Cocoa and human health

Annual Review of Nutrition

Volumn 33, Issue , 2013, Pages 105-128

  Ellam, Samantha ^a   Williamson, Gary ^a  

^a UNIVERSITY OF LEEDS   (United Kingdom)

Author keywords

Cardiovascular disease; Flavonoid; Flavonol; Magnesium; Polyphenol; Theobromine

Indexed keywords

BIOLOGICAL MARKER; CHOLESTEROL; EPICATECHIN; FLAVONOID; MAGNESIUM; NICOTINAMIDE ADENINE DINUCLEOTIDE; NITRIC OXIDE; THEOBROMINE;

ARTICLE; BLOOD PRESSURE; CACAO; CARDIOVASCULAR DISEASE; CATABOLISM; DRUG BIOAVAILABILITY; DRUG MECHANISM; HUMAN; PRIORITY JOURNAL;

ANIMALS; CACAO; DIET; FLAVONOIDS; FUNCTIONAL FOOD; HEALTH STATUS; HUMANS; MAGNESIUM; NUTRITIVE VALUE; THEOBROMINE;

EID: 84880690800     PISSN: 01999885     EISSN: 15454312     Source Type: Book Series    
DOI: 10.1146/annurev-nutr-071811-150642     Document Type: Article

References (140)

1. Actis-Goretta L, Leveques A, Giuffrida F, Romanov-Michaildis F, Vitron F, et al. 2012. Elucidation of (-)-epicatechin metabolites after ingestion of chocolate by healthy humans. Free Radic. Biol. Med. 53:787-95
2. Afoakwa EO, Paterson A, Fowler M, Ryan A. 2008. Flavor formation and character in cocoa and chocolate: a critical review. Crit. Rev. Food Sci. Nutr. 48:840-57
3. Allen RR, Carson L, Kwik-Uribe C, Evans EM, Erdman JW. 2008. Daily consumption of a dark chocolate containing flavanols and added sterol esters affects cardiovascular risk factors in a normotensive population with elevated cholesterol. J. Nutr. 138:725-31
4. Allgrove J, Farrell E, Gleeson M, Williamson G, Cooper K. 2011. Regular dark chocolate consumption?s reduction of oxidative stress and increase of free-fatty-acid mobilization in response to prolonged cycling. Int. J. Sport Nutr. Exerc. Metab. 21:113-23
5. Appeldoorn MM, Vincken JP, Aura AM, Hollman PC, Gruppen H. 2009. Procyanidin dimers are metabolized by human microbiota with 2-(3,4- dihydroxyphenyl)acetic acid and 5-(3,4-dihydroxyphenyl)-gamma-valerolactone as the major metabolites. J. Agric. Food Chem. 57:1084-92
6. Arab L, Liu W, Elashoff D. 2009. Green and black tea consumption and risk of stroke: a meta-analysis. Stroke 40:1786-92
7. Arnaud MJ, Welsch C. 1979. Metabolic pathway of theobromine in the rat and identification of 2 new metabolites in human urine. J. Agric. Food Chem. 27:524-27
8. Auger C, Mullen W, Hara Y, Crozier A. 2008. Bioavailability of polyphenon E flavan-3-ols in humans with an ileostomy. J. Nutr. 138:S1535-42
9. Baba S, Natsume M, Yasuda A, Nakamura Y, Tamura T, et al. 2007. Plasma LDL and HDLcholesterol and oxidized LDL concentrations are altered in normo-and hypercholesterolemic humans after intake of different levels of cocoa powder. J. Nutr. 137:1436-41
10. Baba S, Osakabe N, Kato Y, Natsume M, Yasuda A, et al. 2007. Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. Am. J. Clin. Nutr. 85:709-17
11. Bacon J.R., RhodesMJ. 2000. Binding affinity of hydrolyzable tannins to parotid saliva and to proline-rich proteins derived from it. J. Agric. Food Chem. 48:838-43
12. Balzer J, Rassaf T, Heiss C, Kleinbongard P, Lauer T, et al. 2008. Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients: a double-masked, randomized, controlled trial. J. Am. Coll. Cardiol. 51:2141-49
13. Berry NM, Davison K, Coates AM, Buckley JD, Howe PR. 2010. Impact of cocoa flavanol consumption on blood pressure responsiveness to exercise. Br. J. Nutr. 103:1480-84
14. Bravo L, Lecumberri E, Mateos R, Ramos S, Izquierdo-Pulido M, Goya L. 2008. A diet rich in dietary fibre from cocoa improves lipid profile. Agro Food Ind. Hi-Tech 19:10-12
15. Brossette T, Hundsdoerfer C, Kroencke KD, Sies H, Stahl W. 2011. Direct evidence that (-)-epicatechin increases nitric oxide levels in human endothelial cells. Eur. J. Nutr. 50:595-99
16. Buijsse B, Feskens EJ, Kok FJ, Kromhout D. 2006. Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study. Arch. Intern. Med. 166:411-17
17. Buijsse B, Weikert C, Drogan D, Bergmann M, Boeing H. 2010. Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults. Eur. Heart J. 31:1616-23
18. Buscicchio G, Piemontese M, Gentilucci L, Ferretti F, Tranquilli AL. 2012. The effects of maternal caffeine and chocolate intake on fetal heart rate. J. Matern. Fetal Neonatal Med. 25:528-30
19. Camfield DA, Scholey A, Pipingas A, Silberstein R, Kras M, et al. 2012. Steady state visually evoked potential (SSVEP) topography changes associated with cocoa flavanol consumption. Physiol. Behav. 105:948-57
20. Carnevale R, Loffredo L, Pignatelli P, Nocella C, Bartimoccia S, et al. 2012. Dark chocolate inhibits platelet isoprostanes via NOX2 down-regulation in smokers. J. Thromb. Haemost. 10:125-32
21. Cassidy A, O?Reilly EJ, Kay C, Sampson L, Franz M, et al. 2011. Habitual intake of flavonoid subclasses and incident hypertension in adults. Am. J. Clin. Nutr. 93:338-47
22. Caton PW, Pothecary MR, Lees DM, Khan NQ, Wood EG, et al. 2010. Regulation of vascular endothelial function by procyanidin-rich foods and beverages. J. Agric. Food Chem. 58:4008-13
23. Cooper KA, Campos-Gimenez E, Jimenez AD, Nagy K, Donovan JL, Williamson G. 2007. Rapid reversed phase ultra-performance liquid chromatography analysis of the major cocoa polyphenols and inter-relationships of their concentrations in chocolate. J. Agric. Food Chem. 55:2841-47
24. Cooper KA, Donovan JL, Waterhouse AL, WilliamsonG. 2008. Cocoa and health: a decade of research. Br. J. Nutr. 99:1-11
25. Cornish HH, Christman AA. 1957. A study of themetabolism of theobromine, thoephylline and caffeine in man. J. Biol. Chem. 228:315-23
26. Crews WD, Harrison DW, Wright JW. 2008. A double-blind, placebo-controlled, randomized trial of the effects of dark chocolate and cocoa on variables associated with neuropsychological functioning and cardiovascular health: clinical findings from a sample of healthy, cognitively intact older adults. Am. J. Clin. Nutr. 87:872-80
27. Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A. 2012. Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care 35:226-32
28. Davison G, Callister R, Williamson G, Cooper KA, Gleeson M. 2012. The effect of acute pre-exercise dark chocolate consumption on plasma antioxidant status, oxidative stress and immunoendocrine responses to prolonged exercise. Eur. J. Nutr. 51:69-79
29. Davison K, Berry NM, Misan G, Coates AM, Buckley JD, Howe PRC. 2010. Dose-related effects of flavanol-rich cocoa on blood pressure. J. Hum. Hypertens. 24:568-76
30. Davison K, Coates AM, Buckley JD, Howe PR. 2008. Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects. Int. J. Obes. 32:1289-96
31. de Freitas V, Mateus N. 2001. Structural features of procyanidin interactions with salivary proteins. J. Agric. Food Chem. 49:940-45
32. Dep. Environ. Food Rural Aff. 2011. Family Food 2010. York, UK: Food Statist. Unit, Defra Food Farming Group
33. Deprez S, Brezillon C, Rabot S, Philippe C, Mila I, et al. 2000. Polymeric proanthocyanidins are catabolized by human colonic microflora into low-molecular-weight phenolic acids. J. Nutr. 130:2733-38
34. Desch S, Kobler D, Schmidt J, Sonnabend M, Adams V, et al. 2010. Low versus higher-dose dark chocolate and blood pressure in cardiovascular high-risk patients. Am. J. Hypertens. 23:694-700
35. Di Giuseppe R, Di Castelnuovo A, Centritto F, Zito F, De Curtis A, et al. 2008. Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population. J. Nutr. 138:1939-45
36. Djousse L, Hopkins PN, North KE, Pankow JS, Arnett DK, Ellison RC. 2011. Chocolate consumption is inversely associated with prevalent coronary heart disease: the National Heart, Lung, and Blood Institute Family Heart Study. Clin. Nutr. 30:182-87
37. Dock W. 1926. The use of theobromine for pain of arteriosclerotic origin. Calif. West. Med. 25:636-38
38. Donovan JL, Crespy V, Oliveria M, Cooper KA, Gibson BB, WilliamsonG. 2006. (+)-catechin ismore bioavailable than (-)-catechin: relevance to the bioavailability of catechin from cocoa. Free Radic. Res. 40:1029-34
39. Donovan JL, Manach C, Rios L, Scalbert A, Remesy C. 2002. Procyanidins are not bioavailable in rats fed a single meal containing a grapeseed extract or the procyanidin dimer B3. J. Nutr. 87:299-306
40. Erdman JW Jr, Balentine D, Arab L, Beecher G, Dwyer JT, et al. 2007. Flavonoids and Heart Health: Proceedings of the ILSI North America Flavonoids Workshop, May 31-June 1, 2005, Washington, DC. J. Nutr. 137:S718-37
41. Faridi Z, Njike VY, Dutta S, Ali A, Katz DL. 2008. Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial. Am. J. Clin. Nutr. 88:58-63
42. Field DT, Williams CM, Butler LT. 2011. Consumption of cocoa flavanols results in an acute improvement in visual and cognitive functions. Physiol. Behav. 103:255-60
43. Flammer AJ, Hermann F, Sudano I, Spieker L, Hermann M, et al. 2007. Dark chocolate improves coronary vasomotion and reduces platelet reactivity. Circulation 116:2376-82
44. Food Stand. Agency. 2006. FSA Nutrient and Food Based Guidelines for UK Institutions. London: Dep. Health, Natl. Health Serv. http://www.food.gov.uk/ multimedia/pdfs/nutguideuk.pdf
45. Food Stand. Agency. 2010. National Diet and Nutrition Survey 2008/2009. London: Dep. Health, Natl. Health Serv.
46. Garcia-Conesa MT, Tribolo S, Guyot S, Tomas-Barberan FA, Kroon PA. 2009. Oligomeric procyanidins inhibit cell migration and modulate the expression of migration and proliferation associated genes in human umbilical vascular endothelial cells. Mol. Nutr. Food Res. 53:266-76
47. Gates S, Miners JO. 1999. Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism. Br. J. Clin. Pharmacol. 47:299-305
48. Gendron ME, Theoret JF, Mamarbachi AM, Drouin A, Nguyen A, et al. 2010. Late chronic catechin antioxidant treatment is deleterious to the endothelial function in aging mice with established atherosclerosis. Am. J. Physiol. Heart Circ. Physiol. 298:H2062-70
49. Gotti R, Furlanetto S, Pinzauti S, Cavrini V. 2006. Analysis of catechins in Theobroma cacao beans by cyclodextrin-modified micellar electrokinetic chromatography. J. Chromatogr. A 1112:345-52
50. Grassi D, Desideri G, Necozione S, Lippi C, Casale R, et al. 2008. Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. J. Nutr. 138:1671-76
51. Gu L, Gonzalez FJ, Kalow W, Tang BK. 1992. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 andCYP2E1. Pharmacogenetics 2:73-77
52. Gu L, House SE, Wu X, Ou B, Prior RL. 2006. Procyanidin and catechin contents and antioxidant capacity of cocoa and chocolate products. J. Agric. Food Chem. 54:4057-61
53. Hamed MS, Gambert S, Bliden KP, Bailon O, Singla A, et al. 2008. Dark chocolate effect on platelet activity, C-reactive protein and lipid profile: a pilot study. South. Med. J. 101:1203-8
54. Hammerstone JF, Lazarus SA, Mitchell AE, Rucker R, Schmitz HH. 1999. Identification of procyanidins in cocoa (Theobroma cacao) and chocolate using high-performance liquid chromatography/mass spectrometry. J. Agric. Food Chem. 47:490-96
55. Heiss C, Jahn S, Taylor M, Real WM, Angeli FS, et al. 2010. 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. 56:218-24
56. Holt RR, Lazarus SA, Sullards MC, Zhu QY, Schramm DD, et al. 2002. Procyanidin dimer B2 [epicatechin-(4 beta-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa. Am. J. Clin. Nutr. 76:798-804
57. Hooper L, Kay C, Abdelhamid A, Kroon PA, Cohn JS, et al. 2012. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Am. J. Clin. Nutr. 95:740-51
58. Jalil AMM, Ismail A, Chong PP, HamidM, Kamaruddin SHS. 2009. Effects of cocoa extract containing polyphenols and methylxanthines on biochemical parameters of obese-diabetic rats. J. Sci. Food Agric. 89:130-37
59. Janszky I, Mukamal KJ, Ljung R, Ahnve S, Ahlbom A, Hallqvist J. 2009. Chocolate consumption and mortality following a first acute myocardial infarction: the Stockholm Heart Epidemiology Program. J. Int. Med. 266:248-57
60. Khan N, Monagas M, Llorach R, Urpi-Sarda M, Rabassa M, et al. 2010. Targeted and metabolomic study of biomarkers of cocoa powder consumption: effects on inflammatory biomarkers in patients at high risk of cardiovascular disease. Agro Food Ind. Hi-Tech 21:54-57
61. Kida K, Suzuki M, Matsumoto N, Nanjo F, Hara Y. 2000. Identification of biliary metabolites of (-)-epigallocatechin gallate in rats. J. Agric. Food Chem. 48:4151-55
62. KimH, Keeney PG. 1984. (-)-Epicatechin content in fermented and unfermented cocoa beans. J. Food Sci. 49:1090-92
63. Kohri T, Matsumoto N, Yamakawa M, Suzuki M, Nanjo F, et al. 2001. Metabolic fate of (-)-[4-H-3]epigallocatechin gallate in rats after oral administration. J. Agric. Food Chem. 49:4102-12
64. KPMG.2012. The Chocolate of Tomorrow. Teddington, UK:Haymarket Netw. http://www.kpmg.com/UK/en/IssuesAndInsights/ArticlesPublications/Documents/PDF/ Market%20Sector/Retail-and-Consumer-Goods/chocolate-of-tomorrow.pdf
65. Landberg R, Sun Q, Rimm EB, Cassidy A, Scalbert A, et al. 2011. Selected dietary flavonoids are associated with markers of inflammation and endothelial dysfunction in U.S. women. J. Nutr. 141:618-25
66. LawMR, Morris JK, Wald NJ. 2009. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. Br. Med. J. 338:b1665
67. Lelo A, Birkett DJ, Robson RA, Miners JO. 1986. Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man. Br. J. Clin. Pharmacol. 22:177-82
68. Lettieri-Barbato D, Villano D, Beheydt B, Guadagni F, Trogh I, Serafini M. 2012. Effect of ingestion of dark chocolates with similar lipid composition and different cocoa content on antioxidant and lipid status in healthy humans. Food Chem. 132:1305-10
69. Loffredo L, Carnevale R, Perri L, Catasca E, Augelletti T, et al. 2011. NOX2-mediated arterial dysfunction in smokers: acute effect of dark chocolate. Heart 97:1776-81
70. Manach C, Williamson G, Morand C, Scalbert A, Remesy C. 2005. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 81:S230-42
71. McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. 2012. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am. J. Clin. Nutr. 95:454-64
72. Mellor DD, Sathyapalan T, Kilpatrick ES, Beckett S, Atkin SL. 2010. High-cocoa polyphenol-rich chocolate improves HDL cholesterol in type 2 diabetes patients. Diabetic Med. 27:1318-21
73. MillerKB, Hurst WJ, PayneMJ, Stuart DA, Apgar J, et al. 2008. Impact of alkalization on the antioxidant and flavanol content of commercial cocoa powders. J. Agric. Food Chem. 56:8527-33
74. MillerKB, Stuart DA, SmithNL, LeeCY, McHale NL, et al. 2006. Antioxidant activity and polyphenol and procyanidin contents of selected commercially available cocoa-containing and chocolate products in the United States. J. Agric. Food Chem. 54:4062-68
75. Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong CP, et al. 2007. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am. J. Clin. Nutr. 85:895-909
76. Monagas M, Khan N, Andres-Lacueva C, Casas R, Urpi-Sarda M, et al. 2009. Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular disease. Am. J. Clin. Nutr. 90:1144-50
77. Monahan KD, Feehan RP, Kunselman AR, Preston AG, Miller DL, LottMEJ. 2011. Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults. J. Appl. Physiol. 111:1568-74
78. MostofskyE, LevitanEB, Wolk A, MittlemanMA.2010. Chocolate intake and incidence of heart failure: a population-based prospective study of middle-aged and elderly women. Circ. Heart Fail. 3:612-16
79. Muniyappa R, Hall G, Kolodziej TL, Karne RJ, Crandon SK, Quon MJ. 2008. Cocoa consumption for 2 wk enhances insulin-mediated vasodilatation without improving blood pressure or insulin resistance in essential hypertension. Am. J. Clin. Nutr. 88:1685-96
80. Musaad S, Haynes EN. 2007. Biomarkers of obesity and subsequent cardiovascular events. Epidemiol. Rev. 29:98-114
81. Nanetti L, Raffaelli F, Tranquilli AL, Fiorini R, Mazzanti L, Vignini A. 2012. Effect of consumption of dark chocolate on oxidative stress in lipoproteins and platelets in women and in men. Appetite 58:400-5
82. Neilson AP, Ferruzzi MG.2011. Influence of formulation and processing on absorption andmetabolism of flavan-3-ols from tea and cocoa. Annu. Rev. Food Sci. Technol. 2:125-51
83. Neilson AP, Sapper TN, Janle EM, Rudolph R, Matusheski NV, Ferruzzi MG. 2010. Chocolatematrix factors modulate the pharmacokinetic behavior of cocoa flavan-3-ol phase II metabolites following oral consumption by Sprague-Dawley rats. J. Agric. Food Chem. 58:6685-91
84. Neukam K, Stahl W, Tronnier H, Sies H, Heinrich U. 2007. Consumption of flavanol-rich cocoa acutely increases microcirculation in human skin. Eur. J. Nutr. 46:53-56
85. Nishiwaki S, Iwashita M, Goto N, Hayashi M, Takada J, et al. 2011. Predominant copper deficiency during prolonged enteral nutrition through a jejunostomy tube compared to that through a gastrostomy tube. Clin. Nutr. 30:585-89
86. Njike VY, Faridi Z, Shuval K, Dutta S, Lay CD, et al. 2011. Effects of sugar-sweetened and sugar-free cocoa on endothelial function in overweight adults. Int. J. Cardiol. 149:83-88
87. Nozaki T, Sugiyama S, Koga H, Sugamura K, Ohba K, et al. 2009. Significance of amultiple biomarkers strategy including endothelial dysfunction to improve risk stratification for cardiovascular events in patients at high risk for coronary heart disease. J. Am. Coll. Cardiol. 54:601-8
88. Ortega N, Reguant J, Romero MP, Macia A, MotilvaMJ. 2009. Effect of fat content on the digestibility and bioaccessibility of cocoa polyphenol by an in vitro digestionmodel. J. Agric. Food Chem. 57:5743-49
89. Osakabe N, Yamagishi M. 2009. Procyanidins in Theobroma cacao reduce plasma cholesterol levels in high cholesterol-fed rats. J. Clin. Biochem. Nutr. 45:131-36
90. Panneerselvam M, Tsutsumi YM, Bonds JA, Horikawa YT, Saldana M, et al. 2010. Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation. Am. J. Physiol. Heart Circ. Physiol. 299:H1604-9
91. Persson IA, Persson K, Hagg S, Andersson RG. 2011. Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers-a nutrigenomics perspective. J. Cardiovasc. Pharmacol. 57:44-50
92. Piconi L, Quagliaro L, Ceriello A. 2003. Oxidative stress in diabetes. Clin. Chem. Lab. Med. 41:1144-49
93. Quinones M, Muguerza B, Miguel M, Aleixandre A. 2011. Evidence that nitric oxide mediates the blood pressure lowering effect of a polyphenol-rich cocoa powder in spontaneously hypertensive rats. Pharmacol. Res. 64:478-81
94. QuinonesM, Sanchez D, Muguerza B, Moulay L, Laghi S, et al. 2010. Long-term intake of CocoanOX attenuates the development of hypertension in spontaneously hypertensive rats. Food Chem. 122:1013-19
95. QuinonesM, Sanchez D, Muguerza B, MiguelM, Aleixandre A. 2011. Mechanisms for antihypertensive effect of CocoanOX, a polyphenol-rich cocoa powder, in spontaneously hypertensive rats. Food Res. Int. 44:1203-8
96. Ramirez-Sanchez I, Maya L, Ceballos G, Villarreal F. 2010. (-)-Epicatechin activation of endothelial cell endothelial nitric oxide synthase, nitric oxide, and related signaling pathways. Hypertension 55:1398-405
97. Ramirez-Sanchez I, Maya L, Ceballos G, Villarreal F. 2011. (-)-Epicatechin induces calcium and translocation independent eNOS activation in arterial endothelial cells. Am. J. Physiol. Cell Physiol. 300:C880-87
98. Ramos S, Moulay L, Granado-Serrano AB, Vilanova O, Muguerza B, et al. 2008. Hypolipidemic effect in cholesterol-fed rats of a soluble fiber-rich product obtained from cocoa husks. J. Agric. Food Chem. 56:6985-93
99. Ridker PM. 2003. Cardiology Patient Page. C-reactive protein: a simple test to help predict risk of heart attack and stroke. Circulation 108:e81-85
100. Ried K, Sullivan T, Fakler P, Frank OR, Stocks NP. 2010. Does chocolate reduce blood pressure? A meta-analysis. BMC Med. 8:11
101. Rios LY, Bennett RN, Lazarus SA, Remesy C, Scalbert A, Williamson G. 2002. Cocoa procyanidins are stable during gastric transit in humans. Am. J. Clin. Nutr. 76:1106-10
102. Rios LY, Gonthier MP, Remesy C, Mila I, Lapierre C, et al. 2003. Chocolate intake increases urinary excretion of polyphenol-derived phenolic acids in healthy human subjects.Am. J. Clin. Nutr. 77:912-18
103. Risner CH. 2008. Simultaneous determination of theobromine, (+)-catechin, caffeine, and (-)-epicatechin in standard reference material baking chocolate 2384, cocoa, cocoa beans, and cocoa butter. J. Chromatogr. Sci. 46:892-99
104. Rodopoulos N, Hojvall L, Norman A. 1996. Elimination of theobromine metabolites in healthy adults. Scand. J. Clin. Lab. Investig. 56:373-83
105. Sanchez D, Quinones M, Moulay L, Muguerza B, Miguel M, Aleixandre A. 2010. Changes in arterial blood pressure of a soluble cocoa fiber product in spontaneously hypertensive rats. J. Agric. Food Chem. 58:1493-501
106. Sanchez D, QuinonesM, Moulay L, Muguerza B, MiguelM, Aleixandre A. 2011. Soluble fiber-enriched diets improve inflammation and oxidative stress biomarkers in Zucker fatty rats. Pharmacol. Res. 64:31-35
107. SarriaB, MateosR, Sierra-Cinos JL, GoyaL, Garcia-DizL, Bravo L. 2012. Hypotensive, hypoglycaemic and antioxidant effects of consuming a cocoa product inmoderately hypercholesterolemic humans. Food Funct. 3:867-74
108. Sathyapalan T, Beckett S, Rigby AS, Mellor DD, Atkin SL. 2010. High cocoa polyphenol rich chocolate may reduce the burden of the symptoms in chronic fatigue syndrome. Nutr. J. 9:55
109. Scholey AB, French SJ, Morris PJ, Kennedy DO, Milne AL, Haskell CF. 2010. Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J. Psychopharmacol. 24:1505-14
110. Serra A, Macia A, Romero MP, Valls J, Blade C, et al. 2009. Bioavailability of procyanidin dimers and trimers and matrix food effects in in vitro and in vivo models. Br. J. Nutr. 103:944-52
111. Shively CA, Tarka SM, Arnaud MJ, Dvorchik BH, Passananti GT, Vesell ES. 1985. High levels of methylxanthines in chocolate do not alter theobromine disposition. Clin. Pharmacol. Therapeut. 37:415-24
112. Shlipak MG, Ix JH, Bibbins-Domingo K, Lin F, Whooley MA. 2008. Biomarkers to predict recurrent cardiovascular disease: the Heart and Soul Study. Am. J. Med. 121:50-57
113. Shoji T, Masumoto S, Moriichi N, Akiyama H, Kanda T, et al. 2006. Apple procyanidin oligomers absorption in rats after oral administration: analysis of procyanidins in plasma using the Porter method and high-performance liquid chromatography/tandemmass spectrometry. J. Agric. Food Chem. 54:884-92
114. Si HW, Fu Z, Babu PVA, Zhen W, LeRoith T, et al. 2011. Dietary epicatechin promotes survival of obese diabetic mice and Drosophila melanogaster. J. Nutr. 141:1095-100
115. Smetanova L, Stetinova V, Kholova D, Kvetina J, Smetana J, Svoboda Z. 2009. Caco-2 cells and Biopharmaceutics Classification System (BCS) for prediction of transepithelial transport of xenobiotics (model drug: caffeine). Neuroendocrinol. Lett. 30:s101-5
116. Sola R, Valls RM, Godas G, Perez-Busquets G, Ribalta J, et al. 2012. Cocoa, hazelnuts, sterols and soluble fiber cream reduces lipids and inflammation biomarkers in hypertensive patients: a randomized controlled trial. PLoS ONE 7:e31103
117. Sorond FA, Lipsitz LA, Hollenberg NK, Fisher NDL. 2008. Cerebral blood flow response to flavanolrich cocoa in healthy elderly humans. Neuropsychiatr. Dis. Treat. 4:433-40
118. SteffenY, Schewe T, SiesH. 2007. (-)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. Biochem. Biophys. Res. Commun. 359:828-33
119. Schnorr O, Brossette T, Momma TY, Kleinbongard P, Keen CL, et al. 2008. Cocoa flavanols lower vascular arginase activity in human endothelial cells in vitro and in erythrocytes in vivo. Arch. Biochem. Biophys. 476:211-15
120. Stoupi S, Williamson G, Drynan JW, Barron D, Clifford MN. 2010. A comparison of the in vitro biotransformation of (-)-epicatechin and procyanidin B2 by human faecal microbiota. Mol. Nutr. Food Res. 54:747-59
121. Stoupi S, Williamson G, Viton F, Barron D, King LJ, et al. 2010. In vivo bioavailability, absorption, excretion, and pharmacokinetics of [14C]procyanidin B2 in male rats. Drug Metab. Dispos. 38:287-91
122. Tarka SM, Arnaud MJ, DvorchikBH, Vesell ES. 1983. Theobromine kinetics andmetabolic disposition. Clin. Pharmacol. Therapeut. 34:546-55
123. Tassaneeyakul W, Birkett DJ, McManus ME, Tassaneeyakul W, Veronese ME, et al. 1994. Caffeine metabolism by human hepatic cytochromes p450: contributions of 1A2, 2E1 and 3A isoforms. Biochem. Pharmacol. 47:1767-76
124. Taub PR, Ramirez-Sanchez I, Ciaraldi TP, Perkins G, Murphy AN, et al. 2012. Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa. Clin. Transl. Sci. 5:43-47
125. Thielecke F, Boschmann M. 2009. The potential role of green tea catechins in the prevention of the metabolic syndrome-a review. Phytochemical 70:11-24
126. Tholstrup T, TengKT, RaffM.2011. Dietary cocoa butter or refined olive oil does not alter postprandial hsCRP and IL-6 concentrations in healthy women. Lipids 46:365-70
127. Tzounis X, Rodriguez-Mateos A, Vulevic J, Gibson GR, Kwik-Uribe C, Spencer JP. 2011. Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, doubleblind, crossover intervention study. Am. J. Clin. Nutr. 93:62-72
128. Urpi-Sarda M, MonagasM, KhanN, Lamuela-RaventosRM, Santos-BuelgaC, et al. 2009. Epicatechin, procyanidins, and phenolic microbial metabolites after cocoa intake in humans and rats. Anal. Bioanal. Chem. 394:1545-56
129. van den Bogaard B, Draijer R, Westerhof BE, van den Meiracker AH, van Montfrans GA, van den Born BJ. 2010. Effects on peripheral and central blood pressure of cocoa with natural or high-dose theobromine: a randomized, double-blind crossover trial. Hypertension 56:839-46
130. Vinson JA, Proch J, Bose P, Muchler S, Taffera P, et al. 2006. Chocolate is a powerful ex vivo and in vivo antioxidant, an antiatherosclerotic agent in an animal model, and a significant contributor to antioxidants in the European and American diets. J. Agric. Food Chem. 54:8071-76
131. Volpe SL. 2012. Magnesium. In Present Knowledge in Nutrition, ed. JW Erdman, IA MacDonald, SH Zeisel, pp. 459-74. Oxford, UK: Wiley-Blackwell. 10th ed.
132. Wannamethee SG, Whincup PH, Shaper AG, Rumley A, Lennon L, Lowe GD. 2009. Circulating inflammatory and hemostatic biomarkers are associated with risk of myocardial infarction and coronary death, but not angina pectoris, in older men. J. Thromb. Haemost. 7:1605-11
133. Westphal S, Luley C. 2011. Flavanol-rich cocoa ameliorates lipemia-induced endothelial dysfunction. Heart Vessels 26:511-15
134. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. 2003. The clinical implications of endothelial dysfunction. J. Am. Coll. Cardiol. 42:1149-60
135. Williams S, Tamburic S, Lally C. 2009. Eating chocolate can significantly protect the skin from UV light. J. Cosmet. Dermatol. 8:169-73
136. Williamson G, Clifford MN. 2010. Colonic metabolites of berry polyphenols: the missing link to biological activity? Br. J. Nutr. 104:S48-66
137. Williamson G, Dionisi F, Renouf M. 2011. Flavanols from green tea and phenolic acids from coffee: critical quantitative evaluation of the pharmacokinetic data in humans after consumption of single doses of beverages. Mol. Nutr. Food Res. 55:864-73
138. WorldHealthOrgan. 2011. Global Atlas on CardiovascularDisease Prevention and Control. Geneva:World Health Organ. http://whqlibdoc.who.int/publications/ 2011/9789241564373-eng.pdf
139. Yamazaki KG, Romero-Perez D, Barraza-Hidalgo M, Cruz M, Rivas M, et al. 2008. Short-and longterm effects of (-)-epicatechin on myocardial ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 295:H761-67
140. Yamazaki KG, Taub PR, Barraza-Hidalgo M, Rivas MM, Zambon AC, et al. 2010. Effects of (-)-epicatechin on myocardial infarct size and left ventricular remodeling after permanent coronary occlusion. J. Am. Coll. Cardiol. 55:2869-76