Chocolate and Coronary Heart Disease: A Systematic Review

Curr Atheroscler Rep (2011) 13:447 452 DOI 10.1007/s11883-011-0203-2 NUTRITION (WILLIAM S. HARRIS, SECTION EDITOR) Chocolate and Coronary Heart Disease: A Systematic Review Owais Khawaja & J. Michael Gaziano & Luc Djoussé Published online: 6 September 2011 # Springer Science+Business Media, LLC 2011 Abstract Coronary heart disease (CHD) is the leading cause of death in the United States. The high content of polyphenols and flavonoids present in cocoa has been reported to play an important protective role in the development of CHD. Although studies have demonstrated beneficial effects of chocolate on endothelial function, blood pressure, serum lipids, insulin resistance, and platelet function, it is unclear whether chocolate consumption influences the risk of CHD. This article reviews current evidence on the effects of cocoa/chocolate on clinical and subclinical CHD, CHD risk factors, and potential biologic mechanisms. It also discusses major limitations of currently available data and future directions in the field. O. Khawaja : J. M. Gaziano : L. Djoussé Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA, USA O. Khawaja e-mail: oajaz@yahoo.com J. M. Gaziano e-mail: JMGAZIANO@PARTNERS.ORG J. M. Gaziano : L. Djoussé Geriatric Research, Education, and Clinical Center (GRECC), Boston Veterans Affairs Healthcare System, Boston, MA, USA O. Khawaja : J. M. Gaziano : L. Djoussé (*) Divisions of Aging, Brigham and Women s Hospital and Harvard Medical School, 1620 Tremont St, OBC, 3rd floor, Boston, MA 02120, USA e-mail: ldjousse@rics.bwh.harvard.edu J. M. Gaziano Division of Preventive Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA, USA Keywords Chocolate. Cocoa. Flavanol. Polyphenols. Coronary heart disease. Blood pressure. Epicatechin. Catechin Introduction In the United States, approximately 19.2 million men and 8.4 million women have a history of heart attack, angina pectoris, or both [1]. In 2007, coronary heart disease (CHD) death rates per 100,000 people were about 165.6 for white men, 191.6 for black men, 94.2 for white women, and 121.5 for black women [2]. Numerous studies have demonstrated beneficial effects of lifestyle modification, such as diet and exercise, on the prevention of CHD [3 6]. The high content of polyphenols present in grains, fruits, vegetables, nuts, tea, and cocoa has been reported to play an important role in reducing the risk of CHD [7, 8]. Although the Dietary Approaches to Stop Hypertension (DASH) trial emphasized the importance of fruit and vegetables, whole grains, low-fat dairy products, and low sodium intake for cardiovascular health, limited data are available in the literature on the role of cocoa products, including chocolate, on CHD risk. Chocolate consists of a number of raw and processed foods derived from the seeds of the tree Theobroma cacao [9]. Cocoa was first introduced in Europe during the 16th century. Almost 75% percent of the world s cocoa bean production occurs in West Africa [9]. Cocoa-rich chocolate is well known for its good taste, and an average American consumes about 5.3 kg of chocolate per year [10]. Most of the chocolate is a combination of cocoa solids, cocoa butter or other fats, and sugar. Milk chocolate also contains milk powder or condensed milk, whereas white chocolate contains cocoa butter, sugar, and milk without any cocoa solids. Dark chocolate contains added fat and sugar to the cacao mixture.

448 Curr Atheroscler Rep (2011) 13:447 452 Cocoa products contain polyphenols and flavonoids. Catechins, including catechin and its isomer epicatechin, are types of flavonoids with strong anti-oxidant properties [11]. Cocoa contains high concentrations of epicatechin and has been noted to have anti-oxidant content that is two times higher than that of red wine and almost three times higher than that of green tea [12]. Gu et al. [13] demonstrated that milk chocolate contains 5 to 12 mg of catechin per 100 g, 18 to 24 μg of epicatechin per 100 g, and 0.22 to 0.31 mg of procyanidins per 100 g; for dark chocolate, the corresponding concentrations were 11 to 33 mg, 52 to 125 μg, and 0.85 to 1.99 mg per 100 g, respectively. Chocolate also contains important minerals such as potassium, zinc, selenium, and magnesium along with other nutrients including vitamin E, saturated fat (60%), monounsaturated fat (35%), and linoleic acid (3%) that might lower the risk of CHD [7, 14]. Despite available knowledge on nutrients contained in cocoa products, there are limited data on the effects of chocolate on clinical and subclinical CHD. Hence, this review first evaluates available data on the effects of cocoa on clinical and subclinical CHD, CHD death, CHD risk factors, and potential biologic mechanisms. Then, it discusses major limitations of currently available data and future directions in the field. Chocolate Consumption and Coronary Heart Disease Although studies have demonstrated beneficial effects of chocolate on various CHD risk factors, including endothelial function [15 17], blood pressure (BP) [18, 19], serum lipids [20, 21], insulin resistance [18, 22], and platelet function [23, 24], little is known about the effects of chocolate on CHD events. We summarized studies that have examined associations between chocolate/cocoa consumption and CHD prevalence, cardiovascular disease (CVD), and all-cause mortality in Table 1. In a cross-sectional study, Djousse et al. [25 ] reported an inverse relation between chocolate consumption and prevalent CHD in 4,970 participants of the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Self-reported chocolate consumption was inversely associated with the prevalence of CHD with an odds ratio (OR) of 1.01 (95% CI, 0.76 1.37), 0.74 (95% CI, 0.56 0.98), and 0.43 (95% CI, 0.28 0.67) for chocolate consumption of 1 to 3 times per month, 1 to 4 times per week, and 5 times per week, respectively. In another prospective cohort study, Lewis et al. [26 ] reported that chocolate consumption of 1 time per week was associated with a 35% lower risk of CHD compared with intake of <1 time per week (multivariable adjusted relative risk of 0.65 [95%CI, 0.46 0.94]). Chocolate Consumption and Subclinical Coronary Heart Disease Shiina et al. [27] in a single-blinded, randomized trial, studied the effects of flavonoid- rich dark chocolate among 39 healthy men by measuring coronary flow velocity reserve (CFVR) via noninvasive transthoracic Doppler echocardiography (TTDE). Flavonoid-rich dark chocolate consumption was noted to improve CFVR (3.38±0.49 before and 4.28± 0.85 after dark chocolate intake; P<0.01), whereas there was no significant change noted in CFVR among those with white chocolate consumption (3.28±0.49 before and 3.16± 0.49 after white chocolate intake; P=0.44), independent of changes in the BP, lipid profile, or other oxidative stress parameters. In a cross-sectional study, Djousse et al. [28 ] demonstrated an association between chocolate consumption and calcified atherosclerotic plaques in coronary arteries (CAC) in 2,217 participants of the NHLBI Family Heart Study. They found an inverse association between chocolate consumption and CAC with an OR of 0.94 (95% CI, 0.66 1.35), 0.78 (95% CI, 0.53 1.13), and 0.68 (95% CI, 0.48 0.97) for chocolate consumption of 1 to 3 times per month, once per week, and 2 times per week, respectively, compared to no chocolate intake as the reference group. Chocolate Consumption and Coronary Heart Disease Mortality Janszky et al. [29 ] observed a strong inverse association between chocolate consumption and mortality in post myocardial infarction patients for people with chocolate consumption of less than once per month, up to once per week, and twice or more per week, (HR of 0.73 [95% CI, 0.41 1.31), 0.56 [95% CI, 0.32 0.99], and 0.34 [95% CI, 0.17 0.70], respectively). The Iowa Women s Health Study reported an inverse association between catechin and epicatechin intake and CHD mortality in post-menopausal women after 13 years of follow-up [30]. In another study, Buijsse et al. [31] reported a relative risk (RR) of 0.50 (95% CI, 0.32 0.78) for cardiovascular mortality and an RR of 0.53 (95% CI, 0.39 0.72) for all-cause mortality in elderly men when comparing the highest to the lowest tertile of cocoa intake. Mink et al. [32] demonstrated a lower risk of CHD, CVD, and total mortality (RR 0.88 [95% CI, 0.78 0.99], 0.91 [95% CI, 0.83 0.99], and 0.90 [95% CI, 0.86 0.95], respectively) for those consuming any anthocyanidin versus none; an RR of 0.90 (95% CI, 0.86 0.95) for incident CHD, and 0.88 (95% CI, 0.82 0.96) for total mortality comparing the highest to the lowest quintile of flavanone consumption among post-menopausal women. A similar pattern of decreased cardiovascular-related death rates among those consuming flavanol-rich cocoa as their

Curr Atheroscler Rep (2011) 13:447 452 449 Table 1 Chocolate/cocoa and coronary heart disease mortality Study Variables studied Study design Participants OR (95% CI), RR (95% CI), or HR Djousse et al. [25 ] (NHLBI Family Heart Study) Lewis et al. [26 ] Shiina et al. [27] Djousse et al. [28 ] (NHLBI Family Heart Study) Janszky et al. [29 ] (Stockholm Heart Epidemiology Program) Buijsse et al. [31] (Zutphen Elderly Study) Bayard et al. [33] Chocolate consumption and prevalent CHD Chocolate consumption and ASVD Acute effect of flavonoid-rich dark chocolate on coronary circulationbyttde Chocolate consumption and CAC Chocolate and mortality following first AMI Cocoa intake and CVD mortality Effect of flavonol-rich cocoa beverage on mortality Cross-sectional 4,970 OR: 1.01 (0.76 1.37), 0.74 (0.56 0.98), and 0.43 (0.28 0.67) for subjects consuming 1 3/month, 1 4/week, and 5+/week, respectively (P for trend <0.0001) Cohort study 1,216 OR: 0.76 (0.60 0.97) with an event rate of 158 (27.3%) versus 132 (20.7%) for chocolate consumption <1/week versus 1/week, respectively Randomized, single blind 35 CFVR of 3.38±0.49 before intake, 4.28±0.85 after intake for dark chocolate (P<0.01) vs 3.28±0.49 before intake, 3.16±0.49 after intake for white non-flavonoid chocolate (P=0.44) Cross-sectional 2,217 OR: 0.94 (0.66 1.35), 0.78 (0.53 1.13), and 0.68 (0.48 0.97) for chocolate consumption of 0, 1 3/month, 1/week, and 2+/week, respectively (P for trend 0.022) Cohort study 1,169 HR: 0.73 (0.41 1.31), 0.56 (0.32 0.99), and 0.34 (0.17 0.70) for chocolate consumption of <1/month, 1/week, and 2/week, respectively Prospective study 470 RR for men in the highest tertile was 0.50 (0.32-0.78; P=0.004 for trend) for cardiovascular mortality and 0.53 (0.39 0.72; P<0.001) for all-cause mortality Case control study 77,375 in Panama and 548 in San Blas Mean age-adjusted death rate/100,000 over 5 years due to CVD (8.7±3.02) was much lower in exposed vs non-exposed group (43.94±0.64) AMI acute myocardial infarction; ASVD atherosclerotic vascular disease; CAC calcified atherosclerotic plaques in coronary arteries; CFVR coronary flow velocity reserve; CHD coronary heart disease; CVD cardiovascular disease; HR hazard ratio; NHLBI National Heart, Lung, and Blood Institute; OR odds ratio; RR relative risk; TTDE trans-thoracic Doppler echocardiography main beverage were also noted in an observational study by Bayard et al. [33]. Potential Biological Mechanisms of Chocolate Consumption and Coronary Heart Disease Chocolate contains antioxidants that can scavenge free radicals and reduce oxidative stress, thereby reducing the risk of CHD [34]. Polyphenols may improve endothelial function. The mechanism may involve polyphenol-induced nitric oxide (NO) synthesis via redox-sensitive activation of the phosphatidylinositol3-kinase/akt pathway; an alternative mechanism could be an increased intracellular free calcium concentration and activation of endothelial estrogen receptors [15]. Increased endothelial NO production leads to endothelium-dependent relaxation [16, 17, 35]. In a randomized, controlled, double-blind, cross-over trial [36], there was a 47% improvement of endothelial vasomotor function in the high-flavanol group compared with the low-flavanol group after 1 month of intervention in 16 CHD patients. There was also an increased number of endothelial progenitor cells, which are critical for repair of vasculature and endothelial function, along with a decrease in systolic blood pressure among subjects in the high-flavanol group compared with people in the low-flavanol group [36]. Epicatechin at low doses has also been shown to reduce myocardial infarct size in mice [37]. Chocolate Consumption and Coronary Heart Disease Risk Factors Chocolate Consumption and BP Flavanol-rich chocolate and cocoa products have BP-lowering effects and thereby have gained interest as a non-pharmacologic treatment option for hypertension [38, 39]. Grassi et al. [18] studied the effects of flavanol-rich dark chocolate on BP in hypertensive patients with impaired glucose tolerance. They noted a 3.83-mm Hg decrease in systolic and 3.92-mm Hg decrease in diastolic BP among those who received flavanolrich dark chocolate compared with subjects assigned to flavanol-free white chocolate. However, another trial [40]

450 Curr Atheroscler Rep (2011) 13:447 452 failed to observe any beneficial effects of 50 g/d of dark chocolate containing 70% cocoa on BP. In another study, Persson et al. [41] showed that dark chocolate significant inhibited angiotensin-converting enzyme activity and increased NO in human endothelial cells (P<0.01). As reviewed in a meta-analysis [19], there was a significant BP-lowering effect for cocoa/chocolate with a mean change in systolic BP of 3.2±1.9 mmhg and diastolic BP of 2.0±1.3mmHg(P=0.003). Chocolate Consumption and Serum Lipids Chocolate consumption has been shown to lower plasma cholesterol. Grassi et al. [18] reported that dark chocolate was associated with a decrease in total cholesterol ( 6.5%; P<0.0001) and low-density lipoprotein (LDL) cholesterol ( 7.5%; P<0.0001). No effect of dark chocolate was observed on the concentrations of serum high-density lipoprotein (HDL) cholesterol or triglycerides (TG). Mellor et al. [21] also demonstrated a cholesterol-lowering effect of polyphenol-rich chocolate along with an increase of HDL cholesterol (1.16±0.08 vs 1.26±0.08 mmol/l; P=0.05) and no effect on markers of inflammation, insulin resistance, or weight. Jia et al. [20], in their meta-analysis, demonstrated that short-term chocolate consumption lowered LDL cholesterol by 5.87 mg/dl and total cholesterol by 5.82 mg/dl. The changes seen were highly dependent on the dose of cocoa consumption and health status of the patients, with no effects observed in healthy participants. In a recent meta-analysis by Tokede et al. [42 ], intervention with dark chocolate was associated with a statistically significant reduction in serum LDL ( 5.90 [95% CI, -10.47 to 1.32] mg/dl) and total cholesterol ( 6.23 [95% CI, 11.60 to 0.85] mg/dl). However, no statistically significant effect was seen on serum HDL ( 0.76 [95% CI, 3.02 to 1.51] mg/dl) or triglyceride ( 5.06 [95% CI, 13.45 to 3.32] mg/dl). The observed effect was stronger in subjects with high cardiovascular disease risk and in studies with a shorter duration of follow-up. Chocolate Consumption and Insulin Resistance Grassi et al. [18], in their interventional study, found that flavanol-rich dark chocolate led to a decreased insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]; P<0.0001), enhanced insulin sensitivity (Insulin Sensitivity Index [ISI], ISI(0); P<0.05) as well as improved beta-cell function (P=0.035); in contrast, flavanol-free white chocolate had no effects. In another study, Davison et al. [22] found that an intervention with high flavanol led to a 0.31% reduction in HOMA-IR. Comparable findings have been reported in other studies and suggest beneficial effects of flavanol- rich compounds on cardiovascular disease risk factors [43]. Chocolate Consumption and Inflammatory Markers di Giuseppe et al. [44] reported a J- shaped association between dark chocolate and C-reactive protein levels. A beneficial effect of cocoa powder on inflammatory markers (expression of VLA-4, CD40, and CD36 in monocytes, as well as serum concentrations of endothelium-derived adhesion molecules P-selectin and intracellular adhesion molecule-1) has been reported by other investigators [45]. These results underscore the potential benefits of cocoa polyphenols in the modulation of inflammatory mediators. Chocolate Consumption and Platelets Cocoa products have been shown to exert an inhibitory effect on platelet aggregation in various studies [23, 46, 47]. Potential mechanisms include reduced ADP/collageactivated platelet-related primary hemostasis, possibly due to a reduction in activated glycoprotein IIb/IIIa surface proteins [23]. Innes et al. [24] reported a reduction in platelet aggregation after consumption of 100 g of dark chocolate among healthy volunteers. Stearic acid, commonly found in chocolate, has also been shown to reduce mean platelet volume, which serves as an index of platelet activation among humans [48]. Major Limitations of Current Data on Chocolate and Coronary Heart Disease Although chocolate consumption has been shown to be associated with a number of beneficial effects on CHD, there are several gaps in the current literature. Most of the trials conducted were short term, making it difficult to assess long-term effects of chocolate on CHD and other cardiovascular endpoints. Limited prospective studies have been conducted to assess long-term effect of dark chocolate and account for dietary change over time. Few epidemiologic studies have separated dark from milk chocolate, suggesting that observed beneficial effects of total chocolate might have underestimated the true relation between dark chocolate and cardiovascular endpoint/risk factors. At this point, it is unclear what amount of chocolate is optimal given the lack of uniformity in dosage in randomized trials. Most of the studies conducted did not specify the exact type or amount of chocolate used in individual studies. Likewise, limited data are available on polyphenolic content in chocolate or cocoa used in intervention studies. Lastly, there was heterogeneity in the quality of studies reviewed, making it more difficult to interpret the data.

Curr Atheroscler Rep (2011) 13:447 452 451 Future Perspectives Further research is needed to better elucidate the underlying physiologic mechanisms by which chocolate/cocoa powder favorably influence the risk of CHD. Special attention will need to be given to potential confounding by other dietary or lifestyle factors, especially in observational studies. Future studies should carefully consider the dosage, polyphenol content, type, duration, and frequency of cocoa/chocolate consumption. With steady progress in genomics, proteomics, transcriptomics, and other areas, future studies may consider the role of genetics and gene-environment interaction on the beneficial effects of chocolate/cocoa on CHD. Increased caloric intake with cocoa consumption in the form of chocolate, due to addition of fats, milk, or sugar, will also need to be analyzed in future studies (as supplemental calories from chocolate may lead to weight gain if consumed in larger amounts). Longterm, double-blind, randomized controlled trials with hard clinical endpoints are needed before recommending cocoa or its products as a treatment option in patients with high risk for CHD or for healthy individuals. In the meantime, it would be safer to consume dark chocolate only in moderate amounts (ie, as substitute for sugared candy) while keeping track of the overall daily energy intake. Conclusions Based on the available data from observational and interventional studies, there is ample evidence in support of beneficial effects of cocoa/dark chocolate on CHD risk. Future studies are needed to confirm current data and elucidate underlying physiologic mechanisms and identify the optimum daily dosage. Disclosure O. Khawaja: none; J.M. Gaziano: none; L. Djoussé s institution received an investigator-initiated grant. References Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Heart Attack and Angina Statistics. 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