Cardioprotective effects of cocoa: clinical evidence from randomized clinical intervention trials in humans.

Cocoa is an important source of polyphenols, which comprise 12-18% of its total dry weight. The major phenolic compounds in cocoa and cocoa products are mainly flavonoids such as epicatechin, catechin, and proanthocyanidins. These products contain higher amounts of flavonoids than other polyphenol-rich foods. However, the bioavailability of these compounds depends on other food constituents and their interactions with the food matrix. Many epidemiological and clinical intervention trials have concluded that the ingestion of flavonoids reduces the risk factors of developing cardiovascular disease. This review summarizes the new findings regarding the effects of cocoa and chocolate consumption on cardiovascular risk factors. The mechanisms involved in the cardioprotective effects of cocoa flavonoids include reduction of oxidative stress, inhibition of low-density lipoproteins oxidation and platelet aggregation, vasodilatation of blood vessels, inhibition of the adherence of monocytes to vascular endothelium, promotion of fibrinolysis, and immunomodulatory and anti-inflammatory activity. Scientific evidence supports a cause and effect relationship between consumption of cocoa flavonoids and the maintenance of normal endothelium-dependent vasodilation, which contributes to normal blood flow. However, larger randomized trials are required to definitively establish the impact of cocoa and cocoa products consumption on hard cardiovascular outcomes.

[1]  Peter Libby,et al.  Inflammation and cardiovascular disease mechanisms. , 2006, The American journal of clinical nutrition.

[2]  M. Serafini,et al.  Nutrition: Milk and absorption of dietary flavanols , 2003, Nature.

[3]  R. Lamuela-Raventós,et al.  Effect of milk on the urinary excretion of microbial phenolic acids after cocoa powder consumption in humans. , 2010, Journal of agricultural and food chemistry.

[4]  R. Lamuela-Raventós,et al.  Review: Health Effects of Cocoa Flavonoids , 2005 .

[5]  D. Caruso,et al.  Hydroxytyrosol excretion differs between rats and humans and depends on the vehicle of administration. , 2003, The Journal of nutrition.

[6]  T. Rassaf,et al.  Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial. , 2008, Journal of the American College of Cardiology.

[7]  H. Sies,et al.  Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. , 2005, Journal of the American College of Cardiology.

[8]  Liliana Jiménez,et al.  Polyphenols: food sources and bioavailability. , 2004, The American journal of clinical nutrition.

[9]  J. Gaziano,et al.  Effects of cocoa products/dark chocolate on serum lipids: a meta-analysis , 2011, European Journal of Clinical Nutrition.

[10]  S. Glantz,et al.  Improvement of endothelial function with dietary flavanols is associated with mobilization of circulating angiogenic cells in patients with coronary artery disease. , 2010, Journal of the American College of Cardiology.

[11]  J. Blumberg,et al.  Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. , 2008, The Journal of nutrition.

[12]  N. Stocks,et al.  Effect of cocoa on blood pressure. , 2012, The Cochrane database of systematic reviews.

[13]  E. Rimm,et al.  Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. , 2012, The American journal of clinical nutrition.

[14]  R. Muniyappa,et al.  Cocoa consumption for 2 wk enhances insulin-mediated vasodilatation without improving blood pressure or insulin resistance in essential hypertension. , 2008, The American journal of clinical nutrition.

[15]  M. Lean,et al.  Milk decreases urinary excretion but not plasma pharmacokinetics of cocoa flavan-3-ol metabolites in humans. , 2009, The American journal of clinical nutrition.

[16]  E. Feskens,et al.  Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study. , 2006, Archives of internal medicine.

[17]  S. Wolffram,et al.  Bioavailability of quercetin in pigs is influenced by the dietary fat content. , 2004, The Journal of nutrition.

[18]  V. Fogliano,et al.  Polyphenols and Human Health: A Prospectus , 2011, Critical reviews in food science and nutrition.

[19]  E. Anklam,et al.  Analysis of procyanidins in chocolate by reversed-phase high-performance liquid chromatography with electrospray ionisation mass spectrometric and tandem mass spectrometric detection. , 2001, Journal of chromatography. A.

[20]  J. German,et al.  Chocolate procyanidins decrease the leukotriene-prostacyclin ratio in humans and human aortic endothelial cells. , 2001, The American journal of clinical nutrition.

[21]  Ian Harvey,et al.  Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. , 2008, The American journal of clinical nutrition.

[22]  C. Fraga,et al.  Regular Consumption of a Flavanol-rich Chocolate can Improve Oxidant Stress in Young Soccer Players , 2005, Clinical & developmental immunology.

[23]  F. Ruschitzka,et al.  Dark chocolate improves endothelial and platelet function , 2005, Heart.

[24]  K. Poutanen,et al.  Impact of Dietary Polyphenols on Carbohydrate Metabolism , 2010, International journal of molecular sciences.

[25]  P. Kris-Etherton,et al.  Effects of sugar-sweetened and sugar-free cocoa on endothelial function in overweight adults. , 2011, International journal of cardiology.

[26]  J. Buckley,et al.  Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects , 2008, International Journal of Obesity.

[27]  A. Waterhouse,et al.  Milk Does Not Affect the Bioavailability of Cocoa Powder Flavonoid in Healthy Human , 2007, Annals of Nutrition and Metabolism.

[28]  W. Klaus,et al.  Chocolate and blood pressure in elderly individuals with isolated systolic hypertension. , 2003, JAMA.

[29]  C. Kelly Effects of theobromine should be considered in future studies. , 2005, The American journal of clinical nutrition.

[30]  S. Necozione,et al.  Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. , 2005, The American journal of clinical nutrition.

[31]  G. Schuler,et al.  Effect of cocoa products on blood pressure: systematic review and meta-analysis. , 2010, American journal of hypertension.

[32]  L. Grivetti,et al.  Food of the gods: cure for humanity? A cultural history of the medicinal and ritual use of chocolate. , 2000, The Journal of nutrition.

[33]  M. Serafini,et al.  Plasma antioxidants from chocolate , 2003, Nature.

[34]  E. Evans,et al.  Daily consumption of a dark chocolate containing flavanols and added sterol esters affects cardiovascular risk factors in a normotensive population with elevated cholesterol. , 2008, The Journal of nutrition.

[35]  A. Villablanca,et al.  Chronic Consumption of Flavanol-rich Cocoa Improves Endothelial Function and Decreases Vascular Cell Adhesion Molecule in Hypercholesterolemic Postmenopausal Women , 2006, Journal of cardiovascular pharmacology.

[36]  K. Kondo,et al.  Plasma LDL and HDL cholesterol and oxidized LDL concentrations are altered in normo- and hypercholesterolemic humans after intake of different levels of cocoa powder. , 2007, The Journal of nutrition.

[37]  L. Mazzanti,et al.  Effect of consumption of dark chocolate on oxidative stress in lipoproteins and platelets in women and in men , 2012, Appetite.

[38]  H. Sies,et al.  Endothelial Function, Nitric Oxide, and Cocoa Flavanols , 2006, Journal of cardiovascular pharmacology.

[39]  C. Vlachopoulos,et al.  Effect of dark chocolate on arterial function in healthy individuals. , 2005, American journal of hypertension.

[40]  Debra L. Miller,et al.  Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults. , 2011, Journal of applied physiology.

[41]  K. Lee,et al.  Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine. , 2003, Journal of agricultural and food chemistry.

[42]  P. Kroon,et al.  Impact of dietary polyphenols on human platelet function--a critical review of controlled dietary intervention studies. , 2010, Molecular nutrition & food research.

[43]  B. Sarriá,et al.  Hypotensive, hypoglycaemic and antioxidant effects of consuming a cocoa product in moderately hypercholesterolemic humans. , 2012, Food & function.

[44]  I. Meredith,et al.  Acute and chronic effects of flavanol-rich cocoa on vascular function in subjects with coronary artery disease: a randomized double-blind placebo-controlled study. , 2006, Clinical science.

[45]  B. Prendergast,et al.  Antiplatelet therapy and vascular disease: an update , 2010, Therapeutic advances in cardiovascular disease.

[46]  R. Lamuela-Raventós,et al.  Cocoa consumption reduces NF-κB activation in peripheral blood mononuclear cells in humans. , 2013, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[47]  M. Shrime,et al.  Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies. , 2011, The Journal of nutrition.

[48]  N. Stocks,et al.  Does chocolate reduce blood pressure? A meta-analysis , 2010, BMC medicine.

[49]  R. Lamuela-Raventós,et al.  The effects of milk as a food matrix for polyphenols on the excretion profile of cocoa ( − )-epicatechin metabolites in healthy human subjects , 2008, British Journal of Nutrition.

[50]  G. Davison,et al.  The effect of acute pre-exercise dark chocolate consumption on plasma antioxidant status, oxidative stress and immunoendocrine responses to prolonged exercise , 2012, European Journal of Nutrition.

[51]  M. Gershwin,et al.  Effect of Cocoa Procyanidins on the Secretion of Interleukin-4 in Peripheral Blood Mononuclear Cells , 2000 .

[52]  P. Bose,et al.  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. , 2006, Journal of agricultural and food chemistry.

[53]  P. Meisel Hypertension, diabetes: chocolate with a single remedy? , 2005, Hypertension.

[54]  J. Blumberg,et al.  Protective Effects of Flavanol-Rich Dark Chocolate on Endothelial Function and Wave Reflection During Acute Hyperglycemia , 2012, Hypertension.

[55]  V. Njike,et al.  Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial. , 2008, The American journal of clinical nutrition.

[56]  F. Ruschitzka,et al.  Cardiovascular effects of flavanol-rich chocolate in patients with heart failure. , 2012, European heart journal.

[57]  M. McCullough,et al.  Associations between flavonoids and cardiovascular disease incidence or mortality in European and US populations. , 2012, Nutrition reviews.

[58]  R. Lamuela-Raventós,et al.  Regular consumption of cocoa powder with milk increases HDL cholesterol and reduces oxidized LDL levels in subjects at high-risk of cardiovascular disease. , 2012, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[59]  A. Minihane,et al.  Biomarkers of the intake of dietary polyphenols: strengths, limitations and application in nutrition research , 2007, British Journal of Nutrition.

[60]  J. Buckley,et al.  Impact of cocoa flavanol consumption on blood pressure responsiveness to exercise. , 2010, The British journal of nutrition.

[61]  Elena Lecumberri,et al.  Caracterización de la fibra de cacao y su efecto sobre la capacidad antioxidante en suero de animales de experimentación , 2006 .

[62]  Olga Pechanova,et al.  Hypertension, nitric oxide, oxidants, and dietary plant polyphenols. , 2010, Current pharmaceutical biotechnology.

[63]  N. Stocks,et al.  Effect of chocolate on blood pressure , 2010 .

[64]  L. Goya,et al.  Cocoa flavonoids up-regulate antioxidant enzyme activity via the ERK1/2 pathway to protect against oxidative stress-induced apoptosis in HepG2 cells. , 2010, The Journal of nutritional biochemistry.

[65]  P. Ridker,et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. , 2000, The New England journal of medicine.

[66]  H. Sies,et al.  Vascular effects of cocoa rich in flavan-3-ols. , 2003, JAMA.

[67]  C. Keen,et al.  Cocoa and wine polyphenols modulate platelet activation and function. , 2000, The Journal of nutrition.

[68]  G. Beecher,et al.  Concentrations of proanthocyanidins in common foods and estimations of normal consumption. , 2004, The Journal of nutrition.

[69]  馬場 星吾 Cocoa powder enhances the level of antioxidative activity in rat plasma , 2003 .

[70]  M. O'Rourke,et al.  Mechanical factors in arterial aging: a clinical perspective. , 2007, Journal of the American College of Cardiology.

[71]  K. Murphy,et al.  Dietary flavanols and procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function. , 2003, The American journal of clinical nutrition.

[72]  C. Roberts,et al.  Oxidative stress and metabolic syndrome. , 2009, Life sciences.

[73]  S. Tiberti,et al.  Flavonoids, vascular function and cardiovascular protection. , 2009, Current pharmaceutical design.

[74]  C. Kwik-Uribe,et al.  Cocoa Flavanols and Platelet and Leukocyte Function: Recent In Vitro and Ex Vivo Studies in Healthy Adults , 2006, Journal of cardiovascular pharmacology.

[75]  D. Baer,et al.  Effect of cocoa and green tea on biomarkers of glucose regulation, oxidative stress, inflammation and hemostasis in obese adults at risk for insulin resistance , 2012, European Journal of Clinical Nutrition.

[76]  J. Blumberg,et al.  Cocoa Reduces Blood Pressure and Insulin Resistance and Improves Endothelium-Dependent Vasodilation in Hypertensives , 2005, Hypertension.

[77]  E. Offord,et al.  Plasma kinetics in man of epicatechin from black chocolate , 1999, European Journal of Clinical Nutrition.

[78]  J. Buckley,et al.  Dose-related effects of flavanol-rich cocoa on blood pressure , 2010, Journal of Human Hypertension.

[79]  P. Hollman,et al.  Addition of milk does not affect the absorption of flavonols from tea in man , 2001, Free radical research.

[80]  G. Kennedy,et al.  Dark chocolate inhibits platelet aggregation in healthy volunteers , 2003, Platelets.

[81]  M. Castell,et al.  Epicatechin, procyanidins, and phenolic microbial metabolites after cocoa intake in humans and rats , 2009, Analytical and bioanalytical chemistry.

[82]  C. Keen,et al.  Food effects on the absorption and pharmacokinetics of cocoa flavanols. , 2003, Life sciences.

[83]  L. Ghiadoni,et al.  Endothelial dysfunction in hypertension. , 2001, Journal of cardiovascular pharmacology.

[84]  S. Paul,et al.  Flavonoid-Rich Dark Chocolate Improves Endothelial Function and Increases Plasma Epicatechin Concentrations in Healthy Adults , 2004, Journal of the American College of Nutrition.

[85]  L. Kiemeney,et al.  Fruits and vegetables consumption and the risk of histological subtypes of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) , 2009, Cancer Causes & Control.

[86]  C. Lehmann,et al.  Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. , 2007, JAMA.

[87]  R. Lamuela-Raventós,et al.  Flavanol and flavonol contents of cocoa powder products: influence of the manufacturing process. , 2008, Journal of agricultural and food chemistry.

[88]  F. Violi,et al.  Dark chocolate inhibits platelet isoprostanes via NOX2 down‐regulation in smokers , 2012, Journal of thrombosis and haemostasis : JTH.

[89]  G. Williamson Bioavailability and health effects of cocoa polyphenols , 2009, Inflammopharmacology.

[90]  E. Kilpatrick,et al.  High‐cocoa polyphenol‐rich chocolate improves HDL cholesterol in Type 2 diabetes patients , 2010, Diabetic medicine : a journal of the British Diabetic Association.

[91]  S. Kropf,et al.  Flavanol-rich cocoa drink lowers plasma F(2)-isoprostane concentrations in humans. , 2004, Free radical biology & medicine.

[92]  N. Suzuki,et al.  Polyphenols in chocolate, which have antioxidant activity, modulate immune functions in humans in vitro. , 1997, Cellular immunology.

[93]  C. Fraga,et al.  Procyanidin dimer B2 [epicatechin-(4beta-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa. , 2002, The American journal of clinical nutrition.

[94]  Gary Williamson,et al.  Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. , 2005, The American journal of clinical nutrition.

[95]  T. Rassaf,et al.  Sustained Increase in Flow-Mediated Dilation After Daily Intake of High-Flavanol Cocoa Drink Over 1 Week , 2007, Journal of cardiovascular pharmacology.

[96]  An Pan,et al.  Dietary flavonoid intakes and risk of type 2 diabetes in US men and women. , 2012, The American journal of clinical nutrition.

[97]  C. Keen,et al.  Flavanols and Platelet Reactivity , 2005, Clinical & developmental immunology.

[98]  R. Lamuela-Raventós,et al.  Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular disease. , 2009, The American journal of clinical nutrition.

[99]  D. Seals,et al.  Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase. , 2009, American journal of physiology. Heart and circulatory physiology.

[100]  J. Salonen,et al.  Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans. , 2004, Free radical biology & medicine.