquor, 5 oz of wine, or 12 oz of beer. However, higher intakes of ethanol have been linked to increased mortality (12, 97). From these observations, the relation between alcohol intake and mortality is described as U- or J-shaped, in which abstainers or heavy drinkers do not, but moderate drinkers do, experience the protective effects of alcohol (26, 42). Furthermore, the benefits associated with light to moderate drinking do not extend to all patient groups and are most apparent in middle-aged men and women, especially those who are at increased risk for cardiovascular disease (37, 114). Thus the reduction in total mortality is generally attributed to a reduction in atherosclerotic risk.
Atherosclerosis, a dynamic and progressive disease arising from the combination of endothelial dysfunction and inflammation (56, 86), manifests itself clinically when it involves the coronary arteries, the extracranial carotid arteries, or the vasculature of the lower extremities. Moderate consumption of wine and other alcoholic beverages appear to reduce the risk of morbidity and mortality related to the presentation of atherosclerotic disease.
Coronary Heart Disease
Epidemiological evidence confirms an association between moderate alcohol intake and a reduced risk of coronary heart disease (CHD) in populations. A meta-analysis (19) of 51 epidemiological studies concluded that the protective effects of alcohol were most pronounced at moderate doses. The risk of CHD decreased by ∼20% [relative risk (RR) = 0.80, 95% confidence interval (CI): 0.78–0.83] when 0 to 2 drinks of alcohol were consumed per day (19). The lower risk of CHD in moderate drinkers has been observed in a variety of patient populations, including apparently healthy adults (4, 13, 65), patients with a history of myocardial infarction (MI) (27, 68), and diabetic patients (2, 20, 92, 99).
Results from the Health Professionals Follow-up Study suggest that the consumption of alcohol at least 3 to 4 days per week is inversely associated with the risk of myocardial infarction (65). A group of 38,077 male health professionals, who were free of cardiovascular disease at baseline, were followed for 12 years. After the consideration of the confounding factors of age, smoking status, body mass index (BMI), use of aspirin, exercise, family history, and presence of hypertension or diabetes, the consumption of alcohol 3 to 4 days per week decreased the risk of MI by 32% (RR = 0.68, 95% CI: 0.55–0.84), regardless of the type of alcoholic beverage consumed. Results from the Physicians' Health Study confirm that moderate alcohol consumption decreases the risk for MI (RR = 0.65, 95% CI: 0.52–0.81) (13) and further suggest protection against angina (RR = 0.69, 95% CI: 0.59–0.81) (13) and sudden cardiac death (RR = 0.21, 95% CI: 0.08–0.56) (4) in apparently healthy males. Self-reported moderate alcohol consumption in the year before MI, among patients in the onset study, was associated with reduced mortality following infarction (52, 67). In this prospective cohort study, patients who consumed seven or more alcoholic drinks per week had lower cardiovascular mortality compared with abstainers [2.4 vs. 6.3 deaths per 100 person-years; hazard ratio (HR): 0.38, 95% CI: 0.25–0.55] (67). Finally, moderate alcohol consumption also appears to lower the risk of congestive heart failure based on findings in the Framingham cohort (116).
The cardioprotective benefits derived from alcohol extend to patients at increased risk for mortality from CHD, namely, patients with diabetes or those who have already suffered from an MI. Atherosclerosis causes most of the death and much of the disability in patients with diabetes (8). Light to moderate alcohol consumption appears to be associated with a lower risk of Type 2 diabetes mellitus (DM) among both young women (113) and middle-aged men (3), possibly due to beneficial effects on insulin sensitivity (24). In healthy postmenopausal women who were randomized to consume 0 to 30 g of alcohol per day (∼2 to 3 drinks/day) for 8 wk as part of a controlled diet, 30 g/day of alcohol significantly increased insulin sensitivity by 7.2% and reduced fasting insulin concentration by 19.2% (24). In addition to lowering the risk of diabetes in healthy patients, alcohol use is also inversely associated with the risk of CHD mortality in older-onset DM subjects (99) and in middle-aged diabetic men (2) and women (92). These observations suggest that moderate alcohol consumption by patients with DM is associated with similar risk reductions in CHD as in nondiabetic subjects.
Patients who have suffered an MI may also potentially benefit from moderate alcohol intake. Among male physicians with a history of MI, two to three drinks per week was associated with lower mortality, having a relative risk of death of 0.7 compared with nondrinkers (68). Patients within the Lyon Diet Heart Study who survived a recent MI and consumed about two drinks per day had a reduction in cardiovascular complications by 59% compared with abstainers (27).
A recent meta-analysis reported that light to moderate alcohol consumption may be protective against total and ischemic stroke (76). From 35 observational studies (19 cohort studies), consumption of approximately one drink per day was associated with a reduced relative risk of total stroke (RR = 0.83, 95% CI: 0.75–0.91) and ischemic stroke (RR = 0.80, 95% CI: 0.67–0.96) (76). However, the risk of stroke increased with heavier alcohol consumption. The protective effect of moderate alcohol consumption on ischemic stroke appears to be quite generalized across diverse populations. The Northern Manhattan Stroke Study, a population-based study designed to determine stroke incidence, risk factors, and prognosis, reported that consuming up to two drinks per day was significantly protective for ischemic stroke (odds ratio 0.51, 95% CI: 0.39–0.67) in elderly, multiethnic, urban subjects (87). Results from the US Nurses' Health Study suggested a protective relationship between moderate drinking and ischemic stroke among middle-aged women (93), a finding that was paralleled in middle-aged men participating in the Physicians' Health Study (10). However, in the Framingham cohort, alcohol intake was only associated with a lower risk of stroke among subjects aged 60 to 69 yr (33). Furthermore, alcohol consumption appears to be safe and may even reduce the risk of cardiovascular mortality in men with preexisting cerebrovascular disease (CVD) (49).
Peripheral Arterial Disease
An association between moderate alcohol intake and decreased prevalence of peripheral arterial disease (PAD) appears to exist based on epidemiological evidence. In the Physicians' Health Study, daily drinkers (≥7 drinks/wk) had a relative risk of PAD of 0.68 (95% CI: 0.52–0.89) compared with individuals who consumed <1 drink per week after controlling for age, smoking status, and treatment assignment (14). Intermittent claudication, the clinical hallmark of PAD, developed less frequently in subjects in the Framingham Heart Study who consumed one to two drinks per day (34). With the use of a multivariate Cox regression model, the lowest intermittent claudication risk emerged at levels of 13–24 g of ethanol per day (1 to 2 drinks/day) for men and 7–12 g of ethanol per day (0.5 to 1 drink/day) in women (34). The inverse association between alcohol consumption and PAD was also found in nonsmoking men and women (106). Even though the protective effect is present regardless of the type of alcoholic beverage consumed, results from the Edinburgh Artery Study suggested that less severe peripheral arterial insufficiency, as determined by a higher ankle-brachial pressure index, was more evident with the consumption of wine than with spirits or beer (50).
Is Red Wine Better?
From the epidemiological data, alcohol intake is associated with a reduction in CHD, CVD, and PAD. However, the lower rate of CHD in France compared with other developed countries suggested that the consumption of red wine provided superior vascular protection and explained this apparent French Paradox (21, 94). Support for a more pronounced cardioprotective effect for red wine compared with other alcoholic beverages first emerged from the Copenhagen Heart Study, which was performed prospectively over 12 years in 13,285 men and women (44). The results from this study suggested that subjects with low to moderate intake of wine had half the risk of dying from cardiovascular and cerebrovascular disease as those who never drank wine. Beer and spirit drinkers did not experience this advantage. These results were reinforced when the same group performed pooled cohort studies in which the type of alcohol consumed, smoking status, educational level, physical activity, and BMI were assessed at baseline (43). Compared with nondrinkers, light drinkers who avoided wine had a RR for death from all causes of 0.90 (95% CI: 0.82–0.99), whereas those who drank wine had a RR of 0.66 (95% CI: 0.55–0.77) (43). The authors concluded that wine intake may have a beneficial effect on all cause mortality that is additive to the protection afforded by alcohol. The additional benefit of wine compared with other alcoholic beverages is supported by a meta-analysis of wine intake in relation to vascular risk (30). With the pooled data from 13 studies involving 209,418 subjects, the risk reduction of vascular disease associated with wine intake was 32%, whereas the risk reduction for beer consumption was determined to be 22% (30). However, other studies and reviews have failed to see the dominant effect of wine (81). A large prospective cohort study among 128,934 adult members of a Northern California prepaid health care program concluded that moderate consumption of any form of alcohol reduced cardiovascular risk without any major additional benefits associated with drinking red wine (53, 54).
Explanations for these contradictory results may include differences in the risk factor patterns among beer, spirit, and wine drinkers (82), the pattern of alcohol consumption, the presence of other confounding lifestyle factors, or alternatively, differences in the type of wine consumed. European, but not American, studies have generally found a greater reduction in cardiovascular risk associated with red wine consumption compared with other alcoholic beverages (107). Recent research (107, 109) suggests that red wines differ in their vasodilating ability based on the type of grape and the country of origin, suggesting that the type of red wine consumed may influence the apparent protective effect that is conferred. Furthermore, wine drinkers tend to have a healthier diet (98) and are generally members of higher socioeconomic groups (69) compared with beer or spirit drinkers, factors that may influence the interpretation of previous reports. Most of the epidemiological studies to date fail to clearly define the type of alcohol consumed and the circumstances under which it is consumed, for example, regularly only with meals or exclusively as weekend binges. As Mann and Folts (61) point out, rather than using “alcohol consumption,” authors would be more accurate in saying “alcoholic beverage consumption” because beer, wine, and spirits contain substances other than pure ethanol that may exert beneficial or harmful health effects. It may be the balance between these beneficial and harmful attributes that help explain the differences observed among population groups and, more importantly, in individual patients. Therefore, future studies should focus on clearly differentiating between the types of alcoholic beverages consumed, identifying confounding factors that exist including socioeconomic status and diet, and assessing the pattern of consumption to assist with dispelling the confusion that exists within the current literature regarding specific beverage effects.
VASCULAR DISEASE AND THE BENEFICIAL EFFECTS OF RED WINE
Epidemiological studies provide the initial evidence suggesting moderate wine consumption is associated with a reduction in cardiovascular risk. A second type of evidence related to biological plausibility lends support to these observations (40). A series of in vitro and in vivo studies suggest that the polyphenolic compounds in red wine, in addition to ethanol, may play an active role in limiting the initiation and progression of atherosclerosis (see Fig. 1). Polyphenolic substances in wine are usually subdivided into two groups, the flavonoids and nonflavonoids (100). The most common flavonoids in red wine are flavonols such as quercetin and flavon-3-ols such as tannins and catechin, whereas among the nonflavonoids, resveratrol is best known (100).
Promotion of Endothelial Function
The vascular endothelium, located at the interface of blood and tissue, is able to sense changes in hemodynamic forces and blood-borne signals and react by synthesizing and releasing vasoactive substances (102). Vascular homeostasis is maintained by a balance between endothelium-derived relaxing and contracting factors. With disruption of this balance, mediated by inflammatory and traditional cardiovascular risk factors, the vasculature becomes susceptible to atheroma formation. Both the alcohol and polyphenolic compounds found in red wine appear to favorably maintain endothelial function and thus limit atherosclerosis.
Nitric oxide (NO) is the key endothelium-derived relaxing factor that plays a pivotal role in the regulation of vascular tone and vasomotor function (64). NO protects against vascular injury, inhibits leukocyte adhesion to the endothelium, and limits platelet aggregation (25, 38). However, in response to the traditional cardiovascular risk factors, such as hypertension, diabetes, and hypercholesterolemia, the endogenous defences of the vascular endothelium begin to break down. The ethanol content of red wine, and especially its polyphenolic compounds, may be able to limit this descent toward endothelial dysfunction by enhancing NO-mediated vasodilation (31). In vitro, ethanol appears to increase the expression of endothelial NO synthase and NO production in aortic endothelial cells (101). Red wine polyphenols, in particular resveratrol, appear to further enhance endothelial NO synthase expression and activity and subsequent NO release from endothelial cells (55, 108, 109). Red wine, and not white or rosé wines, inhibits endothelin-1 synthesis (18), a potent vasoconstrictor that is seen as a key factor in the development of vascular disease and atherosclerosis. These in vitro data have been supported by results in humans, which suggest that the consumption of red wine, compared with white wine or vodka, led to a greater increase in coronary flow-velocity reserve (90). Thus this vasodilatory effect appears to be enhanced by the polyphenolic components of red wine.
One of the most important alterations with regular alcohol consumption is an increase in plasma levels of high-density lipoprotein (HDL) (29, 39). A meta-analysis examining the effect of moderate alcohol intake, not differentiating between the type of alcoholic beverage consumed, on lipids found that a 16.8% reduction in risk of CHD could be directly attributable to increased HDL concentration from the consumption of 30 g of alcohol (∼2.5 drinks) per day (83). One to two drinks per day of any alcoholic beverage increases HDL by ∼12% on average (58). Alcohol has been demonstrated to act directly on the liver by increasing the synthesis of apolipoprotein (Apo) A-I (23) and to enhance lipoprotein lipase activity (71), leading to enhanced formation of HDL cholesterol. In human subjects, elevations in HDL cholesterol were believed to be related to the alcohol-induced increase in transport rates of the major HDL apolipoproteins apoA-I and -II (29). Elevations in HDL may serve to shuttle low-density lipoprotein (LDL) cholesterol back to the liver for reprocessing, reducing the cholesterol available for endothelial activation and atheroma formation. In addition to this alcohol-mediated effect, red wine possesses antioxidant activity.
Impairment of Plaque Initiation and Progression
The oxidation of LDL cholesterol not only increases its uptake by macrophages resulting in foam cell formation, but oxidized LDL (oxLDL) causes endothelial activation and changes its biological characteristics in part by reducing the intracellular concentration of NO (17, 57). These changes promote fatty streak atheroma formation. Thus, if LDL oxidation is reduced, atherosclerotic plaque formation may be decreased. The phenolic substances in red wine, and not the alcohol component, have potent antioxidant properties that inhibit the formation of oxLDL in vitro (35), as well as macrophage-mediated LDL oxidation (7). Some in vivo studies in rabbits (22, 116), hamsters (105), and mice (45) suggest that the antioxidant properties of wine limit early atherosclerotic plaque formation and progression. However, a reduction in mature atherosclerosis in Apo-E-deficient mice was not observed with red wine treatment, although <60% of these treated mice had measurable blood ethanol levels (9). Human studies suggest that the consumption of red wine (62) or alcohol-free red wine (89) leads to a significant increase in serum antioxidant activity, which may reduce the susceptibility of LDL to oxidation in vivo (70), limiting the extent of atheroma formation. However, to date, the results from clinical trials assessing the use of antioxidant therapies to reduce cardiovascular events have been disappointing. The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study suggested that supplementation with a combination of vitamin E and slow-release vitamin C slowed down ultrasonographically documented common carotid artery atherosclerotic progression in hypercholesterolemic persons (88). However, other studies, including large, randomized clinical trials such as Heart Outcomes Prevention Evaluation (HOPE) and Supplementation en Vitamines et Mineraux Antioxidants (SU.VI.MAX) have failed to see any cardiovascular benefit. One arm of the HOPE trial (60) evaluated the effects of vitamin E in patients at high risk for cardiovascular events. Vitamin E had a neutral effect on the composite of MI, stroke, or cardiovascular death (RR = 1.03, 95% CI 0.88–1.21; P = 0.70), suggesting that the daily administration of 400 IU vitamin E for an average of 4.5 years to high-risk patients had no effect on adverse cardiovascular outcomes. The SU.VI.MAX study (46) was a randomized, double-blind, placebo-controlled primary prevention trial involving 13,017 French adults who took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of β-carotene, 100 mg of selenium, and 20 mg of zinc, or a placebo. The study, with a mean follow-up of 7.5 years, failed to detect a difference in ischemic cardiovascular disease incidence or all-cause mortality between the groups.
Inflammatory activation of the endothelium is marked by the increased expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), secondary to nuclear factor-κ B (NF-κB) transcriptional activity. Red wine inhibits NF-κB activation in peripheral blood mononuclear cells (11) and in human endothelial cells (73), resulting in a downregulation of VCAM-1 (16). Wine further limits monocyte migration into the arterial intima by inhibiting the expression of monocyte chemotactic protein-1 (MCP-1). Fatty streak evolution toward a complex lesion is typified by the proliferation of vascular smooth muscle cells (VSMCs) and their migration toward the intima. Red wine polyphenols impair this progression, inhibiting both VSMC migration (48) and proliferation (6, 47, 48, 85). In addition to these polyphenol-mediated anti-inflammatory actions, alcohol itself may also attenuate atherosclerosis, in part through an anti-inflammatory mechanism, by reducing plasma C-reactive protein (CRP) levels (5, 91). The inflammatory marker CRP represents one of the strongest independent predictors of vascular death in a number of settings (77–79) in which wine consumption may be beneficial. CRP elicits a multitude of effects on endothelial biology favoring a proatherosclerotic phenotype (96) such as decreasing NO release (104), upregulating adhesion molecules (103), and stimulating VSMC proliferation and migration (111). In the Pravastatin Inflammation/CRP Evaluation Study, the moderate consumption of any alcoholic beverage, compared with no or only occasional alcohol intake, was associated with lower CRP plasma concentrations (5).
Plaque Destabilization, Rupture, and Thrombosis
Disruption of a vulnerable atherosclerotic plaque, on exposure to hemodynamic stresses, can trigger thrombosis culminating in acute MI. Both the alcohol and polyphenolic compounds in red wine appear to have antithrombotic action. Erosion of the plaque surface, characterized by areas of endothelial cell desquamation, exposes a prothrombotic surface, making subendothelial collagen, tissue factor, and von Willebrand factor accessible to components in the circulation, resulting in coagulation and thrombin formation. Overall, light-to-moderate alcohol consumers have lower levels of fibrinogen, von Willebrand factor, and factor VII, with wine drinkers additionally having lower plasminogen activator inhibitor antigen-1 levels (63, 66), suggesting a reduction in hemostasis. Furthermore, any form of alcohol consumption also increases antithrombin-III activity (84), and based on results from the Physicians' Health Study, is associated with increased tissue plasminogen activator concentrations (80). In vitro, alcohol induced the expression of tissue-type plasminogen activator in human endothelial cells, resulting in enhanced fibrinolytic activity (1). Both resveratrol and quercetin have been demonstrated to decrease the expression of tissue factor by activated, human endothelial cells (32). The polyphenolic compounds in red wine also exert an effect on platelet aggregation. Resveratrol and other polyphenolic compounds decrease platelet aggregation, possibly by interfering with prostaglandin synthesis and ADP-mediated aggregation (28, 72, 112). Similarly, ethanol inhibits in vitro platelet secretion and aggregation, in part by inhibiting phospholipase A2 secretion and activity (74, 95). In vivo, platelet aggregation was inhibited after healthy human volunteers consumed purple grape juice, suggesting grape-derived flavonoids and not just ethanol, may contribute to the apparent antithrombotic effect of red wine (36) (see Fig. 2).
WILL A GLASS OF RED WINE A DAY KEEP ATHEROSCLEROSIS AT BAY?
Despite the observational data derived from epidemiological studies and the biological plausibility from in vitro and in vivo experimental research, there is insufficient evidence to encourage patients who do not drink to start consuming red wine as part of a strategy to protect against atherosclerosis. In this era of evidence-based medicine, a large-scale, randomized control trial, assessing the effects of red wine intake versus a nonalcoholic placebo, would be required to ensure that there is legitimacy to both the epidemiological and biological data (41). Only based on the favorable results of such a study may physicians be justified in recommending the consumption of red wine for cardiovascular protection. However, whether such a clinical trial is ethical based on the well-documented toxic effects of alcohol is questionable. Too much alcohol consumption has been shown repeatedly to contribute to cardiovascular disorders such as alcoholic cardiomyopathy, high blood pressure, and arrhythmias. Excessive alcohol use can lead to liver cirrhosis, cancers, pancreatitis, neurological disorders, motor vehicle accidents, and addiction. Individuals with a personal or family history of alcohol abuse or liver disease should avoid drinking alcohol. Nevertheless, many medical societies view light ethanol use as being potentially beneficial to the cardiovascular system, although no formal recommendations for light alcohol consumption are made (11a, 15, 88a). The American Heart Association recommends that alcohol use should be an item of discussion between the physician and the patient (41). It is clear that physicians should continue to advise heavy drinkers to reduce consumption and to help alcoholics overcome their addiction. Also, there is no justification to recommend alcohol consumption as a preventative measure to nondrinkers considering there are several well-proven therapies for cardiovascular risk reduction such as exercise, smoking cessation, blood pressure control, and cholesterol lowering that do not have the undesirable effects of wine (40). For those patients who are established moderate drinkers, based on the current knowledge, abstention should not be enforced, but also increasing alcohol consumption for the purposes of cardioprotection is not justified. Hence, physicians should make individualized recommendations about alcohol drinking for patients with or without the clinical manifestations of atherosclerosis.
In conclusion, even though there are numerous studies extolling the virtues of red wine and other alcoholic beverages, there is insufficient clinical evidence to firmly conclude that the consumption of wine prevents cardiovascular disease. Though biologically plausible and epidemiologically convincing, the cardiovascular protection afforded by red wine will remain unknown until a randomized, clinical trial is performed. Only then will it be known if red wine is truly protective or if it deserves to be categorized with vitamin E in the cardiovascular literature as a therapy that did not hold up in clinical trials (60). Thus patients should not be advised to drink wine for health, but rather, if they do drink moderately, to drink to health.
- Copyright © 2005 by the American Physiological Society