Article by Stuart J. Adams, Nutritionist , Author and Speaker
Most well-designed population studies have demonstrated a ‘J curve’ relationship between wine consumption and the risk of cardiovascular disease. [1-5] This means that people who do not drink alcohol at all (abstainers) and those who consume more than 30 g/day of alcohol (approx 2.5 standard drink)s have an increase risk of death from all causes, higher blood pressure levels as well as poorer liver function.
On the other hand, moderate alcohol intake (1-2 drinks/day) is associated with decreased Coronary Heart Disease (CHD) risk in both men and women. Small daily doses seem to have a more protective effect than an equal single daily dose. Moderate doses of alcoholic beverages also have a protective effect in individuals who have already suffered a myocardial infarct (heart attack), by reducing the risk of subsequent heart attacks. This observed J–shape relationship is especially consistent among drinkers of red wine. This association gained particular attention amongst the French population, because despite their high intake of saturated fats and other particularly unhealthy foods, their rate of heart disease was relatively low due to their wine intake; a phenomenon known as the “French paradox” . 
Red wine possesses several potentially heart-healthy mechanisms, including favorable effect on blood clotting, endothelial function and serum lipids (most notably the ability to raise levels of HDL ‘good’ cholesterol).
The cardio-protective effects observed in red wine drinkers are thought to be attributed at least in part to the moderate alcohol intake, but especially due the polyphenolic compounds red wine possesses; most notably, a flavonoid called resveratrol. Laboratory studies have revealed that resveratrol possesses several cardio-protective actions as well as cancer-protective effects. This may explain why some population studies have found a slight decrease in the risk of some cancers among moderate red wine drinkers.
It is very important to note however that higher alcohol consumption significantly increases the risk of many cancers; especially breast cancer in women. Along with smoking and obesity, alcohol consumption is perhaps the most significant lifestyle factor known to increase the risk of cancer, as well as other diseases such as liver problems.
Consequently, 1 to 2 glasses of red wine (with a meal) for men and 1 glass for women, several days of the week, may help to fight heart disease. Any more than that however may be doing more harm than good.
Red Wine & Cardiovascular Disease Risk Factors
Wine & CHD: Epidemiology
A prospective cohort study following 6,051 men and 7,234 women, 30-70 years of age for 10-12 years, showed a significant decreased risk for Coronary Artery Disease among wine drinkers. Compared to non-wine drinkers, people who consumed several glasses of wine per day had a 50% reduced risk of death from all causes. The intake of beer or spirits however was not associated with risk reduction. (figure 1)
A recent case-control study conducted in Spain also found that a moderate alcohol intake, particularly from wine, significantly decreased the risk of heart attacks.
A meta-analysis of 13 epidemiological studies which examined the association between wine intake and cardiovascular disease (11 on Coronary Heart Disease and 2 on Stroke) among over 201 thousand people was published in 2002.
The results showed that moderate wine drinkers had a 32% average decreased risk of cardiovascular disease compared to non-drinkers. A J-shaped curve was observed for the relation between wine and cardiovascular disease risk, as very heavy consumption increased the risk in a linear fashion. The same meta-analysis looked at 15 studies examining the risk in relation to beer drinking, however the results were less consistent.
Figure 2. shows the Relative Risks or Odds Ratios for different categories of wine intake (dose-response curves), as reported by the original investigators. The black line indicates the predicted model using data from all studies.
Ten of the 13 studies showed a dose-response relationship between wine intake and Cardiovascular Disease (7 on CHD and 3 on Stroke) involving a total of 176,042 people. When only the 7 prospective cohort studies were considered, a more evident inverse relationship was found and this was used to construct the average dose-response curve in Figure 3. [The best fitting model was used to construct an average dose-response curve.]
Although a maximum reduction was predicted at 750 mL/day,(equivelant to 1 bottle of wine), statistical significance was only reached up to the amount of 150 mL/day. (1.5 glasses) This is shown by the vertical lines which represent 95% confidence intervals. This basically means that although the average highest protection was found to be approx 750 ml / day, the ranges at this level were very large, therefore only the smaller doses were considered to be a more reliable source because the highest and lowest ranges of risk were not so extreme.
Mechanisms: How Red Wine Protects Against Atherosclerosis
Alcohol, particularly red wine, has been shown to be able to increase serum concentrations of HDL “good” cholesterol. This was first discovered when a 69 year old man in Germany who had a family history of high “bad” cholesterol, was found to have significantly high levels of HDL “good” cholesterol. Even though he was nearly 70 years old, he showed no signs of atherosclerosis. Knowing that the man was a heavy drinker of red wine, his physicians asked him to stop drinking for 21 days, and then go back to his usual drinking habits for an additional 21 days. They tested his blood throughout this time to see whether any significant changes occurred. During the time he stopped drinking, his HDL “good” cholesterol levels reduced to almost one quarter of what they were to begin with. After he began drinking as per usual again, they went back up to what they were to begin with. It appeared that this mans red wine drinking was causing his high HDL levels which protected him from developing atherosclerosis. 
Since then, a multitude of studies have been performed both in animals and humans to examine the relationship between alcohol, wine and particularly red wine in relation to cholesterol levels, atherosclerosis as well as other risks and protective effects associated with heart disease.
A 3-week long study involving premenopausal women on the contraceptive pill and postmenopausal women investigated the effect of red wine consumption with dinner on serum lipoprotein levels. Red grape juice (non-fermented) was used as a control. The results showed that after wine consumption, the overall HDL “good” cholesterol level was increased in postmenopausal women, whilst the LDL “bad” cholesterol levels were reduced in premenopausal women as compared with those who received only grape juice.  Another 2-week long study involving 20 healthy males found that red wine, but not white wine, significantly increased HDL levels by 26% and increased plasma apolipoprotein A-I levels by 12%. 
Several other human trials have shown that red wine consumption increases the levels of HDL “good” cholesterol,  including a study involving 10 males between 18 – 21 years old with normal cholesterol status that drank no other alcohol than red wine for 4 weeks. The results showed HDL levels were increased by 25%.
Studies in France have also found that drinkers of red wine have higher levels of HDL “good” cholesterol and apolipoprotein A1 ( a substance found in HDL known to prevent the accumulation of cholesterol loaded white blood cells which deposit on the arterial wall as “foam cells”; a prominent early feature of atherosclerotic lesion formation ) than non-drinkers.
Effect on Vascular Endothelium
Another important process in the development of atherosclerosis is the proliferation of smooth muscle cells from the outer layer of the arteries into the inner layer called the tunic intima. This causes the arteries to narrow and lose their elasticity which leads to formation of atherosclerotic plaques and eventually blocks the arteries. This proliferation occurs when platelets secrete a substance called Platelet Derived Growth Factor (PDGF). Studies in vitro have found that red wine but not white wine, has a beneficial effect on these vascular smooth muscle cells by interfering with the biochemical pathways involved in PDGF, thus having a protective effect by preventing smooth muscle cell proliferation and consequently slowing the development of atherosclerosis. Importantly, the concentrations of red wine shown to inhibit the PDGFR in vitro are similar to levels likely to be found in human blood after red wine consumption.
A recent study had 14 patients with coronary artery disease (CAD) consume either white or red wine with a light meal so that the function of the inner layer of their arteries (endothelium) could be assessed. Endothelial dysfunction has been implicated as a key event in the pathogenesis (causation) of atherosclerosis and myocardial ischaemia (heart attack). After several hours, endothelial function improved nearly three fold from both red and white wine compared with no wine (cordial was used as a control).
An 8-week long randomized crossover trial in Italy investigated the effect of moderate red wine intake on cardiovascular disease risk factors using 48 men and women between 35-65 years old. The results showed that red wine consumption had significant beneficial effects on all the risk factors assessed. Red wine consumption significantly increased HDL “good” cholesterol, decreased the ratio between LDL/HDL (bad and good cholesterol) and increased apolipoprotein A1 ( a substance found in HDL known to prevent the accumulation of cholesterol loaded macrophages which deposit on the arterial wall as foam cells; a prominent early feature of atherosclerotic lesion formation ). Moreover, red wine consumption caused significant decreases in fibrinogen, factor VII , plasma C-reactive protein, and oxidized LDL antibody, whilst causing significant increases total plasma antioxidant capacity. All these factors suggest a protective effect of red wine on cardiovascular disease. 
The Alcohol, the Polyphenols or Both?
Whether the alcohol, the polyphenols or a combination of both are responsible for the cardio protective effect of red wine, has been the subject of recent investigations. Several studies have shown that the non-alcoholic components of red wine, mostly notably the polyphenic flavonoids, can exert protective effects on cardiovascular disease by inhibiting the formation of atherosclerotic plaques in a number of ways. Some of those mechanisms are discussed here:
To assess the effect of red wine on atherosclerosis, rabbits were given a high cholesterol diet for 12 weeks and compared to animals that received the diet plus either red wine or non-alcoholic wine products. The high cholesterol diet induced a significant increase in total and LDL “bad” cholesterol levels. When the rabbits were killed and their arteries were examined, both the rabbits given red wine and those given non-alcoholic wine had significantly less atherosclerotic plaque development in their arteries than those not given wine at all; however the alcoholic red wine gave the most protection. 
Examples of the effect of red wine and non-alcoholic wine products (NAWP) on macroscopic plaque formation in cholesterol-fed rabbits. Aortas were stained with Sudan IV and plaque area was measured by planimetry and reported as percent of total aortic surface. Red staining indicates atherosclerotic plaques. Control animals show more plaques than wine- or NAWP-treated rabbits.
De-alcoholized red wine has also been shown to decrease atherosclerosis in mice. 
The inside layer of the arteries (endothelium) can also release a chemical called nitric oxide (NO) which may protect against the development of atherosclerosis by inhibiting the proliferation of smooth muscle cells into the tunic intima (which causes the arteries to narrow and harden) and by inhibiting platelets and white blood cells from adhering to the inside of the arteries. Red wine polyphonol extract has been shown to significantly increase the release of endothelial nitric oxide by approximately 2-fold; yet another means by which red wine components can protect against the development of atherosclerosis. Other studies have also showed that red wine and purple grape juice can enhance platelet and endothelial production of nitric oxide. [35,36] In fact, endothelial function was significantly improved by purple grape juice consumption in a study involving 15 patients with Coronary Artery Disease.
Adhesion of a type of white blood cell called monocytes to the endothelium plays another important role in the early development of atherosclerosis. Resveratraol has been shown to reduced monocyte cell adhesion to stimulated endothelium. 
Other than Resveratrol and quercetin, another ac tive compound of red wine called Delphinidin has also shown beneficial effects by preserving endothelium integrity, the alteration of which leads to diseases including cardiovascular diseases such as atherosclerosis, and is often associated with cancers.
Animal studies have shown that Resveratrol and red wine flavonoids alone could decrease total cholesterol (TC) in rats.
A study involving postmenopausal women examined the effect that either alcoholic red wine, de-alcoholized red wine or plain water (placebo) had on cardiovascular risk factors such as HDL “good” cholesterol, LDL “bad” cholesterol and vascular compliance (the ability of a blood vessel wall to expand and contract passively with changes in pressure. Increased vascular compliance is associated with an increased risk of high blood pressure and cardiovascular disease.). The results showed that cholesterol status was not affected immediately after red wine consumption; however tests performed on the women after several weeks of daily consumption found that alcoholic red wine decreased LDL “bad” cholesterol and increased HDL “good” cholesterol, whilst the de-alcoholized red wine improved vascular compliance. The authors of this study concluded that the reduction in cardiovascular risk by moderate long-term red wine intake is due to a synergistic effect of both the alcohol and the non-alcoholic polyphenol components found in red wine. 
Another study using 56 healthy young men who consumed either alcoholic red wine, a solution with the same degree of alcohol or de-alcoholized red wine found that the alcoholic red wine had a more beneficial effect by increasing serum HDL cholesterol levels as well as increasing apolipoprotein A1 and other lipoprotein fractions associated with a protective effect. The de-alcoholized wine and the solution with the same concentration of alcohol as the alcoholic red wine did not show the same benefit, implying that the alcohol and the other non-alcoholic components of red wine are more beneficial when consumed together than when only consuming one or the other. 
One of the most important stages in the development of atherosclerosis involves the oxidation of LDL particles. Studies examining the effect of red wine on human lipoproteins have showed a protective antioxidant effect by decreasing oxidation of both HDL and LDL particles,  LDL retention, and LDL aggregation attenuating macrophage foam cell formation and atherosclerosis.  Further investigations have found that red wines ability to inhibit oxidation of lipoproteins is due to the non-alcoholic components, namely its polyphenols. [45, 46]
A study involving 21 male subjects taking de-alcoholized red wine extract or quercetin (another polyphenol flavonoid found in red wine) supplements showed that both could decreased LDL oxidation after 2 weeks.  Furthermore, total plasma antioxidant capacity has also been shown to be increased by alcohol-free red wine as well, but not white wine  .
Recent studies have shown HDL-Cholesterol levels can explain only approximately 50% of the cardio-protective effect of alcoholic beverages. The other 50% may be related to other factors such as decreased platelet activity; that is, a decrease in the ability of blood platelets to form clots, an action sometimes referred to as “thinning the blood”. This is significant because the build up of platelets on the wall of arteries is one of the initiating stages of the development of atherosclerosis. 
The anti-platelet activity of wine is explained not only by its alcohol content but also by the polyphenolic components which occur most heavily in red wine. Furthermore, wine phenolics increase vitamin E levels while decreasing the oxidation of platelets submitted to oxidative stress. This protection afforded by wine has been duplicated in animals with grape phenolics added to alcohol. It appears that wine and wine phenolics in particular, could significantly inhibit platelet aggregation and that this could explain, at least in part, the protective effect of red wine against atherosclerosis and Coronary Heart Disease. 
Tissue factor (TF), the cellular receptor that initiates blood clotting, also plays a primary role in the development of atherosclerosis. Resveratrol and quercetin, two of the polyphenols found in red wine, have been shown to inhibit TF activity in a dose dependant fashion. 
A Synergistic Effect
These studies provide evidence that both the alcohol and the non-alcoholic components of red wine can exert significantly beneficial effects by preventing formation of atherosclerosis, thus reducing the risk of cardiovascular disease. One or two glasses of red wine per day with meals may afford the best protection, as more than this may provide excessive amounts of alcohol and do more harm than good. If one wished to consume more red wine than this, they may wish to use de-alcoholized wine after the first 1 or 2 drinks, as excessive alcohol can be extremely destructive. One or two standard drinks per day would provide the maximum beneficial effect from alcohol, whereas subsequent consumption of de-alcoholized red wine would continue to provide protective effects from the flavonoid portion, without the damage of excess alcohol.
Red Wine and Cancer
Although excessive alcohol intake has been shown to increase the risk of various cancers, there is some evidence to suggest that frequent moderate red wine intake may have some cancer preventing effects, due largely to it’s high level of polyphenols such as Resveratrol and other flavonoids.
A population based cohort study in Europe investigated the association between alcohol intake and mortality from all causes, coronary heart disease and cancer.  Assessment of beer, wine and spirit intake, smoking habits, educational level, physical activity, and body mass index were made of 15,117 men and 13,063 women aged 20 to 98 years. A total of 4,833 participants died throughout this time, of these 1,075 from coronary heart disease and 1,552 of cancer. Compared with non-drinkers, light drinkers who avoided wine did not have a very significant difference in mortality, however those who drank wine had a 34% reduced risk of all causes of death. Furthermore, heavy drinkers who avoided wine were at higher risk of death from all causes than were heavy drinkers who included wine in their alcohol intake. Most importantly, wine drinkers had significantly lower mortality from both coronary heart disease and cancer than did non-wine drinkers.
Later these researchers looked specifically at cancers of the upper digestive tract (mouth and oesophagus). After 13.5 years from the beginning of the study, 156 persons developed upper digestive tract cancer. Compared with non-drinkers, people who drank 7-21 beers or spirits a week but no wine had a 3-fold risk of getting upper digestive tract cancer. On the other hand, those who had the same total alcohol intake but with wine intake was equal to or greater than 30% had a 50% reduced risk. This study did not differentiate between red and white wine consumption however, and it should be noted that other studies not differentiating between the two types of wine have found differing results.
A case-control study in Portugal involved 74 patients diagnosed with gastric cancer and 193 controls from the same hospital ward. The study found that red wine actually increased the risk; however the patients in this study consumed between several glasses and more than a bottle per day. This degree of alcohol consumption is clearly excessive.
A small case-control study in France involving 154 premenopausal female patients diagnosed with primary breast cancer and 154 controls found no protective effect from red wine, but a slightly protective effect from white wine.
One the largest cohort studies to be conducted in the United States involving over 120 thousand females aged 35 - 50 known as the Nurses Health Study (NHS) has been under way since1976. Every 2 years these women are sent surveys to complete regarding dietary and lifestyle habits. A recent analysis of these results has found an inverse relationship between red wine consumption and Basal Cell Carcinoma; the most common form of cancer, affecting 800,000 Americans each year.
The results showed that women whose average red wine intake was up to 5g day, 15g/day and 30 or more g/day had a 10%, 22% and 44% reduced risk respectively.  No other clear protective effect was found among any other type of alcoholic beverage, in fact most alcoholic beverages were associated with an increased risk. However, no significant association between red wine and BCC was seen in the Health Professionals Follup-Up Study (HPFS), a cohort study involving over 50 thousand male health professionals.
A smaller cohort study in Minesota involving 1,508 women looked at breast density, a known risk factor for developing breast cancer. The results suggested a positive trend between breast density and daily alcohol consumption, but other than that, the only significant dietary habit found to have any association was red wine intake, in which an inverse association (protective) was observed among post menopausal women.
The relationship between alcohol consumption and risk of non-Hodgkin’s lymphoma (NHL) was studied in a cohort of 35,156 Iowa women aged 55-69 years who participated in the Iowa Women’s Health Study in 1986. During the 9-year follow-up period, 143 incident cases of NHL were identified.A more frequent intake of red wine was associated with a significantly reduced risk. 
A recent case control study conducted in Western Australia surveyed 753 men aged 40-64 recently diagnosed with prostate cancer, and 703 men of the same age without cancer for comparison (controls). No significant difference in alcohol consumption was found between the cases and controls other than an inverse relationship with red wine. The men who consumed 1-3 glasses per week had a 20% reduced risk, those that had between 4 and 7 glasses per week had a 50% reduced risk, and those that drank 8 or more had a 55% reduced risk. 
A hospital based case-control study assessing alcohol consumption and lung cancer was conducted on 319 subjects (132 cases, 187 controls) in Spain between 1999 and 2000. A very slight but significant association was observed between the risk of lung cancer and white wine consumption. Red wine consumption on the other hand, decreased the risk by nearly 60% with each daily glass of red wine having an inverse association with the development of lung cancer. 
A case-control study in Hawaii and Los Angeles involving 558 women with ovarian cancer and 607 population controls found no overall association of alcohol drinking, but a decreased risk among wine drinkers. Those who specifically drank red wine had a 40% reduced risk of ovarian cancer than never-drinkers. 
Red Wine & Cancer Epidemiology: In Conclusion
Alcohol consumption, especially heavy alcohol consumption, is known to increase the risk of nearly all cancers. The studies discussed here present preliminary evidence to suggest that moderate red wine consumption may offer some protection against certain cancers, but until these results can be replicated in further studies, no clear conclusion can be reached.
Resveratrol: What is it?
Among other polyphenolic flavonoids, resveratrol is thought to be at least in part responsible for the possible anti-cancer effect of red wine. Resveratrol has been found in at least 72 plant species (distributed in 31 genera and 12 families), a number of which are components of the human diet, such as mulberries, grapes, [62,63] red wine,  and peanuts.[65,66] In grapes, especially when exposed to fungal infection,  resveratrol is exclusively synthesized in the grape skins when they are fresh. Because resveratrol is synthesized by grape skins when exposed to fungi, and yeast are a type of fungi, the resveratrol concentrations increase significantly during wine fermentation because yeast is added. Consequently, the resveratrol concentration of wine is much higher than that found in fresh grapes and grape juice. Fresh grape skin contains about 50 to 100 µg of resveratrol per gram, whereas the concentration in red wine is in the range of 1.5 to 3 mg/liter. [68-70]Because the grape skins are not fermented in the production process of white wines, only red wines contain considerable amounts of resveratrol.
Resveratrol and Cancer: Chemoprotective Mechanisms
Resveratrol and its analogs have shown significant anti-cancer properties in laboratory studies. [71,72] Several different molecular mechanisms of the chemo-preventive effects of resveratrol have been studied.  In a number of laboratory studies including cell culture (in vitro) experiments as well as animal (in vivo) experiments, resveratrol has demonstrated anti-cancer activity in the three major stages of carcinogenesis (cancer development); tumour initiation, tumour promotion and tumour progression. 
Its ability to inhibit tumour initiation seems to come from its antioxidant and anti-mutagenic action, as well as its ability to induce phase II drug-metabolizing enzymes. Its ability to inhibit tumour promotion comes about because it can inhibit cyclooxygenase-1 (COX-1) an enzyme that converts arachidonic acid to pro-inflammatory substances that stimulate tumour growth. However, recent investigations have found that resveratrol is not the only chemical in red wine which is responsible for the inactivity of COX-1, as other red wine constituents, namely the catechins and epicatechins, can also inactivate COX-1 due to their peroxidase mediating mechanism. Its tumour progression inhibiting action comes from its ability to induce cell differentiation in cancer cells;  a function that fails to occur in tumours.
Normal healthy cells undergo apoptosis; a programmed cell death which enables new healthy cells to replace the old ones. In tumours, cancerous cells fail to undergo apoptosis, so more cells continue to grow without the old ones dying off. This causes the tumour mass to grow, spread and invade other tissues. Many cancer treating therapies are aimed at causing cancer cells to undergo apoptosis to stop their spread. Resveratrol has been shown to induce apoptosis in human breast cancer cells and leukaemia cells by enhancing expression of CD95L, (a membrane protein that induces apoptosis), whilst not affecting normal healthy cells of the immune system. Resveratrol can also cause cell death in cancer cells by mediation of caspases; a family of proteins within the cells that are one of the main effectors of apoptosis.  Resveratrol has also showed the ability to inhibit the growth of prostate cancer cells whilst leaving normal cells unaffected. 
Laboratory studies have also discovered that among other anti-cancer properties, resveratrol has the ability to inhibit angiogenesis;  the increase in blood vessel growth to cancers. Inhibiting angiogenesis is a method used to starve cancer cells of nutrients, as without this increased blood supply, tumours can not grow.
Animal studies have shown that rats implanted with liver cancer had a dose-dependant suppression in tumour metastases when given resveratrol for 20 days. Resveratrol also decreases triglyceride levels as well as LD “bad” cholesterol levels. Raised levels of these serum lipids are strongly associated with an increased risk of cardiovascular disease. 
Mice implanted with human gastric cancer cells were either given varying doses of resvertatrol or no resveratrol. It was found that resveratrol could significantly inhibit cancer growth (up to 40%) in a dose-dependant manner by inducing apoptosis among the cancer cells. 
A major appealing characteristic of resveratrol’s anti-cancer potential is its minimal toxicity to blood-forming cells. 
Resveratrol and Cancer: In Conclusion
Although these studies provide preliminary evidence to suggest that resveratrol has anti-cancer properties, human trials are needed before resveratrol should be considered as a cancer fighting treatment in humans. These studies do at least provide some reason to explain why red wine consumption may protect against certain cancers. Red wine also contains many other phenolic compounds which although have not been studied as in depth as resveratrol, may also provide beneficial effects to human health.
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