According to AHA report in 2007, Diseases of the Heart is not equivalent to Total Cardiovascular Disease, the latter term is to be used to describe the leading causes of death.
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Data from the 2003 Health Survey for England suggest the prevalence of coronary heart disease (CHD) in England was 7.4% in men and 4.5% in. Combined data from prevalence studies on myocardial infarction suggest that overall about 4% of men and 2% of women in the UK have had a heart attack. Studies on the prevalence of angina in the UK showed that the rate appears to be higher in Scotland than in England. Figures from the 2003 Health Survey for England suggest that about 8% of men and 5% of women aged 55 to 64 and about 17% of men and 8% of women aged 65 to 74 have or have had.
The Heart of England Screening study on heart failure, selected patients by systematic random sampling of all men and women aged over 45 years registered at GP practices in the West Midlands. Over 2% of patients (3% of men and 1.7% of women) screened had definite heart failure. Probable heart failure was seen in around a further 1% of patients, which suggests that more than 3% of people aged 45 and over in the UK have definite or probable heart failure. Heart and circulatory disease is the UK’s biggest killer. In 2002, cardiovascular disease (CVD) caused 39% of deaths in the UK [Retrieved from <http://www.heartstats.org > British Heart Association Statistics web page].
In 1819, an Irish physician named Samuel Black reported, that the French suffer relatively low incidence of coronary heart disease, despite having a diet rich in saturated fat; he called this phenomenon The French Paradox (Ferrieres 2004). It has been suggested that France’s high red wine consumption is a primary factor in the French paradox (Law; Wald 1999). Atherosclerosis is a type of arteriosclerosis. The name comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). It’s the term for the process of fatty substances, cholesterol, cellular waste products, calcium and fibrin (a clotting material in the blood) building up in the inner lining of an artery. The buildup that results is called plaque (AHA 2007).
Pathophysiology of atherosclerosis
Mechanisms contributing to atherogenesis are multiple and complex. A number of theories including the role of dyslipidemia, hypercoagulability, oxidative stress, endothelial dysfunction, and inflammation and infection by certain pathogens, have been propounded from time to time explain this complex phenomenon.
Recently it has been suggested that atherosclerosis is a multifactorial, multistep disease that involves chronic inflammation at every step, from initiation to progression, and that all the risk factors contribute to pathogenesis by aggravating the underlying inflammatory process (Mallika, Goswami and Rajappa, 2007). The possible role of red wine in lowering the potential of atherosclerosis is better understood in the lights of pathophysiological changes that characterize the disorder.
The findings of Boudi and others 2006 indicate that the critical cellular elements of atherosclerotic lesions are endothelial cells, smooth muscle cells, platelets, and leucocytes. They also stated that vasomotor function, the thrombogenicity of the blood vessel wall, the state of activation of the coagulation cascade, the fibrinolytic system, smooth muscle cell migration and proliferation, and cellular inflammation are complex and interrelated biological processes that contribute to atherogenesis and the clinical manifestations of atherosclerosis.
Mechanisms of vascular stiffness
Zieman and others 2005 stated that: Vascular stiffening develops from a complex interaction between stable and dynamic changes involving structural and cellular elements of the vessel wall. Their findings also indicated that these vascular alterations are influenced by haemodynamic forces as well as by “extrinsic factors” such as hormones, salt, and glucose regulation.
The role of lipids
Crowther 2005 explained that: The lipid hypothesis of atherogenesis has been dramatically modified over the last 20 years. In his lecture he added: “Once viewed as the initiating agent of atherothrombosis, it is now recognized that localization and accumulation of lipid occurs in response to earlier changes in the vascular endothelium. Accumulation of lipid is, however, required for the development of the definitive plaque.
Lipid deposition likely starts with the movement of LDL from the blood into the vessel wall. Once within the media three fates can befall the LDL: it may move back into the bloodstream (a hallmark of lesional regression and a process that may be facilitated by some lipid lowering strategies), it may become oxidized (through action of free radicals or direct activity of leukocytes) or it may be taken up by monocyte/macrophages which ultimately become foam cells. Oxidized LDL is particularly atherogenic and is chemotactic for monocyte-macrophages”.
He explained the role played by macrophages as they “bind intra-intimal LDL via a family of novel receptors known as scavenger receptors, which recognize LDL only after it has been oxidized. Uptake of oxidized LDL renders the macrophages less mobile, thereby promoting the accumulation of these lipid-laden cells in the intima. The foam cells retain their metabolic activity and secrete a variety of cytokines and inflammatory mediators. Outcomes of their activation include recruitment and proliferation of smooth muscle cells (which in turn elaborate additional locally active cytokines), further LDL oxidation, recruitment of additional monocyte/foam cells and additional impairment of endothelial function”.
Nitric oxide and nitric oxide synynthase
In the endothelium, nitric oxide (NO) is constitutively generated from the conversion of L-arginine to L-citrullin by the enzymatic action of endothelial NO synthase (eNOS). An impairment of endothelium-dependent relaxation (EDR) is present in atherosclerotic vessels even before vascular structural changes occur, and represents the reduced eNOS-derived NO activity. Because of its multiple biological actions, NO from eNOS is believed to act as an anti-atherogenic molecule. The presence of dysfunctional eNOS may not only impair EDR but also accelerate lesion formation in atherosclerotic vessels (Kawashima 2004).
Pattern of occurrence of atherosclerotic lesions
Zieman and others 2005 showed that stiffness is not uniformly disseminated throughout the vascular tree but is often patchy occurring in central and conduit vessels while sparing more peripheral arteries. Common diseases, such as hypertension and diabetes mellitus, or simply aging itself, amplify the vascular changes that result in artery stiffening and can do so in different, yet synergistic, ways.
Evolution of the atherosclerotic plaque
Crowther 2005 stated that; Evolution of the atherosclerotic plaque is characterized by gradual enlargement over time due to the accumulation of foam cells. He differentiated between slowly growing plaques and rapidly growing ones, “Slowly growing plaques gradually accumulate lipid within foam cells; proliferation of smooth muscle cells and elaboration of intracellular matrix produce the definitive fibrous plaque.
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In general, such plaques tend to have adherent endothelial layers that are not prone to sudden disruption with associated activation of coagulation. Some plaques grow at a much greater rate than would be predicted by simple lipid accumulation and expansion of the components of the fibrous plaque. Cholesterol accumulation within such plaques is due to both “passive” transfer of LDL from the circulation and scavenging of red blood cell membranes deposited during intraplaque hemorrhage. Angiogenic signaling and proliferation of microvessels within the plaque is only now beginning to be understood; however, plaque hemorrhage is likely attributable to bleeding from fragile microvessels that proliferate within the plaque itself”.
Does red wine affect cardiovascular diease: Epidemiological evidence
Drinking red wine has been portrayed by the media as a means of combating heart disease. Do these claims have any real medical basis? The main health benefit of moderate alcohol use appears to be related to its effect on the development of atherosclerosis or the accumulation of fatty plaques in the blood vessels, particularly the coronary arteries that supply the heart. Data from 51 epidemiological studies were studied by Szmitko and Verma, 2005 (a), they showed that the risk of coronary heart disease decreased by approximately 20% when 0 to 2 alcoholic drinks were consumed per day.
The question of is red wine advantageous to other alcoholic beverages was attended by the Copenhagen City Heart Study (after Szmitko and Verma 2005 a), in which 13,285 men and women were observed for 12 years suggested that patients who are used to moderate intake of wine had half the risk of dying from cardiovascular and coronary heart disease or stroke as those who never drank wine. The same study showed that those who drank beer and spirits did not experience this advantage. The additional benefit of red wine is supported further by an analysis of 13 studies involving 209,418 participants.
This analysis showed a 32% risk reduction of atherosclerotic disease with red wine intake, which was greater than the 22% risk reduction for beer consumption. Other studies and reviews have failed to show a beneficial effect for red wine, however, and hence it could be concluded that other lifestyle factors such as diet, exercise, socioeconomic status, or pattern of alcohol consumption may have played a role in giving wine drinkers an advantage in lowered rates of atherosclerosis. The chemical composition of red wine may contribute to its apparent benefit. A series of scientific studies (Szmitko and Verma, 2005-a) suggests that the polyphenolic compounds in red wine such as flavonoids and resveratrol, may play important role in limiting the start and progression of atherosclerosis.
How red wine affects atherosclerosis
Grapes contain a wide variety of polyphenols including resveratrol (stilbene), catechins, flavonoids and its derivatives, flavons, flavonols, and anthocyanins. These compounds present in the red wine possess a number of biological effects that might participate in vascular protection, including anti-aggregatory, antioxidant and free radical scavenging properties. Another therapeutically relevant effect of flavonoids may be their ability to interact with the generation of NO from vascular endothelium, which leads not only to vasodilatation, but also to the expression of genes that protect the cardiovascular system Polyphenols also contribute to the preservation of the integrity of cells belonging to the vascular wall, mainly those in the endothelium, by acting on the signalling cascades implicated in endothelial apoptosis.
Due to their antioxidant properties, diets supplemented with foods containing flavonoids, might also protect different tissues against ischemic damage. Flavonoids reduce oxidative and nitrosative stress leading to cellular death. All these effects of flavonoids might interfere with atherosclerotic plaque development and stability, vascular thrombosis and occlusion and they might therefore explain their vascular protective. Recently, the possible advantage of a moderate wine consumption in patients with chronic renal failure was hypothesized. Therefore, it is expected that the naturally occurring nutritional sources of antioxidants, such as fruits, vegetables, tea or wine, would also attenuate the renal damage caused by oxidative challenges (Pechanova et al 2006).
Promotion of endothelial function
Endothelial dysfunction is an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. Perez-Vizcaino, et al 2006, reviewed the effects of flavonoids, especially quercetin and wine polyphenols, on endothelial function and dysfunction and its potential protective role in hypertension, ischemic heart disease and stroke. In vitro studies showed that flavonoids may exert multiple actions on the NO-guanylyl cyclase pathway, endothelium-derived hyperpolarizing factor(s) and endothelin-1 and protect endothelial cells against apoptosis.
In vivo, flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress and end-organ damage in hypertensive animals. Moreover, some clinical studies have shown that flavonoid-rich foods can improve endothelial function in patients with hypertension and ischemic heart disease. Altogether, the available evidence indicates that quercetin and wine polyphenols might be of therapeutic benefit in cardiovascular diseases even though prospective controlled clinical studies are still lacking.
Oxidative modification in atherosclerosis
There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation.
These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis.
These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an “oxidative response to inflammation” model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis (Stocker and Keaney 2004).
Red wine and nitric oxide (NO)
Szmitko and Verma 2005 (b) in their review article stated that nitric oxide (NO) is the key endothelium-derived relaxing factor that plays a pivotal role in the regulation of vascular tone and vasomotor function, also NO protects against vascular injury, inhibits leukocyte adhesion to the endothelium, and limits platelet aggregation.
Szmitko and Verma 2005(b) reviewed in vitro studies and showed that while ethanol appears to increase the expression of endothelial NO synthase and NO production in aortic endothelial cells, red wine polyphenols, in particular resveratrol, appear to further enhance endothelial NO synthase expression and activity and subsequent NO release from endothelial cells. Red wine, and not white or rose´ wines, inhibits endothelin-1 synthesis, a potent vasoconstrictor that is seen as a key factor in the development of vascular disease and atherosclerosis (Szmitko and Verma 2005-b).
Red wine and Low Density Lipoproteins (LDL)
The oxidation of LDL cholesterol increases its uptake by macrophages resulting in foam cell formation as well as decreasing intracellular concentration of nitric oxide to cause endothelial activation (Szmitko and Verma 2005-b). Thus, if LDL oxidation is reduced, atherosclerotic plaque formation may be decreased (Szmitko and Verma 2005-b). The phenolic substances in red wine have potent antioxidant properties that inhibit the formation of oxLDL in vitro, as well as macrophage-mediated LDL oxidation (Szmitko and Verma 2005-b). Human studies reviewed by Szmitko and Verma 2005 (b) suggest that the consumption of red wine or alcohol-free red wine leads to a significant increase in serum antioxidant activity, which may reduce the susceptibility of LDL to oxidation in vivo, limiting the extent of atheroma formation.
Red wine effects on inflammatory biomarkers in atherosclerosis
Inflammatory activation of the endothelium is marked by the increased expression of inflammatory biomarkers (Szmitko and Verma 2005-b). Estruch et al, 2004 showed that after either gin or wine consumption, plasma fibrinogen decreased by 5 and 9%, respectively, and cytokine IL-1α by 23 and 21%. The expression of LFA-1 [Lymphocyte function-associated antigen-1] (−27%), Mac-1 [Macrophage -1 Antigen] (−27%), VLA-4 [(Very Late Antigen-4] (−32%) and MCP-1 [monocyte chemotactic protein] (−46%) decreased significantly after wine, but not after gin. Wine reduced the serum concentrations of CRP [C-reactive protein] (−21%), VCAM-1 [vascular cell adhesion molecule] (−17%) and ICAM-1 [Intercellular Adhesion Molecule] (−9%).
Effect of red wine on plaque destabilization, rupture, and thrombosis
Disruption of a vulnerable atherosclerotic plaque when exposed to haemodynamic stresses because of slow blood stream can initiate intravascular thrombosis with both the alcohol and polyphenolic compounds in red wine appear to have antithrombotic action (Szmitko and Verma 2005-b).
“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” (Szmitko and Verma 2005-b). 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 suggesting a reduction in haemostasis (Szmitko and Verma 2005-b).
Furthermore, any form of alcohol consumption also increases antithrombin-III activity (after Szmitko and Verma 2005-b), and based on results from the Physicians’ Health Study is associated with increased tissue plasminogen activator concentrations (after Szmitko and Verma 2005-b). In vitro, alcohol induced the expression of tissue-type plasminogen activator in human endothelial cells, resulting in enhanced fibrinolytic activity (Szmitko and Verma 2005-b). Resveratrol and other polyphenolic compounds decrease platelet aggregation, possibly by interfering with prostaglandin synthesis and ADP-mediated aggregation” (Szmitko and Verma 2005-b).
Prudent use of alcohol may be acceptable in the prevention, and even management, of CV disease. It is reasonable to inform patients that beneficial effects occur if they exercise moderation in consumption. Only with great caution should patients who do not drink alcohol begin to imbibe because of the risk of alcohol abuse. It is possible that in the future, genetic testing may identify those at high risk for developing alcohol dependence.
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