Chocolate and Prevention of Cardiovascular Disease: A Systematic Review
© Ding et al; licensee BioMed Central Ltd. 2006
Received: 23 September 2005
Accepted: 03 January 2006
Published: 03 January 2006
Consumption of chocolate has been often hypothesized to reduce the risk of cardiovascular disease (CVD) due to chocolate's high levels of stearic acid and antioxidant flavonoids. However, debate still lingers regarding the true long term beneficial cardiovascular effects of chocolate overall.
We reviewed English-language MEDLINE publications from 1966 through January 2005 for experimental, observational, and clinical studies of relations between cocoa, cacao, chocolate, stearic acid, flavonoids (including flavonols, flavanols, catechins, epicatechins, and procynadins) and the risk of cardiovascular disease (coronary heart disease (CHD), stroke). A total of 136 publications were selected based on relevance, and quality of design and methods. An updated meta-analysis of flavonoid intake and CHD mortality was also conducted.
The body of short-term randomized feeding trials suggests cocoa and chocolate may exert beneficial effects on cardiovascular risk via effects on lowering blood pressure, anti-inflammation, anti-platelet function, higher HDL, decreased LDL oxidation. Additionally, a large body of trials of stearic acid suggests it is indeed cholesterol-neutral. However, epidemiologic studies of serum and dietary stearic acid are inconclusive due to many methodologic limitations. Meanwhile, the large body of prospective studies of flavonoids suggests the flavonoid content of chocolate may reduce risk of cardiovascular mortality. Our updated meta-analysis indicates that intake of flavonoids may lower risk of CHD mortality, RR = 0.81 (95% CI: 0.71–0.92) comparing highest and lowest tertiles.
Multiple lines of evidence from laboratory experiments and randomized trials suggest stearic acid may be neutral, while flavonoids are likely protective against CHD mortality. The highest priority now is to conduct larger randomized trials to definitively investigate the impact of chocolate consumption on long-term cardiovascular outcomes.
Cardiovascular disease (CVD), as a group, is a leading cause of the death in the United States , and worldwide, causing over 16.7 million deaths globally in 2002 . In 1990, greater than 85,000,000 disability-adjusted life-years were lost worldwide due to coronary heart disease (CHD) and stroke; this CVD disease burden is projected to rise to 143,000,000 disability-adjusted life-years by 2020 . Studies suggest cardiovascular diseases may be preventable by lifestyle modifications, such as exercise and nutrition [3–7]. Additionally, the American Heart Association, American Diabetes Association, and the U.S. Preventive Services Task Force have each indicated the likely importance of diet for the prevention of CVD [8–10].
In the American diet, fruits, vegetables, tea, wine and chocolate are major sources of antioxidants, which have been shown to have protective effects against CVD [11, 12]. One class of antioxidants, flavonoids, commonly found in such foods, have attracted great interest in potentially lowering risk of CVD. Since cocoa products contain greater antioxidant capacity and greater amounts of flavonoids per serving than all teas and red wines [12, 13], it is important to explore chocolate's potential effects on CVD.
Since ancient times, chocolate has long been used as a medicinal remedy  and been proposed in medicine today for preventing various chronic diseases [15, 16]. While chocolate has also sometimes been criticized for its saturated fat content, mostly in the form of long-chain stearic acid, chocolate has also been lauded for its antioxidant potential. However, to this date there are no long-term randomized feeding trials of chocolate to assess effects on actual cardiovascular events. Nevertheless, there have been many short-term trials of cocoa and chocolate examining effects on cardiovascular intermediates, and numerous epidemiology studies of stearic acid and flavonoids exploring associations with cardiovascular outcomes.
This systematic review serves to comprehensively evaluate the experimental and epidemiologic evidence of cocoa and chocolate products. Particularly, we focus on the controversial potential benefits of the chocolate components stearic acid and flavonoids; review their overall effects on CVD risk factor intermediates and CVD endpoints; and conduct a meta-analysis of total flavonoid intake and risk of CHD mortality.
We reviewed English-language MEDLINE publications from January 1965 through June 2005 for experimental, observational, and clinical studies of relations between the exposure search terms of chocolate, stearic acid, flavonoids (including flavonols, flavanols, catechins, epicatechins, and procynadins) and the outcome search terms of cardiovascular disease (coronary heart disease, ischemic heart disease, stroke), cholesterol, blood pressure, platelet, oxidation, and thrombosis. Approximately 400 papers were reviewed. Based on the relevance, strength, and quality of the design and methods, 136 publications were selected for inclusion.
We mainly focused on studies in humans, particularly randomized trials of either parallel or cross-over design, and prospective observational studies. Since no randomized trials have yet assessed chocolate in relation to definitive CVD outcomes, prospective observational studies evaluating chocolate sub-components and the risk of CVD outcomes were weighted equally in the overall evaluation. For overall objective evaluation, the strength of the evidence was evaluated by the design and quality of individual studies, the consistency of findings across studies, and the biologic plausibility of possible mechanisms. Finally, consistent with methods of the outdated prior analysis , an updated meta-analysis was conducted and relative risks estimates pooled using a random-effects model .
Stearic acid in chocolate
Saturated fat has long been thought to contribute to atherosclerosis, and thus, adverse for CVD risk. However, stearic acid has been suggested to be a non-atherogenic type of dietary saturated fat. Stearic acid is a long-chain 18:0 saturated fatty acid found commonly in meats and dairy products. Cocoa butter, a fat derived from cocoa plants and predominantly found in dark chocolate , contains an average of 33% oleic acid (cis-18:1 monounsaturated), 25% palmitic acid (16:0 saturated), and 33% of stearic acid . Thought it is generally considered that saturated fats overall adversely increase the total cholesterol and LDL levels [21–23], early studies have also suggested stearic acid may be non-cholesterolemic [21, 22]. This has been confirmed in a series of studies and a meta-analysis of 60 controlled feeding trials which concludes stearic acid neither lowers HDL, nor increases LDL or total cholesterol [24–28]. The meta-analysis also estimates, that per 1% energy isocaloric replacement of stearic acid for carbohydrates, stearic acid intake is predicted to beneficially lower serum triglycerides by -17.0 nmol/L (p < 0.001) . The most recent trial also shows the effects of stearic acid on lipids is even similar to oleic and linoleic acids .
Emerging studies have begun to explain how stearic acid in chocolate may be cholesterol-neutral. One suggested mechanism is stearic acid's lower absorption, which has been found in several animal and human studies [30–33], though only minimally in others [34, 35]. These discrepancies may be attributed to the relative position of stearate on the triglyceride molecule which may affect its relative absorption rate [36, 37]. This might also explain the suggestion that stearic acid from plants sources, such as cocoa, may be different from animal derived sources of stearic acid . Furthermore, some feeding trials found lower absorption of cocoa buttered compared to corn oil , though not in others . However, heterogeneity may be due to the dual-presence of calcium in chocolate, in which other trials found cocoa butter absorption further decreased 13% when supplemented with calcium (1% by weight) , as is done in chocolate manufacturing. Finally, another strongly supported protective mechanism relate to the relatively high percent desaturation of stearic acid to monosaturated oleic acid [35, 42–45], a fat considered hypocholesterolemic [27, 46–48] and protective against coronary heart disease [3, 49].
Two other pathways suggested for potential benefit are stearic acid's potential anti-platelet and blood pressure reductions actions. Feeding trials have shown that stearic acid reduces mean platelet volume [50, 51], an index of platelet activation. However, mixed findings have been observed regarding the relationship between stearic acids and factor VIIc coagulation factor, a predictor of fatal CHD [52–54]. Though an early study suggested that stearic acid may increase factor VIIc , no effect on levels of factor VIIc by stearic acid was observed in two other trials [56, 57]. Moreover, additional trials have refuted the earlier small study and, in fact, shown that stearic acid lowered the levels of factor VIIc coagulation factor compared to palmitic [50, 58] and other saturated fatty acids . As for the relationship between stearic acid and blood pressure, two feeding trials found stearic acid did not adversely affect systolic blood pressure [28, 59]. Furthermore, cross-sectional analysis within the Multiple Risk Factor Intervention Trial even found stearic acid levels may be inversely associated with diastolic blood pressure .
In summary, given the vast majority of studies showing stearic acid has beneficial or neutral effects on blood pressures and clotting parameters, it appears unlikely stearic acid intake would adversely affect CVD risk through these risk factors. Data indicates stearic acid does not adversely affect established traditional lipid risk factors, with even favorable lowering of serum triglycerides if isocalorically replaced for carbohydrates.
Stearic Acid Observational Studies
Summary of Chocolate and Cocoa Feeding Trials
1 meal, pre/post-meal measurement
Cocoa (35 g delipidated), vs. none
Decreased LDL oxidation
1 meal, 2 & 6 hrs
Cocoa beverage (300 ml, 19 g procyanidin), caffeinated beverage (17 mg caffeine), or water
Decreased platelet activation, decreased platelet function
1 meal, 1 week/phase
Procyanidin-rich chocolate (27, 53, 80 g), vs. none
Increased antioxidant capacity, decreased oxidative stress
daily, 2 weeks
Cocoa powder (36 g/day), vs. sugar
Decreased LDL oxidation (increased lag time)
daily, 4 weeks/phase
Cocoa powder (22 g/day) + dark chocolate (12 g/day), vs. average American diet
Decreased LDL oxidation (increased lag time), Increased HDL concentration
1 meal, 2 & 6 hrs, 1 week/phase
Chocolate (35 g, high 4 mg/g vs. low 0.09 mg/g procyanidin)
Increased prostacyclin, decreased leukotriene (likely decreased platelet activation, anti-inflammatory)
1 meal, 2 hrs
Chocolate chips (25 g semi-sweet), vs. none
Decrease platelet function
daily, 6 weeks/phase
Dark chocolate (37 g/day), cocoa powder (31 g/day), vs. none
Decreased LDL oxidizability, marginal HDL increase
1 meal, 1 day/phase
Cocoa beverage (300 ml, 19 g flavanol cocoa powder), cocoa beverage + aspirin, or aspirin
Decreased platelet activation, decreased platelet function, all additive of aspirin effects.
1 meal, 1 day/phase
Cocoa beverages (100 ml, high or low flavan-3-ol)
Increased NO bioactivity, improved endothelial function
1 meal, 4 hrs
Dark (75% cocoa, highest flavonoid content), milk (20% cocoa), or white chocolate (no flavonoids)
Dark chocolate inhibited collagen-induced platelet aggregation
daily, 28 days
Cocoa flavonoid tablets (234 mg), vs. placebo
Decreased platelet function, no difference oxidation status
1 meal, 1 day/phase
Dark chocolate (100 g), dark chocolate (100 g) + milk (200 ml), or 200 g milk chocolate
Increase antioxidant capacity, in absence of milk
daily, 14 days/phase
Dark chocolate (100 g, 500 mg polyphenols), vs. white chocolate (90 g, 0 mg polyphenols)
Lower systolic and diastolic blood pressure with dark chocolate
1 meal, 1 week washout
High flavanol (1.87 mg/ml) vs. low flavanol (0.14 mg/ml) cocoa beverage
Lower levels of lipid peroxidation indicators with high flavanol cocoa beverage
daily, 2 weeks
Chocolate (high vs. low flavonoid)
Improved endothelial function, no difference oxidative stress, lipids with high flavonoid choc.
daily, 3 weeks
Dark chocolate, dark chocolate enriched with cocoa polyphenols, or white chocolate
Increased HDL concentration, no change LDL oxidizability
daily, 15 days/phase
Dark chocolate (100 g, 500 mg polyphenols), vs. white chocolate (90 g, 0 mg polyphenols)
Lower systolic blood pressure, improved insulin sensitivity, lower insulin resistance
1 meal, 1–2–4–8 hrs
Cocoa beverage (high flavonoid); 0.25, 0.38, 0.50 g/kg body weight dose
Reduced susceptibility to free-radical induced hemolysis
1 meal, 1 day/phase
Dark chocolate (100 g, 2.62 g procyanidin), vs. none
Improved endothelial function, vasodilation of brachial artery, no change in blood pressure
daily, 14 days
High flavanol milk chocolate (105 g, 168 mg flavanols) vs. low flavonoid chocolate (<5 mg flavanols)
Lower mean blood pressure, lower LDL cholesterol, lower oxidative stress markers in high flavanol chocolate group
Observational Studies of Stearic Acid and Cardiovascular Outcomes
Stearic acid assessment method
12,763 men, 16 cohorts of 7CS
↑ CHD mortality
Simon [68, 69]
96 cases, 96 controls, USA-MRFIT
↑ CHD incidence
50 men, Australia
↑ CAD progression
71 cases, 60 controls, Japan
80,082 women, USA-nurses
↑ CHD incidence
103 cases, 104 controls, Norway
↓ MI incidence
485 cases, 508 controls, Costa Rica
↑ MI incidence
3591 whites, USA
↑ CHD mortality
On the other hand, several limitations exist for observational studies of stearic acid. First, researchers have cautioned that analyses of dietary stearic acid are very difficult due to high correlations of stearic acid intake with other fatty acids (often r = 0.7 to 0.9), thus impeding optimal study of associations . Additionally, the larger prospective study that found higher risk of CHD also noted chocolate was a very small contributor (5%) of total stearic acid intake, with red meats as primary sources of stearic acid. Finally, since there exists high interconversion of stearic acid to unsaturated fatty acids [35, 42–45], studies involving serum levels of stearic acid do not answer the relevant causal question of dietary intake of stearic acid and risk of disease. The associations of long-term serum stearic acid levels represent the effects of post-conversion stearic acid levels after a large proportion of the original dietary stearic acid has already been converted away to monounsaturated fat, which is well-established to exert protective effects against CVD [3, 27, 46–49].
Thus, relatively little information can be inferred from observational studies of the association of stearic acid and CHD, and no epidemiologic study has, thus far, appropriately and optimally answered the causal question of the association of dietary stearic acid intake and risk of CVD. However, a sufficient body of strong evidence from short term randomized trials suggests stearic acid components in chocolate may be beneficial for cardiovascular health. However, further research in this area is warranted.
Flavonoids in chocolate
Chocolate flavonoids have shown good dose-response bioavailability in humans [11, 78, 79]. There exists several mechanisms of how flavonoids may be protective against CVD; these include: antioxidant, anti-platelet, anti-inflammatory effects, as well as possibly increasing HDL, lowering blood pressure, and improving endothelial function. The body of trials involving chocolate flavonoids is summarized in Table 1.
Central to the pathogenesis of atherosclerosis is the oxidation of low-density lipoprotein (LDL). The chemical structure of flavonoids gives the compound free radical scavenging ability, which means flavonoids may have antioxidant effects . Various studies have confirmed the role of flavanoids as antioxidants in biological systems. Flavanoids in chocolate have been shown to exert potent antioxidant effects in vitro assays under artificial oxidative stress [13, 81–84] as well increase antioxidant capacity as part of various chocolate feeding trials [79, 85–89]. Additionally, because lipid soluble flavonoids may intercalate into the membranes of lipoprotein particles, studies have shown flavonoids to decrease lipid peroxidation of biological membranes . Furthermore, a randomized trial also demonstrated that flavonoid-rich foods can protect human lymphocytes from oxidative damage in vivo .
Additionally, aggregation of platelets at the site of plaque rupture and endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis. Current research has shown that a number of components of chocolate, particularly catechin and epicatechin, have significant antiplatelet effects, quantitatively similar to that of aspirin . Randomized trials studying platelet activation markers, microparticle formation and primary platelet aggregation as end points have found that daily intake of cocoa beverages produces a significant reduction in all these endpoints among healthy volunteers [93–96]. There were also significant correlations between the reduction in these end points and the plasma concentrations of catechin and epicatechin [93–96]. Another study found a significant reduction in platelet activation in groups consuming 100 g of dark chocolate when compared to those consuming similar amounts of white chocolate and milk chocolate . In addition, randomized trials have also shown that consumption of high-flavanoid dark chocolate is associated with a significant improvement of endothelial function, marked by increase in brachial artery flow mediated dilation [98–100], likely mediated by chocolate flavonoids increasing local production of nitric oxide [99, 100].
Chocolate may also influence levels of leukotrienes and prostacyclins. Leukotrienes are potent vasocontrictors, proinflammatory agents and stimulate platelet aggregation, whereas prostacyclin is a vasodilator and inhibits platelet aggregation. Consumption of chocolate with high procyanidin content (147 mg) was shown in a feeding trial to significantly lower the levels of leukotrienes (29%) and increase the levels of prostacyclin (32%) when compared to a group consuming a low procyanidin (3.3 mg) chocolate . In vitro studies have indeed demonstrated chocolate components to inhibit lipoxygenase pathways, which gives rise to proinflammatory leukotrienes [102, 103]. Inflammation is now recognized as another independent mechanism in the pathogenesis of atherosclerosis, with various inflammatory markers having been shown to predict risk of future CVD events [104–108]. In addition to anti-inflammatory effects on the lipoxygenase pathway, cocoa polyphenols have also been shown to decrease inflammation via several mechanisms, namely: inhibition of mitogen induced activation of T cells, polyclonal activation of B cells, reduced expression of interleukin-2 (IL-2) messenger RNA, and reduced secretion of IL-2 by T cells Other have also found chocolate procyanidins can modulate of a variety of other cytokines (e.g. IL-5, TNF-α, TGF-β), reducing their inflammatory effects [110–114].
Furthermore, multiple cocoa feeding trials have also found chocolate to increase HDL cholesterol [85, 86, 115], and decrease blood pressure [116–119]. Finally, there are also suggestive findings in a few trials that indicate high-flavonoid chocolate may also lower LDL cholesterol , and improve insulin sensitivity .
Thus, the large body of evidence from laboratory findings and randomized trials suggest that high-flavonoid chocolate may protect against LDL oxidation, inhibit platelet aggregation, improve endothelial function, increase HDL, lower blood pressure, and reduce inflammation – thereby protective against risk of CVD.
Flavonoid Observational Studies
Mechanistic studies involving stearic acid and flavonoids have only assessed effects on intermediate cardiovascular endpoints. However, one cannot always assume effects from short term trials effects will necessarily translate into long term effects on CVD outcomes. Therefore, one needs to examine observational studies followed to CVD events. While one small study found moderate consumption of candy and chocolate was associated with lower all-cause mortality , this analysis neither isolates chocolate nor CVD events. Thus, in absence of specific studies of chocolate flavonoids and risk of CVD, studies of all flavonoids are the best available evidence to infer risk.
Prospective Studies of Flavonoids and Cardiovascular Outcomes
Hertog [125, 142]*, Keli 
552 to 806 Men, Dutch
5, then 10*
*Update 1997 analysis finds even stronger CHD association 
5133 M+W, Finland
34789 Men, USA
*marginal significance, if past history of CVD
1900 Men, UK
*marginal significance, *milk consumed w/tea
34492 PostM women, Iowa
Hirvonen [126, 129]
23596 Men, Finland
*suggestive, but non-significant
806 men, Dutch
34492 PostM women, Iowa
4807 M+W, Dutch
Total Tea Flavonoids
10054 M+W Finland
also ↓ type 2 diabetes
38445 women, USA
Total Flavonoids → CHD Mortality
RR = 0.81 (95% CI: 0.71–0.92)*
However, the most extensively consistent finding is the association between flavonoid intake and CHD mortality. A total of eight cohort studies found risk of lower CHD mortality with total or specific flavonoid intake [71, 121, 123, 125, 126, 128, 130–132], with one study finding marginally protective association among men with prior CVD conditions . Only one study reported absolutely no association between flavonoid intake and CHD mortality . However, as noted by the authors of one of the studies, a high background consumption of milk with tea intake may have led to the null finding , since milk intake has been shown to prevent the intestinal absorption of flavonoids .
A meta-analysis of the 7 prospective studies prior to September 2001 found that, overall, flavonoids may be protective against CHD mortality . However, this meta-analysis did not include a large subsequent cohort study of 38,445 women , which found a non-significant inverse association between flavonoid intake and CHD mortality. However, results from our updated meta-analysis still indicate a significant protective association exists between flavonoid intake and risk of CHD mortality, RR = 0.81 (95% CI: 0.71–0.92), comparing highest vs. lowest tertiles.
However, a limitation of inference exists in that flavonoids consists of a wide variety of polyphenol compounds, the variety of which may differ between studies due to varying sources of dietary flavonoids. Nonetheless, dark chocolate does contain substantially more flavanols than tea, apple, onions, and red wine . Additionally, chocolate has all the flavonoids of tea , has 4 times the catechins of tea , has many flavonoids not found in tea , and substantially contributes to the total flavonoid intake in the diet of many countries . However, inference from observational studies on the protective effect of flavonoids in chocolate on CVD risk is somewhat indirect and may need to be examined by further studies.
Overall, these epidemiologic findings, combined with the large body of evidence from short term randomized chocolate feeding trials, suggests flavonoid intake from chocolate is likely protective against CVD, particularly CHD mortality. Additionally, given that dark chocolate has substantially higher levels of flavonoids than milk chocolate, and that milk may inhibit absorption of flavonoids – it would be more prudent to consume high flavonoid dark chocolate rather than milk chocolate.
According to the International Cocoa Organization, production has risen from 1.2 million tons per year in 1960 to 3.2 million tons per year in 2004 . Given the rapidly increasing world consumption of chocolate and rising global rates of CVD, it is important to establish chocolate's association with CVD risk. The projected increase in global consumption could have profound effects if chocolate consumption does have implications for CVD.
Based upon our systematic review, multiple lines of evidence from laboratory experiments and randomized trials suggest stearic acid may be neutral, while flavonoids are likely protective against CVD, the latter of which is well supported by prospective observational studies that suggest flavonoids may lower the risk of CHD mortality. Though it has been approximated that eating 50 g of dark chocolate per day may reduce one's risk of CVD by 10.5% (95% CI: 7.0%–13.5%) , such crude estimates were based on results from studies of short duration, extrapolated to long term CVD outcomes. Therefore, the highest priority now is to conduct long-term randomized feeding trials, beyond short term studies of CVD risk factor intermediates, in order to definitively investigate the impact of chocolate consumption on cardiovascular outcomes.
Coronary heart disease
We'd like to thank Dr. Eric Rimm for his encouragement and support.
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