It has been well established that alcohol can cause bodily harm. The ancient idiom, “there is a devil in every berry of the grape”, has long served as a warning of the treacherous consequences of alcohol abuse.

More recently, scientific endeavours have uncovered hidden sources of potential health within the “berry of the grape”. Impressive nutrients contained within the red grape, described by some investigators as “blessings of the grape”, (1) may hold the key to health and longevity for humans. Resveretrol is one such nutrient, having a range of health giving and health preserving biological properties.

RESVERETROL.

Resveretrol is a polyphenol phytoalexin which derives from red grape skins and seeds. It possesses diverse biochemical properties and exerts a variety of physiological actions that have been shown in laboratory studies to retard age related diseases and prolong lifespan. (2) (3).

Resveretrol has anti-oxidant and anti-inflammatory properties, and it’s capacity for offering protection against several common disorders has been documented, such as Alzeimer’disease, (4) prostate cancer (5) breast cancer (6) colon cancer (7). More recent discoveries of it’s hidden potential renders it a therapeutic promise for a number of cardiovascular diseases. (8) (9).

Resveratrol has also been isolated from a variety of berries, some pines, and the roots and stalks of Japanese knot wood. (10).
Within these plant forms Resveretrol provides a natural defence against injury or disease, and in laboratory experiments, Resveratrol has been shown to slow ageing and extend the life spans of widely divergent species, including round worms, fruit flies (11) and fish (12).

Several lines of research indicate that health benefits for humans are likewise possible through the ingestion of dietary or supplemental Resveratrol.

More recently, evidence has emerged indicating that Resveratrol offers cardiovascular protection to humans through it’s support of endothelial tissue lining arterial blood vessels.

ENDOTHELIAL FUNCTION

Arteries are not merely conduits for blood flow throughout the human body. They are, in fact, dynamic, functioning, muscular structures that expand and contract in order to facilitate circulation and maintain optimal blood pressure.

The integrity of blood flow to the peripheral organs is dependent upon the efficiency of the arterial wall, in which each layer provides a specific function that supports healthy vascular activity.

The innermost layer of the arterial wall is composed of endothelial cells whose integrity is crucial for the health of the artery. These cells form a protective barrier preventing toxic substances in the blood from entering the middle layer of elastic smooth muscle.

The endothelial cells also withstand the impact of mechanical forces induced through blood pressure changes within the artery, and are capable of actively secreting substances into the middle layer of the arterial wall to maintain the tone and resilience of the artery. Any threat of injury to the endothelial cells triggers a responsive action within the middle layer of the arterial wall whereby smooth muscle cells migrate towards the site of injury forming a protective layer.

The active endothelial cells also produce substances that cause platelet adhesion to the site of injury, thereby preventing further injury to the arterial wall.

This process of “response to injury” is termed atherosclerosis, since the changes occurring as a result of this process lead to a thickened and hardened arterial wall. (13).

This process is an age-related phenomenon, but may be precipitated prematurely by a wide range of factors, some modifiable, such as high blood pressure, nutrient imbalances, oxidized lipoproteins, excess iron, excess glucose, insulin, cigarette smoke, homocysteine, fibrinogen, infections and toxins.

While atherosclerosis may be a predisposing factor in the onset of coronary artery disease (CAD), it is not the sole cause of CAD, since other factors, such as vasospasm of coronary arteries, or blood emboli formation, may give rise to heart attacks or stokes, even while coronary arteries are free of disease and blood cholesterol levels are normal.
Post-mortem studies of heart-attack victims have shown that in about one out of five of these victims there was no evidence of coronary atherosclerosis. (14).

A recently published study in the 2009 American Heart Journal revealed that almost 75% of patients who were hospitalized for a heart attack had normal or below normal blood cholesterol levels (15).

The prevailing medical paradigm that focuses on costly cholesterol reduction strategies is at risk of ignoring alternative cost effective and beneficial strategies that may provide protection for arteries at risk.

Resveretrol may be a future therapeutic option in this regard.

ENDOTHELIAL DYSFUNCTION.

A common feature of endothelial dysfunction is an abnormality in the production of Nitric Oxide, a vital factor in the maintenance of arterial wall integrity. Nitric Oxide (NO) is produced by the endothelial cells and regulates endothelial cell interactions, arterial wall blood flow, vascular tone and platelet aggregation and adhesion. (platelet stickiness) (16).

These biological events represent a complex cascade of inflammatory changes within the arterial wall, and are collectively referred to as “endothelial dysfunction”, since the end result is an impairment of endothelial integrity and function. The end result of these arterial wall changes may be the formation of plaque, a thickened area of the vessel wall, which comprises macrophages (scavenger white cells), smooth muscle cells, oxidized phospho-lipids, collagen and calcium and platelet adhesion. (Plaque is not a “cholesterol plug obstructing the lumen of arteries, as is depicted by many popular cholesterol lowering agent advertisements.) Plaque may remain stable, or become unstable giving rise to fragmentation and emboli formation, which may impair blood flow to distant organs, causing a stroke or heart attack, or other organ damage.

PLAQUE MEASUREMENT.

Measuring arterial wall thickness is a common end point target for evaluating the success of plaque reducing strategies. However the measurements of coronary intima media thickness (CIMT) fails to take account of the actual lumen width in thickened arteries, and compensatory vasodilation changes that may occur in the thickened artery are not taken account of in evaluating the efficiency of the affected artery. Compensatory vasodilation is a natural cardioprotective phenomenon whereby the body affords protection to arteries at risk of being damaged.

ARTERIAL VASODILATION.

Arterial vasodilation is crucial to the efficiency of blood vessels for maintaining blood flow to end organs, and this effect is made possible through Nitric Oxide production within the arterial wall. Nitric Oxide has several endothelial protecting properties, such as regulation of vascular elasticity, maintaining cardiac contraction and anti-oxidant protection against atherosclerosis. (17) (18) (19) and can also be depleted through the oxidation of lipo-proteins, such as LDL-C, and through the natural ageing process. (20).

Recent evidence indicates that NO production is stimulated by polyphenols within red wine and purple grape juice, and that these effects are independent of plasma lipids in patients with high cholesterol blood levels (21). Resveretrol has been shown to be the isolated polyphenol, which not only stimulates NO production in the arterial wall, but also exhibits anti-oxidant, anti-inflamatory and angiogenesis (new vessel growth) properties.

NITRIC OXIDE SYNTHESIS.

Resveretrol supports endothelial health through the synthesis of Nitric Oxide (NO). and increased resistance to oxidative stress within the arterial wall.(22).

Researchers at the Brandon Cancer Research Institute, New York, confirmed the cardio-protective properties of red wine resveretrol, through it’s in vitro induction of nitric oxide synthase, the enzyme responsible for the biosynthesis of NO. They also demonstrated it’s chemoprotective and /or anti-tumour activity. (23). A study by Italian researchers, likewise, demonstrated the significant production of platelet NO when stimulated by moderate levels of resveretrol, and also increased activity of platelet nitric oxide synthase (NOS). Furthermore, they reported increased phosphorylation of protein kinase B, an activator of the endothelial NOS (eNOS), and phosphorylation of vasodilator-activated protein (VASP), an expression of the biologic activity of NO in platelets.(24).

In the aftermath of blood flow impairment to the heart muscle reperfusion occurs as a restorative mechanism aimed at protecting the muscle from further ischaemic damage. This process is facilitated by NO release. Impairment of NO release will therefore diminish the protective mechanisms of the cardiovascular system, while NO synthesis will aid the repair process. In experimental models Resveretrol was shown to reduce myocardial ischaemic perfusion injury. (25), through NOS stimulation, vasodilation and anoxic tissue reperfusion.

The major contribution to health by Resverertol may thus derive from it’s capacity to limit the progression of atherosclerosis or CAD through NO synthesis, vasodilation and enhanced tissue re-perfusion.

PRECONDITIONING.

Laboratory studies by Prof. Dipak Das indicate that Resveratrol may function as a pharmacological pre-conditioning agent since it fulfils several criteria for preconditioning, including the activation of adenosine receptors. Preconditioning is the most powerful technique known to promote cardioprotection. (26 – 28) and involves several short episodes of reversible ischaemia followed by longer cycles of reperfusion. During this process adenosine is released which exerts it’s anti-ischaemic properties, enabling reperfusion. The process of cyclic ischaemia and reperfusion renders cardiac muscle resistant to subsequent episodes of ischaemic injury.

These properties of adenosine renders it a much used compound in clinical interventive procedures, such as PTCA (percutaneous transluminal coronary angioplasty) and CABG (coronary artery bypass grafting).
Resveretrol appears to stimulate the pathways which facilitate the beneficial role of adenosine on ischaemic tissue through increased expression of adenosine A1 and A3 receptors. (27).

ENDOTHELIAL PROGENITOR CELLS (EPC’s).

Recent lines of research have identified the significance of adult stem cells for cardiac health. These cells are known as endothelial progenitor cells, and are manufactured in bone marrow from where they are released into the circulation and directed to ischaemic tissue for repair purposes. A report in the 2003 New England Journal of Medicine (28) notes a strong correlation between the numbers of circulating EPC’s and a patient’s Framingham risk factor score.

The more EPC’s in a person’s circulation the greater is the inherent protection against cardiovascular disease. Circulating numbers are variable and are reportedly low in certain pathological conditions, such as diabetes, hypertension (29), and CHD (30). They also decline with age. (31). Reduced numbers are associated with endothelial dysfunction and increased numbers have in experimental and clinical studies been associated with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers. (32).
Circulating EPCs play a significant role in neovascularization of ischaemic tissues and in re-endothelization of injured blood vessels. Studies by Balestrieri et al demonstrated that red wine resveratrol prevented the reduction of EPC numbers. (33).
In a study of 45 middle aged men with various degrees of cardiovascular risk, but no history of cardiovascular disease, the levels of circulating EPCs were a better predictor of vascular reactivity than was the presence or absence of conventional risk factors. (34). This study suggests that EPCs may therefore be a surrogate biological marker for vascular function and cumulative cardiovascular risk.
Japanese researchers, investigating endothelial function of the brachial artery in 108 men with CAD, demonstrated a favourable brachial artery response to hyperemic flow (FMD) with alcohol. (35).

Greek researchers performed radioactive intracoronary infusion (ICI) of bone marrow progenitor cells into patients with chronic ischaemic cardiomyopathy and detected a significant number of these cells in the chronic ischaemic myocardium. (36).

Consistent findings that circulating progenitor cells, stimulated through red wine polyphenols, may halt the progression of cardiovascular disease and enhance cardiovascular and general health holds great promise for further research in this field of study.
Resveratrol may well prove to be a novel and effective biomarker in future risk assessment strategies, and holds the promise of being an effective therapeutic tool in regenerative medicine. Further research is needed to determine methods of delivery and the protective and therapeutic levels required for health.

HOW MUCH RESVERATROL IS REQUIRED FOR HEALTH ?

redwine

Since red wine polyphenols protect against oxidative stress, their neutralising effect would more likely be optimised after a meal at which time the ingestion of harmful trans-fats and sugars occurs. The French habit of drinking red wine with a meal may explain the so called “French paradox”, suggested by their lower rates of heart disease despite their reportedly high fat intake. Since healthy saturated fat does not cause cardiac disease, the presumption of a poor dietary fat intake is speculative ! Resveratrol would, in any case, offer antioxidant protection following a meal rich in unhealthy trans-fats or excessive carbohydrates.

The amount of resveratrol found in a glass of red wine has been estimated by Life Extension researchers to be about 4.77mg, although the actual amount is likely to vary, depending on the make and origin of the wine. (37).

In a carefully controlled study Life Extension researchers have demonstrated that 20mg of resveratrol with 100mg of grapeseed extract favourably alters gene expression in a way that might slow ageing, protect against age-related degenerative diseases, and extend life span.

CONCLUSION.

Scientific evidence now supports the notion that red wine, when consumed in moderation, affords numerous health protective benefits, thereby reaffirming the notion of the “blessings of the grape “.

It’s benefits for cardiovascular health have been well researched and are likely to become the focus of more intense scientific research in the future.

Neville S. Wilson. MD.
06, Feb., 2009

Dr Neville Wilson is a Doctor in Maynooth (insert hyperlink with italics to http://leinsterclinic.ie/services/medical-suite/)

htttp://leinsterclinic.ie (insert hyperlink to http://leinsterclinic.ie)

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