Moderate Wine and Alcohol Consumption: Beneficial Effects on Cardiovascular Disease

Summary

Cardiovascular disease, in particular coronary heart disease (CHD) and associated myocardial infarction (MI), is the leading cause of death among adults in the Western world (1). Although CHD is a complex multi-factorial disease, major insights have been gained in our understanding of the etiology underlying the initiation and progression of CHD. The pathogenesis of CHD and the ensuing atherothrombotic complications resulting in MI, involves the complex and often synergistic interplay between multiple dysfunctional cellular and molecular mechanisms that have been altered through interactions with various environmental and/or systemic factors (i. e. CHD risk factors). Typically, these deleterious effects are exerted at the level of the heart muscle, blood vessels and blood components and result in dysfunction in endothelial cells (ECs), smooth muscle cells, cardiac myocytes, blood cells (platelets and monocytes) and plasma components (lipoproteins, fibrinogen, clotting factors, etc.). These combined effects will then contribute further to the initiation and progression of CHD and eventual MI. Consequently, any systemic factors (such as alcohol or wine components) that will reduce, minimize or inhibit these induced dysfunctions will be expected to reduce the overall risk for cardiovascular disease and CHD-related mortality.

Keywords

Alcohol - polyphenols - endothelial cells - platelets - CHD

• References

• 1 Hennekens CH. Alcohol and risk of coronary events. In: Zakhari S, Wassef M. eds. Alcohol and the Cardiovascular System. Washington, DC: U. S. Government Printing Office; 1996: 15-24.
• 2 Gaziano JM, Gaziano TA, Glynn RJ, Sesso HD, Ajani UA, Stampfer MJ, Manson JE, Hennekens CH, Buring JE. Light-to-moderate alcohol consumption and mortality in the Physicians’ Health Study enrollment cohort. J Am Coll Cardiol 2000; 35: 96-105.
• 3 Gordon T, Kannel WB. Drinking habits and cardiovascular disease: The Framingham Study. Am Heart J 1993; 105: 667-73.
• 4 Jackson R, Scragg R, Beaglehole R. Alcohol consumption and risk of coronary heart disease. Br Med J 1991; 303: 211-6.
• 5 Boffetta P, Garfinkel L. Alcohol drinking and mortality among men enrolled in an American Cancer Society prospective study. Epidemiology 1990; 1: 342-8.
• 6 Stampfer MJ, Colditz GA, Willett WC, Speizer FE, Hennekens CH. A prospective study of moderate alcohol consumption and the risk of coronary heart disease and stroke in women. N Engl J Med 1988; 319: 267-73.
• 7 Yano K, Reed DM, McGee DL. Ten-year incidence of coronary heart disease in the Honolulu Heart Program. Am J Epidemiol 1984; 119: 653-66.
• 8 Kozarevic D, McGee D, Vojvodic N, Racic Z, Dawber T, Gordon T, Zuke WJ. Frequency of alcohol consumption and morbidity and mortality: The Yugoslavia cardiovascular disease study. Lancet 1980; 1: 613-6.
• 9 Salonen JT, Puska P, Nissinen A. Intake of spirits and beer and risk of myocardial infarction and death: A longitudinal study in eastern Finland. J Chronic Dis 1983; 36: 533-43.
• 10 Gronbaek M, Deis A, Sorensen TIA, Becker U, Schnorh P, Jensen G. Mortality associated with moderate intakes of wine, beer, or spirits. Br Med J 1995; 310: 1165-9.
• 11 Klatsky AL, Armstrong MA, Friedman GD. Risks of cardiovascular mortality in alcohol drinkers, ex-drinkers and nondrinkers. Am J Cardiol 1990; 66: 1237-42.
• 12 Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992; 339: 1523-6.
• 13 Zakhari S, Wassef M. Alcohol and the Cardiovascular System. Research Monograph – 31. Bethesda, MD: National Institutes of Health; 1996: 3-712.
• 14 Paoletti R, Klatsky AL, Poli A, Zakhari S. Moderate Alcohol Consumption and Cardiovascular Disease. Paoletti R, Klatsky AL, Poli A, Zakhari S. [15]. 2000. Dordrecht/Boston/London: Kluwer Academic Publishers.;
• 15 Papadakis JA, Ganotakis ES, Mikhailidis DP. Beneficial effect of moderate alcohol consumption on vascular disease: myth or reality?. J R Soc Health 2000; 120: 11-5.
• 16 Gordon DJ, Rifkind BM. High density lipoprotein: the clinical implication of recent studies. N Engl J Med 2001; 321: 1311-6.
• 17 Haskell WL, Carnargo Jr C, Williams PT, Vranizan KM, Krauss RM. The effect of cesssation and resumption of moderate alcohol intake on serum high-density-lipoprotein subfractions. A controlled study. N Engl J Med 1984; 310: 805-10.
• 18 Valimaki M, Nikkila EA, Taskinen A, Ylikahri R. Rapid decrease in high density lipoprotein subfractions and post heparin plasma lipase activity after cessation of chronic alcohol intake. Atherosclerosis 1986; 59: 147-53.
• 19 Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, VanDenburgh M, Willett W, Hennekens CH. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction [see comments]. N Engl J Med 1993; 329: 1829-34.
• 20 Malmendier CL, Delcroix C. Effect of alcohol intake on high and low density lipoprotein metabolism in healthy volunteers. Clin Chim Acta 1985; 152: 281-8.
• 21 Lin RC, Lumeng L, Phelps VL. Serum high-density lipoprotein particles of alcohol-fed rats are deficient in apolipoprotein E. Hepatology 1989; 9: 307-13.
• 22 Valimaki M, Taskinen MR, Ylikahri R, Roine R, Kuusi T, Nikkila EA. Comparison of the effects of two different doses of alcohol on serum lipoproteins, HDL-subfractions and apolipoproteins A-I and A-II: a controlled study. Eur J Clin Invest 1988; 18: 472-80.
• 23 Merritt R, Guruge BL, Miller DD, Chaitman BR, Bora PS. Moderate alcohol feeding attenuates postinjury vascular cell proliferation in rabbit angioplasty model. J Cardiovasc Pharmacol 1997; 30: 19-25.
• 24 Langer RD, Criqui MH, Reed DM. Lipoproteins and blood pressure as biological pathways for effect of moderate alcohol consumption on coronary heart disease. Circulation 1992; 85: 910-5.
• 25 Valimaki M, Laitinen K, Ylakahri R, Ehnholm C, Jauhiainen M, Bard JM, Fruchart JC, Taskinen MR. The effect of moderate alcohol intake on serum apolipoprotein A-1-containing lipoproteins and lipoprotein (a). Metabolism 1991; 40: 1168-72.
• 26 Haut MJ, Cowan DH. The effect of ethanol on hemostatic properties of human blood platelets. Am J Med 1974; 56: 22-33.
• 27 Renaud SC, Beswick AD, Fehily AM, Sharp DS, Elwood PC. Alcohol and platelet aggregation: the Caerphilly Prospective Heart Disease Study. Am J Clin Nutr 1992; 55: 1012-7.
• 28 Rubin R, Rand ML. Alcohol and platelet function [Review]. Alcohol Clin Exp Res 1994; 18: 105-10.
• 29 Rubin R. Effect of ethanol on platelet function. Alcohol Clin Exp Res 1999; 23: 1114-8.
• 30 McGregor L, Renaud S. Inhibitory effect of alcohol on platelet functions of rats fed saturated fats. Thromb Res 1981; 22: 221-5.
• 31 Desai K, Owen JS, Wilson DT, Hutton RA. Platelet aggregation and plasma lipoproteins in alcoholics during alcohol withdrawal. Thromb Haemost 1986; 55: 173-7.
• 32 Hillbom ME. What supports the role of alcohol as a risk factor for stroke?. Acta Med Scand Suppl 1987; 717: 93-106.
• 33 Zhang QH, Das K, Siddiqui S, Myers AK. Effects of acute, moderate ethanol consumption on human platelet aggregation in platelet-rich plasma and whole blood. Alcohol Clin Exp Res 2000; 24: 528-34.
• 34 Rand ML, Groves HM, Packham MA, Mustard JF, Kinlough-Rathbone RL. Acute administration of ethanol to rabbits inhibits thrombus formation induced by indwelling aortic catheters. Lab Invest 1990; 63: 742-5.
• 35 Demrow HS, Slane PR, Folts JD. Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. Circulation 1995; 91: 1181-8.
• 36 Benistant C, Rubin R. Ethanol inhibits thrombin-induced secretion by human platelets at a site distinct from phospholipase C or protein kinase C. Biochem J 1990; 269: 489-97.
• 37 Rubin R. Ethanol interferes with collagen-induced platelet activation by inhibition of arachidonic acid mobilization. Arch Biochem Biophys 1989; 270: 99-113.
• 38 Rand ML, Packham MA, Kinlough-Rathbone RL, Fraser MJ. Effects of ethanol on pathways of platelet aggregation in vitro. Thromb Haemost 1988; 59: 383-7.
• 39 Rand ML, Gross PL, Jakowec DM, Packham MA, Mustard JF. In vitro effects of ethanol on rabbit platelet aggregation, secretion of granule contents, and cyclic AMP levels in the presence of prostacyclin. Thromb Haemost 1989; 61: 254-8.
• 40 Stubbs CD, Rubin R. Effect of ethanol on platelet phospholipase A2. Lipids 1992; 27: 255-60.
• 41 Mikhailidis DP, Jeremy JY, Barradas MA, Green N, Dandona P. Effect of ethanol on vascular prostacyclin (prostaglandin I2) synthesis, platelet aggregation, and platelet thromboxane release. Br Med J (Clin Res Ed) 1983; 287: 1495-8.
• 42 Rand ML, Vickers JD, Kinlough-Rathbone RL, Packham MA, Mustard JF. Thrombin-induced inositol trisphosphate production by rabbit platelets is inhibited by ethanol. Biochem J 1988; 251: 279-84.
• 43 Tribouilloy C, Peltier M, Colas L, Senni M, Ganry O, Rey JL, Lesbre JP. Fibrinogen is an independent marker for thoracic aortic atherosclerosis. Am J Cardiol 1998; 81: 321-6.
• 44 Iacoviello L, Zito F, Di Castelnuovo A, de Maat M, Fluft C, Donati MB. Contribution of factor VII, fibrinogen and fibrinolytic components to the risk of ischaemic cardiovascular disease: their genetic determinants. Fibrinol Proteol 1998; 12: 259-76.
• 45 Hendriks HFJ, Gaag vdMS.. Alcohol, coagulation and fibrinolysis. In: Alcohol and Cardiovascular Diseases. Chichester: (Novartis Foundation Symposium) Wiley; 1998: 111-24.
• 46 Dimmitt SB, Rakic V, Puddey IB, Baker R, Baker S, Ostryck R, Adams MJ, Chesterman CN, Burke V, Beilin LJ. The effects of alcohol on coagulation and fibrinolytic factors: a controlled trial. Blood Coagul Fibrinolysis 1998; 9: 39-45.
• 47 Pitsavos C, Skoumas J, Dernellis J, Toutouza M, Doulalas A, Stefanadis C, Toutouzas P. Influence of biological factors on lipid and fibrinogen measurements in young men. An epidemiological study in 2009 recruits. Eur Heart J 1998; 19: 1642-7.
• 48 Scarabin PY, Aillaud MF, Amouyel P, Evans A, Luc G, Ferrieres J, Arveiler D, Juhan-Vague I. Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction – the PRIME Study. Prospective Epidemiological Study of Myocardial Infarction. Thromb Haemost 1998; 80: 749-56.
• 49 Margaglione M, Cappucci G, Colaizzo D, Pirro L, Vecchione G, Grandone E, Di Minno G. Fibrinogen plasma levels in an apparently healthy general population – relation to environmental and genetic determinants. Thromb Haemost 1998; 80: 805-10.
• 50 Mennen LI, Balkau B, Vol S, Caces E, Eschwege E. Fibrinogen: a possible link between alcohol consumption and cardiovascular disease? DESIR Study Group. Arterioscler Thromb Vasc Biol 1999; 19: 887-92.
• 51 Pellegrini N, Pareti FI, Stabile F, Brusamolino A, Simonetti P. Effects of moderate consumption of red wine on platelet aggregation and haemostatic variables in healthy volunteers. Eur J Clin Nutr 1996; 50: 209-13.
• 52 Gorinstein S, Zemser M, Lichman I, Berebi A, Kleipfish A, Libman I, Trakhtenberg S, Caspi A. Moderate beer consumption and the blood coagulation in patients with coronary artery disease. J Intern Med 1997; 241: 47-51.
• 53 Bijnen FC, Feskens EJ, Giampaoli S, Menotti A, Fidanza F, Hornstra G, Caspersen CJ, Mosterd WL, Kromhout D. Haemostatic parameters and lifestyle factors in elderly men in Italy and The Netherlands. Thromb Haemost 1996; 76: 411-6.
• 54 Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999; 99: 237-42.
• 55 Deaciuc IV. Alcohol and cytokine networks. Alcohol 1997; 14: 421-30.
• 56 Nelson S, Bagby GJ, Bainton BG, Summer WR. The effects of acute and chronic alcoholism on tumor necrosis factor and the inflammatory response. J Infect Dis 1989; 160: 422-9.
• 57 Wang Z, Barker TH, Fuller GM. Alcohol at moderate levels decrease fibrinogen expression in vivo and in vitro. Clin Exp Res 1999; 23: 1927-32.
• 58 Meade TW, Chakrabarti R, Haines AP, North WF, Stirling Y. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J 1979; 1 (suppl. 6157): 153-6.
• 59 Ridker PM, Vaughan DE, Stampfer MJ, Glynn RJ, Hennekens CH. Association of moderate alcohol consumption and plasma concentration of endogenous tissue-type plasminogen activator. JAMA 1994; 272: 929-33.
• 60 Hendriks HFJ, Veenstra J, Velthuis-te EJM, Schaafsma G, Kluft C. Effect of moderate dose of alcohol with evening meal on fibrinolytic factors. Br Med J 1994; 308: 1003-6.
• 61 Djousse L, Pankow JS, Arnett DK, Zhang Y, Hong Y, Province MA, Ellison RC. Alcohol consumption and plasminogen activator inhibitor type 1: the National Heart, Lung, and Blood Institute Family Heart Study. Am Heart J 2000; 139: 704-9.
• 62 Sumi H, Hamada H, Tsushima H, Mihara H. Urokinase-like plasminogen activator increased in plasma after alcohol drinking. Alcohol Alcohol 1988; 23: 33-43.
• 63 Laug WE. Ethyl alcohol enhances plasminogen activator secretion by endothelial cells. JAMA 1983; 250: 772-6.
• 64 Venkov CD, Su M, Shry Y, Vaughan DE. Ethanol-induced alterations in the expression of endothelial-derived fibrinolytic components. Fibrinol Proteol 1997; 11: 115-8.
• 65 Aikens ML, Grenett HE, Benza RL, Tabengwa EM, Davis GC, Demissie S, Booyse FM. Ethanol increases surface-localized fibrinolytic activity in cultured endothelial cells. Alcohol Clin Exp Res 1997; 21: 1471-8.
• 66 Aikens ML, Grenett HE, Benza RL, Tabengwa EM, Davis GC, Booyse FM. Alcohol-induced upregulation of plasminogen activators and fibrinolytic activity in cultured human endothelial cells. Alcohol Clin Exp Res 1998; 22: 375-81.
• 67 Grenett HE, Torres JA, Demissie S, Tabengwa EM, Davis GC, Booyse FM. Ethanol transcriptionally upregulates t-PA and u-PA gene expression in cultured human endothelial cells. Alcohol Clin Exp Res 1998; 22: 849-53.
• 68 Grenett HE, Aikens ML, Tabengwa EM, Davis GC, Booyse FM. Ethanol downregulates transcription of the PAI-1 gene in cultured human endothelial cells. Thromb Res 2000; 97: 247-55.
• 69 Grenett HE, Wolkowicz PE, Benza RL, Tresnak JK, Wheeler CG, Booyse FM. Identification of a 251-bp fragment of the PAI-1 gene promoter that mediates the ethanol-induced suppression of PAI-1 expression. Alcohol Clin Exp Res 2001; 25: 629-36.
• 70 Tabengwa EM, Abou-Agag LH, Benza RL, Torres JA, Booyse FM. Ethanol-induced upregulation of candidate plasminogen receptor annexin II in cultured human endothelial cells. Alcohol Clin Exp Res 2000; 24: 754-61.
• 71 Tabengwa EM, Grenett HE, Benza RL, Tresnak JK, Wheeler CG, Booyse FM. Ethanol-induced upregulation of urokinase receptor in cultured human endothelial cells. Alcohol Clin Exp Res 2001; 25: 163-70.
• 72 Abou-Agag LH, Tabengwa EM, Tresnak JK, Wheeler CG, Taylor KB, Booyse FM. Ethanol-induced increased surface-localized fibrinolytic activity in cultured human endothelial cells: kinectic analysis. Alcohol Clin Exp Res 2001; 25: 351-61.
• 73 Miyamoto A, Yang SX, Laufs U, Ruan XL, Liao JK. Activation of guanine nucleotide-binding proteins and induction of endothelial tissue-type plasminogen activator gene transcription by alcohol. J Biol Chem 1999; 274: 12055-60.
• 74 Stemmermann GN, Hayashi T, Resch JA, Chung CS, Reed DM, Rhoads GG. Risk factors related to ischemic and hemorrhagic cerebrovascular disease at autopsy: The Honolulu Heart Study. Stroke 1984; 15: 23-8.
• 75 Donahue RP, Abbott RD, Reed DM, Yano K. Alcohol and hemorrhagic stroke. The Honolulu Heart Program. JAMA 1986; 255: 2311-4.
• 76 Rodgers H, Aitken PD, French JM, Curless RH, Bates D, James OF. Alcohol and stroke. A case-control study of drinking habits past and present. Stroke 1993; 24: 1473-7.
• 77 Palomaki H, Kaste M. Regular light-to-moderate intake of alcohol and the risk of ischemic stroke. Is there a beneficial effect? Stroke 1993; 24: 1828-32.
• 78 Berger K, Ajani UA, Kase CS, Gaziano JM, Buring JE, Glynn RJ, Hennekens CH. Light-to-moderate alcohol consumption and risk of stroke among U. S. male physicians [see comments]. N Engl J Med 1999; 341: 1557-64.
• 79 Sacco RL, Elkind M, Boden-Albala B, Lin IF, Kargman DE, Hauser WA, Shea S, Paik MC. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 1999; 281: 53-60.
• 80 Kojda G, Kottenberg K. Regulation of basal myocardial function by NO [see comments]. Cardiovasc Res 1999; 41: 514-23.
• 81 Loke KE, McConnell PI, Tuzman JM, Shesely EG, Smith CJ, Stackpole CJ, Thompson CI, Kaley G, Wolin MS, Hintze TH. Endogenous endothelial nitric oxide synthase-derived nitric oxide is a physiological regulator of myocardial oxygen consumption. Circ Res 1999; 84: 840-5.
• 82 Khadour FH, O’Brien DW, Fu Y, Armstrong PW, Schulz R. Endothelial nitric oxide synthase increases in left atria of dogs with pacing-induced heart failure. Am J Physiol 1998; 275: H1971-H1978.
• 83 Kanno S, Lee PC, Zhang Y, Ho C, Griffith BP, Shears LL, Billiar TR. Attenuation of myocardial ischemia/reperfusion injury by superinduction of inducible nitric oxide synthase. Circulation 2000; 101: 2742-8.
• 84 Sumeray MS, Rees DD, Yellon DM. Infarct size and nitric oxide synthase in murine myocardium. J Mol Cell Cardiol 2000; 32: 35-42.
• 85 Bolli R, Dawn B, Tang XL, Qiu Y, Ping P, Xuan YT, Jones WK, Takano H, Guo Y, Zhang J. The nitric oxide hypothesis of late preconditioning [editorial; see comments]. Basic Res Cardiol 1998; 93: 325-38.
• 86 Baker CS, Rimoldi O, Camici PG, Barnes E, Chacon MR, Huehns TY, Haskard DO, Polak JM, Hall RJ. Repetitive myocardial stunning in pigs is associated with the increased expression of inducible and constitutive nitric oxide synthases. Cardiovasc Res 1999; 43: 685-97.
• 87 Miyamae M, Diamond I, Weiner MW, Camacho SA, Figueredo VM. Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia-reperfusion injury. Proc Natl Acad Sci USA 1997; 94: 3235-9.
• 88 Suzuki K, Sawa Y, Kaneda Y, Ichikawa H, Shirakura R, Matsuda H. Over-expressed heat shock protein 70 attenuates hypoxic injury in coronary endothelial cells. J Mol Cell Cardiol 1998; 30: 1129-36.
• 89 Su CY, Chong KY, Owen OE, Dillmann WH, Chang C, Lai CC. Constitutive and inducible hsp70s are involved in oxidative resistance evoked by heat shock or ethanol. J Mol Cell Cardiol 1998; 30: 587-98.
• 90 Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 1993; 92: 652-62.
• 91 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9.
• 92 Patel RP, McAndrew J, Sellak H, White CR, Jo H, Freeman BA, DarleyUsmar VM. Biological aspects of reactive nitrogen species. Biochim Biophys Acta 1999; 1411: 385-400.
• 93 Radomski MW, Moncada S. Regulation of vascular homeostasis by nitric oxide. Thromb Haemost 1993; 70: 36-41.
• 94 Lamas S, Perez-Sala D, Moncada S. Nitric oxide: from discovery to the clinic. Trends Pharmacol Sci 1998; 19: 436-8.
• 95 Channon KM, Blazing MA, Shetty GA, Potts KE, George SE. Adenoviral gene transfer of nitric oxide synthase: high level expression in human vascular cells. Cardiovasc Res 1996; 32: 962-72.
• 96 Gaballa MA, Goldman S. Overexpression of endothelium nitric oxide synthase reverses the diminished vasorelaxation in the hindlimb vasculature in ischemic heart failure in vivo. J Mol Cell Cardiol 1999; 31: 1243-52.
• 97 Beckman JS, Koppernol WH. Nitric oxide, superoxide and peroxynitrite: the good, the bad and the ugly. Am J Physiol 1996; 271: 1424-37.
• 98 Ooboshi H, Toyoda K, Faraci FM, Lang MG, Heistad DD. Improvement of relaxation in an atherosclerotic artery by gene transfer of endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol 1998; 18: 1752-8.
• 99 Wu KK. Injury-coupled induction of endothelial eNOS and COX-2 genes: a paradigm for thromboresistant gene therapy. Proc Assoc Am Physicians 1998; 110: 163-70.
• 100 Binsack R, Boersma BJ, Patel RP, Kirk M, Darley-Usmar VM, Barnes S, Parks DA. Enhanced antioxidant activity following chlorination of quercetin by hypochlorous acid. Alcohol Clin Exp Res. in press.
• 101 Gurjar MV, Sharma RV, Bhalla RC. eNOS gene transfer inhibits smooth muscle cell migration and MMP-2 and MMP-9 activity. Arterioscler Thromb Vasc Biol 1999; 19: 2871-7.
• 102 Fang S, Sharma RV, Bhalla RC. Enhanced recovery of injury-caused downregulation of paxillin protein by eNOS gene expression in rat carotid artery. Mechanism of NO inhibition of intimal hyperplasia? Arterioscler Thromb Vasc Biol 1999; 19: 147-52.
• 103 St. Leger SA. Cochrane AL, Moore F. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. Lancet 1979; 1: 1017-29.
• 104 Criqui HM. The reduction of coronary heart disease with light to moderate alcohol consumption: effect or artifact?. Br J Addict 1995; 85: 854-7.
• 105 Soleas GJ, Diamandis EP, Godlberg DM. Wine as a biological fluid: history, production, and role in disease prevention [Review]. J Clin Lab Anal 1997; 11: 287-313.
• 106 Frankel EN, Waterhouse AL, Teissedre PL. Principal phenolic phyto-chemicals in selected California wines and their antioxidant activity in inhibiting oxidation of human low-density lipoproteins. J Agric Food Chem 1995; 43: 390-4.
• 107 Kinsella JE, Frankel EN, German B, Kanner J. Possible mechanisms for the protective role of antioxidants in wine and plant foods. Food Tech 1993; 85-9.
• 108 Lavy A, Fuhrman B, Markel A, Dankner G, Ben-Amotz A, Presser D, Aviram M. Effect of dietary supplementation of red or white wine on human blood chemistry, hematology and coagulation: favorable effect of red wine on plasma high-density lipoprotein. Ann Nutr Metab 1994; 38: 287-94.
• 109 Seigneur M, Bonnet J, Corian B, Benchmial D, Drouillet F, Gouverneur G, Larrue J, Crockett R, Boisseau MR, Ribereau-Gayon P, Bricaud H. Effect of the consumption of alcohol, white wine, and red wine on platelet function and serum lipids. J App Cardiol 1990; 5: 215-22.
• 110 Pace-Asciak CR, Rounova O, Hahn SE, Diamandis EP, Goldberg DM. Wines and grape juices as modulators of platelet aggregation in healthy human subjects. Clin Chim Acta 1996; 246: 163-82.
• 111 Goldberg DM, Garovic-Kocic V, Diamandis EP, Pace-Asciak CR. Wine: does the colour count?. Clin Chim Acta 1996; 246: 183-93.
• 112 Sharpe PC, McGrath LT, McClean E, Young IS, Archbold GP. Effect of red wine consumption on lipoprotein (a) and other risk factors for atherosclerosis. Quarterly J Med 88 1995; [2] 101-8.
• 113 Itakura H, Kondo K, Matsumoto A. Antiatherogenic effects of nonalcoholic ingredients in alcoholic beverages. In: Paoletti R, Klatsky AL, Poli A, Zakhari S. eds. Moderate Alcohol Consumption and Cardiovascular Disease. Dordrecht/Boston/London: Kluwer Academic Publishers; 2000: 73-9.
• 114 van der Gaag MS, Sierksma A, Schaafsma G, van Tol A, Geelhoed-Mieras T, Bakker M, Hendriks HF. Moderate alcohol consumption and changes in postprandial lipoproteins of premenopausal and postmenopausal women: a diet-controlled, randomized intervention study. J Womens Health Gend Based Med 2000; 9: 607-16.
• 115 Whitehead TP, Thorpe GH, Maxwell SR. An enhanced chemiluminescent assay for antioxidant capacity in biological fluids. Lancet 2001; 266: 265-77.
• 116 Kondo K, Matsumoto A, Kurata H, Tanahashi H, Koda H, Amachi T, Itakura H. Inhibition of oxidation of low-density lipoprotein with red wine [letter; comment] [see comments]. Lancet 1994; 344: 1152.
• 117 Fuhrman B, Lavy A, Aviram M. Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation [see comments]. Am J Clin Nutr 1995; 61: 549-54.
• 118 Rifici VA, Stephan EM, Schneider SH, Khachadurian AK. Red wine inhibits the cell-mediated oxidation of LDL and HDL. J Am Coll Nutr 1999; 18: 137-43.
• 119 Folts JD, Demrow HS, Slane PR. Two glasses of red but not white wine inhibits ex-vivo platelet aggregation and increases bleeding time in human volunteers. J Am Coll Cardiol. February, 484A. 1994.
• 120 Struck M, Watkins T, Tomeo A, Halley J, Bierenbaum M, Kenneth L. Jordan Research Group. Effect of red and white wine on serum lipids, platelet aggregation, oxidation products and antioxidants: a preliminary report. Nutr Res 1994; 14: 1811-9.
• 121 Ruf JC, Berger JL, Renaud S. Platelet rebound effect of alcohol withdrawal and wine drinking in rats. Relation to tannins and lipid peroxidation. Arterioscler Thromb Vasc Biol 1995; 15: 140-4.
• 122 Renaud S, Dumont E, Godsey F, Suplisson A, Thevenon C. Platelet functions in relation to dietary fats in farmers from two regions of France. Thromb Haemost 1979; 40: 518-31.
• 123 Aikens MA, Tabengwa EM, Abou-Agag LH, Torres JA, Grenett HE, Wheeler CG, Booyse FM. Red wine, de-alcoholized red wine of polyphenolics increase fibrinolytic activity in cultured human endothelial cells. Alcohol Clin Exp Res. Revised submitted.
• 124 Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P, Coleman R, Elis A, Aviram M. Reduced progression of atherosclerosis in apolipoprotein E-deficient mice following consumption of red wine, or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation. Arterioscler Thromb Vasc Biol 1997; 17: 2744-52.
• 125 Munday JS, Thompson KG, James KA, Manktelow BW. The effect of moderate alcohol consumption as either red or white wine in the C57BL/6 mouse atherosclerosis model. Coron Artery Dis 1999; 10: 97-102.
• 126 Wakabayashi Y. Effect of red wine consumption on low-density lipoprotein oxidation and atherosclerosis in aorta and coronary artery in Watanabe heritable hyperlipidemic rabbits. J Agric Food Chem 1999; 47: 4724-30.
• 127 Klurfield DM, Kritchevsky D. Differential effects of alcoholic beverages on experimental atherosclerosis in rabbits. Exp Mol Pathol 1981; 34: 61-71.
• 128 Pendurthi UR, Williams JT, Rao VM. Resveratrol, a polyphenolic compound found in wine, inhibits tissue factor expression in vascular cells: a possible mechanism for the cardiovascular benefits associated with moderate consumption of wine. Arterioscler Thromb Vasc Biol 1999; 19: 419-26.
• 129 Tsai SH, LinShiau SY, Lin JK. Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol. Br J Pharmacol 1999; 126: 673-80.
• 130 Wadsworth TL, Koop DR. Effects of the wine polyphenolics quercetin and resveratrol on pro- inflammatory cytokine expression in RAW 264.7 macrophages. Biochem Pharmacol 1999; 57: 941-9.
• 131 Kawada N, Seki S, Inoue M, Kuroki T. Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology 1998; 5: 1265-74.
• 132 Lin YL, Lin JK. (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor- B. Mol Pharmacol 1997; 52: 465-72.
• 133 Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue H, Jang M, Pezzuto JM, Dannenberg AJ. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem 1998; 273: 21875-82.
• 134 Iijima K, Yoshizumi M, Hashimoto M, Kim S, Eto M, Ako J, Liang YQ, Sudoh N, Hosoda K, Nakahara K, Toba K, Ouchi Y. Red wine polyphenols inhibit proliferation of vascular smooth muscle cells and down-regulate expression of cyclin A gene. Circulation 2000; 101: 805-11.
• 135 Murase T, Kume N, Hase T, Shibuya Y, Nishizawa Y, Tokimitsu I, Kita T. Gallates inhibit cytokine-induced nuclear tanslocation of NF-κB and expression of leukocyte adhesion molecules in vascular endothelial cells. Arterioscler Thromb Vasc Biol 1999; 19: 1412-20.
• 136 Manach C, Morand C, Texier O, Favier ML, Agullo G, Demigne C, Regerat F, Remesy C. Quercetin metabolites in plasma of rats fed diets containing rutin or quercetin. J Nutr 1995; 125: 1911-22.
• 137 Chen L, Lee MJ, Li H, Yang CS. Absorption, distribution, elimination of tea polyphenols in rats. Drug Metab Dispos 1997; 25: 1045-50.
• 138 Morand C, Crespy V, Manach C, Besson C, Demigne C, Remesy C. Plasma metabolites of quercetin and their antioxidant properties. Am J Physiol 1998; 275: R212-R219.
• 139 Donovan JL, Bell JR, Kasim-Karakas S, German JB, Walzem RL, Hansen RJ, Waterhouse AL. Catechin is present as metabolites in human plasma after consumption of red wine. J Nutr 1999; 129: 1662-8.
• 140 Manach C, Morand C, Crespy V, Demigne C, Texier O, Regerat F, Ramesy C. Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett 1998; 426: 331-6.
• 141 Frankel EN, Waterhouse AL, Kinsella JE. Inhibition of human LDL oxidation by resveratrol. Lancet 1993; 341: 1103-4.
• 142 Teissedre PL, Frankel EN, Waterhouse AL, Peleg H, German JB. Inhibition of in vitro human LDL oxidation by phenolic antioxidants from grapes and wines. J Sci Food Agric 1996; 70: 55-61.
• 143 Chopra M, Fitzsimons PE, Strain JJ, Thurnham DI, Howard AN. Non-alcoholic red wine extract and quercetin inhibit LDL oxidation without affecting plasma antioxidant vitamin and carotenoid concentrations. Clin Chem 2000; 46: 1162-70.
• 144 Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta 1995; 235: 207-19.
• 145 Corvazier E, Maclouf J. Interference of some flavonoids and non-steroidal anti-inflammatory drugs with oxidative metabolism of arachidonic acid by human platelets and neutrophils. Biochim Biophys Acta 1985; 835: 315-21.
• 146 Bertelli AA, Giovannini L, Bernini W, Migliori M, Fregoni M, Bavaresco L, Bertelli A. Antiplatelet activity of cis-resveratrol. Drugs Exp Clin Res 1996; 22: 61-3.
• 147 Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997; 275: 218-20.
• 148 Beretz A, Stierle A, Anton R, Cazenave JP. Role of cyclic AMP in the inhibition of human platelet aggregation by quercetin, a flavonoid that potentiates the effect of prostacyclin. Biochem Pharmacol 1982; 31: 3597-600.
• 149 Mower RL, Landolfi R, Steiner M. Inhibition in vitro of platelet aggregation and arachidonic acid metabolism by flavone. Biochem Pharmacol 1984; 33: 357-63.
• 150 Rapaport SI, Rao LV. The tissue factor pathway: how it has become a “prima ballerina”. Thromb Haemost 1995; 74: 7-17.
• 151 Taubman MB, Fallon JT, Schecter AD, Giesen P, Mendlowitz M, Fyfe BS, Marmur JD, Nemerson Y. Tissue factor in the pathogenesis of atherosclerosis. Thromb Haemost 1997; 78: 200-4.
• 152 Semeraro N, Colucci M. Tissue factor in health and disease. Thromb Haemost 1997; 78: 759-64.
• 153 Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody [corrected and republished article originally printed in Thromb Res 1990 Mar 1; 57 (5): 765-81]. Thromb Res 1990; 59: 421-37.
• 154 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-43.
• 155 Abou-Agag LH, Torres JA, Tabengwa EM, Benza RL, Shows SR, Aikens MA, Grenett HE, Booyse FM. Polyphenolics increase t-PA and u-PA gene transcription in cultured human endothelial cells. Alcohol Clin Exp Res 2001; 25: 155-62.
• 156 Wilson T, Knight TJ, Beitz DC, Lewis DS, Engen RL. Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits. Life Sci 1996; 59: L15-L21.
• 157 Ray PS, Maulik G, Cordis GA, Bertelli AA, Bertelli A, Das DK. The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Radic Biol Med 1999; 27: 160-9.
• 158 Picq M, Prigent AF, Nemoz G, Pacheco H. Selective inhibition of separated forms of cyclic nucleotide phosphodiesterase from rat heart by some pentasubstituted quercetin analogs. Biochem Pharmacol 1982; 31: 2777-82.
• 159 Wu ES, Cole TE, Davidson TA, Dailey MA, Doring KG, Fedorchuk M, Loch III JT, Thomas TL, Blosser JC, Borrelli AR. Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties. J Med Chem 1989; 32: 183-92.
• 160 Andriambeloson E, Magnier C, Haan-Archipoff G, Lobstein A, Anton R, Beretz A, Stoclet JC, Andriantsitohaina R. Natural dietary polyphenolic compounds cause endothelium-dependent vasorelaxation in rat thoracic aorta. J Nutr 1998; 128: 2324-33.
• 161 Chen CK, Pace-Asciak CR. Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta. Gen Pharmacol 1996; 27: 363-6.
• 162 Cishek MB, Galloway MT, Karim M, German JB, Kappagoda CT. Effect of red wine on endothelium-dependent relaxation in rabbits. Clin Sci 1997; 93: 507-11.
• 163 Andriambeloson E, Stoclet JC, Andriantsitohaina R. Mechanism of endothelial nitric oxide-dependent vasorelaxation induced by wine polyphenols in rat thoracic aorta. J Cardiovasc Pharmacol 1999; 33: 248-54.
• 164 Flesch M, Schwarz A, Bohm M. Effects of red and white wine on endothelium-dependent vasorelaxation of rat aorta and human coronary arteries. Am J Physiol 1998; 275: H1183-H1190.
• 165 Dreosti IE. Antioxidant polyphenols in tea, cocoa, and wine. Nutrition 2000; 16: 692-4.
• 166 Xie ML, Lu Q, Gu ZL. Effect of quercetin on platelet aggregation induced by oxyradicals. Chung-Kuo Yao Li Usueh Pao – Acta Pharmabologica Sinica 1996; 17: 334-6.
• 167 Pannala AS, Rice-Evans CA, Halliwell B, Singh S. Inhibition of peroxynitrite-mediated tyrosine nitration by catechin polyphenols. Biochem Biophy Res Commun 1997; 232: 164-8.
• 168 da Silva EL, Piskula MK, Yamamoto N, Moon JH, Terao J. Quercetin metabolites inhibit copper ion-induced lipid peroxidation in rat plasma. FEBS Lett 1998; 430: 405-8.
• 169 Boersma BJ, Patel RP, Kirk M, Jackson PL, Muccio D, Darley-Usmar VM, Barnes S. Chlorination and nitration of soy isoflavones. Arch Biochem Biophys 1999; 368: 265-75.
• 170 Aucamp J, Gaspar A, Hara Y, Apostolides Z. Inhibition of xanthine oxidase by catechins from tea (Camellia sinensis). Anticancer Res 1997; 17: 4381-5.
• 171 Terao J. Dietary flavonoids as antioxidants in vivo: conjugated metabolites of (-)-epicatechin and quercetin participate in antioxidative defense in blood plasma. J Med Invest 1999; 46: 159-68.
• 172 Farhat MY, Lavigne MC, Ramwell PW. The vascular protective effects of estrogen. FASEB J 1996; 10: 615-24.
• 173 Delyani JA, Murohara T, Nossuli TO, Lefer AM. Protection from myocardial reperfusion injury by acute administration of 17 beta-estradiol. J Mol Cell Cardiol 1996; 28: 1001-8.
• 174 Ashby J, Tinwell H, Pennie W, Brooks AN, Lefevre PA, Beresford N, Sumpter JP. Partial and weak oestrogenicity of the red wine constituent resveratrol: consideration of its superagonist activity in MCF-7 cells and its suggested cardiovascular protective effects. J Appl Toxicol 1999; 19: 39-45.
• 175 Gehm BD, McAndrews JM, Chien PY, Jameson JL. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA 1997; 94: 14138-43.
• 176 Turner RT, Evans GL, Zhang M, Maran A, Sibonga JD. Is resveratrol an estrogen agonist in growing rats?. Endocrinology 1999; 140: 50-4.