Advertisement

Dietary Flavonoids as Modulators of NO Bioavailability in Acute and Chronic Cardiovascular Diseases

  • Matthias Totzeck
  • Tienush Rassaf
Chapter
Part of the Nutrition and Health book series (NH)

Abstract

Plant-derived foods contain high amounts of naturally occurring chemicals called polyphenols in addition to their nitrite and nitrate content (Heiss et al. J Am Coll Cardiol. 2010;56(3):218–24; Heiss and Kelm Eur Heart J. 2010;31(13):1554–6; Balzer et al. J Am Coll Cardiol. 2008;51:2141–9; Heiss et al. J Am Coll Cardiol. 2005;46(7):1276–83, JAMA. 2003;290(8):1030–1). These components, when present together, can exert protection in acute disease events, e.g., myocardial infarctions. Endothelial dysfunction, an early stage of coronary artery disease, has been linked to impaired endothelium-derived nitric oxide (NO) bioavailability (Heiss et al. J Am Coll Cardiol. 2006;47:573–9). There is accumulating evidence that plant-derived flavonoids can reverse endothelial dysfunction by modulation of NO bioavailability. This chapter focuses on the role of flavonoids as a dietary approach to prevent the onset and progression of chronic cardiovascular diseases, and to protect the myocardium during acute cardiovascular events.

Keywords

Polyphenols Wine Cocoa Chocolate Coronary artery disease Hypertension 

References

  1. 1.
    Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993;329(27):2002–12.CrossRefPubMedGoogle Scholar
  2. 2.
    Li H, Wallerath T, Munzel T, Forstermann U. Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. Nitric Oxide. 2002;7(3):149–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, et al. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007;56(3):666–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353(10):999–1007.CrossRefPubMedGoogle Scholar
  5. 5.
    Dimmeler S, Zeiher AM. Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? J Mol Med. 2004;82(10):671–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Shantsila E, Watson T, Lip GY. Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol. 2007;49(7):741–52.CrossRefPubMedGoogle Scholar
  7. 7.
    Heiss C, Jahn S, Taylor M, Real WM, Angeli FS, Wong ML, et al. Improvement of endothelial function with dietary flavanols is associated with mobilization of circulating angiogenic cells in patients with coronary artery disease. J Am Coll Cardiol. 2010;56(3):218–24.CrossRefPubMedGoogle Scholar
  8. 8.
    Dimmeler S. Regulation of bone marrow-derived vascular progenitor cell mobilization and maintenance. Arterioscler Thromb Vasc Biol. 2010;30(6):1088–93.CrossRefPubMedGoogle Scholar
  9. 9.
    Meyer C, Heiss C, Drexhage C, Kehmeier ES, Balzer J, Muhlfeld A, et al. Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function. J Am Coll Cardiol. 2010;55(5):454–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Rassaf T, Bryan NS, Kelm M, Feelisch M. Concomitant presence of N-nitroso and S-nitroso proteins in human plasma. Free Radic Biol Med. 2002;33:1590–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Rassaf T, Bryan NS, Maloney RE, Specian V, Kelm M, Kalyanaraman B, et al. NO adducts in mammalian red blood cells: too much or too little? Nat Med. 2003;9:481–2.CrossRefPubMedGoogle Scholar
  12. 12.
    Rassaf T, Kleinbongard P, Preik M, Dejam A, Gharini P, Lauer T, et al. Plasma nitrosothiols contribute to the systemic vasodilator effects of intravenously applied NO: experimental and clinical Study on the fate of NO in human blood. Circ Res. 2002;91(6):470–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Elrod JW, Calvert JW, Gundewar S, Bryan NS, Lefer DJ. Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide. Proc Natl Acad Sci U S A. 2008;105(32):11430–5.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res. 1998;38(2):291–300.CrossRefPubMedGoogle Scholar
  15. 15.
    Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121–35.CrossRefPubMedGoogle Scholar
  16. 16.
    Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation. 1982;66(6):1146–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Bolli R, Marban E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev. 1999;79(2):609–34.PubMedGoogle Scholar
  18. 18.
    Ito H. No-reflow phenomenon and prognosis in patients with acute myocardial infarction. Nat Clin Pract Cardiovasc Med. 2006;3(9):499–506.CrossRefPubMedGoogle Scholar
  19. 19.
    Manning AS, Hearse DJ. Reperfusion-induced arrhythmias: mechanisms and prevention. J Mol Cell Cardiol. 1984;16(6):497–518.CrossRefPubMedGoogle Scholar
  20. 20.
    Heusch G. Stunning–great paradigmatic, but little clinical importance. Basic Res Cardiol. 1998;93(3):164–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008;88(2):581–609.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Skyschally A, Schulz R, Heusch G. Pathophysiology of myocardial infarction: protection by ischemic pre- and postconditioning. Herz. 2008;33(2):88–100.CrossRefPubMedGoogle Scholar
  23. 23.
    Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285(2):H579–88.CrossRefPubMedGoogle Scholar
  24. 24.
    Duranski MR, Greer JJ, Dejam A, Jaganmohan S, Hogg N, Langston W, et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest. 2005;115(5):1232–40.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hamid SA, Totzeck M, Drexhage C, Thompson I, Fowkes RC, Rassaf T, et al. Nitric oxide/cGMP signalling mediates the cardioprotective action of adrenomedullin in reperfused myocardium. Basic Res Cardiol. 2010;105:257–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Hendgen-Cotta UB, Merx MW, Shiva S, Schmitz J, Becher S, Klare JP, et al. Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2008;105(29):10256–61.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Rassaf T, Flogel U, Drexhage C, Hendgen-Cotta U, Kelm M, Schrader J. Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function. Circ Res. 2007;100(12):1749–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Bryan NS, Calvert JW, Elrod JW, Gundewar S, Ji SY, Lefer DJ. Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2007;104(48):19144–9.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr. 2000;130(8S Suppl):2073S–85.PubMedGoogle Scholar
  30. 30.
    Galeotti F, Barile E, Lanzotti V, Dolci M, Curir P. Quantification of major flavonoids in carnation tissues (Dianthus caryophyllus) as a tool for cultivar discrimination. Z Naturforsch C. 2008;63(3–4):161–8.PubMedGoogle Scholar
  31. 31.
    Ververidis F, Trantas E, Douglas C, Vollmer G, Kretzschmar G, Panopoulos N. Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I: Chemical diversity, impacts on plant biology and human health. Biotechnol J. 2007;2(10):1214–34.CrossRefPubMedGoogle Scholar
  32. 32.
    Williamson G, Manach C. Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am J Clin Nutr. 2005;81(1 Suppl):243S–55.PubMedGoogle Scholar
  33. 33.
    Donovan JL, Crespy V, Oliveira M, Cooper KA, Gibson BB, Williamson G. (+)-Catechin is more bioavailable than (−)-catechin: relevance to the bioavailability of catechin from cocoa. Free Radic Res. 2006;40(10):1029–34.CrossRefPubMedGoogle Scholar
  34. 34.
    Donovan JL, Crespy V, Manach C, Morand C, Besson C, Scalbert A, et al. Catechin is metabolized by both the small intestine and liver of rats. J Nutr. 2001;131(6):1753–7.PubMedGoogle Scholar
  35. 35.
    Heiss C, Kelm M. Chocolate consumption, blood pressure, and cardiovascular risk. Eur Heart J. 2010;31(13):1554–6.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Agewall S, Wright S, Doughty RN, Whalley GA, Duxbury M, Sharpe N. Does a glass of red wine improve endothelial function? Eur Heart J. 2000;21(1):74–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Stein JH, Keevil JG, Wiebe DA, Aeschlimann S, Folts JD. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation. 1999;100(10):1050–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Duffy SJ, Keaney Jr JF, Holbrook M, Gokce N, Swerdloff PL, Frei B, et al. Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease. Circulation. 2001;104(2):151–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Balzer J, Rassaf T, Heiss C, Kleinbongard P, Lauer T, Merx MW, et al. Sustained benefits in vascular function through flavanol-containing cocoa in mediated diabetic patients: a double-masked, randomized, controlled trial. J Am Coll Cardiol. 2008;51:2141–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Heiss C, Kleinbongard P, Dejam A, Perre S, Schroeter H, Sies H, et al. Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J Am Coll Cardiol. 2005;46(7):1276–83.CrossRefPubMedGoogle Scholar
  41. 41.
    Heiss C, Dejam A, Kleinbongard P, Schewe T, Sies H, Kelm M. Vascular effects of cocoa rich in flavan-3-ols. JAMA. 2003;290(8):1030–1.CrossRefPubMedGoogle Scholar
  42. 42.
    Heiss C, Finis D, Kleinbongard P, Hoffmann A, Rassaf T, Kelm M, et al. Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1 week. J Cardiovasc Pharmacol. 2007;49:74–80.CrossRefPubMedGoogle Scholar
  43. 43.
    Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK, et al. (−)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A. 2006;103(4):1024–9.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Yu C, Shin YG, Chow A, Li Y, Kosmeder JW, Lee YS, et al. Human, rat, and mouse metabolism of resveratrol. Pharm Res. 2002;19(12):1907–14.CrossRefPubMedGoogle Scholar
  45. 45.
    Hattori R, Otani H, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: role of nitric oxide. Am J Physiol Heart Circ Physiol. 2002;282(6):H1988–95.CrossRefPubMedGoogle Scholar
  46. 46.
    Gurusamy N, Lekli I, Mukherjee S, Ray D, Ahsan MK, Gherghiceanu M, et al. Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovasc Res. 2010;86:103–12.CrossRefPubMedGoogle Scholar
  47. 47.
    Lekli I, Szabo G, Juhasz B, Das S, Das M, Varga E, et al. Protective mechanisms of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin. Am J Physiol Heart Circ Physiol. 2008;294(2):H859–66.CrossRefPubMedGoogle Scholar
  48. 48.
    Mokni M, Limam F, Elkahoui S, Amri M, Aouani E. Strong cardioprotective effect of resveratrol, a red wine polyphenol, on isolated rat hearts after ischemia/reperfusion injury. Arch Biochem Biophys. 2007;457(1):1–6.CrossRefPubMedGoogle Scholar
  49. 49.
    Das S, Cordis GA, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. Am J Physiol Heart Circ Physiol. 2005;288(1):H328–35.CrossRefPubMedGoogle Scholar
  50. 50.
    Wang S, Dusting GJ, May CN, Woodman OL. 3′, 4′-Dihydroxyflavonol reduces infarct size and injury associated with myocardial ischaemia and reperfusion in sheep. Br J Pharmacol. 2004;142(3):443–52.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Wang S, Fei K, Xu YW, Wang LX, Chen YQ. Dihydroxyflavonol reduces post-infarction left ventricular remodeling by preventing myocyte apoptosis in the non-infarcted zone in goats. Chin Med J (Engl). 2009;122(1):61–7.Google Scholar
  52. 52.
    Ramirez-Sanchez I, Maya L, Ceballos G, Villarreal F. (−)-Epicatechin activation of endothelial cell endothelial nitric oxide synthase, nitric oxide, and related signaling pathways. Hypertension. 2010;55:1398–405.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Steffen Y, Schewe T, Sies H. (−)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. Biochem Biophys Res Commun. 2007;359(3):828–33.CrossRefPubMedGoogle Scholar
  54. 54.
    Gasper A, Hollands W, Casgrain A, Saha S, Teucher B, Dainty JR, Venema DP, et al. Consumption of both low and high (−)-epicatechin apple puree attenuates platelet reactivity and increases plasma concentrations of nitric oxide metabolites: a randomized controlled trial. Arch Biochem Biophys. 2014;559:29–37.CrossRefPubMedGoogle Scholar
  55. 55.
    Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003;9(12):1498–505.CrossRefPubMedGoogle Scholar
  56. 56.
    Gago B, Lundberg JO, Barbosa RM, Laranjinha J. Red wine-dependent reduction of nitrite to nitric oxide in the stomach. Free Radic Biol Med. 2007;43(9):1233–42.CrossRefPubMedGoogle Scholar
  57. 57.
    Rocha BS, Gago B, Barbosa RM, Laranjinha J. Diffusion of nitric oxide through the gastric wall upon reduction of nitrite by red wine: physiological impact. Nitric Oxide. 2010;22(3):235–41.CrossRefPubMedGoogle Scholar
  58. 58.
    Hirai M, Hotta Y, Ishikawa N, Wakida Y, Fukuzawa Y, Isobe F, et al. Protective effects of EGCg or GCg, a green tea catechin epimer, against postischemic myocardial dysfunction in guinea-pig hearts. Life Sci. 2007;80(11):1020–32.CrossRefPubMedGoogle Scholar
  59. 59.
    Potenza MA, Marasciulo FL, Tarquinio M, Tiravanti E, Colantuono G, Federici A, et al. EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR. Am J Physiol Endocrinol Metab. 2007;292(5):E1378–87.CrossRefPubMedGoogle Scholar
  60. 60.
    Chang WT, Shao ZH, Vanden Hoek TL, McEntee E, Mehendale SR, Li J, et al. Cardioprotective effects of grape seed proanthocyanidins, baicalin and wogonin: comparison between acute and chronic treatments. Am J Chin Med. 2006;34(2):363–5.CrossRefPubMedGoogle Scholar
  61. 61.
    Florian T, Necas J, Bartosikova L, Klusakova J, Suchy V, Naggara EB, et al. Effects of prenylated isoflavones osajin and pomiferin in premedication on heart ischemia-reperfusion. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2006;150(1):93–100.CrossRefPubMedGoogle Scholar
  62. 62.
    Pataki T, Bak I, Kovacs P, Bagchi D, Das DK, Tosaki A. Grape seed proanthocyanidins improved cardiac recovery during reperfusion after ischemia in isolated rat hearts. Am J Clin Nutr. 2002;75(5):894–9.PubMedGoogle Scholar
  63. 63.
    Toufektsian MC, de Lorgeril M, Nagy N, Salen P, Donati MB, Giordano L, et al. Chronic dietary intake of plant-derived anthocyanins protects the rat heart against ischemia-reperfusion injury. J Nutr. 2008;138(4):747–52.PubMedGoogle Scholar
  64. 64.
    Yamazaki KG, Romero-Perez D, Barraza-Hidalgo M, Cruz M, Rivas M, Cortez-Gomez B, et al. Short- and long-term effects of (−)-epicatechin on myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2008;295(2):H761–7.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Suparto IH, Williams JK, Fox JL, Yusuf JT, Sajuthi D. Effects of hormone therapy and dietary soy on myocardial ischemia/reperfusion injury in ovariectomized atherosclerotic monkeys. Menopause. 2008;15(2):256–63.CrossRefPubMedGoogle Scholar
  66. 66.
    Shao ZH, Wojcik KR, Dossumbekova A, Hsu C, Mehendale SR, Li CQ, et al. Grape seed proanthocyanidins protect cardiomyocytes from ischemia and reperfusion injury via Akt-NOS signaling. J Cell Biochem. 2009;107(4):697–705.CrossRefPubMedGoogle Scholar
  67. 67.
    Wan LL, Xia J, Ye D, Liu J, Chen J, Wang G. Effects of quercetin on gene and protein expression of NOX and NOS after myocardial ischemia and reperfusion in rabbit. Cardiovasc Ther. 2009;27(1):28–33.CrossRefPubMedGoogle Scholar
  68. 68.
    Imamura G, Bertelli AA, Bertelli A, Otani H, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: an insight with iNOS knockout mice. Am J Physiol Heart Circ Physiol. 2002;282(6):H1996–2003.CrossRefPubMedGoogle Scholar
  69. 69.
    Graf BA, Ameho C, Dolnikowski GG, Milbury PE, Chen CY, Blumberg JB. Rat gastrointestinal tissues metabolize quercetin. J Nutr. 2006;136(1):39–44.PubMedGoogle Scholar
  70. 70.
    Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase-dependent pathway is cardioprotective. Circ Res. 2002;90(4):377–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Xi J, Wang H, Mueller RA, Norfleet EA, Xu Z. Mechanism for resveratrol-induced cardioprotection against reperfusion injury involves glycogen synthase kinase 3beta and mitochondrial permeability transition pore. Eur J Pharmacol. 2009;604(1–3):111–6.CrossRefPubMedGoogle Scholar
  72. 72.
    Ling H, Lou Y. Total flavones from Elsholtzia blanda reduce infarct size during acute myocardial ischemia by inhibiting myocardial apoptosis in rats. J Ethnopharmacol. 2005;101(1–3):169–75.CrossRefPubMedGoogle Scholar
  73. 73.
    Hao Y, Sun Y, Xu C, Jiang X, Sun H, Wu Q, et al. Improvement of contractile function in isolated cardiomyocytes from ischemia-reperfusion rats by ginkgolide B pretreatment. J Cardiovasc Pharmacol. 2009;54(1):3–9.CrossRefPubMedGoogle Scholar
  74. 74.
    Ji ES, Yue H, Wu YM, He RR. Effects of phytoestrogen genistein on myocardial ischemia/reperfusion injury and apoptosis in rabbits. Acta Pharmacol Sin. 2004;25(3):306–12.PubMedGoogle Scholar
  75. 75.
    Sato M, Bagchi D, Tosaki A, Das DK. Grape seed proanthocyanidin reduces cardiomyocyte apoptosis by inhibiting ischemia/reperfusion-induced activation of JNK-1 and C-JUN. Free Radic Biol Med. 2001;31(6):729–37.CrossRefPubMedGoogle Scholar
  76. 76.
    Fisher ND, Hughes M, Gerhard-Herman M, Hollenberg NK. Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens. 2003;21(12):2281–6.CrossRefPubMedGoogle Scholar
  77. 77.
    Grassi D, Lippi C, Necozione S, Desideri G, Ferri C. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr. 2005;81(3):611–4.PubMedGoogle Scholar
  78. 78.
    Engler MB, Engler MM, Chen CY, Malloy MJ, Browne A, Chiu EY, et al. Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr. 2004;23(3):197–204.CrossRefPubMedGoogle Scholar
  79. 79.
    Vlachopoulos C, Aznaouridis K, Alexopoulos N, Economou E, Andreadou I, Stefanadis C. Effect of dark chocolate on arterial function in healthy individuals. Am J Hypertens. 2005;18(6):785–91.CrossRefPubMedGoogle Scholar
  80. 80.
    Grassi D, Mulder TP, Draijer R, Desideri G, Molhuizen HO, Ferri C. Black tea consumption dose-dependently improves flow-mediated dilation in healthy males. J Hypertens. 2009;27(4):774–81.CrossRefPubMedGoogle Scholar
  81. 81.
    Faridi Z, Njike VY, Dutta S, Ali A, Katz DL. Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial. Am J Clin Nutr. 2008;88(1):58–63.PubMedGoogle Scholar
  82. 82.
    Horn P, Amabile N, Angeli FS, Sansone R, Stegemann B, Kelm M, Springer ML, et al. Dietary flavanol intervention lowers the levels of endothelial microparticles in coronary artery disease patients. Br J Nutr. 2014;111(7):1245–52.CrossRefPubMedGoogle Scholar
  83. 83.
    Taubert D, Berkels R, Roesen R, Klaus W. Chocolate and blood pressure in elderly individuals with isolated systolic hypertension. JAMA. 2003;290(8):1029–30.CrossRefPubMedGoogle Scholar
  84. 84.
    Taubert D, Roesen R, Lehmann C, Jung N, Schomig E. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. JAMA. 2007;298(1):49–60.CrossRefPubMedGoogle Scholar
  85. 85.
    Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension. 2005;46(2):398–405.CrossRefPubMedGoogle Scholar
  86. 86.
    Hodgson JM, Puddey IB, Burke V, Watts GF, Beilin LJ. Regular ingestion of black tea improves brachial artery vasodilator function. Clin Sci (Lond). 2002;102(2):195–201.CrossRefGoogle Scholar
  87. 87.
    Grassi D, Desideri G, Necozione S, Ruggieri F, Blumberg JB, Stornello M, Ferri C. Protective effects of flavanol-rich dark chocolate on endothelial function and wave reflection during acute hyperglycemia. Hypertension. 2012;60(3):827–32.CrossRefPubMedGoogle Scholar
  88. 88.
    West SG, McIntyre MD, Piotrowski MJ, Poupin N, Miller DL, Preston AG, Wagner P, Groves LF, Skulas-Ray AC. Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults. Br J Nutr. 2014;111(4):653–61.CrossRefPubMedGoogle Scholar
  89. 89.
    Flammer AJ, Sudano I, Wolfrum M, Thomas R, Enseleit F, Periat D, Kaiser P, et al. Cardiovascular effects of flavanol-rich chocolate in patients with heart failure. Eur Heart J. 2012;33(17):2172–80.CrossRefPubMedGoogle Scholar
  90. 90.
    Heiss C, Lauer T, Dejam A, Kleinbongard P, Hamada S, Rassaf T, et al. Plasma nitroso compounds are decreased in patients with endothelial dysfunction. J Am Coll Cardiol. 2006;47:573–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of CardiologyWest-German Heart and Vessel Center, University Hospital Essen, University of Duisburg-EssenEssenGermany

Personalised recommendations