European Heart Journal (2007) 28, 1683–1693 Review 
doi:10.1093/eurheartj/ehm149 

The red wine hypothesis: from concepts to 
protective signalling molecules 

Lionel H. Opie* and Sandrine Lecour 

Department of Medicine, Faculty of Health Sciences, Hatter Cardiovascular Research Institute, University of Cape Town, 
Private Bag 3, 7935 Observatory, South Africa 

Received 30 January 2007; revised 28 March 2007; accepted 5 April 2007; online publish-ahead-of-print 7 June 2007 

KEYWORDS 
Wine; 
Alcohol; 
We review evidence for and against the ‘red wine hypothesis’, whereby red wine is more likely to 
confer cardiovascular benefits than white. As background, there is a strong epidemiological and 
mechanistic evidence for J-shaped relation between alcohol intake and total mortality. However, epi-
Resveratrol; 
Molecular mechanisms; 
Sirtuin 
demiological data favouring a specific benefit of red over white wine are not strong and the ‘French 
paradox’ could at least in part be explained by confounding factors. More convincing evidence is that 
human studies with de-alcoholized red but not white wine show short-term cardiovascular benefits. 
The specific components of the de-alcoholized wine that are active on cardiovascular endpoints, are 
the polyphenols found in red wine, especially resveratrol. The effects of resveratrol on isolated 
tissues or organs are well-described including molecular mechanisms leading to decreased arterial 
damage, decreased activity of angiotensin-II, increased nitric oxide, and decreased platelet aggregation. Anti-ischaemic effects include stimulation of prosurvival paths, decreased LDL-oxidation, atheroma, and on the ischaemic-beneficial metabolic changes. Most recently, the agonist effect of 
resveratrol on the anti-senescence factor sirtuin has lessened cell death in myocytes from failing 
hearts. Mechanistic feasibility strengthens the case for prospective therapeutic trials of alcohol vs. 
red wine vs. resveratrol, for example in those with heart failure. 

Introduction 

The harmful effects of risk factors for cardiovascular disease 
as often linear, as in the case of cigarette smoking and blood 
lipid abnormalities.1 For alcohol, however, the situation is 
different, with data for moderate-dose cardiovascular 
benefits2 and high-dose harm. This article will first review 
the increasing evidence for this dose-related protection, 
then evaluate the proposal that wine is more protective 
than other alcoholic drinks, and thereafter examine the 
hypothesis that red wine is more protective than white. 
Important arguments favouring this hypothesis derive from 
the role of specific protective chemical polyphenols found 
both in red wine and de-alcoholized red wine. Putative molecular mechanisms involve newly described signals and 
paths that may help to explain the proposed protective qualities of moderate amounts of red wine. 

The J-shaped mortality curve: still 
controversial? 

The major and consistent finding is that alcohol consumption, from whatever source, appears to have a J-shaped 
curve, whereby a modest intake is beneficial and either no 
intake or an increased intake is harmful. This relation has 

* Corresponding author. Tel: þ27 21 406 6358; fax: þ27 21 447 8789. 
E-mail address: lionel.opie@uct.ac.za 
been established in a series of studies starting with the Framingham study,3 followed by the British Doctors Study,4 the 
Cancer Prevention study on about 490 000 persons,5 the 
Nurses Health Study,6 the Physicians’ Health Study,7 the 
British Heart Study,8 the Multiple Risk Factor Intervention 
Trial,9 and the Copenhagen City Heart Trial,4,5,7,10,11 
However, the issue of confounding factors has bedevilled 
these findings as shown by two opposing views.12,13 Of particular relevance is a meta-analysis of mortality in 34 
outcome studies on more than 1 million subjects.14 Nearly 
100 000 deaths were analysed to show a clear J-relationship 
with decreased total mortality associated with two to four 
daily drinks for men and one to two for women vs. abstinence or higher drinking rates.14 Of note in relation to the 
controversy regarding the significance of confounding 
factors, adjustment for social factors, and dietary markers 
made the J-shaped dip shallower and shorter, yet still 
evident.14 The J-shaped mortality curve might in part be 
explained by less myocardial infarction6,15 and in part by 
less incident heart failure,16 but not by decreased 
hypertension.17 

Regarding mechanistic studies, these are many and difficult to explain by the confounding hypothesis. One established mechanism of the cardiovascular benefit is through 
a consistently reported increase in plasma high-density lipoprotein (HDL)-cholesterol levels, thought to be the result of 
increased hepatic synthesis. The definitive study shows that 

& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org 


L.H. Opie and S. Lecour 
a genetic variation in hepatic alcohol dehydrogenase, which 
slows the rate of ethanol metabolism, is associated with 
higher plasma HDL-levels and lower rates of myocardial 
infarction.18 This was a prospective study with a high rate 
of completeness of follow-up data, and part of the carefully 
monitored Physicians’ Health and Nurses’ Health studies. 
The benefits found in moderate drinkers were profoundly 
altered by the presence or absence of the ADH3 genotype, 
which is contrary to the confounding hypothesis. About 
half of the benefit of moderate drinking can be related to 
increased HDL-levels.19 Other possible protective mechanisms include anti-platelet,20 anti-coagulatory,19,21 improved 
glucose control,19 and anti-inflammatory effects as shown in 
the MONICA study.22 The latter were more evident in moderate drinkers than in abstainers or heavy drinkers. When 
given acutely for 8 weeks, ethanol reduced triglyceride 
and insulin levels.23 Of these effects, those on HDL, fibrinogen, and insulin sensitivity have been established in randomized prospective studies,19 which are especially difficult to 
explain by the confounding hypothesis. Alcohol also has detrimental high-dose (0.6–0.9 g/Kg body weight) pro-oxidant 
effects in humans,24 which together with liver damage 
may contribute to the right-hand upward slope of the 
J-curve. 

Is no alcohol really harmful? 

In a large multinational study, no alcohol intake was 
a harmful risk factor for myocardial infarction, especially 
in women.2 The first and most obvious explanation would 
be the lack of the benefit of moderate alcohol intake 
on HDL-cholesterol and, as will be discussed, the absence 
of the postulated non-ethanolic benefits of red wine. 
Alcohol has beneficial effects on insulin and triglyceride 
levels,23 and abstinence is a risk factor for new type 2 
diabetes.25 Alcohol gives experimental cardioprotection 
against ischaemic-reperfusion injury in isolated hearts.26,27 
There is, however, another explanation for the harm of no 
alcohol intake, which is the recurring problem of confounding factors which are difficult totally to exclude in epidemiological studies. Nonetheless, confounding was discounted in 
the study on British doctors,12 and also in a very large and 
up-to-date meta-analysis.14 Yet, Americans who take no 
alcohol have a different and generally less cardioprotective 
lifestyle from moderate drinkers.13,28 Regular alcohol 
intake, generally as wine and with meals, is part of the Mediterranean diet29 and the beneficial Mediterranean lifestyle. 
In France, moderate alcohol and wine drinkers smoke less 
and have a higher socio-economic status than abstainers.30 
However, confounding factors do not mean that the 
J-shaped protection is lost. Thus men with a healthy lifestyle not only have a lower rate of myocardial infarction 
but achieve increased protection by moderate alcohol 
intake.15 Those who take no alcohol might be disadvantaging 
themselves, not only for lack of alcohol, but also for lack of 
a beneficial lifestyle. 

Alcohol and blood pressure 

Here there is no J-shaped curve. A common opinion is that 
wine intake reduces blood pressure (BP) because wine is a 
relaxant. This only holds for an early effect within hours.31 
In long term, the opposite holds. A series of recent articles 

show that in normal persons, alcohol but not de-alcoholized 
red wine elevates BP by about 2–3 mmHg.31–33 Conversely, 
alcohol reduction in those men who are ‘fairly heavy drinkers’ (3 drinks per day) reduces BP by a similar degree.34 
Even such small differences may have relatively important epidemiological implications. In hypertensive men, the 
alcohol-induced rise is even greater.35 These adverse BP 
data neither exclude alternative benefits such as decreased 
aortic stiffness,36 nor changes in the pattern of arterial wave 
deflections with decreased central systolic BP.37 Overall, for 
any given level of BP, a lower all-cause mortality is associated with a moderate wine intake (,3 glasses daily).38 
This being an observational study, confounding factors are 
again difficult to exclude. 

Patterns of drinking 

Its regular intake is protective,19 especially in males.39 
Binge-drinking (more than three drinks per hour of any 
variety of alcohol) is associated with increased mortality 
after myocardial infarction.19 Binge-drinking is one of 
several lifestyle factors that may counter the J-shaped 
curve.40 Regarding the BP, there is little or no pressure rise 
if alcohol is taken with meals.41 Fitting in with the effect 
of wine in relation to meals, basic research suggests that 
red wine could protect against some effects of post-prandial 
lipaemia.42 While some other indirect evidence also supports the concept of the benefits of wine with meals,29 
there was no relation to meals in American men who predominantly drink liquor and beer.43 

Wine vs. other alcoholic drinks 

As already mentioned, many studies have related alcohol to 
the J-shaped beneficial curve.14 An important claim is that 
wine may have benefits that, for example, beer or spirits 
lack. For example, Gronbaek found all-cause mortality 
reduced in wine but not in non-wine drinkers in his study 
on 24 523 Danes over 10 years.10 In a meta-analysis on 
209 418 persons, consumption of wine but not that of beer 
was protective.11 Klatsky followed-up 128 934 adults in 
Northern California for up to 20 years.44 The J-shaped 
curve was once again confirmed. Drinkers of any type of 
wine had a lower mortality risk than did beer or liquor drinkers, in part because wine drinkers were the lighter drinkers. Renaud’s group studied 36 250 healthy French men, 
also to show that moderate wine but not other alcohol 
types reduced all-cause mortality over 12–18 years.45 
These impressive data from three entirely different 
countries must be balanced against other studies that 
differ and the recurrent problem of confounding factors. 
Thus, the type of alcohol made no difference to its protective effect on myocardial infarction in the 38 077 participants in the US male health professions study over 
12 years of follow-up.43 Moderate consumption of both wine 
and beer equally decreased inflammatory markers such as 
C-reactive protein.22 The real problem is that there are very 
few long-term prospective studies comparing the possible 
beneficial effects of the types of alcohol on cardiovascular 
outcomes or total mortality while fully allowing for confounding factors. According to such factors, wine drinkers 
have a more healthy diet than beer drinkers with increased 
intake of fruit, vegetables, and fibre.28,30,46 In the British 


The red wine hypothesis 

Regional Heart study, 7735 men drawn at random were 
followed-up for an average of 16.8 years.47 Wine drinkers 
had a lower age-adjusted risk of coronary heart disease 
and all-cause mortality than did beer and spirits drinkers, 
but the wine drinkers also had a better life style (for 
example, much less smoking). Thus the wine vs. beer data 
suggest, but do not conclusively give the benefit to wine. 

The red wine hypothesis 

It is often thought that epidemiological data from France 
strongly suggests a protective effect of red wine despite 
a high-fat diet (the ‘French paradox’). This idea goes 
back to St Leger et al.48 who in 1979 found an inverse 
relation between coronary heart disease mortality and 
wine consumption, with France having the lowest mortality. 
The jump to the specific benefit of red wine was made in 
1993 when Frankel et al. showed that red wine diluted 
1000-fold and contained 10 mmol/L of total phenols that 
inhibited the oxidation of LDL more than a-tocopherol, an 
established antioxidant.49 The antioxidant mechanisms 
involved are scavenging of peroxyl radicals as well as chelation of redox metal ions such a copper.50 Indirect evidence 
favouring the ‘French paradox’ and the red wine hypothesis 
is that the French habitually drink wine with their meals 
(which are often fatty) and this wine is most often red. Furthermore, Alsace, a white-wine drinking region of France, 
has a much higher mortality (about 50% higher) than red 
wine-drinking Mediterranean areas,51 despite having a 
lower mean serum cholesterol level.20 However, such comparisons need to take into account the many confounding 
inter-regional differences in diet and life style.30 Furthermore, there are several other explanations for the French 
paradox, including the ‘time lag’ hypothesis which states 
that the French diet had low fat in the past and that it 
takes about 30 years for any dietary pattern to manifest 
itself in mortality data.52 A PubMed search could uncover 
no good epidemiological study firmly to establish any clinical 
outcome benefit of red vs. white wine drinking in Europe. 

Most large-scale epidemiological data coming from North 
America suggest that there is no difference between white 
and red wine,43,44,53 thus concluding that alcohol intake 
rather than wine colour predicts the eventual cardiovascular 
outcome. Again there may be confounding factors. The 
pattern of wine drinking could be different, with less wine 
with meals and more prior to meals in America than in 
Europe. Furthermore, American and French diets are typically very different, for example with much more wine 
used in cooking in France. Marinating meat in red wine substantially decreases formation of potentially toxic heterocyclic amines54 and of lipid peroxides.55 

French vs. German reds: effects on nitric oxide 

French red wine is better than German reds in the induction 
of human endothelial nitric oxide synthase (eNOS) in human 
umbilical vein endothelial cells.56 Presumably, this is a class 
effect although only six French and three German wines 
were studied. In view of the similar effects on nitric oxide 
production by two French reds, the one barrel-fermented 
and the other not,56 it is very unlikely that better French 
than German oak can explain these differences. While the 
human inclination is to add such basic observations to the 

known better aroma, palate, and after-taste of French vs. 
German reds, we still await a large comparative epidemiological study proving the proposed superior cardioprotective 
effects of French red wines. 

Red vs. white wine or vodka: comparative studies 

In normal human volunteers, drinking an unspecified amount 
of red wine but not white or vodka increased coronary flow-
velocity reserve.57 Drinking red wine raised HDL-cholesterol 
and plasma antioxidant status more than did an equivalent 
dose of white wine when given to healthy volunteers.58 Furthermore, in vascular smooth muscle cells, pre-incubation 
with red wine but not white inhibited the platelet-derived 
growth factor beta-receptor (PDGF) that is crucial in the 
development of atherosclerosis.59 Conversely, incubating 
white wine with grape skins (that contain the polyphenols 
found in red wine) and alcohol endowed white wine with a 
similar power of inhibition of LDL-oxidation to that possessed by red wine.60 In human mononuclear cells incubated 
with VLDL (very low-density lipoproteins), drinking moderate doses of red wine but not vodka inhibited the activation 
of nuclear factor (NF)-kappa-B61 during post-prandial lipaemia, thus providing an anti-inflammatory mechanism.42 This 
effect was simulated by antioxidants contained in red wine. 
These comparative studies support the red wine hypothesis. 

Red wine: protective effects beyond alcohol 

The conclusive studies showing that red wine has qualities 
‘beyond alcohol’ are those on de-alcoholized red wine, 
which has cardiovascular protective effects in short-term 
studies on humans.37,62 In patients with coronary artery 
disease, 250 mL of de-alcoholized Greek red wine decreased 
arterial stiffness and improved the augmentation index, 
as derived from arterial wave reflection patterns.37 A 
similar dose of de-alcoholized red wine decreased adverse 
post-smoking arterial wave reflections and lessened the 
rise in systolic BP.62 Brachial artery flow-mediated vasodilation was improved by 250–500 mL of de-alcoholized red 
wine.63,64 Ingestion of purple grape juice in patients with 
coronary artery disease (about 640 mL/day for 14 days) similarly improved brachial flow.65 The purple grape juice also 
reduced LDL-cholesterol susceptibility to oxidation, with 
the benefits being attributed to flavonoids. Alcohol-free 
red but not white wine greatly increased plasma antioxidant 
capacity 50 min after ingestion.66 Red wine incubated with 
human plasma strongly inhibited LDL-oxidation and uptake 
of LDL by macrophages, and the active components were 
catechins and flavonols, whereas ethanol had no effect.50 

All these human studies are among the most powerful 
arguing for the benefit of red (but not white) wine beyond 
alcohol. Supporting data comes from dogs with stenosed coronary arteries, in whom administration of French blended 
red wine, apparently verging on vintage in age, eliminated 
cyclic flow reductions caused by periodic acute platelet-
mediated thrombus formation.67 This markedly beneficial 
effect was also achieved by purple grape juice, but about 

2.5 times greater volume was required than in the case of 
red wine. White wine was not protective, so that the explanation must again lie in the effects of red wine beyond 
alcohol. Experimentally, the benefit of the red wine lies in 
the polyphenols, found in de-alcoholized red wine extracts 

L.H. Opie and S. Lecour 
which improve endothelial nitric oxide release,68 and revert 
the prothrombotic effects of a cholesterol-rich diet.69 
De-alcoholized red but not white wine decreased atherosclerosis in apolipoprotein E gene-deficient mice.70 
However, there is no strict clinical proof that these 
‘beyond alcohol’ effects operate in red wine drinkers to 
give clinically significant cardiovascular protection. Rather, 
there is only indirect observational evidence in a case– 
control study that links high dietary anthocyanidin intake 
to reduce the risk for acute myocardial infarction independent of alcohol intake.71 

Specific protective chemicals in red wine: 
molecular effects 

Polyphenol extracts 

Red wine polyphenol extracts have experimental cardioprotective properties,72 and may counter one of the mechanisms underlying atherosclerosis, namely thrombin-induced 
matrix invasion of vascular smooth muscle cells.73 An 
extract of Cabernet Sauvignon suppressed endothelin-1 synthesis and release in bovine aortic endothelial cells.74 
Another polyphenol extract protected against angiotensin-
II-induced hypertension in rats by blunting endothelial dysfunction and promoting formation of nitric oxide.75 Yet, 
another polyphenol extract increased eNOS promoter and 
nitric oxide release in human umbilical endothelial cells.68 
Of the possible polyphenol components tested, the activity 
only resided in resveratrol which is a stilbene derivative 
found in grape skins, and hence found much more in red 
than white wine. Resveratrol also was an active component 
of a red wine polyphenol extract that transcriptionally inhibited the expression of endothelial vascular cell adhesion 
molecule, VCAM-1.76 Besides the polyphenols currently 
attracting most attention are resveratrol and the procyanidins (the latter are flavan-3-ols and hence part of the flavonoid family). 

Resveratrol 

Antioxidant effect 

Dosing animals with resveratrol gives a variety of cardioprotective results (Table 1) of which the strong antioxidant 
properties are perhaps the best known,26 and could 
explain the inhibition of LDL oxidation.49 The antioxidant 
effect on LDL is also linked to increased expression of the 
paraoxonase-1 gene.77 Other antioxidant effects are widespread, including cardioprotection where it offsets the 
adverse pro-oxidant qualities of alcohol.26 Furthermore, 
resveratrol inhibits the inflammatory response by suppressing 
prostaglandin biosynthesis78 and by downregulating the gene 
expression of intercellular adhesion molecule-1 (ICAM-1) 
and NF-k-B, the latter taken as an indirect biomarker of oxidative stress.79 The NF-k-B signalling pathway can be evoked 
by oxidative stress and is in turn inhibited by resveratrol80 
(Figure 1). Not surprisingly, TNF-a-induced activation of 
NF-k-B is attenuated by resveratrol and this sequence is in 
part mediated by an antioxidant effect,81 which in turn 
reduces platelet activation.82 This sequence can also explain 
the resveratrol-induced inhibition of oxidative stress in platelets induced by TNF-a.83 Resveratrol inhibits angiotensin-II 
(A-II)-induced cardiomyocyte hypertrophy, which is clearly 
linked to its antioxidant effects, because it inhibited the 

A-II-induced production of reactive oxygen species (ROS).84 
As the cellular redox state influences so many reactions, and 
is sensitive to both free radicals and to resveratrol,80 it is 
likely but usually assumed rather than directly proven that 
the antioxidant effect of resveratrol could play a major role 
in at least some of the other protective mechanisms now to 
be discussed. 

Proposed vascular protective mechanisms 

Resveratrol acts through multiple mechanisms (Figure 1), 
including the antioxidant effects on platelet formation 
already discussed. Resveratrol vasodilates isolated human 
small arteries,61 in response to oestrogen-receptor stimulation with formation of nitric oxide. The vasodilation is 
absent in arteries from patients with coronary artery 
disease.61,85 The mechanism involves increased formation 
and release of nitric oxide associated with increased eNOS 
activity.68,86 Although there is no direct evidence linking 
such increased eNOS activity to platelets, there is a well-
known effect of nitric oxide in inhibiting the activation of 
platelets. Links between resveratrol and reduced platelet 
aggregation87 could also be mediated by TNF-a.88 Resveratrol 
at a concentration of only 0.1 mmol/L increases the activity of 
NF-k-B, which lies on the TNF-a signalling pathway, in human 
endothelial cells after overnight incubation, thereby providing the mechanism for a possible anti-inflammatory and 
anti-platelet-effect.89 Increased post-infarct neovascularization is a long-term benefit.90 Resveratrol interferes with 
angiotensin-II and epidermal growth factor signalling in vascular smooth muscle cells, which may be a long-term mechanism for inhibition of atherosclerosis.91 Furthermore, 
inhibition of angiotensin-II and increased synthesis of nitric 
oxide could, in part, explain renoprotective effects92 and 
BP reduction in some renal models.93 

Cardiac fibroblasts 

Resveratrol (5–25 mmol/L) pretreatment inhibited growth 
paths stimulated by angiotensin-II, epidermal growth factor, 
or transforming growth factor-b, which are essential in 
fibroblast proliferation and differentiation.94 Thus resveratrol is potentially anti-fibrotic. 

Metabolic effects of resveratrol 

Resveratrol in high doses shifts the physiology of middle-aged 
obese mice, with features resembling the metabolic syndrome in humans, towards those of non-obese mice on a standard diet.95 The metabolic changes included increased insulin 
sensitivity, decreased circulating free fatty acids, decreased 
insulin-like growth factor (IGF-1), increased activity of the 
energy-sensing enzyme, AMP-activated protein kinase 
(AMPK), increased activity of peroxisome proliferatoractivated receptor-gamma coactivator-alpha (PGC-1a), and 
increased mitochondrial number (Figure 2). These diverse 
effects are mediated by sirtuin (see next paragraph). 
Whether similar trends can be achieved by the very much 
lower resveratrol dose associated with red wine drinking is 
a subject for future research. 

Pharmacological preconditioning by resveratrol 

In several studies, resveratrol decreases ischaemic-reperfusion 
damage (Table 1). A burst of short perfusion by resveratrol or 
pretreatment before the onset of ischaemic-reperfusion injury 
stimulates a plethora of preconditioning-like survival paths 


The red wine hypothesis 

Table 1 Concentrations of resveratrol that have relevant cardiovascular effects on isolated tissues or organs 

Tissue Concentration Effect Reference 
Human coronary artery endothelial 0.1–10 mmol/L Inhibits TNF-a-induced NF-k-B activation and 81 
cells 0.0228–2.28 mg/L inflammatory markers 

Human umbilical vein endothelial 0.1 mmol/L Increased the inhibitor of TNF-a (NF-k-B) 

89 
cells 
Human umbilical vein endothelial 1–10 mmol/L Increased eNOS promoter and nitric oxide release 

68 
cells 
Human umbilical vein endothelial 10–100 mmol/L Increased eNOS promoter activity and eNOS protein 

86 
cells levels 
Human umbilical vein endothelial 5–100 mmol/L Inhibition of tissue factor activity 132 

cells 
Human endothelial progenitor cells 1.0 mmol/L Increased activity vs. decrease with 50 mM 96 
Human hepatoma cells 5–10 mmol/L Increased expression of paraoxonase-1 gene 77 
Human platelets, ASA-resistant 10 mmol/L Reduced platelet aggregation 87 
Human small arteries, subcutaneous 0.3–30 mmol/L Dilation but not in those with coronary heart disease 61 
Rat neonatal ventricular myocytes 0.1–100 mmol/L Inhibited A-II-induced phosphorylation of ERK and 84 

A-II-induced increase of ROS levels 
Rat aortic smooth muscle cells 0.05–50 mmol/L Inhibition of A-II and epidermal growth factor-mediated 91 
growth signalling path 
Rat cardiac fibroblasts 5–25 mmol/L Inhibition of signalling paths mediated by A-II, epidermal 94 

and transforming growth factors 
Ischaemic-reperfused rat heart 10 mmol/L Expression of anti-apoptotic Bcl-2 99 
Ischaemic-reperfused rat heart 10 mmol/L Preconditioning of heart via adenosine-3 receptor 99 

and survival paths 
Ischaemic-reperfused rat heart, Gavage 2.5 mg/kg Less infarct size and apoptosis via survival paths 97 
after pretreatment 
Ischaemic-reperfused rat heart, 18.5 mmol/L in blood after Less post-reperfusion depressed function 133 

after pretreatment i.p injection 
Ischaemic-reperfused rat heart 10 mmol/L Decreased infarct size 26 
Ischaemic-reperfused rat heart 10 mmol/L Less ischaemic-reperfusion injury 134 
Myocytes from failing mice hearts 0.5 mmol/L–0.114 mg/L Inhibits falling levels of sirtuin (inhibitor of cell death) 104 

Note the wide range of concentrations used of resveratrol, always in trans form (molecular weight ¼ 228 g/mol); for relation to circulating concentrations 
likely to be found after red wine intake in humans, see text. TNF, tumour necrosis factor; NF, nuclear factor; A-II, angiotensin-II; ERK, extracellular signal-
regulated kinase; ROS, reactive oxygen species. 

Figure1Proposedmultiplevascularprotectivemechanismsofresveratrol.
ROS,reactiveoxygenspecies;NF-k-B,nuclearfactorkappaB;eNOS,endo-
thelialnitricoxidesynthase;TNFa,tumournecrosisfactoralpha;Ang-II,
angiotensinII;VSMC,vascularsmoothmusclecells.
involving signalling molecules such phosphatidyl-inositol-3phosphate (P-I-3)-kinase-Akt (Figure 2). Other preconditioning-
associated proteins include mitogen-activated protein (MAP) 
kinase kinase,96 and p38-MAP kinase-beta.97 These signals are, 
at least in part, mediated by the adenosine 3-receptor,98,99 and 
involve nitric oxide.98,100 An important prosurvival signal is activation of the antiapoptotic enzyme Bcl-2.99 The overlap of 
some of these paths (P-I-3-kinase-Akt) with those stimulated by 

insulin, may explain the insulin-like effect of resveratrol in 
diabetic rats.101 

Effects on sirtuin (anti-senescent) proteins 

These effects of resveratrol are the focus of current 
research (Figure 3). A high resveratrol diet opposes the 
effects of a high fat diet in mice, increasing insulin sensitivity, decreasing myocardial and aortic damage, and 
prolonging lifespan.95 Mechanistically, at least some of 
these effects can be related to the recent discovery that 
resveratrol is an agonist of the sirtuins (also called SIRT proteins, Silent Information Regulator Two) which belong to the 
histone deacetylase family.102 By deacetylation they inactivate the histone senescence factor p53. Conversely, overexpression of sirtuins limits premature cellular senescence.103 
Activation of sirtuins by resveratrol can experimentally 
prolong the life of myocytes from failing hearts and 
decrease myocyte death induced by angiotensin-II.104 Furthermore, resveratrol protects against Alzheimer-like neurodegeneration by increasing sirtuin activity and, thereby, 
inhibiting adverse NF-k-B signalling,105 thus, experimentally 
protecting both heart and brain via sirtuins in high doses.104 

Resveratrol: male vs. female differences 

Resveratrol stimulates the oestrogen E-beta receptors in 
vascular endothelial cells,61 and functions as an agonist for 


L.H. Opie and S. Lecour 
Figure 2 Proposed anti-ischaemic protective mechanisms of resveratrol. 
Those myocardial signalling paths involved in resveratrol pharmacological 
preconditioning are shown on the left, and those giving metabolic protection on the right. Note multiple antioxidant effects. P-I-3 kinase, 
phosphatidyl-inositol-3 phosphate-kinase; Akt, protein kinase B; BcL-2, 
mitochondrial anti-apoptotic protein; NF-k-B, nuclear factor kappa-B; LDL, 
low-dentistry lipoprotein; PGC-1a, peroxisome proliferator-activated receptor-
gamma coactivator-alpha; IGF-1, insulin-like growth factor; AMPK, AMP-
activated protein kinase; mito, mitochondria. Outlines of heart and atheroma 
modified from Opie LH Heart Physiology, from Cell to Circulation, Lippincott, 
Williams and Wilkins, Philadelphia, 2004, with permission. 


Figure 3 Proposed effect of resveratrol in countering heart failure by acting 
as an agonist to sirtuin, considered as a longevity factor. Hypothetically, heart 
failure induces overactivity of poly(ADP-ribose) polymerase (PARP), a multifunctional DNA-bound nuclear enzyme, that inhibits NAD-dependent paths 
thereby decreasing the activity of sirtuin. The proposal is that resveratrol, 
by increasing the activity of sirtuin, deacetylates and inhibits the 
pro-apoptotic effector p53 (a transcription factor). The result is that resveratrol protects cells from failing hearts against PARP-mediated cell death. For 
concepts and data, see Pillai et al.104 and Smith.131 NAD, nicotinamide 
adenine dinucleotide. Figure of heart from Drugs for the Heart, 6th edn., 
(Eds) Opie LH and Gersh B, Elsevier Saunders, Philadelphia, 2005, with 
permission. 

oestrogen receptor-mediated transcriptions albeit at a much 
higher concentration than oestradiol.85 In general, women 
are more susceptible to the harmful effects of alcohol, 
with limits of two drinks/day vs. four in men,14 because 
lower levels of the enzyme alcohol dehydrogenase give 
higher blood levels than with comparable doses in males. 

It would be intriguing to imagine that women could offset 
this gender disadvantage of alcohol by drinking red rather 
than white wine, but there are no supporting data. 

Resveratrol pharmacokinetics 

Are the protective concentrations used in such studies 
within the range that could be expected after drinking red 
wine? (Tables 1 and 2). Resveratrol itself exists in two 
forms, cis-and trans-forms that are in equilibrium and 
have similar biological activities, so that the total resveratrol concentration is relevant. However, it varies substantially between wines (Table 2). Resveratrol is only one of 
several stilbenes in red wine although the best studied. 
In Brazilian red wine, the total stilbene consumption from 
drinking half a bottle of some types of red wine per day is 
about 11 mg,106 which if all were absorbed could give a 
peak total stilbene concentration of about 10 mmol/L, or 
about 4 mmol/L of resveratrol. This potential peak value 
compares well with the lowest in vitro resveratrol concentration having an in vitro biological effect (0.1–0.3 mmol/L; 
Table 1), and raises the theoretical possibility that therapeutic resveratrol levels could be reached by drinking highresveratrol red wines. Proof of this hypothesis requires 
studies in humans of red wine dosage and related resveratrol 
blood levels. In one study, after 25 mg of resveratrol, as 
would be found in 2.5 L of some red wines (Table 2), peak 
total (free and conjugated) resveratrol was about 450 mg/L 
or about 2 mmol/L,107 20-fold more than the lowest resveratrol concentrations experimentally active (Table 1). Thus half 
a bottle of such wine should still give enough resveratrol to be 
active. However, the calculation assumes that resveratrol 
conjugates are active, which has not yet been studied. The 
peak free circulating unconjugated resveratrol was just 
about 5 nmol/L,107 which is 20-fold below the lowest effective concentration reported. In another study, a dose of 1 g 
as in 10 L of some red wines, gave higher peak free 

Table 2 Concentrations of resveratrol in various wine varietals 

Wine varietal Country of Resveratrol Reference 
origin concentration 
Pinot noir Australian 13.4 mg/L¼59 mmol/L 
135 
Pinot noir Californian 5.5 mg/L 135 
Pinot noir Burgundy 4.4 mg/L 135 
Pinot noir Spanish 5.1 mg/L 136 
Cabernet Australian 1.7 mg/L 135 
Sauvignon 
Cabernet California 0.9 mg/L 135 
Sauvignon 
Rhone valley France 3.6 mg/L 135 
reds 
Bordeaux reds France 3.9 mg/L 135 
Red, varietal Switzerland 5.0–12.3 mg/L 135 
not stated 
Red, varietal Brazil 18.0 mg/L 135 
not stated 
Red grape – 0.5 mg/L 110 
juice 

Concentration of resveratrol in red wines for comparison with concentrations used in various isolated tissue or organ experiments shown in 
Table 1. 


The red wine hypothesis 

resveratrol levels of 1–2 mmol/L.108 Thus, 1 L of such red 
wine would give levels of 100–200 nmol/L, just within the 
bottom end of the therapeutic range (Table 2). Oral administration of resveratrol to rats in doses similar to a ‘reasonable’ 
wine intake gives plasma resveratrol levels of 0.1 mmol/L,109 
about one-third of the lowest concentration that can relax 
isolated human small arteries,61 and one-fifth of the lowest 
concentration that protects mycocytes from failing 
hearts,104 but about twice the lowest level that interferes 
with signalling by angiotensin-II.91 

There are two further relevant issues. First, the plasma 
concentrations of the conjugated glucoside form, piceid, 
can be about six times higher than that of free resveratrol.110 The biological activity of these conjugated compounds is not known. Secondly, with prolonged daily dosing 
of rats with an amount of resveratrol found in 250 mL of 
some red wines, there is substantial accumulation in the 
liver, and further metabolic fates are unknown.109 Overall, 
resveratrol concentrations reached by drinking within the 
safe limits of some red wines might be just within or 
below the therapeutic range, judged by isolated tissue 
experiments. 

Procyanidins 

Resveratrol is not the only protective agent in red wine. 
Red wine contains a large number of other potentially 
active flavonoids, especially the flavan-3-ols which include 
procynanidins and proanthocyanidins (Table 3). Proanthocyanidin, like resveratrol, is a strong antioxidant and both 
equally reduce experimental myocardial infarct size and 
apoptosis in isolated rat hearts.26 The mechanisms include 
a preconditioning-like effect, shown by induction of heat 
shock protein (HSP) 70. Taking inhibition of endothelin-1 
production by aortic endothelial cells as another endpoint, 
oligomeric procyanidins inhibit ET-1 synthesis at concentrations similar to those in some red wines, with some correlation between the procyanidin activity of the wine varietal 
and the longevity.111 Oligomeric procyanidins are also inhibitors of ACE activity, in concentrations similar to those found 
in red wines.112 The antioxidant effect of red wine on LDL 
oxidation is mediated chiefly by catechins but also by the 

Table 3 Potentially active polyphenols in wine125 

Polyphenols have multiple aromatic rings possessing hydroxyl 
groups 

A. Flavonoids 
Anthocyanins: cyanidin, delphindin (both as glycosides) 
Flavonols: quercetin, as glycoside 
Flavan-3-ols (not found as glycosides): 
Monomers: catechins 
Oligomers: procyanidins,111 
Polymers: proanthocyanidins (oligomers and polymers 
contain catechins and epicatechin) 

B. Non-flavonoids 
Resveratrol 
Peceid, conjugated resveratrol glycoside 
Gallic acid 
Others 
The italicized polyphenols are those most clearly linked to beneficial 
changes in cardiovascular experiments. 

flavonol and polymeric anthocyanidins.50 However, there 
are few strict studies relating post-ingestion blood levels 
found in humans to cardioprotective concentrations in isolated tissues. In this regard, flavonoids of the catechin 
family inhibited the PDGF beta-receptor when used in concentrations similar to those found in the blood after drinking 
red wine.59 

Other active ingredients of red wine 

Of the many other polyphenolic components of red wine, the 
less well-studied flavonoids include quercetin and catechin,75 which also have properties of potential cardiovascular importance. In a dietary study in over 10 000 persons for 
1 year, those with a higher flavonoid intake, particularly 
quercetin, had less coronary heart disease.113 Both quercetin and catechin given orally can retard progression of atherosclerosis in apolipoprotein E-deficient mice, acting by 
reduction of the susceptibility of LDL to oxidation and aggregation.114 In humans, plasma catechin rises to about 
75 nmol/L soon after the equivalent of one to two glasses 
of red wine.115 These levels contrast with those experimentally protective, such as 50 mmol/L.114 De-alcoholized red 
wine decreased atherosclerosis in apolipoprotein E gene-
deficient mice, acting by phenolic acids not listed in 
Table 3.70 The mechanism involved decreased LDL oxidation 
associated with decreased alpha-tocopheroxyl radicals, the 
oxidation product of vitamin E. Thus protective effects of 
vitamin E could be facilitated, overcoming the otherwise 
adverse excess pro-oxidant effects. In mice, a daily dose 
of Cabernet Sauvignon similar in dose to half a bottle of 
wine per day for humans, and with a long list of potentially 
active polyphenols, was neuroprotective against experimental Alzheimer’s disease.116 Multiple mechanisms of benefit of 
various ingredients seem probable. What is still missing are 
human data on the pharmacokinetics and bioavailability of 
the polyphenols found in red wine.117 Nonetheless of note, 
at least one laboratory effect of polyphenols, namely inhibition of thrombin-induced matrix invasion of vascular 
smooth muscle cells, can be found in concentrations 
similar to those achieved after moderate red wine 
ingestion.73 

Proposed protective components in white wine 
and beer 

White wine may have different protective qualities 

Red and white wine have equal effects on fibrinolytic factors 
in a short-term cross-over study.118 Equal effects on 
collagen-induced platelet aggregation are also reported.119 
In addition, white wines may contain anti-inflammatory protective substances that lessen cytokine release, as also 
found in extra virgin olive oil.120 Thereby, the inflammatory 
reaction that promotes atherosclerosis could be lessened. 

De-alcoholized beer may also give some protection 

Some epidemiological studies have not shown less protection by beer than wine drinking.22 De-alcoholized beer inhibits platelet and thrombogenic activity in young adults.121 
However, the dose was high (3 L) so that if translated into 
the amount of alcohol in standard beer, such intake would 
be harmful. 


L.H. Opie and S. Lecour 
Overall perspective 

There are several sequential proposals leading from observational population studies. Thus (i) only modest alcohol 
intake gives a J-shaped pattern of protection; (ii) wine is 
more protective than beer; and (iii) red wine is more protective than white. Of these, the J-shaped curve is best established, but in every case confounding factors are difficult to 
exclude.107,122 However, in the case of the J-shaped curve, 
the genetic links between alcohol dehydrogenase activity, 
increased HDL-cholesterol, and decreased myocardial 
infarction, and the prospective trial data on HDL, fibrinogen, 
and insulin, are powerful arguments against confounding. 
Moderate red wine drinking could be, at least in part, a surrogate for a healthy life style. In this case the cardiovascular 
data with de-alcoholized red but not white wine and 
studies on isolated tissues or organs give decisive mechanistic insights that strengthen the case already made for 
randomized prospective controlled trials with cardiovascular endpoints.122 The first trial should simply compare 
alcohol with red wine with abstinence, for example in post-
infarct patients.107 Similar prospective studies would be 
needed conclusively to prove the red-better-than-white 
wine hypothesis. 

As these studies may never be done, attention has shifted 
to the beneficial components of red wine. Resveratrol 
remains as the most powerful of the polyphenols and one 
of the most likely to give biological protection.123 The 
recent discovery that resveratrol is an agonist of the sirtuin 
(SIRT) proteins may lead to a dose-response trial of resveratrol and red wine in heart failure patients. However, pharmacokinetic data remain incomplete. Experimentally, other 
polyphenolic components of red wine also play a protective 
role. One hypothesis would be that no single component 
of red wine confers all the benefit, but rather several components contribute by different mechanisms. For example, 
resveratrol and procyanidins are both antioxidants, but 
resveratrol interacts with SIRT, whereas the procyanidins 
inhibit endothelin-1 synthesis. 

Given that there will always be wine drinkers, do current 
data help in choice of wine? First, all drinkers of any alcohol 
should avoid overdosing and binge-drinking. Then they 
should consider the incomplete but emerging evidence 
that red wine is more cardioprotective (and possibly, neuroprotective) than white. Furthermore, as red wine-drinkers 
can choose a specific varietal, pinot noir is high both in 
resveratrol124 and in procyanidins.125 The price of pinot is 
high enough to ensure drinking only in moderate amounts 
and preferably with meals. Some may be influenced by the 
neuroprotective qualities of Cabernet Sauvignon given in 
low doses to rodents. And others, especially those influenced by American epidemiological data, will settle for 
ethanol as the major cardioprotective agent in wine. Teetotallers will be consoled by the substantial data linking 
de-alcoholized red wine to experimental cardiovascular 
benefits and turn to purple grape juice. Hopefully, in the 
future, low alcohol yet still protective wines will make 
their debut.126 

Special patient groups who need abstinence 
or specific limitations 

Those with gout are traditionally warned against red wine, 
which does increase blood uric acid levels.127 Those with 

alcoholic cardiomyopathy may not take any alcohol, 
despite the ‘ambiguous’ effects of ethanol on myocardial 
function.128 Those with atrial fibrillation should be safer 
with less than 35 drinks/week.19 Hypertensive males 
may need to limit drinks to not more than two/day34,129 
with, presumably, even fewer for hypertensive females. 
However, as alcohol only elevates BP by a few millimetres 
of mercury, a reasonable alternative would be to monitor 
by BP measurements the contrasting policies of (i) allowing 
the normal moderate amounts of alcohol while watching the 
BP and, if needed, adjusting doses of anti-hypertensive 
drugs; and (ii) keeping the medication unchanged but 
cutting the alcohol. Post-myocardial infarction, moderate 
alcohol does not impose a greater risk of overt heart 
failure on those already having systolic dysfunction.130 
Also, it is important to remember that alcohol interacts 
with many drugs such as nitroglycerin, anxiolytics, neuroleptics, and oral contraceptives. 

Summary 

There are strong epidemiological data favouring the view 
that modest alcohol but neither zero nor more than 
modest intake beneficially reduces total mortality and 
cardiovascular risk. As there is only a narrow window of 
opportunity for optimal intake, it becomes important to 
consider which is the most beneficial type of alcohol. The 
‘red-better-than white’ hypothesis rests on1 human studies 
showing short-term cardiovascular benefits achieved by 
de-alcoholized red but not white wine; and2 many studies 
on isolated tissues or organs assessing the effects of polyphenols in red wine, especially resveratrol. Thus, red wine 
potentially has beneficial effects ‘beyond alcohol’. The molecular mechanisms involved are many and complex as 
revealed by studies on isolated tissues or organs. Besides, 
the well known antioxidant effects of polyphenols, resveratrol effects include activation of preconditioning-like pro-
survival signalling paths similar to those responding to 
insulin, anti-apoptotic protection mediated by the anti-
senescence factor sirtuin, and inhibition of adverse signalling by TNF-a, NF-k-B, angiotensin-II, and growth factors 
(epidermal and transforming growth factor-beta). Mechanistic feasibility strengthens the case for prospective therapeutic trials. 

Acknowledgements 

We would like to thank D. Blackhurst for very helpful comments. 

Conflict of interest: none declared. 

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