(Circulation. 1995;91:1182-1188.)
© 1995 American Heart Association, Inc.
Articles |
Administration of Wine and Grape Juice Inhibits In Vivo Platelet Activity and Thrombosis in Stenosed Canine Coronary Arteries
From the Cardiology Section, University of Wisconsin-Madison, Madison, Wisc.
Correspondence to John D. Folts, PhD, Professor of Medicine, Director, Coronary Thrombosis Research Laboratory, University of Wisconsin-Madison, Cardiology Section, Clinical Sciences Center H6/379, 600 Highland Ave, Madison, WI 53792.
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Abstract |
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Background Moderate daily consumption of alcoholic beverages is a negative risk factor for the development of atherosclerosis and coronary artery disease (CAD), especially in France and other Mediterranean areas where red wine is regularly consumed with meals. Platelets contribute to the development of atherosclerosis, CAD, and acute arterial thrombus formation.
Methods and Results Anesthetized dogs were prepared with the Folts model of mechanically stenosed coronary arteries and intimal damage. Periodic acute platelet-mediated thrombus formation occurred, causing cyclic flow reductions (CFRs) in coronary blood flow. The CFRs were eliminated by the administration of 1.62±1.12 mL/kg red wine intravenously (IV) and 4.0 mL/kg intragastrically (IG). The CFRs were abolished by 2.04±1.42 mL/kg of grape juice IV and 10 mL/kg IG. White wine did not have significant results in eliminating the CFRs, either IV (2.0 mL/kg) or IG (4.0 mL/kg), decreasing the slopes of the CFRs only slightly.
Conclusions Pure ethanol has been shown to inhibit
platelet aggregation in vitro, ex vivo, and in vivo, although a blood
alcohol content (BAC) of 
0.2 g/dL is usually required. The BAC of
dogs administered the red wine–saline solution intravenously was 0.028
g/dL, much less than is usually necessary for platelet inhibition with
pure ethanol. Because red wine and grape juice, but not white wine,
abolished the CFRs, this suggests there are compounds present in
red wine and grape juice that are not present or are present in
a lower concentration in white wine. Wine and grape juice contain a
wide variety of naturally occurring compounds, including fungicides,
tannins, anthocyanins, and phenolic flavonoids (including flavonols and
flavones). These compounds have shown platelet inhibition in vitro by a
variety of proposed mechanisms. Perhaps the biological activity of
these compounds can explain the platelet-inhibitory properties of red
wine and grape juice that are observed without high levels of ethanol.
Key Words: alcohol • thrombosis • platelets
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The French Paradox" (as it has been publicized by both the scientific and popular news media) deals with interesting yet confusing statistics regarding the lifestyle and rate of myocardial infarction of the French people. The French eat 3.8 times as much butter and 2.8 times as much lard as Americans, and they have higher serum cholesterol levels and higher blood pressure than Americans.1 Other risk factors for cardiovascular disease, such as body mass index and cigarette smoking, are comparable, yet Americans have a 2.5-fold greater rate of death due to ischemic (coronary) heart disease than the French.2
A number of hypotheses have been proposed to account for this paradox. The "Mediterranean diet" may play a role in explaining this paradox. The French drink very little milk and eat a large amount of fresh vegetables, fruits, and wine.2 3
Autopsy, geographic, case-control, cohort, clinical, and epidemiological studies have shown that there is an inverse relation between alcohol consumption and coronary artery disease (CAD).3 Moore and Pearson3 reviewed case-control and cohort studies showing that moderate alcohol consumption reduces the risk of CAD to 0.4% to 0.7% compared with nondrinkers. Since 1986, seven separate studies have corroborated the theory of decreased CAD risk with moderate alcohol consumption.3 4 Because wine5 and alcohol consumption6 7 8 have been shown to decrease platelet aggregation, the cardioprotective effects of alcohol may be in part related to platelet activity.
In the past 20 years, it has become apparent that platelets contribute to the rate of development of atherosclerosis and CAD through several mechanisms.9 In addition, platelet-mediated thrombus formation plays a key role in unstable angina, myocardial infarction, restenosis after angioplasty, and atherectomy.9 10 11 One way to study the platelet-inhibitory effects of various compounds in vivo is by using an in vivo model such as the Folts coronary thrombosis model of platelet aggregation and thrombus formation.12 13
Platelet-mediated thrombi periodically form in the stenosed coronary artery, followed by distal embolization. This produces cyclic reductions in measured coronary blood flow that are called cyclic flow reductions (CFRs). We have shown that the CFRs in mechanically stenosed canine arteries can be eliminated by platelet inhibitors such as aspirin or prostacyclin12 and the nitric oxide donor sodium nitroprusside.14 We have also shown that 1.0 mL/kg of pure ethanol inhibits platelets in this model, producing an average blood alcohol content (BAC) of 0.24 g/dL.15 Preliminary studies suggested that red wine inhibited platelet activity and coronary thrombosis in vivo.16
To determine the antithrombotic, antiplatelet activity of wine, we decided to study the effectiveness of red and white wine in the Folts in vivo model. We also sought to determine if grape juice, a compound that is similar yet is without alcohol, would have a platelet-inhibitory effect. This would help to clarify the cardioprotective importance of the ethanol content of wine.
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Methods |
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Forty-seven adult mongrel dogs of either sex were anesthetized as follows. We have previously shown that barbiturates, commonly used as anesthetic agents, inhibit platelet activity at plasma levels of 10-4 mol/L.17 These levels are often achieved in animals administered 30 mg/kg of sodium pentobarbital.17 To minimize the circulating plasma levels of pentobarbital, we developed a new method of administering barbiturate anesthesia. The dogs were premedicated with 3 mg/kg morphine sulfate IM followed by 5 mg/kg of the short-acting dissociative anesthetic ketamine (Vetalar) administered intravenously. This allowed us to perform a cutdown on the brachial artery in the right front leg and advance a catheter into the brachiocephalic artery. In dogs, this artery supplies three fourths of the blood flow to the brain via the left vertebral artery. Sodium pentobarbital (5 mg/kg) given in this artery completely anesthetizes the brain and produces a plasma concentration of only 0.7 mg/dL. All subsequent pentobarbital is also given through this catheter. This produces a properly anesthetized brain but minimizes the depression of other organ systems by pentobarbital.18
After the dogs were properly anesthetized, a left thoracotomy was performed and the left circumflex coronary artery was dissected. An electromagnetic flow probe was placed around the artery to measure blood flow. The coronary artery was squeezed 2 to 3 mm distal to the flow probe with a special surgical clamp to produce intimal and medial damage. A plastic constricting occluder was then placed around the outside of that portion of the artery to produce a 70% stenosis. Blood pressure and the ECG of each animal were also monitored. When the instrumentation was in place, each dog was observed until CFRs due to platelet-mediated coronary artery occlusion were occurring at regular intervals (approximately 30 to 45 minutes).
Group 1: Red Wine
After the control period, 15 dogs were
given an intravenous
infusion of red wine diluted in saline. The red wine (1987
Chateauneuf-du-Pape) was 13% alcohol by volume. To determine how much
red wine might be needed to eliminate the CFRs, 2 mL/kg of red wine was
diluted in 200 mL of saline. The solution was then given intravenously
at a rate of 20 drops per minute. The intravenous infusion was
continued until all had been given or until the CFRs were abolished.
When the CFRs were eliminated, the volume of the remaining wine–saline
solution was measured and subtracted from the starting volume. This
permitted calculation of the minimum effective intravenous dose of wine
needed to abolish the CFRs as well as calculation of the exact amount
of ethanol given in that amount of wine. A blood sample was taken when
the CFRs were abolished or all of the wine–saline solution had been
given to determine the BAC.
In addition, because wine is normally processed by the stomach after consumption, animals were instrumented as described above, except that the red wine was given directly through a gastric tube with the tip placed in the duodenum. Five dogs were administered 4 mL/kg of red wine IG. We anticipated an increase in time for gastrointestinal absorption in the anesthetized animals due to depressed gastric motility.
Group 2: White Wine
After the control period, seven dogs were
administered an
intravenous infusion of white wine diluted in saline. The white wine,
(1990 Chateau Villotte Bordeaux) was 12% alcohol by volume. To
determine how much white wine might be needed to eliminate the CFRs, 2
mL/kg of white wine was diluted in 200 mL of saline. The solution was
then given intravenously at a rate of 20 drops per minute. The
intravenous infusion was continued until all had been given or until
the CFRs were abolished. The minimum effective dose was calculated as
described for group 1. A blood sample was taken when the CFRs were
abolished or all of the wine–saline solution had been given to
determine the BAC.
To test the gastrointestinal absorption of white wine, five dogs were instrumented as described above and received 4 mL/kg of white wine IG.
Group 3: Grape Juice
After the control observation period,
five dogs were
administered an intravenous infusion of grape juice diluted in saline.
The grape juice used was Welch's 100% natural purple grape juice with
no sugar, artificial flavors, or colors added. To determine how much
grape juice might be needed to eliminate the CFRs, 4 mL/kg of grape
juice was diluted in 400 mL of saline. The solution was then given
intravenously at a rate of 20 drops per minute. The intravenous
infusion was continued until all had been given or until the CFRs were
abolished. The minimum effective dose was then calculated as described
for group 1.
In addition, animals were instrumented as described above, except that the grape juice was given intragastrically as in groups 1 and 2. Three doses of grape juice were administered: two dogs received 6 mL/kg, three dogs received 8 mL/kg, and five dogs received 10 mL/kg.
Whole-blood aggregation studies were performed on the five animals who received 10 mL/kg of grape juice by stomach tube. Blood was collected by a fresh puncture in the exposed left atrial appendage and placed in 1:10 vol of 3.2% sodium citrate. The blood was diluted 1:1 with saline and studied with a Chronolog Whole Blood Aggregometer.19 The aggregation response to collagen (Chrono-Par) before administration of the beverage was compared with the aggregation response to the same dose of collagen after the beverage.
High-Performance Liquid Chromatography Analysis
The red wine,
white wine, and grape juice were analyzed by
high-performance liquid chromatography analysis for two naturally
occurring flavonoid compounds—quercetin and rutin—and we searched
for
the fungicide resveratrol by standard biochemical
techniques.20
All values are reported as mean±1 SD, and statistical significance expressed by P values was determined by Student's t test.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Group 1: Red Wine
CFRs were observed during the initial observation period for all of the dogs. Elimination of the CFRs occurred in all animals with the infusion of the red wine–saline solution (Fig 1
). The
average time for elimination of the CFRs was 5.2±2.8 minutes. The
average amount of red wine needed to inhibit platelet activity and
abolish the CFRs was 1.62±1.12 mL/kg with an average alcohol content
of 0.21±0.15 mL/kg. The BAC after elimination of the CFRs was
0.028±0.021 g/dL. The CFRs were abolished for approximately 1 hour, at
which time the study was terminated.
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In the five anesthetized dogs
administered 4 mL/kg red wine by gastric
tube, the CFRs were eliminated in all animals after an average of
113±32 minutes (Fig 2). The slopes of the CFRs during
this time period decreased gradually. The average ethanol content of
the red wine given was 0.52 mL/kg and produced an average BAC of
0.036±0.013 g/dL. The CFRs were abolished for approximately 1 hour, at
which time the study was terminated.
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Group 2: White Wine
CFRs were observed during the initial
observation period for all
of the dogs. The intravenous white wine–saline infusion had an ethanol
content of approximately 0.24 mL/kg and produced an average BAC of
0.020±0.006 g/dL. At this concentration, the white wine did not
abolish the CFRs. The average slopes of the CFRs (in
mL/min2, calculated using the best-fit line through
the CFR) decreased slightly from -18.96±4.95 mL/min2
before the infusion to -16.26±4.13 ml/min2 after the
infusion, suggesting minimal inhibition of in vivo platelet activity
(P=.16).
In the five dogs administered 4 mL/kg white
wine by gastric tube, the
CFRs were not eliminated in any of the animals (Fig 3).
The average ethanol concentration of the wine–saline solution was 0.48
mL/kg and produced an average BAC of 0.024±0.015 g/dL after the
administration. The slopes of the CFRs were not significantly different
after intragastric administration of the white wine. The average slope
of the CFRs was -18.47±3.56 mL/min2 before the wine
and
-14.85±5.35 ml/min2 (P=.09) after the
intragastric administration of white wine.
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Group 3: Grape Juice
CFRs were observed during the initial
observation period for all
dogs. Elimination of the CFRs occurred in 4 of the 5 animals
administered the intravenous infusion of the grape juice–saline
solution (Fig 4). The remaining dog showed a decrease in
the slopes of the CFRs (P<.03), and spontaneous
embolizations of thrombi were observed. The average time for
elimination of the CFRs was 15.3±9.0 minutes. The average amount of
grape juice needed to abolish the CFRs was 2.04±1.42 mL/kg. The
inhibitory effect of the intravenous grape juice lasted approximately
45 minutes, and then the experiment was terminated.
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The dogs
administered 6 or 8 mL/kg of grape juice IG showed platelet
inhibition by a decrease in the slopes of the CFRs and spontaneous
embolizations of thrombi, yet the CFRs were not completely eliminated
in every animal at a given dose. The CFRs in the five dogs administered
10 mL/kg were completely abolished after an average of 95±33
minutes. The amount of intragastric grape juice
necessary to abolish the CFRs was 2.5-fold greater than the amount of
intragastric red wine administered. The aggregation response to
collagen before the grape juice administration was compared with the
response when the CFRs were eliminated (Fig 5). The studies
showed a
67.6±19.7% decrease in aggregation in response to the same
concentration of collagen (P<.01).
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High-Performance Liquid Chromatography Analysis
The red wine
used in this study contained 119 mg/L of quercetin,
76 mg/L of rutin, and nondetectable levels of the fungicide
resveratrol. The white wine we used contained 25 mg/L of quercetin, 14
mg/L of rutin, and 9 mg/L of resveratrol. The grape juice we used
contained 86 mg/L of quercetin, 82 mg/L of rutin, and nondetectable
levels of resveratrol. The total high-performance liquid chromatography
absorbance counts of the three standards tested and unidentified
compounds (possible flavonoids) in the red wine were 2.7-fold greater
than those in the grape juice.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Many epidemiological studies have investigated the relative cardioprotective benefits of different types of alcoholic beverages.2 3 4 Renaud and DeLogeril,21 Nanji,22 and St Leger et al23 have suggested that wine consumption is responsible for the low levels of CAD mortality in countries with high wine consumption. Both Nanji and St Leger et al found an inverse association between CAD mortality and wine consumption (r=-.75 and -.65, respectively) but reported a positive correlation between CAD mortality and beer consumption (r=.60 and .27). In case-control studies, Hennekens et al24 give the relative risk of CAD mortality for light to moderate drinkers (
2 oz of ethanol per day) as 0.3 for those
consuming beer or wine and 0.2 for those consuming liquor. Klatsky and
Armstrong25 give the relative risk as 0.7 for those
preferring beer or wine but calculates the relative risk as 1.0 to 1.1
for those preferring liquor. Numerous studies have attributed the observed cardioprotective effects of alcohol consumption to an increase in plasma HDL cholesterol levels,4 26 yet some scientists believe that a higher HDL cholesterol level does not fully explain the cardioprotective effects of moderate alcohol consumption.27 28 Seigneur et al5 studied platelet aggregation and lipid levels of human volunteers who consumed red wine or white wine for a 15-day study period. The consumption of either red or white wine increased HDL levels and the consumption of red wine decreased ADP-induced platelet aggregation.
The Folts coronary thrombosis model is an on-line in vivo bioassay for platelet activity producing CFRs in coronary blood flow.11 The CFRs were abolished by both the red wine and the grape juice when administered intravenously and intragastrically. Administration of the white wine did not produce significant results in eliminating the CFRs, either intravenously or intragastrically and only slightly decreased the slope of the CFRs. These results suggest that there are compounds present in red wine and grape juice that are not present or are present in a lower concentration in white wine that may be antithrombotic and platelet inhibitory.
Red wine and grape juice were also effective as antiplatelet, antithrombotic compounds when administered intragastrically, suggesting that the active ingredients are absorbed and transported to the bloodstream. Many investigators have used the Folts cyclic flow model to study platelet inhibitors given intravenously.29 30 31 Torr et al32 were the first to study a drug in the Folts model given by stomach tube. Because the CFRs will continue for 3 to 4 hours if no antiplatelet agent is given,29 30 31 it is reasonable to study drugs (or foods) given by stomach tube.
Pure ethanol has been shown to inhibit platelet aggregation in vitro,
ex vivo, and in vivo, although a BAC of 0.2 g/dL is
required.6 15 We previously demonstrated in this
model
that an average of 1.0 mL/kg of pure ethanol dissolved in saline and
administered intravenously eliminates the CFRs, producing an average
peak BAC of 0.24 g/dL.24 The BAC of the dogs that received
the red wine–saline solution intravenously was 0.028 g/dL, 12% of the
BAC of the dogs that received pure ethanol.
Because the amount of ethanol necessary to eliminate the CFRs is greatly reduced when red wine rather than pure ethanol was given, there must be active platelet inhibitors in the red wine in addition to the ethanol. These compounds may be the same antiplatelet compounds that provide the antithrombotic activity of grape juice.
It has been proposed that the protective effects of wine, specifically red wine, may be due to a large number of naturally occurring constituents in the beverage. Wine contains a wide variety of compounds, including naturally occurring fungicides, tannins, anthocyanins, and phenolic flavonoids (including flavonols and flavones).33 Frankel et al34 have shown that phenolic substances in red wine inhibit the oxidation of human LDL cholesterol. The bioflavonoid quercetin found in red wine also exhibits antioxidant capabilities and is more potent than vitamin E.34
The naturally occurring flavonoids found in wine, grape juice, and other foods have been shown to decrease platelet aggregation in vitro,35 36 37 inhibit platelet aggregation on blood-superfused collagen strips in vivo,38 and cause platelet disaggregation of preformed platelet thrombi in vitro.38 Our group has shown that the flavonoids quercetin (given intravenously or intragastrically) and rutin (given intravenously) inhibit platelet activity, eliminating the CFRs in the Folts in vivo model.39
There also is evidence that flavonoids inhibit the production of thromboxane A2,37 perhaps by inhibiting platelet cyclooxygenase activity.35 37 Especially interesting are the studies demonstrating that quercetin increases platelet cAMP levels40 and that quercetin35 40 potentiates the increase in cAMP induced by prostaglandin I2. Flavonoids (particularly quercetin, kaempferol, apigenin, and amentoflavone) have been shown to inhibit cAMP and cGMP phosphodiesterases.41 42 The inhibition of cAMP or cGMP phosphodiesterases would raise the platelet levels of cAMP or cGMP. This in turn would lower platelet cystolic calcium levels and decrease the level of in vivo platelet activity.43
It is therefore possible to speculate that the cardioprotective effects of red wine consumption observed in the French and other populations may be attributed in part to the ethanol content of the wine and in part to the antioxidant and platelet-inhibitory properties of other naturally occurring compounds in the wine. Because platelet adhesion to damaged endothelium and subsequent platelet aggregation are major steps in both thrombosis and atherogenesis, the long-term inhibition of platelet activity by the consumption of flavonoid-containing foods and beverages may retard atherogenesis and prevent thrombosis on a daily basis. The potentially beneficial effects of alcoholic beverages and fruit juices on CAD warrants further study.
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Acknowledgments |
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This work was supported by the Nutricia Research Foundation (The Hague, Netherlands) and the Rennebohm Foundation.
Received July 6, 1994; revision received September 6, 1994; accepted September 28, 1994.
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 J. Lefevre, S.-E. Michaud, P. Haddad, S. Dussault, C. Menard, J. Groleau, J. Turgeon, and A. Rivard Moderate consumption of red wine (cabernet sauvignon) improves ischemia-induced neovascularization in ApoE-deficient mice: effect on endothelial progenitor cells and nitric oxide FASEB J, December 1, 2007; 21(14): 3845 - 3852. [Abstract] [Full Text] [PDF]
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 L. H. Opie and S. Lecour The red wine hypothesis: from concepts to protective signalling molecules Eur. Heart J., July 2, 2007; 28(14): 1683 - 1693. [Abstract] [Full Text] [PDF]
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 J. Lin, K. M. Rexrode, F. Hu, C. M. Albert, C. U. Chae, E. B. Rimm, M. J. Stampfer, and J. E. Manson Dietary Intakes of Flavonols and Flavones and Coronary Heart Disease in US Women Am. J. Epidemiol., June 1, 2007; 165(11): 1305 - 1313. [Abstract] [Full Text] [PDF]
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P. Castilla, R. Echarri, A. Davalos, F. Cerrato, H. Ortega, J. L. Teruel, M. F. Lucas, D. Gomez-Coronado, J. Ortuno, and M. A Lasuncion Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects Am. J. Clinical Nutrition, July 1, 2006; 84(1): 252 - 262. [Abstract] [Full Text] [PDF]
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 A. Davalos, C. Fernandez-Hernando, F. Cerrato, J. Martinez-Botas, D. Gomez-Coronado, C. Gomez-Cordoves, and M. A. Lasuncion Red Grape Juice Polyphenols Alter Cholesterol Homeostasis and Increase LDL-Receptor Activity in Human Cells In Vitro J. Nutr., July 1, 2006; 136(7): 1766 - 1773. [Abstract] [Full Text] [PDF]
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P. Pignatelli, S. Di Santo, B. Buchetti, V. Sanguigni, A. Brunelli, and F. Violi Polyphenols enhance platelet nitric oxide by inhibiting protein kinase C-dependent NADPH oxidase activation: effect on platelet recruitment FASEB J, June 1, 2006; 20(8): 1082 - 1089. [Abstract] [Full Text] [PDF]
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 P. E. Szmitko and S. Verma Antiatherogenic potential of red wine: clinician update Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2023 - H2030. [Abstract] [Full Text] [PDF]
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J. A Vita Polyphenols and cardiovascular disease: effects on endothelial and platelet function Am. J. Clinical Nutrition, January 1, 2005; 81(1): 292S - 297S. [Abstract] [Full Text] [PDF]
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 M. Dell'Agli, A. Busciala, and E. Bosisio Vascular effects of wine polyphenols Cardiovasc Res, September 1, 2004; 63(4): 593 - 602. [Abstract] [Full Text] [PDF]
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D. Shanmuganayagam, M. R. Beahm, H. E. Osman, C. G. Krueger, J. D. Reed, and J. D. Folts Grape Seed and Grape Skin Extracts Elicit a Greater Antiplatelet Effect When Used in Combination than When Used Individually in Dogs and Humans J. Nutr., December 1, 2002; 132(12): 3592 - 3598. [Abstract] [Full Text] [PDF]
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G. Imamura, A. A. Bertelli, A. Bertelli, H. Otani, N. Maulik, and D. K. Das Pharmacological preconditioning with resveratrol: an insight with iNOS knockout mice Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H1996 - H2003. [Abstract] [Full Text] [PDF]
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C. Auger, B. Caporiccio, N. Landrault, P. L. Teissedre, C. Laurent, G. Cros, P. Besancon, and J.-M. Rouanet Red Wine Phenolic Compounds Reduce Plasma Lipids and Apolipoprotein B and Prevent Early Aortic Atherosclerosis in Hypercholesterolemic Golden Syrian Hamsters (Mesocricetus auratus) J. Nutr., June 1, 2002; 132(6): 1207 - 1213. [Abstract] [Full Text] [PDF]
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 K. Iijima, M. Yoshizumi, M. Hashimoto, M. Akishita, K. Kozaki, J. Ako, T. Watanabe, Y. Ohike, B. Son, J. Yu, et al. Red Wine Polyphenols Inhibit Vascular Smooth Muscle Cell Migration Through Two Distinct Signaling Pathways Circulation, May 21, 2002; 105(20): 2404 - 2410. [Abstract] [Full Text] [PDF]
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T. Pataki, I. Bak, P. Kovacs, D. Bagchi, D. K Das, and A. Tosaki Grape seed proanthocyanidins improved cardiac recovery during reperfusion after ischemia in isolated rat hearts Am. J. Clinical Nutrition, May 1, 2002; 75(5): 894 - 899. [Abstract] [Full Text] [PDF]
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I. Bernatova, O. Pechanova, P. Babal, S. Kysela, S. Stvrtina, and R. Andriantsitohaina Wine polyphenols improve cardiovascular remodeling and vascular function in NO-deficient hypertension Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H942 - H948. [Abstract] [Full Text] [PDF]
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J. D. Folts, J. Keevil, J. H. Stein, E. Fisher, and I. J. Goldberg Wine and Your Heart Response Circulation, November 27, 2001; 104 (22): e130 - e130. [Full Text] [PDF]
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W. H. Briggs, J. D. Folts, H. E. Osman, and I. L. Goldman Administration of Raw Onion Inhibits Platelet-Mediated Thrombosis in Dogs J. Nutr., October 1, 2001; 131(10): 2619 - 2622. [Abstract] [Full Text] [PDF]
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 M. Diebolt, B. Bucher, and R. Andriantsitohaina Wine Polyphenols Decrease Blood Pressure, Improve NO Vasodilatation, and Induce Gene Expression Hypertension, August 1, 2001; 38(2): 159 - 165. [Abstract] [Full Text] [PDF]
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J. E. Freedman, C. Parker III, L. Li, J. A. Perlman, B. Frei, V. Ivanov, L. R. Deak, M. D. Iafrati, and J. D. Folts Select Flavonoids and Whole Juice From Purple Grapes Inhibit Platelet Function and Enhance Nitric Oxide Release Circulation, June 12, 2001; 103(23): 2792 - 2798. [Abstract] [Full Text] [PDF]
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 S. J. Duffy, J. A. Vita, M. Holbrook, P. L. Swerdloff, and J. F. Keaney Jr Effect of Acute and Chronic Tea Consumption on Platelet Aggregation in Patients With Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 1084 - 1089. [Abstract] [Full Text] [PDF]
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 M. Krenz, C. P. Baines, X.-M. Yang, G. Heusch, M. V. Cohen, and J. M. Downey Acute ethanol exposure fails to elicit preconditioning-like protection in in situ rabbit hearts because of its continued presence during ischemia J. Am. Coll. Cardiol., February 1, 2001; 37(2): 601 - 607. [Abstract] [Full Text] [PDF]
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 I. J. Goldberg, L. Mosca, M. R. Piano, and E. A. Fisher Wine and Your Heart : A Science Advisory for Healthcare Professionals From the Nutrition Committee, Council on Epidemiology and Prevention, and Council on Cardiovascular Nursing of the American Heart Association Stroke, February 1, 2001; 32(2): 591 - 594. [Full Text] [PDF]
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I. J. Goldberg, L. Mosca, M. R. Piano, and E. A. Fisher Wine and Your Heart : A Science Advisory for Healthcare Professionals From the Nutrition Committee, Council on Epidemiology and Prevention, and Council on Cardiovascular Nursing of the American Heart Association Circulation, January 23, 2001; 103(3): 472 - 475. [Full Text] [PDF]
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 E. Middleton Jr., C. Kandaswami, and T. C. Theoharides The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer Pharmacol. Rev., December 1, 2000; 52(4): 673 - 751. [Abstract] [Full Text] [PDF]
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P. Pignatelli, F. M Pulcinelli, A. Celestini, L. Lenti, A. Ghiselli, P. P. Gazzaniga, and F. Violi The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide Am. J. Clinical Nutrition, November 1, 2000; 72(5): 1150 - 1155. [Abstract] [Full Text] [PDF]
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F. Visioli, L. Borsani, and C. Galli Diet and prevention of coronary heart disease: the potential role of phytochemicals Cardiovasc Res, August 18, 2000; 47(3): 419 - 425. [Abstract] [Full Text] [PDF]
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D. Rein, S. Lotito, R. R. Holt, C. L. Keen, H. H. Schmitz, and C. G. Fraga Epicatechin in Human Plasma: In Vivo Determination and Effect of Chocolate Consumption on Plasma Oxidation Status J. Nutr., August 1, 2000; 130(8): 2109S - 2114. [Abstract] [Full Text]
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B. Fuhrman, M. Rosenblat, T. Hayek, R. Coleman, and M. Aviram Ginger Extract Consumption Reduces Plasma Cholesterol, Inhibits LDL Oxidation and Attenuates Development of Atherosclerosis in Atherosclerotic, Apolipoprotein E-Deficient Mice J. Nutr., May 1, 2000; 130(5): 1124 - 1131. [Abstract] [Full Text]
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J. G. Keevil, H. E. Osman, J. D. Reed, and J. D. Folts Grape Juice, But Not Orange Juice or Grapefruit Juice, Inhibits Human Platelet Aggregation J. Nutr., January 1, 2000; 130(1): 53 - 56. [Abstract] [Full Text]
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A.-N. Feng, Y.-L. Chen, Y.-T. Chen, Y.-Z. Ding, and S.-J. Lin Red Wine Inhibits Monocyte Chemotactic Protein-1 Expression and Modestly Reduces Neointimal Hyperplasia After Balloon Injury in Cholesterol-Fed Rabbits Circulation, November 30, 1999; 100(22): 2254 - 2259. [Abstract] [Full Text] [PDF]
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J. H. Stein, J. G. Keevil, D. A. Wiebe, S. Aeschlimann, and J. D. Folts Purple Grape Juice Improves Endothelial Function and Reduces the Susceptibility of LDL Cholesterol to Oxidation in Patients With Coronary Artery Disease Circulation, September 7, 1999; 100(10): 1050 - 1055. [Abstract] [Full Text] [PDF]
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J. L. Donovan, J. R. Bell, S. Kasim-Karakas, J. B. German, R. L. Walzem, R. J. Hansen, and A. L. Waterhouse Catechin Is Present as Metabolites in Human Plasma after Consumption of Red Wine J. Nutr., September 1, 1999; 129(9): 1662 - 1668. [Abstract] [Full Text]
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 J-P BROUSTET Wine and health Heart, May 1, 1999; 81(5): 459 - 460. [Full Text]
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J. D. Folts, A. I. Schafer, J. Loscalzo, J. T. Willerson, and J. E. Muller A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials J. Am. Coll. Cardiol., February 1, 1999; 33(2): 295 - 303. [Abstract] [Full Text] [PDF]
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 K. Sudhir Medical Therapy for Coronary Artery Disease: Primary and Secondary Prevention Asian Cardiovasc Thorac Ann, December 1, 1998; 6(4): 245 - 249. [Abstract] [Full Text] [PDF]
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H. E. Osman, N. Maalej, D. Shanmuganayagam, and J. D. Folts Grape Juice but Not Orange or Grapefruit Juice Inhibits Platelet Activity in Dogs and Monkeys (Macaca fasciularis) J. Nutr., December 1, 1998; 128(12): 2307 - 2312. [Abstract] [Full Text]
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M. Flesch, A. Schwarz, and M. Bohm Effects of red and white wine on endothelium-dependent vasorelaxation of rat aorta and human coronary arteries Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1183 - H1190. [Abstract] [Full Text] [PDF]
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M. Serafini, G. Maiani, and A. Ferro-Luzzi Alcohol-Free Red Wine Enhances Plasma Antioxidant Capacity in Humans J. Nutr., June 1, 1998; 128(6): 1003 - 1007. [Abstract] [Full Text]
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S. Kiechl, J. Willeit, G. Rungger, G. Egger, F. Oberhollenzer, and E. Bonora Alcohol Consumption and Atherosclerosis: What Is the Relation? : Prospective Results From the Bruneck Study Stroke, May 1, 1998; 29(5): 900 - 907. [Abstract] [Full Text] [PDF]
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 K. Sudhir Review : Recent Advances in the Prevention of Coronary Artery Disease: Focus on Primary Prevention Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1998; 3(1): 77 - 83. [Abstract] [PDF]
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