Chocolate Flavonoids in the Prevention of Arterial Disease
- 4.1k Downloads
Chocolate, which provides a concentrated source of energy because of its high-fat content, belongs to a class of polyphenols known as flavonoids, which contain such celebrated foods as red grapes, tea, soy, and garlic.
Dark chocolate contains the highest amount of flavonoid-rich cocoa.
Both short- and long-term ingestion of chocolate products result in an increase in serum antioxidant capacity and a decrease in LDL oxidation, both linked to reduced heart disease risk.
Health benefits from chocolate consumption related to cardiovascular disease include the health neutrality of its saturated fatty acid (stearic acid) and protective effects of its flavonols, including flavanols and procyanidins.
Health benefits from chocolate consumption related to cardiovascular disease prevention include anti-inflammatory functions, which prevent development of fatty streaks in the beginning stages of the atherosclerotic process.
KeywordsChocolate flavonoids Heart disease prevention Increased antioxidant capacity Decreased LDL oxidation Increased chocolate consumption worldwide
Cardiovascular disease is the leading cause of death worldwide, claiming millions of deaths in both industrialized and developing nations. With over 17 million deaths a year, the World Health Organization (WHO) has labeled diseases of the heart a pandemic that recognizes no border . Of the 13 million heart attack and stroke deaths each year, most of the deaths come from developing nations. Massive public health campaigns representing collaboration between the WHO and member health agencies have begun to make small strides in certain regions through education, preventive services, and treatment .
While cardiovascular disease rates are decreasing slightly, environmental factors, such as nutrition, physical activity, and smoking, play a crucial role in the development of this chronic and deadly disease. Studies have demonstrated a link between excessive intake of saturated fat consumption and heart disease, indicating a critical role of diet in heart disease prevention . High intake of saturated fat, along with genetic disposition, may be a primary risk factor for dyslipidemia and elevated low-density lipoprotein cholesterol. Long-term consequences of avoiding preventative measures may result in clogging of the arteries or oxidative damage. Oxidative damage in the pathophysiology of cardiovascular disease is a multifactorial process involving low-density lipoprotein (LDL) cholesterol, inflammation, and vasoconstriction, which results in the formation of atherosclerotic plaques and thrombosis.
For years, public health officials and nutrition experts have emphasized fruit and vegetable consumption for its role in displacing fat consumption and increasing antioxidant and phytochemical content. Diets rich in plant-based foods contain significant amounts of fiber, water, vitamins, and minerals and are low in sodium, saturated fats, and trans fats.
With recent advances in food analysis technology, chocolate, previously considered to play a minute role in human nutrition, has recently been making headlines with regard to its possible cardioprotective characteristics. Chocolate, which provides a concentrated source of energy because of its high-fat content, belongs to a class of polyphenols known as flavonoids, which contain such celebrated foods as red grapes, tea, soy, and garlic. Cocoa contains many oligomeric polymers of the flavonoids, which include flavonol, procyanidin, and anthocyanidin, and the phenolic compounds caffeic acid, chlorogenic acid, p-coumaric acid, phenylacetic acid, and phloretic acid . While some flavonoid contents are lost in the fermentation and production of chocolate, its potential for supplying polyphenol-rich health benefits should not be disregarded. Dark chocolate contains the highest amount of flavonoid-rich cocoa. However, when milk is added to chocolate and produces one of the most popular forms of chocolate, the milk contributes small amounts of protein, vitamins, and minerals, and substantial amounts of added saturated fat. The primary fat found in chocolate is cocoa butter, which contains the saturated fatty acid, stearic acid. This fatty acid, the flavonoid content of chocolate, and subsequent effects on lipoprotein oxidation, inflammation biomarkers, platelet aggregation, vasodilation, as well as cardiovascular health, in general, have become frequent topics of current research .
With chocolate’s reputation for overconsumption, high calories, and added sugars, cocoa and chocolate products are still under scrutiny by many health professionals for reported health claims. This chapter provides a background into the historical origins and uses of chocolate as well as its production and composition. It also provides a review of the rapidly increasing research literature available about the role of chocolate in cardiovascular health and the potential for this world-renowned and highly desirable sweet to aid in the prevention of diseases of the heart.
The cacao tree is a delicate tropical plant that grows 15–25 ft tall in the shade of trees of other crops in hot, rainforest climates. In fact, cacao can only be cultivated within a 20° span of the equator. Before being introduced to Spain and Europe during the colonization period, the cacao tree, or cocoa, originated from the Central or South American region . The first European to discover chocolate was Christopher Columbus in 1502; however, it was a second discovery by Hernan Cortes in 1528 that resulted in chocolate being introduced to the European world. Today, cocoa is grown in Central and South America, the Caribbean, and in West African countries such as Ivory Coast and Ghana, which produce most of the world’s supply .
The words cocoa and chocolate originated from the Mayan and Aztec terms cacao and cacahuatl and have their origins in reported divine discoveries by Gods in the Central and South American mountains . The scientific name, Theobroma cacao, means “food of the Gods,” appropriately referenced by the ancient cultures that first cultivated and enjoyed the cocoa beans, which are actually seeds. Cocoa grows in oval-shaped pods ranging an average of 10 in. and is orange to orange-yellow color when mature. The insides of the pods are filled with a cream-colored pulp holding anywhere from 20 to 50 cocoa beans. Cocoa has two main species, Criollo and Forastero . While Forastero, found mainly in Brazil and Africa, is more prevalent because of its higher yield and easy cultivation, Criollo, found in Central America and the Caribbean, is better known for its exceptional quality and grade.
The existing views and uses of chocolate have changed considerably from the early days of its discovery. The Mesoamerican cultures viewed chocolate as magical and mystical. It played an important role in the diet for individuals of royalty, wealth, and power . Chocolate had many uses, ranging from medication to currency, and was originally served as a frothy drink to warriors, merchants, and individuals of nobility. Far from the cocoa beverage known today, Mayan and Aztec cocoa beverage consisted of a frothy drink served cold, spicy, and bitter, with honey, corn, or seasonings such as pepper occasionally being added .
Most of the present varieties of chocolate have until recently been considered to have little nutritional value. However, in ancient times, the unprocessed cocoa was valued and used for its healing properties for many health problems or complications. Cocoa was considered to reduce intestinal and nervous distress, inflammation, infection, fever, and gout; have anticancer effects; stimulate the kidney; prolong longevity; and treat tuberculosis. Of significance to this chapter is the fact that chocolate was viewed as being of value for strengthening the heart and for treatment of angina. The medical concept of using chocolate for various ailments continued until the twentieth century, when an impartial and more scientific review of these beliefs began to develop .
Since that time, the uses and cultivation of chocolate have continued to evolve and have extended globally. When cocoa was introduced to the Spanish, sugar and other flavors such as vanilla were added and served steaming hot. Following the traditions of the Aztecs and Mayans, it was reserved for aristocrats, royalty, and the most noble of men. Kept secret from the rest of Europe for almost a hundred years, drinking chocolate as both a fashionable and medicinal drink quickly spread across Europe’s elite after Spain built its first cocoa processing plant in 1580 .
For hundreds of years, the production of chocolate was unchanged and too expensive for consumption by the masses because of the high costs associated with cocoa grinding. However, during the era of the Industrial Revolution, many changes to the preparation methods of chocolate occurred that resulted in the varieties and uses of chocolate that we know today .
Today, the production and manufacturing of chocolate has become a precise and detailed science. After roasting and removal of the dried bean fragments, the concentrated pieces of cocoa are then grinded to liquefy the cocoa butter, creating nonalcoholic chocolate liquor . At this stage, the chocolate liquor can be used to make either cocoa powder or chocolate using different processes. Which one is produced depends on whether the cocoa butter is removed from the liquor during processing. Flavonoid-rich chocolate liquor is a bitter liquid used in many delicious baking recipes. Another common baking ingredient is creamy cocoa butter, the vegetable fat from the cocoa bean extracted from the chocolate liquor. Whether being consumed as sweet white, milk, or dark chocolate or used as a soft creamy mixture for coating, dipping, or glazing, chocolate is available in many sweet or bitter varieties. Dark chocolate, available as a dark, semisweet, or bittersweet treat, is the darkest of eating chocolate and is high in chocolate liquor with minimal added sweeteners. Milk chocolate is made using minimal amounts of chocolate liquor and offers the least amount of flavonoids. Subsequently, the addition of an alkaline during the production of dark and milk chocolate contributes to a reduction of flavonoid content.
Chocolate contains important nutrients that can contribute to the prevention of cardiovascular diseases: lipids, minerals, and polyphenols. From the cocoa plant to the commercially available chocolate, the benefits of chocolate outweigh the problems of excess calorie consumption.
Cocoa butter is the source of fat in chocolate. Cocoa butter contains saturated fatty acids, stearic acid (18:0, 35%) and palmitic acid (16:0, 25%), and the unsaturated fatty acid oleic acid (18:1, 35%) [4, 9]. While saturated fatty acid consumption is associated with increased cardiovascular disease risk, stearic acid does not raise plasma LDL cholesterol and has been considered cholesterol neutral [10, 11]. Stearic acid is metabolically different from the other long-chain saturated fatty acids. Several animal and human studies have reported a lower absorption rate for stearic acid as compared to other fatty acids [12, 13]. Another significant factor in its relative absorption rate may be where the stearic acid appears on the triglyceride molecule [14, 15]. Recently, a study found that the lipid composition in chocolate might prevent LDL oxidation while modulate the rate of cholesterol absorption . However, more research is needed to establish the exact mechanisms for the distinct neutral cholesterolemic effects of chocolate lipids.
Cocoa beans contain several minerals, and the amount present in processed chocolate depends greatly on the amount of cocoa bean solids present. Dark chocolate has a higher mineral content than milk chocolate . Adequate amounts of calcium, iron, magnesium, phosphorus, potassium, sodium, and zinc can be found in 41 g or a 14.5-ounce serving of cocoa, dark chocolate, and milk chocolate . Calcium, potassium, and magnesium consumption have been related to the prevention of cardiovascular disease owing to their role in reducing blood pressure . In fact, magnesium is required for normal heart rhythms, muscle, and nerve function. Magnesium deficiency is associated with elevated C-reactive protein, blood pressure, and cholesterol as well as arrhythmias and tachycardia . An ounce of dark chocolate contains about 35 mg of magnesium, and a six-ounce bar will provide about half the DRI (320–400 mg). Milk chocolate only contains about half of the magnesium of dark chocolate and owing to the sugar content may result in increased urinary magnesium losses .
Cocoa and chocolate contain larger oligomeric procyanidins that may contribute to more protective health benefits. Procyanidin oligomers have been identified in raw cocoa and in dark chocolate . Chocolate contains more total procyanidin content by weight compared to wine, cranberry juice, and many varieties of apples. Over 10% of the weight of cocoa powder is flavonoids. However, when compared by serving size, the procyanidin content in chocolate and apples is equivocal. Apples offer more procyanidins per kilocalorie on average than chocolate, 1.3 and 0.9 mg/kcal, respectively . High-cocoa liquor chocolate contains a substantial level of procyanidins, up to decamers, and because of the partial alkalization, dark chocolate contains a lower level. Additionally, the procyanidin content in cocoa is closely related to its oxygen radical absorbance capacity (ORAC) values, which indicates that procyanidins are the primary contributors to cocoa antioxidant capacity .
Bioavailability of Active Components
Under the acidic conditions of stimulated gastric juice, oligomeric procyanidins are hydrolyzed to monomer and dimeric units so that large quantities of epicatechins may be released and absorbed into the small intestine . However, in vivo investigation of gastric contents every 10 min after cocoa beverage ingestion until the stomach was emptied showed no changes in the HPLC profile of procyanidins, and no depolymerization of cocoa procyanidins occurred in the stomach  keeping its stability in the gastric tissue . The discrepancies may be explained by the increased duration of exposure and increased pH levels in the in vitro study. Received into the small intestine intact, the high molecular weight of cocoa procyanidins is too high for absorption. The major compound present in the portal vein after ingestion of dimer units is likely to be epicatechin, which is conjugated to only a small extent and not subject to O-methylation. Although epicatechin dimers are not extensively absorbed, it is likely they are bioavailable in the forms of epicatechin monomers . The dimeric procyanidins (−)-epicatechin and (+)-catechin have been detected in the plasma of human subjects within 30 min of ingesting flavanol-rich cocoa and reached maximum concentrations by the second hour . A recent investigation estimating the amounts of phenolic acids formed by the microflora and excreted in the urine of humans subjects after consumption of polyphenol-rich chocolate resulted in the excretion of the following six phenolic acids: m-hydroxyphenylpropionic acid, ferulic acid, 3,4-dihydroxyphenylacetic acid, m-hydroxyphenylacetic acid, vanillic acid, and m-hydroxybenzoic acid. These phenolic acids also contribute to antioxidant protection and suggest that the antioxidant effects of chocolate may not be solely expressed by the absorption of catechin molecules but also by the absorption of microbial phenolic acid metabolites .
Role of Chocolate Components in Cardiovascular Disease
Catechin/epicatechin concentrations found in fooda
Flavanol content, mg/kg or mg/L
Both short- and long-term ingestion of chocolate products results in an increase in serum antioxidant capacity and a decrease in LDL oxidation [34, 35, 36]. LDL oxidation plays a significant role in the development of atherosclerotic lesions in cardiovascular disease (CVD). The potential for chocolate to reduce the risk of CVD by preventing LDL oxidation has been verified by both in vitro and in vivo studies via modulation of the enzymes involved in oxidation, 5-lipoxygenase and cyclooxygenases [37, 38]. However, a diet plentiful in fruits, vegetables, and other antioxidant-rich foods is not to be neglected [34, 35, 36].
Circulating plasma lipoproteins are susceptible to oxidation. Once oxidized, lipoproteins can accumulate and adhere to arterial walls. This process signals the influx of monocytes to the injured site. When the monocytes enter the endothelium, they convert into macrophages. Oxidized LDL is picked up by the macrophages and converted into foam cells, which in turn stimulate the release of immune mediating cytokines, leukocytes, and additional monocytes, which leads to plaque formation and accumulation .
Inflammation is the body’s first immune response to damage, infection, or irritation. Inflammation is affected by many cellular components in the blood such as transcription factors and lipoxygenases. During the atherogenic process, the inflammatory response plays a major role in CVD progression . The inflammatory response is stimulated by a cascade of events within the endothelial and subendothelial areas of the arteries. Endothelial dysfunction activates proinflammatory enzymes, which produce free radicals, thus contributing to injury [31, 32]. The inflammatory response promotes the development of fatty streaks seen in the beginning stages of the atherosclerotic process, which may lead to more severe arterial lesions distinctive of coronary heart disease. Thus, it is important to limit the chronic inflammatory response. The biomarker serum C-reactive protein has been used as a measure of inflammation.
The inflammatory response within the body starts with an injury or stimulus. The result of the injury or other stimulus is the release of phospholipase A2, which stimulates the release of arachidonic acid. Arachidonic acid can then either be metabolized by cyclooxygenase 1 and 2 (COX-1 COX-2) or by the 5-lipoxygenase pathway. The COX pathway is responsible for the production of prostaglandins. COX-1 is responsible for baseline levels of prostaglandins, and COX-2 produces prostaglandins through activation (inflammatory response). COX-1, which is found in platelets, activates thromboxane A2 (TXA2), causes blood vessels to constrict, and promotes platelet aggregation. COX-2, by contrast, is expressed in blood vessels and activates prostaglandin I2 (PGI2), which dilates blood vessels and prevents the activation of platelets. Imbalance on the ratio TXA2: PG is related with the formation of a thrombus and infarction [41, 42]. The flavanols in chocolate seem to inhibit the activity of cyclooxygenase and to increase PGI2, preventing further platelet aggregation and inducing vasodilation , protecting the heart from damage.
Modulation of NF-kappa B Pathway
One component in chocolate that has an effect on anti-inflammatory response is epigallocatechin gallate (EGCG) (a plant flavonol). Epigallocatechin gallate is a flavonol found in dark chocolate that has been shown to inhibit NF-κB activation in human cell lines  by keeping the IκB/NF-κB complex. This complex prevents the translocation of NF-κB into the nucleus and further transcription of mRNA for proinflammatory cytokines, interleukin-1 beta, IL-2, and TNF-alpha, among others . Chronic inflammation secondary to the activation of these cytokines leads to permanent damage to the muscle of the heart or heart failure .
Nitric Oxide Pathway Induction
Oligomeric flavonoids found in cocoa and chocolate may also be an important dietary source of protection against oxidative stress, which may occur in states of inflammation. One form of oxidative stress is associated with increased production of nitric oxide and peroxynitrite, which leads to tissue damage. When (−)-epicatechin and respective procyanidin oligomers isolated from the seeds of Theobroma cacao were examined for their ability to protect against peroxynitrite-dependent oxidation and nitration reactions, the tetrameric oligomers were more efficient than the monomeric epicatechin . However, studies suggest that the intermediary procyanidins do not directly react with peroxynitrite but most likely with reactive oxidizing/nitrating intermediaries [45, 46]. Nitric oxide (NO) is a precursor to the prooxidant and nitrating intermediaries and can be affected by chocolate consumption. NO levels were shown to increase in individuals with diminished endothelial function who consumed a high-level flavonol cocoa drink; however, subjects with normal endothelial function did not receive the same beneficial effect. Therefore, the flavonols found in chocolate protect against peroxynitrate and could play an important anti-inflammatory role, which may have more than one mechanism of action related to oxidative stress .
Another function of cocoa flavanols is to aid in the function of NO in increasing the transcription of the phase II antioxidant enzymes involved in endothelial normal function  and preventing platelet aggregation . This benefit is warranted by different mechanisms: inhibition of oxidative processes via blocking phospholipase activity and further peroxide production, inhibiting platelets aggregation receptors and lipooxygenase and cyclooxygenase pathways .
Control of Hypertension
The benefits of chocolate increasing endothelial NO, and thus reducing oxidation, have been shown to reduce blood pressure. A study conducted in hypertensive patients receiving 6 g of dark chocolate for 18 weeks found a significant reduction in blood pressure and increased level of NO  when compared to white chocolate. Although studies looking for the modulation of blood pressure via inhibition of angiotensin-converting enzymes in vitro have evidenced the effect of chocolate lowering blood pressure, more research is needed to see effects in humans . The amount of stearic fatty acids in cocoa has been associated also with lower diastolic pressure in humans , but the exact mechanism must be elucidated.
Reduction of Atherosclerosis
Risk factor for the formation of the atherogenic plaque is the oxidation of LDL cholesterol and lipid. Several studies have shown that the consumption of chocolate increased high-density lipoproteins (HDL; good cholesterol), lowered triglycerides , inhibited LDL oxidation, and reduced total cholesterol . The consumption of nonfermentable fiber (cellulose and bran) in unprocessed cocoa can also contribute to reduce total fat and cholesterol absorption . The mechanism by which the flavonoid catechin (found mostly in dark chocolate) reduces serum cholesterol is via a reduction in its absorption when using the rodent model .
The suppression of platelet aggregation is thought to play a role in decreasing the thrombolytic activity of blood platelets, thus potentially reducing cardiovascular damage. Research conducted both in vitro and in vivo has demonstrated chocolate’s ability to suppress platelet activation [54, 55, 56]. The effects of cocoa beverages provided to subjects showed platelet suppression in both nonstimulated and stimulated platelets, while also decreasing platelet activation marker expression [54, 55].
Whole chocolate’s effect on platelet activity has also shown beneficial results. Researchers found that after consumption of dark chocolate, platelet aggregation was inhibited whereas no effect was seen in those consuming white or milk chocolate . This effect is thought to be derived from the flavonoids effect on altering eicosanoid synthesis. A recent study tested the efficacy of a high-flavonol chocolate bar, containing 148 mg of flavonols, to a control group who consumed a chocolate bar containing 3.33 mg of flavonols . The consumption of this high-procyanidin chocolate resulted in an increase in plasma prostacyclin concentrations and a decrease in both the plasma leukotriene concentration and the plasma leukotriene prostacyclin ratio. This ability of flavonols to modulate eicosanoid synthesis may be due to the flavonol’s capacity to affect enzymes that synthesize or degrade eicosanoids. Flavonols can also modulate enzymes in the leukotriene-synthesizing process by inhibiting 5-lipoxygenase. Inhibition of 5-lipoxygenase issues a cascading effect, which in turn inhibits production of leukotrienes. One of these leukotrienes is leukotriene A4 (LTA4), and LTA4 is then converted to leukotriene B4 (LTB4). LTB4’s function is platelet aggregation. Flavonols inhibition of 5-lipoxygenase through this process ultimately leads to a decrease in platelet aggregation.
Improving Insulin Resistance
Flavanols have been shown to improve insulin sensitivity in nondiabetic obese patients with hyperglycemia receiving 100 g of dark chocolate for 15 days . Most of the benefits are associated with the anti-inflammatory properties and the benefits to the endothelial tissue.
How Much Chocolate?
Evidence of the cardioprotective effects of chocolate
Vasodilation via NO synthesis
176–185 mg of flavonols in 2 h
Heiss et al. 2005 
Reduction in blood pressure
6 g of dark chocolate containing 30 mg of polyphenols/day for 18 weeks
Taubert et al. 2007 
Reduction in inflammation (lowered C-reactive protein), increase in HDL
700 mg of dark chocolate rich in flavonoids/day for 1 week
Hamed et al. 2008 
Reduction of 5% of LDL cholesterol
81–163 mg of cocoa powder with epicatechin for 4 weeks
Mild hypercholesterolemic patients
Baba et al. 2007 
Reduction in total cholesterol
37 g of dark chocolate bar for 6 weeks
Crews et al. 2008 
Increase in serum antioxidant capacity and a decrease in LDL oxidation
22 g of cocoa powder, 16 g of dark chocolate
Regular consumption of chocolate and its flavonols is increasing worldwide. Chocolate and the flavonols in chocolate are not simply preferred foods due to their flavor and texture but have many potentially beneficial and multifaceted effects on organs and tissues. Health benefits from chocolate consumption related to CVD include the health neutrality of its saturated fatty acid (stearic acid) and protective effects of its flavonols, including flavanols and procyanidins, mostly found in dark chocolate. These include antioxidant capacity and ability to prevent LDL oxidation and reduce development of atherosclerotic lesions, anti-inflammatory functions which prevent development of fatty streaks in the beginning stages of the atherosclerotic process, and suppression of platelet aggregation through several mechanisms potentially reducing cardiovascular damage. Much of this research, while promising, has been conducted through short-term trials of chocolate consumption. Long-term trials are needed to confirm these beneficial health effects and CVD risk reduction before chocolate can be recommended as a healthful food. The current research suggests that chocolate can be included as part of a healthy diet with potential health benefits and without adverse CVD consequences, especially within a calorie-controlled diet that does not promote obesity.
- 1.World Health Organization. The Atlas of heart disease and stroke. Available at: http://www.who.int/cardiovascular_diseases/resources/atlas/en/. Accessed 1 Mar 2006.
- 5.Chocolate Manufacturers Association. The story of chocolate. Available at: www.chocolateusa.org. Accessed 23 Feb 2006.
- 6.Dillinger TL, Barriga P, Escarcega S, Jimenez M, Lowe DS, Grivetti LE. Food for the Gods: cure for humanity? A cultural history of the medicinal and ritual uses of chocolate. J Nutr. 2000;30:2057S–72.Google Scholar
- 7.Morton M, Morton F. Chocolate: an illustrated history. New York: Crown Publishers; 1986.Google Scholar
- 8.Telly C. Chocolate: its quality and flavor (which is the world’s best chocolate). In: Szogyi A, editors. Chocolate: food of the gods. Westport: Greenwood Press; 1997:165–166; USDA (2005) National Nutrient Database for Standard Reference, Release 18. Available at: http://www.ars.usda.gov/ba/bhnrc/ndl. Accessed 23 Jan 2006.
- 10.Kris-Etherton PM, Derr JA, Mitchell DC. The role of fatty acid saturation on plasma lipids, lipoproteins and apoliproteins: effects of whole food diets high in cocoa butter, olive oil, soybean oil, dairy butter and milk chocolate on the plasma lipids of young men. Metabolism. 1993;42:130–4.PubMedCrossRefGoogle Scholar
- 15.Brink EJ, Haddeman E, de Fouw NJ, Westrate JA. Positional distribution of stearic acid-rich, structured triacylglycerol and dietary calcium concentration determines the apparent absorption of these fatty acids in rats. J Nutr. 1995; 125:2379–2387.Google Scholar
- 17.USDA. 2005. National nutrient database for standard reference, Release 18. Available at: http://www.ars.usda.gov/ba/bhnrc/ndl. Accessed 23 Jan 2006.
- 18.Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP). Expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001; 285:2486–2498.Google Scholar
- 32.Ding EL, Hutfless SM, Ding X, Girotra S. Chocolate and prevention of cardiovascular disease: a systematic review. Nutr Metab (Lond). 2006; 3:2. (BioMed Central ISSN 1743–7075).Google Scholar
- 35.Wan Y, Vinson JA, Etherton TD, Proch J, Lazarus SA, Kris-Etherton PM. Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans. Am J Clin Nutr. 2002;74:596–602.Google Scholar
- 47.Sies H, Schewe T, Heiss C, Kelm M. Cocoa polyphenols and inflammatory mediators. Am J Clin Nutr. 2005;8:304S–12.Google Scholar
- 60.Crews WD Jr, Harrison DW, Wright JW. 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. 2008;87(4):872–80.PubMedGoogle Scholar