http://informahealthcare.com/ijf ISSN: 0963-7486 (print), 1465-3478 (electronic) Int J Food Sci Nutr, Early Online: 1–5 ! 2015 Informa UK Ltd. DOI: 10.3109/09637486.2015.1007453
RESEARCH ARTICLE
Coffee bean polyphenols ameliorate postprandial endothelial dysfunction in healthy male adults Ryuji Ochiai1, Yoko Sugiura1, Kazuhiro Otsuka1, Yoshihisa Katsuragi1, and Teruto Hashiguchi2 Health Care Food Research Laboratories, Kao Corporation, Tokyo, Japan and 2Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Abstract
Keywords
To reveal the effect of coffee bean polyphenols (CBPs) on blood vessels, this study aimed to investigate the effect of CBPs on acute postprandial endothelial dysfunction. Thirteen healthy non-diabetic men (mean age, 44.9 ± 1.4 years) consumed a test beverage (active: containing CBPs, placebo: no CBPs) before a 554-kcal test meal containing 14 g of protein, 30 g of fat and 58 g of carbohydrates. Then, a crossover analysis was performed to investigate the timedependent changes in flow-mediated dilation (FMD) in the brachial artery. In the active group, the postprandial impairment of FMD was significantly improved, the two-hour postprandial nitric oxide metabolite levels were significantly increased and the six-hour postprandial urinary 8-epi-prostaglandin F2a levels were significantly reduced compared to the placebo group. The test meal increased the levels of blood glucose, insulin and triglycerides in both groups with no significant intergroup differences. These findings indicate that CBPs intake ameliorates postprandial endothelial dysfunction in healthy men.
Chlorogenic acid, coffee, endothelial function, flow-mediated dilation, nitric oxide, polyphenol
Introduction Coffee is the most popular beverage worldwide, and there are many studies of the effects of brewed coffee on human health. Coffee intake has been shown to produce protective effects against various diseases, such as type 2 diabetes, hypertension, Alzheimer’s disease and Parkinson’s disease, in epidemiological studies (Eskelinen et al., 2009; Hernan et al., 2002; Jee et al., 1999; van Dam et al., 2002). It has been suggested that these benefits are attributable to coffee polyphenols and include various functions in addition to antioxidant activity (Ranheim & Halvorsen, 2005; Suzuki et al., 2006; Teraoka et al., 2012). Coffee bean polyphenols (CBPs) are composed of several phenolic compounds, which largely consist of chlorogenic acids (CQAs) (Clifford, 1999). The nine major CQAs in coffee include 5-caffeoylquinic acid (CQA), 3-CQA, 4-CQA, 3,4-dicaffeoylquinic acid (diCQA), 3,5-diCQA, 4,5-diCQA, 3-feruloylquinic acid (FQA), 4-FQA and 5-FQA. 5-Caffeoylquinic acid (formerly called 3-CQA or CQA) is the main component of both green and roasted beans. Roasting reduces the CQA content, particularly that of diCQA (Stalmach et al., 2010). A cup of coffee contains 20–675 mg CQAs, and the daily intake of CQAs by a coffee drinker is as much as 1 g (Clifford, 1999). Additionally, in Japan, a cup of coffee contains approximately 300 mg of chlorogenic acids (Fukushima et al., 2009). Although continuous administration of chlorogenic acids, the main components of CBPs, has been reported to improve vascular endothelial function in rats (Suzuki et al., 2006), no study
History Received 16 September 2014 Revised 4 January 2015 Accepted 11 January 2015 Published online 10 February 2015
has shown the effect of long-term consumption of coffee on endothelial function in humans. In our previous studies, continuous consumption of green coffee bean extracts containing high levels of CBPs or coffee containing reduced hydroxyhydroquinone levels enhanced endothelial function (Ochiai et al., 2004, 2009). There were no effects in the studies of coffee or chlorogenic acid (Mubarak et al., 2012; Papamichael et al., 2005), but decaffeinated coffee improved endothelial function (Buscemi et al., 2009, 2010). Our group also reported an improvement in peripheral vascular endothelial function following intake of CBPs concomitant with glucose loading (Ochiai et al., 2014). It is of clinical importance to evaluate the acute effects of CBPs on vascular function because an increase in postprandial glucose and fat is a risk factor for heart disease (Cavalot et al., 2006; Hyson et al., 2003). According to Kawano et al., diabetic and impaired glucose tolerance subjects exhibited decreased endothelial function in glucose tolerance tests (Kawano et al., 1999). However, considering real-life situations, it is important to study the effects, not only of glucose loading but also of dietary intake, on endothelial function. Therefore, to test our hypothesis that preprandial CBPs intake ameliorates postprandial endothelial dysfunction, we conducted a randomized acute clinical intervention study with a crossover design and measured flow-mediated dilation (FMD) to assess the acute effects of ingesting a CBP-containing beverage before test meal intake in healthy, non-diabetic men.
Methods and materials Correspondence: Ryuji Ochiai, Health Care Food Research Laboratories, Kao Corporation, 2-1-3, Bunka, Sumida-ku, Tokyo 131-8501, Japan. Tel: +81 3 5630 7456. Fax: +81 3 5630 7260. E-mail: ochiai.ryuuji@ kao.co.jp
Subjects The subjects consisted of 13 healthy Japanese men aged 30–60 years upon initiation of the study. The subjects were recruited
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through the in-house mail system. No subject was a smoker, taking medications or undergoing lifestyle interventions. Subjects were also excluded and considered to be ineligible if they had allergies or hypersensitivity as determined by the physician in charge. The Human Ethics Committee of Kao Corporation approved the study protocol. All subjects provided written informed consent. The present study was conducted under the supervision of the chief investigator in accordance with the Declaration of Helsinki.
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Materials The sample beverages consisted of a CBP beverage containing 600 mg of chlorogenic acids (equivalent to two cups of coffee) in 100 mL of water (active beverage) and a placebo beverage containing no CBPs in the same bottles and with the same volume and taste as the active beverage. These test beverages were prepared for this study, and both beverages were less than 10 kcal. The CBPs were extracted from coffea canephora green coffee beans using a hot water extraction method and decaffeinated by activated carbon, and then dry powder was produced by spray drying (Ochiai et al., 2014). The caffeine level was adjusted to below the limit of detection because it impairs vascular function (Papamichael et al., 2005). The composition of the CBPs consisted of 5-CQA, 3-CQA, 4-CQA, 3,4-diCQA, 3,5-diCQA, 4,5-diCQA, 3-FQA, 4-FQA and 5-FQA and was assessed by highperformance liquid chromatography, which revealed a caffeoylquinic acid content of 80.7%. The composition of the CQAs consisted of 58.3% CQA (total 3-CQA, 4-CQA and 5-CQA), 19.9% feruloylquinic acid (total 3-FQA, 4-FQA and 5-FQA) and 21.8% dicaffeoylquinic acid (3,4-diCQA, 3,5-diCQA and 4,5diCQA). The test meal consisted of 70 g of cookies, two slices of cheese and 200 mL potage soup and provided 554 kcal of energy, 14 g of protein, 30 g of fat and 58 g of carbohydrates. Study design A double-blinded, randomized crossover trial was conducted to investigate the acute effect of a single intake of the active or placebo beverage on postprandial vascular endothelial function with a washout period of at least 7 days. The order of beverages was randomly determined for each subject and not revealed by the researchers until the data validation was completed. Subjects consumed a meal from the market before 21:00 PM on the night before each study session, followed by fasting (only water was allowed). On the day of the session, the subjects entered the experimental room at 8:00 AM and urinated. Then, their body mass index, body temperature and blood pressure were measured, and they completed a survey on their current health conditions before starting the experiment. At 8:30 AM, baseline blood and urine samples were taken, and blood pressure measurements and FMD were performed. At 9:00 AM, the subjects consumed the test meal within 15 min after consuming the test beverage (active or placebo). Blood and urine sampling and measurements of blood pressure and FMD were then performed at 1, 2, 4 and 6 h after the meal. After a washout period of one week, the second experiment was conducted using the other test beverage and the same test meal. Throughout the study period, the subjects remained in the experimental room where the temperature and humidity were maintained at 25 ± 2 C and 50%, respectively. Measurement of endothelial function, blood pressure and pulse rate The FMD method was used to assess vascular endothelial function (Celermajer et al., 1992).
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Subjects rested in a supine position for at least 20 min before initiating FMD measurements. A blood pressure cuff was placed on the forearm contralateral to the dominant hand, and the blood pressure and pulse rate were measured. Endothelium-dependent vasodilation of the brachial artery was determined by ultrasonography using a semi-automatic device (UNEXEF 18G; Unex Co. Ltd., Aichi, Japan). The brachial artery diameter in the supraelbow area of the upper arm was measured from a B-mode image using a 10 MHz linear array transducer. The obtained measurement was used as the resting brachial diameter, and after a 5-min occlusion period (by inflating the upper arm blood pressure cuff to 200 mmHg), changes in the diameter were measured for 5 min. The longitudinal images of brachial artery were continuously recorded, and the FMD was calculated by the maximum change in the diameter after cuff release compared to the baseline diameter. All measurements of FMD were made by a single technician blinded to treatments allocation. Biochemical measurements Blood and urine samples were collected at 0 (baseline), 1, 2, 4 and 6 h after consuming the test beverage and test meal. The following parameters were measured: plasma glucose, serum insulin, serum triglycerides, serum free fatty acids, serum total cholesterol, plasma nitric oxide metabolites, urinary thiobarbituric acidreactive substances (TBARSs), urinary 8-epi-prostaglandin F2a and urinary creatinine. These measurements were performed by LSI Medience Corp. (Tokyo, Japan). Hydrogen peroxide in urine samples was determined by the oxidation of ferrous ions to ferric ions using the BIOXYTECH H2O2-560 assay kit (OXIS International Inc., Portland, OR). Measurements of urinary hydrogen peroxide were performed at our laboratory. Statistical analysis The primary endpoint was the effect of CBP (i.e. the primary component, chlorogenic acids) intake before the test meal on FMD. Analysis of variance with a linear mixed model was used to analyze the FMD, blood pressure, and hematological and urinary findings. Within-group comparisons of baseline and postprandial FMD, blood pressure, and hematological and urinary findings were performed using Dunnett’s multiple comparisons test, and between-group comparisons were performed using a Wilcoxon test. All statistical tests were two-tailed, and a value of p50.05 was regarded as statistically significant. We assumed postprandial FMD values (%) of 1.5% improvement and a standard deviation (SD) of 1.64%. A sample size of 12 participants was calculated from the d value obtained in a paired t-test with ¼ 0.05 and power ¼ 0.8. Statistical analyses were performed using SPSS 19.0J for Windows (SPSS Japan Inc., Tokyo, Japan).
Results All of the enrolled and randomized 13 eligible men completed the study and were included in the analysis. Their background characteristics are shown in Table 1. Pre- and postprandial blood pressure and FMD are shown in Table 2, and hematological and urinary findings are shown in Table 3. There was a significant decrease in the baseline and 6 h postprandial FMD values in the placebo group. There was a significant group-by-time interaction for FMD. In particular, after 6 h, the postprandial FMD was significantly higher in the active group (that ingested CBPs) than in the placebo group. In addition, the systolic blood pressure 2 h postprandial was significantly higher than the baseline value in the active group, but was not significantly different between the active and placebo groups. Similarly, the 1-h postprandial diastolic blood pressure was significantly higher than the baseline
CBPs ameliorate postprandial endothelial dysfunction
DOI: 10.3109/09637486.2015.1007453
value in the active group, but was not significantly different between the groups. As shown in Table 3, postprandial blood glucose, insulin, triglycerides, free fatty acids and total cholesterol levels were significantly increased from the baseline values in both the groups, but the differences between the groups were not significant. The levels of nitric oxide metabolites were significantly higher than the baseline levels in both groups, and the 2-h postprandial levels in the active group were significantly higher than in the placebo group. Urinary hydrogen peroxide and TBARS levels were also significantly increased in both groups, with no significant difference between the groups. Furthermore, the levels of urinary 8-epi-prostaglandin F2a were significantly lower in both groups compared to baseline levels, and the 6-h postprandial level was significantly lower in the active group than in the placebo group.
blood glucose, urinary hydrogen peroxide and TBARS levels after the test meal. The present results obtained using actual meals are similar to the results of glucose loading in a previous study (Ochiai et al., 2014). Interestingly, the 2-h postprandial nitric oxide metabolites, indicators of vascular endothelial function, were significantly higher in the active group than in the placebo group, which suggests that CBPs ameliorate vascular endothelial function by enhancing the bioavailability of nitric oxide. However, the 2-h postprandial FMD did not differ significantly between the groups, presumably because postprandial oxidative stress was increased. In the placebo group, a decreased FMD compared with baseline was noted 4 h after the meal and achieved significance 6 hours after the meal. Unlike glucose loading alone, which rapidly decreases the FMD, a meal of approximately 500 kcal caused a gradual decrease in FMD because it contains carbohydrates as well as lipids and proteins. In this study, a significant decrease in FMD was observed 6 h after the meal, at this time cholesterol levels were significantly higher than baseline levels. CBPs have been reported to decrease vascular endothelial function after the intake of carbohydrates and lipids (O’Keefe et al., 2008). This study suggests that including both carbohydrate and lipid intake reduces vascular endothelial function over a longer time compared to carbohydrates alone. In addition, the 6-h postprandial urinary 8-epi-prostaglandin F2a levels were significantly lower in the active group than in the placebo group. 8-Epi-prostaglandin F2a is a biomarker of lipid peroxidation in the cell membrane (Meagher et al., 2000). This maker has also been reported to be increased by smoking and eating in addition to arteriosclerosis (Morrow, 2005; Sakano et al., 2009). These findings suggest that CBPs suppress the activation of lipid peroxidation pathways after a meal. In a previous study, a single intake of CBPs ameliorated peripheral endothelial dysfunction following glucose loading through the action of chlorogenic acids (Ochiai et al., 2014). In the present study, chlorogenic acids ameliorated high fat postprandial endothelial dysfunction. Altogether with previous studies (Ochiai et al., 2014), our data suggest that chlorogenic acids may improve postprandial endothelial dysfunction induced by carbohydrate-rich and fat-rich diets. There are several limitations to this study. First, we did not investigate endothelium-independent vasodilation. Second, we did not assess the dose-dependent effect of CBPs or the serum levels of chlorogenic acids. Moreover, we did not evaluate females. Additionally, food and drugs may also influence the
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Discussion This study found that the decrease in vascular endothelial function that typically occurs after a meal is suppressed by the intake of a CBP-containing beverage, thus supporting our hypothesis. Because we provided a meal instead of glucose loading to subjects, our findings strongly indicate that CBPs affect vascular function within the context of real dietary situations. Although chlorogenic acids have been reported to suppress glucose absorption (Matsui et al., 2004), no such suppression was observed in this study, suggesting that CBPs do not suppress glucose or fat absorption. The Cmax of the CBP metabolites, 5-CQA, 3-CQA, 4-CQA, 3-FQA, 4-FQA and 5-FQA, occurs approximately 1 h after a meal (Stalmach et al., 2009). Chlorogenic acid is a well-known antioxidant (Nakatani et al., 2000), but there were no differences between the groups in Table 1. Participant characteristics (n ¼ 13).
Age (years) Height (cm) Body weight (kg) BMI (kg/m2) Coffee drinking status, n (%) 1 cup/day 1 cup/week
Value
Range
44.9 ± 1.4 172.7 ± 1.7 65.5 ± 2.4 21.9 ± 0.6
30–50 165.7–180.3 55.8–80.6 19.5–26.6
11 (85%) 2 (15%)
BMI; body mass index. Values are expressed as the means ± SE or percentages.
Table 2. Postprandial blood pressure and flow-mediated dilation (FMD) with and without coffee polyphenols. Time after test meal Baseline SBP (mmHg) Active 114 ± 2 Placebo 116 ± 2 DBP (mmHg) Active 74 ± 2 Placebo 74 ± 2 FMD (%) Active 5.8 ± 0.8 Placebo 5.9 ± 1.1
1h
p Value Group
Time
GT
121 ± 1y 118 ± 2
0.684
0.003
0.180
75 ± 2 72 ± 3
75 ± 2 74 ± 2
0.835
0.040
0.190
5.8 ± 0.9 5.0 ± 0.6
5.6 ± 0.9* 4.0 ± 0.7y
0.151
0.017
0.031
2h
4h
119 ± 1y 117 ± 2
119 ± 1y 116 ± 2
70 ± 1y 72 ± 2
73 ± 1 73 ± 1
5.3 ± 0.8 6.3 ± 1.0
6.5 ± 0.9 5.8 ± 0.7
116 ± 2 119 ± 2
3
6h
SBP, systolic blood pressure; DBP, diastolic blood pressure; FMD, flow-mediated dilation; Group, treatment effects; Time, time effects; G T, interactions between treatment and time. Values are expressed as the means ± SE. Group p value denotes the group effect by linear mixed-model analysis. Time p value denotes the time effect by linear mixed-model analysis. G T p value denotes the interactions between the treatment and time effect by linear mixed-model analysis. yp50.05 compared with baseline, Dunnett’s test. *p50.05 compared with the placebo group, Wilcoxon’s test.
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Table 3. Postprandial urinalysis and blood chemistry parameters with and without coffee polyphenols. Time after test meal
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Baseline
1h
Blood glucose (mg/dL) Active 85.8 ± 1.8 90.8 ± 4.9 Placebo 86.5 ± 2.0 91.6 ± 5.2 Insulin (lIU/mL) Active 3.1 ± 0.4 13.7 ± 1.6y Placebo 2.9 ± 0.4 13.6 ± 1.8y Triglycerides (mg/dL) Active 74 ± 10 Placebo 69 ± 9 Free fatty acids (mEq/L) Active 0.4 ± 0.0 Placebo 0.4 ± 0.0 Total cholesterol (mg/dL) Active 179 ± 8 Placebo 181 ± 9 Nitric oxide metabolites (lmol/L) Active 26.5 ± 1.8 Placebo 24.1 ± 1.4 Urinary H2O2 (mmol/mgCr) Active 23.0 ± 3.5 35.0 ± 6.2y Placebo 25.8 ± 4.0 39.5 ± 6.8y Urinary TBARS (ng/mgCr) Active 11.0 ± 0.8 10.7 ± 0.9 Placebo 10.7 ± 0.7 10.2 ± 0.7 Urinary 8-epi-prostaglandin F2a (pg/mgCr) Active 216 ± 14 Placebo 224 ± 20
p Value 4h
6h
Group
Time
GT
78.1 ± 1.5 77.8 ± 1.4
79.5 ± 1.7 79.2 ± 2.1
0.854
0.001
0.999
9.7 ± 1.0y 8.7 ± 1.1y
2.5 ± 0.3 2.3 ± 0.4
2.1 ± 0.3 1.7 ± 0.2
0.435
0.001
0.982
125 ± 16y 113 ± 11y
125 ± 21y 117 ± 18y
82 ± 14 84 ± 15
0.235
0.001
0.811
0.2 ± 0.0y 0.2 ± 0.0y
0.5 ± 0.0y 0.4 ± 0.0
0.7 ± 0.0y 0.7 ± 0.0y
0.590
0.001
0.560
177 ± 8 179 ± 9
182 ± 8 184 ± 10
184 ± 8y 187 ± 10y
0.060
0.001
0.992
38.1 ± 3.7y,* 30.1 ± 2.3y
32.7 ± 4.3y 27.7 ± 2.7
22.2 ± 2.2 20.0 ± 1.3
0.001
0.001
0.359
36.3 ± 5.0y 34.7 ± 4.2
27.6 ± 3.1 29.6 ± 3.1
34.5 ± 4.8y 34.9 ± 6.2
0.457
0.001
0.914
12.1 ± 0.8y 12.0 ± 0.7
12.3 ± 0.6y 12.5 ± 0.8y
11.1 ± 0.6 10.9 ± 0.6
0.491
0.001
0.908
227 ± 14* 253 ± 16
0.191
0.022
0.112
2h 84.7 ± 4.0 85.3 ± 3.3
225 ± 12 217 ± 12
TBARS, thiobarbituric acid-reactive species; Group, treatment effects; Time, time effects; G T, interactions between treatment and time. Values are expressed as the means ± SE. Group p value denotes the group effect by linear mixed-model analysis. Time p value denotes the time effect by linear mixed-model analysis. G T p value denotes the interaction between the treatment and time effect by linear mixed-model analysis. yp50.05 compared with baseline, Dunnett’s test. *p50.05 compared with the placebo group, Wilcoxon’s test.
measurements of TBARS (Halliwell et al., 1993). Therefore, interpretation of the oxidative stress data from this study should be carefully undertaken. Nevertheless, the present findings seem to indicate that CBPs ameliorate postprandial endothelial dysfunction. This study demonstrates that preprandial beverages containing CBPs ameliorate postprandial endothelial function and suppress the increase of lipid-oxidation in healthy men. Therefore, CBPs might have the potential to prevent cardiovascular disease. Further studies with larger samples are needed to confirm these findings.
Acknowledgements The authors thank the subjects, the professional physicians and Ms. S. Tsurimaki, who participated in this study, for their cooperation.
Declaration of interest This study was supported financially by Kao Corporation. Ryuji Ochiai, Yoko Sugiura, Kazuhiro Otsuka and Yoshihisa Katsuragi are Kao Corporation employees.
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Cavalot F, Petrelli A, Traversa M, Bonomo K, Fiora E, Conti M, Anfossi G, et al. 2006. Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the san luigi Gonzaga diabetes study. J Clin Endocrinol Metab 91:813–819. Celermajer DS, Sorensen KE, Gooch VM, Miller OI, Sullivan ID, Lloyd JK, Deanfied JE, Spiegelhalter DJ. 1992. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:1111–1115. Clifford MN. 1999. Chlorogenic acids and other cinnamates – nature, occurrence and dietary burden. J Sci Food Agric 79:362–372. Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M. 2009. Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J Alzheimers Dis 16: 85–91. Fukushima Y, Ohie T, Yonekawa Y, Yonemoto K, Aizawa H, Mori Y, Watanabe M, et al. 2009. Coffee and green tea as a large source of antioxidant polyphenols in the Japanese population. J Agric Food Chem 57:1253–1259. Halliwell B, Chirico S. 1993. Lipid peroxidation: its mechanism, measurement, and significance. Am J Clin Nutr 57:715S–725S. Hernan MA, Takkouche B, Caamano-Isorna F, Gestal-Otero JJ. 2002. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Ann Neurol 52:276–284. Hyson D, Rutledge JC, Berglund L. 2003. Postprandial lipemia and cardiovascular disease. Curr Atheroscler Rep 5:437–444. Jee SH, He J, Whelton PK, Suh I, Klag MJ. 1999. The effect of chronic coffee drinking on blood pressure: a meta-analysis of controlled clinical trials. Hypertension 33:647–652. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T. 1999. Hyperglycemia rapidly suppresses flow-mediated endotheliumdependent vasodilation of brachial artery. J Am Coll Cardiol 34: 146–154.
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Papamichael CM, Aznaouridis KA, Karatzis EN, Karatzi KN, Stamatelopoulos KS, Vamvakou G, Lekakis JP, Mavrikakis ME. 2005. Effect of coffee on endothelial function in healthy subjects: the role of caffeine. Clin Sci 109:55–60. Ranheim T, Halvorsen B. 2005. Coffee consumption and human health – beneficial or detrimental? – Mechanisms for effects of coffee consumption on different risk factors for cardiovascular disease and type 2 diabetes mellitus. Mol Nutr Food Res 49:274–284. Sakano N, Wang DH, Takahashi N, Wang B, Sauriasari R, Kanbara S, Sato Y, et al. 2009. Oxiative stress biomarkers and lifstyles in Japanese healthy people. J Clin Biochem Nutr 44:185–195. Stalmach A, Mullen W, Barron D, Uchida K, Yokota T, Cavin C, Steiling H, et al. 2009. Metabolite profiling of hydroxycinnamate derivatives in plasma and urine following the ingestion of coffee by humans: identification of biomarkers of coffee consumption. Drug Metab Dispos 37:1749–1758. Stalmach A, Steiling H, Willamson G, Crozier A. 2010. Bioavailability of chloogenic acids following acute ingestion of coffee by humans with an ileostomy. Arch Biochem Biophys 501:98–105. Suzuki A, Yamamoto N, Jokura H, Yamamoto M, Fujii A, Tokimitsu I, Saito I. 2006. Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats. J Hypertens 24:1065–1073. Teraoka M, Nakaso K, Kusumoto C, Katano S, Tajima N, Yamashita A, Zushi T, et al. 2012. Cytoprotective effect of chlorogenic acid against a-synuclein-related toxicity in catecholaminergic PC12 cells. J Clin Biochem Nutr 51:122–127. van Dam RM, Feskens EJ. 2002. Coffee consumption and risk of type 2 diabetes mellitus. Lancet 360:1477–1478.
RESEARCH ARTICLE
Coffee bean polyphenols ameliorate postprandial endothelial dysfunction in healthy male adults Ryuji Ochiai1, Yoko Sugiura1, Kazuhiro Otsuka1, Yoshihisa Katsuragi1, and Teruto Hashiguchi2 Health Care Food Research Laboratories, Kao Corporation, Tokyo, Japan and 2Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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1
Abstract
Keywords
To reveal the effect of coffee bean polyphenols (CBPs) on blood vessels, this study aimed to investigate the effect of CBPs on acute postprandial endothelial dysfunction. Thirteen healthy non-diabetic men (mean age, 44.9 ± 1.4 years) consumed a test beverage (active: containing CBPs, placebo: no CBPs) before a 554-kcal test meal containing 14 g of protein, 30 g of fat and 58 g of carbohydrates. Then, a crossover analysis was performed to investigate the timedependent changes in flow-mediated dilation (FMD) in the brachial artery. In the active group, the postprandial impairment of FMD was significantly improved, the two-hour postprandial nitric oxide metabolite levels were significantly increased and the six-hour postprandial urinary 8-epi-prostaglandin F2a levels were significantly reduced compared to the placebo group. The test meal increased the levels of blood glucose, insulin and triglycerides in both groups with no significant intergroup differences. These findings indicate that CBPs intake ameliorates postprandial endothelial dysfunction in healthy men.
Chlorogenic acid, coffee, endothelial function, flow-mediated dilation, nitric oxide, polyphenol
Introduction Coffee is the most popular beverage worldwide, and there are many studies of the effects of brewed coffee on human health. Coffee intake has been shown to produce protective effects against various diseases, such as type 2 diabetes, hypertension, Alzheimer’s disease and Parkinson’s disease, in epidemiological studies (Eskelinen et al., 2009; Hernan et al., 2002; Jee et al., 1999; van Dam et al., 2002). It has been suggested that these benefits are attributable to coffee polyphenols and include various functions in addition to antioxidant activity (Ranheim & Halvorsen, 2005; Suzuki et al., 2006; Teraoka et al., 2012). Coffee bean polyphenols (CBPs) are composed of several phenolic compounds, which largely consist of chlorogenic acids (CQAs) (Clifford, 1999). The nine major CQAs in coffee include 5-caffeoylquinic acid (CQA), 3-CQA, 4-CQA, 3,4-dicaffeoylquinic acid (diCQA), 3,5-diCQA, 4,5-diCQA, 3-feruloylquinic acid (FQA), 4-FQA and 5-FQA. 5-Caffeoylquinic acid (formerly called 3-CQA or CQA) is the main component of both green and roasted beans. Roasting reduces the CQA content, particularly that of diCQA (Stalmach et al., 2010). A cup of coffee contains 20–675 mg CQAs, and the daily intake of CQAs by a coffee drinker is as much as 1 g (Clifford, 1999). Additionally, in Japan, a cup of coffee contains approximately 300 mg of chlorogenic acids (Fukushima et al., 2009). Although continuous administration of chlorogenic acids, the main components of CBPs, has been reported to improve vascular endothelial function in rats (Suzuki et al., 2006), no study
History Received 16 September 2014 Revised 4 January 2015 Accepted 11 January 2015 Published online 10 February 2015
has shown the effect of long-term consumption of coffee on endothelial function in humans. In our previous studies, continuous consumption of green coffee bean extracts containing high levels of CBPs or coffee containing reduced hydroxyhydroquinone levels enhanced endothelial function (Ochiai et al., 2004, 2009). There were no effects in the studies of coffee or chlorogenic acid (Mubarak et al., 2012; Papamichael et al., 2005), but decaffeinated coffee improved endothelial function (Buscemi et al., 2009, 2010). Our group also reported an improvement in peripheral vascular endothelial function following intake of CBPs concomitant with glucose loading (Ochiai et al., 2014). It is of clinical importance to evaluate the acute effects of CBPs on vascular function because an increase in postprandial glucose and fat is a risk factor for heart disease (Cavalot et al., 2006; Hyson et al., 2003). According to Kawano et al., diabetic and impaired glucose tolerance subjects exhibited decreased endothelial function in glucose tolerance tests (Kawano et al., 1999). However, considering real-life situations, it is important to study the effects, not only of glucose loading but also of dietary intake, on endothelial function. Therefore, to test our hypothesis that preprandial CBPs intake ameliorates postprandial endothelial dysfunction, we conducted a randomized acute clinical intervention study with a crossover design and measured flow-mediated dilation (FMD) to assess the acute effects of ingesting a CBP-containing beverage before test meal intake in healthy, non-diabetic men.
Methods and materials Correspondence: Ryuji Ochiai, Health Care Food Research Laboratories, Kao Corporation, 2-1-3, Bunka, Sumida-ku, Tokyo 131-8501, Japan. Tel: +81 3 5630 7456. Fax: +81 3 5630 7260. E-mail: ochiai.ryuuji@ kao.co.jp
Subjects The subjects consisted of 13 healthy Japanese men aged 30–60 years upon initiation of the study. The subjects were recruited
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through the in-house mail system. No subject was a smoker, taking medications or undergoing lifestyle interventions. Subjects were also excluded and considered to be ineligible if they had allergies or hypersensitivity as determined by the physician in charge. The Human Ethics Committee of Kao Corporation approved the study protocol. All subjects provided written informed consent. The present study was conducted under the supervision of the chief investigator in accordance with the Declaration of Helsinki.
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Materials The sample beverages consisted of a CBP beverage containing 600 mg of chlorogenic acids (equivalent to two cups of coffee) in 100 mL of water (active beverage) and a placebo beverage containing no CBPs in the same bottles and with the same volume and taste as the active beverage. These test beverages were prepared for this study, and both beverages were less than 10 kcal. The CBPs were extracted from coffea canephora green coffee beans using a hot water extraction method and decaffeinated by activated carbon, and then dry powder was produced by spray drying (Ochiai et al., 2014). The caffeine level was adjusted to below the limit of detection because it impairs vascular function (Papamichael et al., 2005). The composition of the CBPs consisted of 5-CQA, 3-CQA, 4-CQA, 3,4-diCQA, 3,5-diCQA, 4,5-diCQA, 3-FQA, 4-FQA and 5-FQA and was assessed by highperformance liquid chromatography, which revealed a caffeoylquinic acid content of 80.7%. The composition of the CQAs consisted of 58.3% CQA (total 3-CQA, 4-CQA and 5-CQA), 19.9% feruloylquinic acid (total 3-FQA, 4-FQA and 5-FQA) and 21.8% dicaffeoylquinic acid (3,4-diCQA, 3,5-diCQA and 4,5diCQA). The test meal consisted of 70 g of cookies, two slices of cheese and 200 mL potage soup and provided 554 kcal of energy, 14 g of protein, 30 g of fat and 58 g of carbohydrates. Study design A double-blinded, randomized crossover trial was conducted to investigate the acute effect of a single intake of the active or placebo beverage on postprandial vascular endothelial function with a washout period of at least 7 days. The order of beverages was randomly determined for each subject and not revealed by the researchers until the data validation was completed. Subjects consumed a meal from the market before 21:00 PM on the night before each study session, followed by fasting (only water was allowed). On the day of the session, the subjects entered the experimental room at 8:00 AM and urinated. Then, their body mass index, body temperature and blood pressure were measured, and they completed a survey on their current health conditions before starting the experiment. At 8:30 AM, baseline blood and urine samples were taken, and blood pressure measurements and FMD were performed. At 9:00 AM, the subjects consumed the test meal within 15 min after consuming the test beverage (active or placebo). Blood and urine sampling and measurements of blood pressure and FMD were then performed at 1, 2, 4 and 6 h after the meal. After a washout period of one week, the second experiment was conducted using the other test beverage and the same test meal. Throughout the study period, the subjects remained in the experimental room where the temperature and humidity were maintained at 25 ± 2 C and 50%, respectively. Measurement of endothelial function, blood pressure and pulse rate The FMD method was used to assess vascular endothelial function (Celermajer et al., 1992).
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Subjects rested in a supine position for at least 20 min before initiating FMD measurements. A blood pressure cuff was placed on the forearm contralateral to the dominant hand, and the blood pressure and pulse rate were measured. Endothelium-dependent vasodilation of the brachial artery was determined by ultrasonography using a semi-automatic device (UNEXEF 18G; Unex Co. Ltd., Aichi, Japan). The brachial artery diameter in the supraelbow area of the upper arm was measured from a B-mode image using a 10 MHz linear array transducer. The obtained measurement was used as the resting brachial diameter, and after a 5-min occlusion period (by inflating the upper arm blood pressure cuff to 200 mmHg), changes in the diameter were measured for 5 min. The longitudinal images of brachial artery were continuously recorded, and the FMD was calculated by the maximum change in the diameter after cuff release compared to the baseline diameter. All measurements of FMD were made by a single technician blinded to treatments allocation. Biochemical measurements Blood and urine samples were collected at 0 (baseline), 1, 2, 4 and 6 h after consuming the test beverage and test meal. The following parameters were measured: plasma glucose, serum insulin, serum triglycerides, serum free fatty acids, serum total cholesterol, plasma nitric oxide metabolites, urinary thiobarbituric acidreactive substances (TBARSs), urinary 8-epi-prostaglandin F2a and urinary creatinine. These measurements were performed by LSI Medience Corp. (Tokyo, Japan). Hydrogen peroxide in urine samples was determined by the oxidation of ferrous ions to ferric ions using the BIOXYTECH H2O2-560 assay kit (OXIS International Inc., Portland, OR). Measurements of urinary hydrogen peroxide were performed at our laboratory. Statistical analysis The primary endpoint was the effect of CBP (i.e. the primary component, chlorogenic acids) intake before the test meal on FMD. Analysis of variance with a linear mixed model was used to analyze the FMD, blood pressure, and hematological and urinary findings. Within-group comparisons of baseline and postprandial FMD, blood pressure, and hematological and urinary findings were performed using Dunnett’s multiple comparisons test, and between-group comparisons were performed using a Wilcoxon test. All statistical tests were two-tailed, and a value of p50.05 was regarded as statistically significant. We assumed postprandial FMD values (%) of 1.5% improvement and a standard deviation (SD) of 1.64%. A sample size of 12 participants was calculated from the d value obtained in a paired t-test with ¼ 0.05 and power ¼ 0.8. Statistical analyses were performed using SPSS 19.0J for Windows (SPSS Japan Inc., Tokyo, Japan).
Results All of the enrolled and randomized 13 eligible men completed the study and were included in the analysis. Their background characteristics are shown in Table 1. Pre- and postprandial blood pressure and FMD are shown in Table 2, and hematological and urinary findings are shown in Table 3. There was a significant decrease in the baseline and 6 h postprandial FMD values in the placebo group. There was a significant group-by-time interaction for FMD. In particular, after 6 h, the postprandial FMD was significantly higher in the active group (that ingested CBPs) than in the placebo group. In addition, the systolic blood pressure 2 h postprandial was significantly higher than the baseline value in the active group, but was not significantly different between the active and placebo groups. Similarly, the 1-h postprandial diastolic blood pressure was significantly higher than the baseline
CBPs ameliorate postprandial endothelial dysfunction
DOI: 10.3109/09637486.2015.1007453
value in the active group, but was not significantly different between the groups. As shown in Table 3, postprandial blood glucose, insulin, triglycerides, free fatty acids and total cholesterol levels were significantly increased from the baseline values in both the groups, but the differences between the groups were not significant. The levels of nitric oxide metabolites were significantly higher than the baseline levels in both groups, and the 2-h postprandial levels in the active group were significantly higher than in the placebo group. Urinary hydrogen peroxide and TBARS levels were also significantly increased in both groups, with no significant difference between the groups. Furthermore, the levels of urinary 8-epi-prostaglandin F2a were significantly lower in both groups compared to baseline levels, and the 6-h postprandial level was significantly lower in the active group than in the placebo group.
blood glucose, urinary hydrogen peroxide and TBARS levels after the test meal. The present results obtained using actual meals are similar to the results of glucose loading in a previous study (Ochiai et al., 2014). Interestingly, the 2-h postprandial nitric oxide metabolites, indicators of vascular endothelial function, were significantly higher in the active group than in the placebo group, which suggests that CBPs ameliorate vascular endothelial function by enhancing the bioavailability of nitric oxide. However, the 2-h postprandial FMD did not differ significantly between the groups, presumably because postprandial oxidative stress was increased. In the placebo group, a decreased FMD compared with baseline was noted 4 h after the meal and achieved significance 6 hours after the meal. Unlike glucose loading alone, which rapidly decreases the FMD, a meal of approximately 500 kcal caused a gradual decrease in FMD because it contains carbohydrates as well as lipids and proteins. In this study, a significant decrease in FMD was observed 6 h after the meal, at this time cholesterol levels were significantly higher than baseline levels. CBPs have been reported to decrease vascular endothelial function after the intake of carbohydrates and lipids (O’Keefe et al., 2008). This study suggests that including both carbohydrate and lipid intake reduces vascular endothelial function over a longer time compared to carbohydrates alone. In addition, the 6-h postprandial urinary 8-epi-prostaglandin F2a levels were significantly lower in the active group than in the placebo group. 8-Epi-prostaglandin F2a is a biomarker of lipid peroxidation in the cell membrane (Meagher et al., 2000). This maker has also been reported to be increased by smoking and eating in addition to arteriosclerosis (Morrow, 2005; Sakano et al., 2009). These findings suggest that CBPs suppress the activation of lipid peroxidation pathways after a meal. In a previous study, a single intake of CBPs ameliorated peripheral endothelial dysfunction following glucose loading through the action of chlorogenic acids (Ochiai et al., 2014). In the present study, chlorogenic acids ameliorated high fat postprandial endothelial dysfunction. Altogether with previous studies (Ochiai et al., 2014), our data suggest that chlorogenic acids may improve postprandial endothelial dysfunction induced by carbohydrate-rich and fat-rich diets. There are several limitations to this study. First, we did not investigate endothelium-independent vasodilation. Second, we did not assess the dose-dependent effect of CBPs or the serum levels of chlorogenic acids. Moreover, we did not evaluate females. Additionally, food and drugs may also influence the
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Discussion This study found that the decrease in vascular endothelial function that typically occurs after a meal is suppressed by the intake of a CBP-containing beverage, thus supporting our hypothesis. Because we provided a meal instead of glucose loading to subjects, our findings strongly indicate that CBPs affect vascular function within the context of real dietary situations. Although chlorogenic acids have been reported to suppress glucose absorption (Matsui et al., 2004), no such suppression was observed in this study, suggesting that CBPs do not suppress glucose or fat absorption. The Cmax of the CBP metabolites, 5-CQA, 3-CQA, 4-CQA, 3-FQA, 4-FQA and 5-FQA, occurs approximately 1 h after a meal (Stalmach et al., 2009). Chlorogenic acid is a well-known antioxidant (Nakatani et al., 2000), but there were no differences between the groups in Table 1. Participant characteristics (n ¼ 13).
Age (years) Height (cm) Body weight (kg) BMI (kg/m2) Coffee drinking status, n (%) 1 cup/day 1 cup/week
Value
Range
44.9 ± 1.4 172.7 ± 1.7 65.5 ± 2.4 21.9 ± 0.6
30–50 165.7–180.3 55.8–80.6 19.5–26.6
11 (85%) 2 (15%)
BMI; body mass index. Values are expressed as the means ± SE or percentages.
Table 2. Postprandial blood pressure and flow-mediated dilation (FMD) with and without coffee polyphenols. Time after test meal Baseline SBP (mmHg) Active 114 ± 2 Placebo 116 ± 2 DBP (mmHg) Active 74 ± 2 Placebo 74 ± 2 FMD (%) Active 5.8 ± 0.8 Placebo 5.9 ± 1.1
1h
p Value Group
Time
GT
121 ± 1y 118 ± 2
0.684
0.003
0.180
75 ± 2 72 ± 3
75 ± 2 74 ± 2
0.835
0.040
0.190
5.8 ± 0.9 5.0 ± 0.6
5.6 ± 0.9* 4.0 ± 0.7y
0.151
0.017
0.031
2h
4h
119 ± 1y 117 ± 2
119 ± 1y 116 ± 2
70 ± 1y 72 ± 2
73 ± 1 73 ± 1
5.3 ± 0.8 6.3 ± 1.0
6.5 ± 0.9 5.8 ± 0.7
116 ± 2 119 ± 2
3
6h
SBP, systolic blood pressure; DBP, diastolic blood pressure; FMD, flow-mediated dilation; Group, treatment effects; Time, time effects; G T, interactions between treatment and time. Values are expressed as the means ± SE. Group p value denotes the group effect by linear mixed-model analysis. Time p value denotes the time effect by linear mixed-model analysis. G T p value denotes the interactions between the treatment and time effect by linear mixed-model analysis. yp50.05 compared with baseline, Dunnett’s test. *p50.05 compared with the placebo group, Wilcoxon’s test.
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Table 3. Postprandial urinalysis and blood chemistry parameters with and without coffee polyphenols. Time after test meal
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Baseline
1h
Blood glucose (mg/dL) Active 85.8 ± 1.8 90.8 ± 4.9 Placebo 86.5 ± 2.0 91.6 ± 5.2 Insulin (lIU/mL) Active 3.1 ± 0.4 13.7 ± 1.6y Placebo 2.9 ± 0.4 13.6 ± 1.8y Triglycerides (mg/dL) Active 74 ± 10 Placebo 69 ± 9 Free fatty acids (mEq/L) Active 0.4 ± 0.0 Placebo 0.4 ± 0.0 Total cholesterol (mg/dL) Active 179 ± 8 Placebo 181 ± 9 Nitric oxide metabolites (lmol/L) Active 26.5 ± 1.8 Placebo 24.1 ± 1.4 Urinary H2O2 (mmol/mgCr) Active 23.0 ± 3.5 35.0 ± 6.2y Placebo 25.8 ± 4.0 39.5 ± 6.8y Urinary TBARS (ng/mgCr) Active 11.0 ± 0.8 10.7 ± 0.9 Placebo 10.7 ± 0.7 10.2 ± 0.7 Urinary 8-epi-prostaglandin F2a (pg/mgCr) Active 216 ± 14 Placebo 224 ± 20
p Value 4h
6h
Group
Time
GT
78.1 ± 1.5 77.8 ± 1.4
79.5 ± 1.7 79.2 ± 2.1
0.854
0.001
0.999
9.7 ± 1.0y 8.7 ± 1.1y
2.5 ± 0.3 2.3 ± 0.4
2.1 ± 0.3 1.7 ± 0.2
0.435
0.001
0.982
125 ± 16y 113 ± 11y
125 ± 21y 117 ± 18y
82 ± 14 84 ± 15
0.235
0.001
0.811
0.2 ± 0.0y 0.2 ± 0.0y
0.5 ± 0.0y 0.4 ± 0.0
0.7 ± 0.0y 0.7 ± 0.0y
0.590
0.001
0.560
177 ± 8 179 ± 9
182 ± 8 184 ± 10
184 ± 8y 187 ± 10y
0.060
0.001
0.992
38.1 ± 3.7y,* 30.1 ± 2.3y
32.7 ± 4.3y 27.7 ± 2.7
22.2 ± 2.2 20.0 ± 1.3
0.001
0.001
0.359
36.3 ± 5.0y 34.7 ± 4.2
27.6 ± 3.1 29.6 ± 3.1
34.5 ± 4.8y 34.9 ± 6.2
0.457
0.001
0.914
12.1 ± 0.8y 12.0 ± 0.7
12.3 ± 0.6y 12.5 ± 0.8y
11.1 ± 0.6 10.9 ± 0.6
0.491
0.001
0.908
227 ± 14* 253 ± 16
0.191
0.022
0.112
2h 84.7 ± 4.0 85.3 ± 3.3
225 ± 12 217 ± 12
TBARS, thiobarbituric acid-reactive species; Group, treatment effects; Time, time effects; G T, interactions between treatment and time. Values are expressed as the means ± SE. Group p value denotes the group effect by linear mixed-model analysis. Time p value denotes the time effect by linear mixed-model analysis. G T p value denotes the interaction between the treatment and time effect by linear mixed-model analysis. yp50.05 compared with baseline, Dunnett’s test. *p50.05 compared with the placebo group, Wilcoxon’s test.
measurements of TBARS (Halliwell et al., 1993). Therefore, interpretation of the oxidative stress data from this study should be carefully undertaken. Nevertheless, the present findings seem to indicate that CBPs ameliorate postprandial endothelial dysfunction. This study demonstrates that preprandial beverages containing CBPs ameliorate postprandial endothelial function and suppress the increase of lipid-oxidation in healthy men. Therefore, CBPs might have the potential to prevent cardiovascular disease. Further studies with larger samples are needed to confirm these findings.
Acknowledgements The authors thank the subjects, the professional physicians and Ms. S. Tsurimaki, who participated in this study, for their cooperation.
Declaration of interest This study was supported financially by Kao Corporation. Ryuji Ochiai, Yoko Sugiura, Kazuhiro Otsuka and Yoshihisa Katsuragi are Kao Corporation employees.
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