The Antiinflammatory Effects of Purple Grape Juice Consumption in Subjects with Stable Coronary Artery Disease
http://www.100md.com
《动脉硬化血栓血管生物学》
Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA
To the Editor:
Moderate consumption of red wine is associated with a reduction in cardiovascular disease,1–4 and some of the cardioprotective effects have been attributed to the distinct polyphenolic compounds present in red wine and purple grape products. These polyphenols possess multiple biological effects, including antioxidant and free radical–scavenging properties5,6 as well as inhibition of platelet activation.7 The growing interest in the presumed benefits of wine in protecting against coronary heart disease coupled with the inherent limitations in promoting alcohol consumption8,9 has led to the examination of the potential beneficial vascular properties of alternative purple grape products. The effect of these flavonoid-rich substances in subjects with cardiovascular disease taking aspirin is unknown. In addition, their impact on the inflammatory properties of platelets has not been studied.
A double blind crossover study was conducted, in which 20 subjects with previously diagnosed coronary disease on standard medications were randomly assigned to drink either placebo or purple grape juice (PGJ; 7cc/kg/d, Welch’s Concord) for 14 days separated by a 2-week washout period. All patients maintained aspirin treatment (8 of 20 81 mg/d; 12 of 20 325 mg/d). Mean age was 63±9 (range 42 to 76) with 17 male and 3 female participants, 10 of 20 had hypertension, and 4 of 20 were active tobacco users. Medications included ACE inhibitor (8 of 20), diuretic therapy (2 of 20), calcium channel blocker (4 of 20), statin (18 of 20), ?-blocker (18 of 20), warfarin (2 of 20), and clopidogrel (2 of 20).
Venous blood was obtained from subjects in the fasting state at visits 1 to 4. Washed platelets were used to measure aggregation using ADP, thrombin receptor activating peptide (TRAP), or phorbol ester (PMA) as the platelet agonist. To quantitate markers of platelet activation, plasma TXB2 levels (Cayman Chemical) and human soluble P-selectin levels (R&D Systems) were measured by enzyme-linked immunoassay and, respectively. Markers of inflammation were measured in plasma (C-reactive protein , DiaPharma; and interleukin -8, BD Biosciences). Soluble CD40L release was measured in serum through the use of an enzyme-linked immunoassay (R&D Systems). To quantify platelet derived nitric oxide (NO) production, a microelectrode was used.10 Aggregation with lucigenin detection was used to detect platelet superoxide production.10
Baseline platelet aggregation was suppressed secondary to aspirin treatment, but there was no additional inhibition with PGJ or placebo using ADP, TRAP, or PMA as the platelet agonist. Indices of platelet thrombotic function and aggregation did not change with PGJ or placebo juice intake (P-selectin, platelet-derived NO, or TXB2 levels). General inflammatory markers (CRP, IL-8) were unaffected; however, platelet-dependent inflammatory markers were significantly decreased after consumption of PGJ with significantly lower superoxide release (Table 1). Platelet activation leads to surface expression and shedding of the inflammatory mediator CD40L, and a significant decrease in the mean value of sCD40L levels was observed with PGJ versus placebo consumption (Table 1). HDL also significantly increased with PGJ consumption (Table 2).
TABLE 1. Platelet and Inflammatory Function after Consumption of PGJ or Placebo Control
TABLE 2. Clinical Laboratory Data after Consumption of PGJ or Placebo Control
Consumption of red wine and purple grape juice have previously been shown to have antithrombotic and vasodilatory properties due to antioxidant effects as well as enhanced bioactive NO.11 The relevance of the antithrombotic properties in subjects with cardiovascular disease taking aspirin was not known. Findings from this study indicate that consumption of PGJ fails to add to the platelet inhibitory effects of aspirin as measured by markers of platelet function including aggregation, thromboxane B2, and P-selectin. However, the role of platelets in inflammatory-dependent vascular processes is of growing interest, and consumption of PGJ appears to attenuate some of these effects, specifically sCD40L release, despite aspirin intake. It is established that CD40–CD40L interactions are central in immune responses and inflammation, but more recently ligation of CD40 on vascular cells and platelets has been shown to contribute to the pathogenesis of atherosclerotic, thrombotic, and inflammatory processes.12,13
In summary, PGJ contains specific flavonoids that may attenuate cardiovascular disease and, specifically, inhibit thrombosis. However, there has been a paucity of clinical studies directly examining this question. In this study, consumption of PGJ did not alter clinical variables or platelet activation in subjects with cardiovascular disease, but did suppress levels of platelet-dependent superoxide and sCD40L release. These findings suggest that consumption of purple grape juice, although not providing an additive antithrombotic effect for patients already on aspirin, may suppress platelet-dependent inflammatory indices that have been recently linked to cardiovascular disease.
Acknowledgments
Dr. Freedman is supported by National Institutes of Health grants RO1AG08226, NIH RO1HL62267, and an Established Investigator Award from the American Heart Association. This project was partially supported by an unrestricted grant from Welch’s. We would like to thank Monica Holbrook for her assistance in recruiting subjects.
References
Renaud S, DeLorgeril M. Wine, alcohol, platelets and the French Paradox for coronary artery heart disease. Lancet. 1992; 296: 320–331.
St. Leger A, Cochrane A, Moore F. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. Lancet. 1979; 124: 1017–1020.
Klatsky A, Friedman G, Siegelaub A. Alcohol use and cardiovascular disease: the Kaiser–Permanente experience. Circulation. 1981; 32–41.
Rimm E, Giovannucci E, Willet W, Colditz G, Acheriori A, Rosner B, Stampfer M. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet. 1991; 338: 464–468.
Fragopoulou E, Antonopoulou S, Nomikos T, Demopoulos CA. Structure elucidation of phenolic compounds from red/white wine with antiatherogenic properties. Biochim Biophys Acta. 2003; 1632: 90–99.
Carluccio MA, Siculella L, Ancora MA, Massaro M, Scoditti E, Storelli C, Visioli F, Distante A, De Caterina R. Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler Thromb Vasc Biol. 2003; 23: 622–629.
Freedman JE, Parker C, 3rd, Li L, Perlman JA, Frei B, Ivanov V, Deak LR, Iafrati MD, Folts JD. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation. 2001; 103: 2792–2798.
Vogel RA. Alcohol, heart disease, and mortality: a review. Rev Cardiovasc Med. 2002; 3: 7–13.
Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, Griel AE, Etherton TD. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med. 2002; 113 Suppl 9B: 71S–88S.
Freedman JE, Loscalzo J, Barnard MR, Alpert C, Keaney JF, Jr., Michelson A. Nitric oxide released from activated platelets inhibits platelet recruitment. J Clin Invest. 1997; 100: 350–356.
Folts JD. Potential health benefits from the flavonoids in grape products on vascular disease. Adv Exp Med Biol. 2002; 505: 95–111.
Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998; 391: 591–594.
Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature. 1998; 394: 200–203.(Anne R. Albers; Sonia Var)
To the Editor:
Moderate consumption of red wine is associated with a reduction in cardiovascular disease,1–4 and some of the cardioprotective effects have been attributed to the distinct polyphenolic compounds present in red wine and purple grape products. These polyphenols possess multiple biological effects, including antioxidant and free radical–scavenging properties5,6 as well as inhibition of platelet activation.7 The growing interest in the presumed benefits of wine in protecting against coronary heart disease coupled with the inherent limitations in promoting alcohol consumption8,9 has led to the examination of the potential beneficial vascular properties of alternative purple grape products. The effect of these flavonoid-rich substances in subjects with cardiovascular disease taking aspirin is unknown. In addition, their impact on the inflammatory properties of platelets has not been studied.
A double blind crossover study was conducted, in which 20 subjects with previously diagnosed coronary disease on standard medications were randomly assigned to drink either placebo or purple grape juice (PGJ; 7cc/kg/d, Welch’s Concord) for 14 days separated by a 2-week washout period. All patients maintained aspirin treatment (8 of 20 81 mg/d; 12 of 20 325 mg/d). Mean age was 63±9 (range 42 to 76) with 17 male and 3 female participants, 10 of 20 had hypertension, and 4 of 20 were active tobacco users. Medications included ACE inhibitor (8 of 20), diuretic therapy (2 of 20), calcium channel blocker (4 of 20), statin (18 of 20), ?-blocker (18 of 20), warfarin (2 of 20), and clopidogrel (2 of 20).
Venous blood was obtained from subjects in the fasting state at visits 1 to 4. Washed platelets were used to measure aggregation using ADP, thrombin receptor activating peptide (TRAP), or phorbol ester (PMA) as the platelet agonist. To quantitate markers of platelet activation, plasma TXB2 levels (Cayman Chemical) and human soluble P-selectin levels (R&D Systems) were measured by enzyme-linked immunoassay and, respectively. Markers of inflammation were measured in plasma (C-reactive protein , DiaPharma; and interleukin -8, BD Biosciences). Soluble CD40L release was measured in serum through the use of an enzyme-linked immunoassay (R&D Systems). To quantify platelet derived nitric oxide (NO) production, a microelectrode was used.10 Aggregation with lucigenin detection was used to detect platelet superoxide production.10
Baseline platelet aggregation was suppressed secondary to aspirin treatment, but there was no additional inhibition with PGJ or placebo using ADP, TRAP, or PMA as the platelet agonist. Indices of platelet thrombotic function and aggregation did not change with PGJ or placebo juice intake (P-selectin, platelet-derived NO, or TXB2 levels). General inflammatory markers (CRP, IL-8) were unaffected; however, platelet-dependent inflammatory markers were significantly decreased after consumption of PGJ with significantly lower superoxide release (Table 1). Platelet activation leads to surface expression and shedding of the inflammatory mediator CD40L, and a significant decrease in the mean value of sCD40L levels was observed with PGJ versus placebo consumption (Table 1). HDL also significantly increased with PGJ consumption (Table 2).
TABLE 1. Platelet and Inflammatory Function after Consumption of PGJ or Placebo Control
TABLE 2. Clinical Laboratory Data after Consumption of PGJ or Placebo Control
Consumption of red wine and purple grape juice have previously been shown to have antithrombotic and vasodilatory properties due to antioxidant effects as well as enhanced bioactive NO.11 The relevance of the antithrombotic properties in subjects with cardiovascular disease taking aspirin was not known. Findings from this study indicate that consumption of PGJ fails to add to the platelet inhibitory effects of aspirin as measured by markers of platelet function including aggregation, thromboxane B2, and P-selectin. However, the role of platelets in inflammatory-dependent vascular processes is of growing interest, and consumption of PGJ appears to attenuate some of these effects, specifically sCD40L release, despite aspirin intake. It is established that CD40–CD40L interactions are central in immune responses and inflammation, but more recently ligation of CD40 on vascular cells and platelets has been shown to contribute to the pathogenesis of atherosclerotic, thrombotic, and inflammatory processes.12,13
In summary, PGJ contains specific flavonoids that may attenuate cardiovascular disease and, specifically, inhibit thrombosis. However, there has been a paucity of clinical studies directly examining this question. In this study, consumption of PGJ did not alter clinical variables or platelet activation in subjects with cardiovascular disease, but did suppress levels of platelet-dependent superoxide and sCD40L release. These findings suggest that consumption of purple grape juice, although not providing an additive antithrombotic effect for patients already on aspirin, may suppress platelet-dependent inflammatory indices that have been recently linked to cardiovascular disease.
Acknowledgments
Dr. Freedman is supported by National Institutes of Health grants RO1AG08226, NIH RO1HL62267, and an Established Investigator Award from the American Heart Association. This project was partially supported by an unrestricted grant from Welch’s. We would like to thank Monica Holbrook for her assistance in recruiting subjects.
References
Renaud S, DeLorgeril M. Wine, alcohol, platelets and the French Paradox for coronary artery heart disease. Lancet. 1992; 296: 320–331.
St. Leger A, Cochrane A, Moore F. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. Lancet. 1979; 124: 1017–1020.
Klatsky A, Friedman G, Siegelaub A. Alcohol use and cardiovascular disease: the Kaiser–Permanente experience. Circulation. 1981; 32–41.
Rimm E, Giovannucci E, Willet W, Colditz G, Acheriori A, Rosner B, Stampfer M. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet. 1991; 338: 464–468.
Fragopoulou E, Antonopoulou S, Nomikos T, Demopoulos CA. Structure elucidation of phenolic compounds from red/white wine with antiatherogenic properties. Biochim Biophys Acta. 2003; 1632: 90–99.
Carluccio MA, Siculella L, Ancora MA, Massaro M, Scoditti E, Storelli C, Visioli F, Distante A, De Caterina R. Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler Thromb Vasc Biol. 2003; 23: 622–629.
Freedman JE, Parker C, 3rd, Li L, Perlman JA, Frei B, Ivanov V, Deak LR, Iafrati MD, Folts JD. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation. 2001; 103: 2792–2798.
Vogel RA. Alcohol, heart disease, and mortality: a review. Rev Cardiovasc Med. 2002; 3: 7–13.
Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, Griel AE, Etherton TD. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med. 2002; 113 Suppl 9B: 71S–88S.
Freedman JE, Loscalzo J, Barnard MR, Alpert C, Keaney JF, Jr., Michelson A. Nitric oxide released from activated platelets inhibits platelet recruitment. J Clin Invest. 1997; 100: 350–356.
Folts JD. Potential health benefits from the flavonoids in grape products on vascular disease. Adv Exp Med Biol. 2002; 505: 95–111.
Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998; 391: 591–594.
Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature. 1998; 394: 200–203.(Anne R. Albers; Sonia Var)