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© 2007 American Society for Nutrition J. Nutr. 137:1436-1441, June 2007

Nutrition and Disease

Plasma LDL and HDL Cholesterol and Oxidized LDL Concentrations Are Altered in Normo- and Hypercholesterolemic Humans after Intake of Different Levels of Cocoa Powder1

Seigo Baba2,*, Midori Natsume2, Akiko Yasuda2, Yuko Nakamura2, Takaaki Tamura3, Naomi Osakabe3, Minoru Kanegae2 and Kazuo Kondo4

2 Food and Health R&D Laboratories, Meiji Seika Kaisha Ltd., Saitama, 350-0289 Japan; 3 Strategic Information and Ingredient Development Department, Healthcare and Provisions Division, Meiji Seika Kaisha Ltd., Saitama, 104-8002 Japan; and 4 Institute of Environmental Science for Human Life, Ochanomizu University, Tokyo, 112-8610 Japan

* To whom correspondence should be addressed. E-mail: seigo_baba{at}meiji.co.jp.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Cocoa powder is rich in polyphenols, such as catechins and procyanidins, and has been shown in a variety of subject models to inhibit oxidized LDL and atherogenesis. Our study evaluated plasma LDL cholesterol and oxidized LDL concentrations following the intake of different levels of cocoa powder (13, 19.5, and 26 g/d) in normocholesterolemic and mildly hypercholesterolemic humans. In this comparative, double-blind study, we examined 160 subjects who ingested either cocoa powder containing low-polyphenolic compounds (placebo-cocoa group) or 3 levels of cocoa powder containing high-polyphenolic compounds (13, 19.5, and 26 g/d for low-, middle-, and high-cocoa groups, respectively) for 4 wk. The test powders were consumed as a beverage after the addition of hot water, twice each day. Blood samples were collected at baseline and 4 wk after intake of the test beverages for the measurement of plasma lipids. Plasma oxidized LDL concentrations decreased in the low-, middle-, and high-cocoa groups compared with baseline. A stratified analysis was performed on 131 subjects who had a LDL cholesterol concentrations of ≥3.23 mmol/L at baseline. In these subjects, plasma LDL cholesterol, oxidized LDL, and apo B concentrations decreased, and the plasma HDL cholesterol concentration increased, relative to baseline in the low-, middle-, and high-cocoa groups. The results suggest that polyphenolic substances derived from cocoa powder may contribute to a reduction in LDL cholesterol, an elevation in HDL cholesterol, and the suppression of oxidized LDL.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Intervention trials and prospective studies have shown that hypercholesterolemia, especially increased concentrations of LDL cholesterol, leads to the development of atherosclerosis (1,2). In contrast, prospective studies have demonstrated a negative correlation between plasma HDL cholesterol and cardiovascular disease (3). There is also evidence that oxidized LDL has a pathogenic role in the development of atherosclerosis (4). Uptake of oxidized LDL by macrophages and smooth muscle cells leads to the formation of fatty streaks, a key event in early atherosclerosis. These vascular lesions accumulate large amounts of lipids such as cholesterol ester. These findings suggest that improvement in LDL and HDL cholesterol and inhibition of oxidized LDL concentrations may result in the prevention of atherosclerotic lesions.

Prospective studies have demonstrated a negative correlation between the consumption of plant polyphenols and mortality from both coronary and ischemic heart diseases (5–7). Studies in both rats and humans also reported that intake of these polyphenols suppressed LDL cholesterol concentrations and susceptibility of LDL to oxidation and increased HDL cholesterol concentrations (8–10).

A systematic review indicates that cacao may have beneficial effects on human health and protects against cardiovascular disease (11). Cacao beans are used as an ingredient in cocoa and chocolate and are known to be rich in polyphenols, such as catechin, epicatechin, procyanidin B2 (dimer), procyanidin C1 (trimer), cinnamtannin A2 (tetramer), and other oligometric procyanidins (12). In previous studies, we showed that the intake of polyphenolic-rich fractions derived from cocoa powder increased the resistance of LDL to oxidation and suppressed the formation of atherosclerosis in hypercholesterolemic rabbits (13). Studies we carried out in healthy human subjects also showed a decrease in LDL cholesterol concentrations, increases in HDL cholesterol concentrations, and a resistance of LDL to oxidation following the intake of dairy cocoa powder (14,15).

To further delineate the role of cocoa powder in atherogenesis protection, we examined the effects of different intake levels of cocoa powder on plasma concentrations of LDL cholesterol, HDL cholesterol, and oxidized LDL in normocholesterolemic and mildly hypercholesterolemic human subjects.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Materials. Cocoa powder was prepared by roasting, cracking, and compressing fermented and dried cacao beans imported from Ecuador. The catechin, epicatechin, procyanidin B2, and procyanidin C1 content in the powder was measured as epicatechin equivalent values by a partially modified HPLC method (12). Other reagents used in the study were analytical and HPLC grade, commercially available products of analytical and HPLC grade.

    Subjects. One hundred and sixty healthy Japanese male (n = 69) and female (n = 91) subjects participated in the study. The eligibility criteria were as follows: 1) age 20–70 y; 2) total cholesterol in the range 5.01–7.89 mmol/L; 3) HDL cholesterol ≤2.07 mmol/L; 4) no use of antihyperlipidemic drugs; 5) no regular consumption of supplements affecting lipid metabolism; 6) alcohol consumption ≤25 g/d; 7) no extreme exercise habits; 8) no history of diabetes, renal disease or hepatic disease; 9) no familial hyperlipidemia; 10) no pregnancy or planned pregnancy. The study was approved by and performed under the guidelines of the ethics committee of the Hirokuni Clinic, with informed consent being obtained from each of the subjects prior to commencement of the study. At baseline, the characteristics of the study group were: 49 ± 9 y of age, body weight 64.4 ± 12.6 kg, BMI 24.2 ± 3.5 kg/m2, plasma total cholesterol 6.14 ± 0.68 mmol/L, LDL cholesterol 3.91 ± 0.63 mmol/L, and HDL cholesterol 1.50 ± 0.31 mmol/L.

    Experimental design. Because plasma cholesterol was the main physiological indicator in this study, the subjects were divided into 4 groups, according to plasma total, LDL, and HDL cholesterol concentrations, to ensure that the level of these indicators in the 4 groups were similar. The subjects were then instructed to consume 1 of the following test powders daily for 4 wk: 1) a mixture of 26 g placebo cocoa (mixture of nutrient components of cocoa flavor) and 12 g/d sugar (placebo-cocoa group); 2) a mixture of 13 g of cocoa powder containing high-polyphenolic compounds, 12 g placebo cocoa, and 12 g/d sugar (low-cocoa group); 3) a mixture of 19.5 g of cocoa powder containing high-polyphenolic compounds, 6.5 g placebo cocoa, and 12 g/d sugar (middle-cocoa group); 4) a mixture of 26 g of cocoa powder containing high-polyphenolic compounds and 12 g/d sugar (high-cocoa group) (Table 1). A small amount of cocoa powder containing low-polyphenolic compound was added to the placebo cocoa to provide a cocoa flavor. The nutritional components, such as carbohydrate, fat, protein, dietary fiber, and caffeine in the placebo cocoa and in cocoa containing high-polyphenolic compounds were adjusted to the same levels. The test powders were consumed as a beverage after the addition of hot water, and the test drinks were consumed twice each day, before noon and during the afternoon. At baseline and at 4 wk, the subjects fasted for 12 h, and then blood samples were collected from the intermediate cubital vein into a tube. Body weight, blood pressure, and heart rate were also measured at the beginning and end of the study. Morning urine samples were collected at baseline, 2 wk and 4 wk and used for the qualitative analysis by HPLC (16) of catechins, caffeine and theobromine, for the purpose of checking the consumption of the test powders. To ensure that the same dinners were consumed by all the subjects, we arranged home deliveries to each subject 1 wk before consumption of the test powders and during the 4-wk study period. We also gave clear guidance on the need for the subjects to maintain their normal diets for breakfast, lunch, drinks, and incidental foods. In addition, to check that the normal diets had been maintained, the subjects kept complete dietary records throughout the study. The 3-d food records were analyzed with the Excel FFQ (Kenpakusha) on d –3 to –1, 11 to 13, and 25 to 27 of each dietary period. The subjects were also advised to avoid any supplements and all other cacao products and to lead their usual lifestyle throughout the study.


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  		TABLE 1 Composition of the daily intake test powders

 
    Plasma lipids and oxidative LDL. The concentrations of plasma total, LDL, and HDL cholesterol, triacylglycerol, apo A1, apo A2 and apo B at baseline and at 4 wk were assayed using automated systems (H-7700, Hitachi High-Technologies).

The monoclonal antibody, DLH3, was used to quantify the concentration of oxidized LDL in plasma at baseline and at 4 wk (17). This assay was carried out using a commercially available ELISA kit (MX, Kyowa Medex) according to the manufacturer's instructions.

    Statistics. All the statistical analyses were performed using SPSS for Windows, version 12.0J (SPSS Japan). A 1-way ANOVA was used to compare the baseline data of the 4 groups and if there was no difference observed between the groups, group x time interactions were analyzed using repeated-measures ANOVA. Comparisons within each group over time were carried out using paired, 2-tailed t tests. A stratified analysis of plasma lipids was also performed that included 131 subjects who had LDL cholesterol concentrations ≥3.23 mmol/L at baseline. If a variable was not normally distributed, the data were logarithmically transformed prior to analysis. The data are expressed as means ± SD. Significance was determined at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Subject characteristics and dietary records. BMI, systolic and diastolic blood pressure, and heart rate did not differ among the 4 groups at baseline. No subject reported adverse events resulting from cocoa intake at the interviews conducted throughout the study. The groups also did not differ in daily energy and nutrient intakes during the 3-d periods that dietary records were collected (Table 2).


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  		TABLE 2 Daily energy and nutrient intakes of the participants1

 
    Plasma lipids. The baseline plasma lipid concentrations did not differ among the 4 groups (Table 3). The concentrations of LDL cholesterol did not change within a group or differ among the groups during the study. However, the stratified analysis of subjects with baseline LDL cholesterol concentrations ≥3.23 mmol/L showed that LDL cholesterol concentrations at 4 wk were significantly lower than at baseline in the low-, middle-, and high-cocoa groups. The concentrations of apo B at 4 wk were significantly lower than at baseline in the middle- and high-cocoa groups in the analysis of all the subjects, and were significantly lower than at baseline in the low-, middle-, and high-cocoa groups in the LDL stratified analysis. The concentrations of HDL cholesterol at 4 wk were significantly higher than at baseline in all 4 groups in the analysis of all the subjects, and were significantly higher than at baseline in the low-, middle-, and high-cocoa groups in the LDL stratified analysis.


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  		TABLE 3 Plasma cholesterol, triacylglycerol, and lipoprotein concentrations in normo- and hypercholesterolemic subjects before and after 4 wk of consuming various levels of cocoa powder1

 
    Plasma oxidized LDL. The plasma concentrations of plasma oxidized LDL at baseline did not differ among the 4 groups Table 4. Analysis of all the subjects and the LDL stratified analysis both indicated that concentrations of oxidized LDL, expressed as kU/L plasma, at 4 wk were significantly lower than at baseline in the low-, middle-, and high-cocoa groups. The concentrations of oxidized LDL, expressed as U/µmol LDL cholesterol, were significantly lower at 4 wk than at baseline in the low- and middle-cocoa groups in the analysis of all subjects, and were significantly lower than at baseline in the middle- and high-cocoa groups in the LDL stratified analysis.


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  		TABLE 4 Plasma oxidized LDL in the 4 study groups at baseline and at 4 wk1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
The results of this study showed that consumption of cocoa powder at a dosage of ≥13 g/d for 4 wk decreased the concentrations of plasma LDL cholesterol and oxidized LDL, in addition to increasing baseline plasma HDL cholesterol concentrations in mildly hypercholesterolemic humans. These effects were especially evident in subjects who had a baseline LDL cholesterol concentration ≥3.23 mmol/L.

Previous studies report that polyphenol-rich cocoa and chocolate reduce LDL cholesterol in humans. In an earlier study, we found that consumption of 26 g/d of cocoa powder for 12 wk reduced plasma LDL cholesterol by 11% in healthy men (14). We calculated that consumption of 26 g of cocoa powder provided an intake of 459 µmol (133 mg)/d of epicatechin and catechin. A similar study in healthy subjects carried out by Fraga et al. (18) showed that an intake of 105 g/d of milk chocolate for 14 d also decreased plasma LDL cholesterol by 15% compared with baseline values. The milk chocolate provided 134 µmol (39 mg)/d of epicatechin and catechin. In addition, Grassi et al. (19) reported that consumption of 100 g/d of dark chocolate for 15 d, in patients with essential hypertension, reduced plasma LDL cholesterol by 12% compared with baseline values. The dark chocolate provided 303 µmol (88 mg)/d of epicatechin and catechin (19). In the present study, a reduction in LDL cholesterol concentrations of between 4.4 to 5.0% occurred following the intake of ≥13 g/d of cocoa powder compared with baseline in subjects with baseline LDL cholesterol concentrations ≥3.23 mmol/L. We calculated that the consumption of cocoa powder provided 279–562 µmol (81–163 mg)/d of epicatechin and catechin. These different results may have been caused by inconsistencies in the experimental conditions, such as variability in the ingredients or habits of the subjects, or differences in ethnicity and analytical conditions. However, in general, the earlier reports support our finding of a reduction in LDL cholesterol at doses of polyphenolic compounds similar to those used in our study.

The LDL cholesterol-lowering effect in plasma has been demonstrated for various polyphenols, including tea catechins, genistein, daizein, naringenin, hesperetin, and polyphenols in red wine (8,20–22). These polyphenols have the ability to 1) inhibit cholesterol absorption in the digestive tract, 2) inhibit LDL biosynthesis by lowering the activity and/or expression of hydroxymethylglutaryl-CoA synthase, hydroxymethylglutaryl-CoA reductase, acyl CoA:cholesterol acyltransferase, and microsomal transfer protein in the liver, 3) suppress hepatic secretion of apolipoprotein B100 and 4) increase expression of LDL receptors in the liver. In a previous study, we showed that the intake of polyphenolic-rich fractions derived from cocoa powder decreased plasma cholesterol concentrations and increased fecal excretion of cholesterol in high cholesterol–fed rats, and also that procyanidins dose-dependently reduced micellar solubility of cholesterol (N. Osakabe and M. Yamagishi, unpublished data). These mechanisms may also apply to polyphenols in cocoa powder in humans, although further studies are required to confirm this possibility.

In this study, daily consumption of cocoa powder for 4 wk reduced not only the concentration of oxidized LDL expressed as kU/L plasma, but also the concentration of oxidized LDL expressed as U/µmol LDL cholesterol. There are numerous reports on the in vitro and in vivo antioxidative activity of polyphenolic substances extracted from cacao. Previous studies showed that intake of polyphenolic-rich fractions derived from cocoa powder increased the resistance of oxidized LDL in hypercholesterolemic rabbits (13). Studies in humans also showed similar results, with the intake of cocoa and chocolate being associated with a reduction in the susceptibility of LDL to oxidation (23–25). These results suggest that the reduction in the concentrations of oxidized LDL in plasma may not result from a reduction in LDL cholesterol but rather from a protective effect against the susceptibility of LDL to oxidation.

In a previous study on the consumption of cocoa powder, we observed a negative correlation between plasma oxidized LDL and urinary epicatechin (15). This result suggested that polyphenols from cocoa powder may contribute to the resistance of LDL to oxidation. In this regard, it has been reported that polyphenols, such as catechin and quercetin, may be incorporated onto the surface of LDL particles, and that these polyphenols increase the resistance of oxidized LDL by either scavenging chain-initiating oxygen radicals or chelating transitional metal ions (26,27).

In this study, consumption of cocoa powder increased the concentration of HDL cholesterol compared with baseline. Previous studies also reported that polyphenol-rich dark chocolate and cocoa powder increased plasma HDL cholesterol (15,28). In an earlier study we also observed a positive correlation between urinary catechin excretion and plasma HDL cholesterol (15). These findings suggest that absorbed polyphenolic substances in cocoa powder, such as catechins, may affect plasma HDL cholesterol concentration. Intake of flavonoids other than catechins was also shown to increase plasma HDL concentration in both humans and animals (10,29,30). The mechanism(s) by which polyphenolic compounds elevate plasma HDL cholesterol concentrations remains unclear. Lamon-Fava et al. (31,32) showed that the increase and regulation of apolipoprotein A1 expression induced by genistein was mediated by the mitogen-activated protein kinase signaling pathway.

Cocoa powder contains caffeine and theobromine. In this study, the nutritional components, such as carbohydrate, fat, protein, fiber, and caffeine, in the placebo cocoa and cocoas containing high-polyphenolic compounds were adjusted to the same levels. However, the control beverage was adjusted to control for the theobromine content of the cocoa group drink. Wan et al. (25) reported that cocoa powder and chocolate had favorable effects on LDL oxidative susceptibility and HDL cholesterol concentrations in comparison with a diet that was controlled for fat, protein, carbohydrate, cholesterol, fiber, caffeine, and theobromine contents. This result indicates that polyphenolic compounds from cocoa powder and chocolate may contribute to these favorable effects.

There are numerous reports that improvement in LDL and HDL cholesterol concentrations and inhibition of oxidized LDL may reduce the development of atherosclerotic lesions. Our study demonstrated that the daily intake of cocoa powder at a dosage of ≥13 g/d for 4 wk had favorable effects on LDL and HDL cholesterol and oxidized LDL concentrations in plasma, especially in subjects with LDL cholesterol concentrations ≥3.23 mmol/L. Because polyphenolic substances derived from cocoa powder contribute to these effects, we suggest that the intake of polyphenol-rich foods, such as cocoa, tea, wine, fruit, and vegetables should lead to a decrease in the incidence of atherosclerotic disease. Moreover, the consumption of a balanced daily diet is important for the promotion of human health.


   FOOTNOTES
 
1 Author disclosures: S. Baba, M. Natsume, A. Yasuda, Y. Nakamura, T. Tamura, N. Osakabe, M. Kanegae, and K. Kondo, no conflicts of interest. Back

Manuscript received 10 January 2007. Initial review completed 22 February 2007. Revision accepted 5 April 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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