Introduction
Endothelial dysfunction occurs in the early stage of atherosclerosis and plays an important role in the development of atherosclerotic conditions, resulting in cardiovascular complications [
1,
2]. Measurements of flow-mediated vasodilation (FMD) as an index of endothelium-dependent vasodilation in the brachial artery have been widely used in clinical research to evaluate endothelial function [
3‐
6]. Endothelial dysfunction has been shown to be an independent predictor of cardiovascular events [
7‐
10]. Postprandial hyperglycemia is associated with endothelial dysfunction and is a risk factor for cardiovascular events [
11,
12]. Acute hyperglycemia induces oxidative stress, which is a key trigger of endothelial dysfunction by reducing nitric oxide (NO) bioavailability [
11,
12]. Therefore, it is important to determine interventions that can restore endothelial function under the condition of postprandial hyperglycemia.
Coffee is a popular beverage that is consumed worldwide. Coffee contains an abundance of polyphenols, which is the major source of dietary antioxidants [
13,
14]. Drinking coffee is associated with lower risks of metabolic syndrome, diabetes, and coronary heart disease [
15‐
19]. However, there have been conflicting results regarding the association between coffee drinking and risk of cardiovascular disease [
19‐
23]. The effect of coffee on endothelial function is also controversial [
24‐
27]. One possible reason for the different results of studies is that the contents of chlorogenic acids, which are the most abundant antioxidants in coffee, may vary depending on several factors [
16]. Coffee has a complex chemical mixture with hundreds of compounds. Roasting coffee results in the loss of chlorogenic acids and generation of hydroxyhydroquinone [
28]. A previous study showed that hydroxyhydroquinone inhibits the chlorogenic acid-induced restoration of endothelial function in a rat model of hypertension [
29]. It has also been shown that hydroxyhydroquinone increased the production of reactive oxygen species in a dose-dependent manner [
30]. Some clinical studies have shown that coffee with a high content of chlorogenic acids and a low content of hydroxyhydroquinone is effective for reducing blood pressure [
31,
32].
However, there is no information on the effects of a combination of chlorogenic acids and hydroxyhydroquinone on endothelial function in humans. Therefore, in this study, we evaluated acute effects of coffee with a high content of chlorogenic acids and different contents of hydroxyhydroquinone on endothelial function, especially postprandial endothelial dysfunction, in patients with borderline or stage 1 hypertension.
Discussion
This study is the first single-blind, randomized, placebo-controlled, crossover trial to evaluate the acute effects of coffee with a high content of chlorogenic acids and different contents of hydroxyhydroquinone on postprandial endothelial dysfunction in patients with borderline or stage 1 hypertension. A single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone restored postprandial endothelial dysfunction by decreasing in oxidative stress.
Epidemiologic studies have shown that coffee drinking is associated with lower risk of cardiovascular disease [
15,
17‐
19]. In the present study, single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone, but not single intake of coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone or placebo coffee, significantly improved postprandial endothelial dysfunction. In addition, changes in FMD after drinking the test beverage with a high content of chlorogenic acids and low content of hydroxyhydroquinone positively correlated with changes in levels of chlorogenic acids. These findings suggest that dietary intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone is a healthy habit to improve endothelial function.
Oxidative stress has been shown to play a critical role in the maintenance and development of endothelial dysfunction by reducing the bioavailability of NO [
1,
2]. Plasma levels of 8-isoprostane, a marker of oxidative stress, were increased in patients with vascular disease [
39]. In the present study, single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone, but not single intake of coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone or placebo coffee, decreased circulating 8-isoprostane levels. In addition, coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone improved FMD in patients who had high levels of 8-isoprostane. These findings suggest that the beneficial effects of coffee with a high content of chlorogenic acids and low level of hydroxyhydroquinone on endothelial function are induced, at least in part, by a decrease in oxidative stress.
A major compound in coffee is caffeine. It is well known that caffeine influences systemic hemodynamics, including elevation of blood pressure and vascular function [
40,
41]. Although both coffee with and without caffeine have similar associations with cardiovascular disease [
15,
42], in the present study, to avoid the effects of caffeine on systemic hemodynamics and endothelial function, the test beverages contained the same amounts of caffeine.
A recent meta-analysis revealed antihypertensive effects of chlorogenic acids [
43]. Suzuki et al. [
29] reported that hydroxyhydroquinone inhibits the antihypertensive effect of chlorogenic acids in spontaneous hypertensive rats. These findings suggest that coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone has a beneficial effect in patients with hypertension. Indeed, long-term intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone was shown to be effective for reducing blood pressure in patients with mild hypertension [
31,
32]. Therefore, we enrolled patients with borderline or stage 1 hypertension in this study. In the present study, acute intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone did not alter blood pressure in these subjects (Table
3). Several investigators, including us, have reported that caffeine intake is associated with acute increase in blood pressure [
40,
41]. Conversely, chronic caffeine consumption was shown to have no significant effect on blood pressure [
41]. In the case of acute coffee intake, interaction of chlorogenic acids and caffeine may regulate changes in blood pressure. It is likely that the antioxidant effect of chlorogenic acids, not the blood pressure-lowering effect of chlorogenic acids, is involved in the restoration of postprandial endothelial dysfunction.
Some studies have shown that acute administration of coffee has a harmful effect on endothelial function in healthy subjects [
24,
25], while other studies have shown that coffee improves endothelial function [
26,
27]. In addition, the association between coffee drinking and risk of cardiovascular disease remains inconclusive [
15,
17‐
23]. The reason for the controversial results remains unclear. Hydroxyhydroquinone inhibits the chlorogenic acid-induced restoration of endothelial function and increases production of reactive oxygen species in a dose-dependent manner [
29,
30]. To evaluate the effects of hydroxyhydroquinone on endothelial function, we compared the effects of coffees with a high content of chlorogenic acids and different contents of hydroxyhydroquinone in Study 1. We confirmed that intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone, but not intake of coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone, improved postprandial endothelial dysfunction. Intake of coffee with reduced hydroxyhydroquinone per se also may be beneficial for maintenance of vascular function and prevention of cardiovascular events.
Study limitations
The present study has a number of limitations. First, the number of patients was relatively small. A single-blind, randomized, placebo-controlled, crossover trial was performed to increase the power of the study. We confirmed that a single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone was effective for restoring postprandial endothelial dysfunction in both Study 1 and Study 2. Second, we evaluated the acute effects of chlorogenic acids and chlorogenic acids with different hydroxyhydroquinone contents on endothelial function. Long-term interventions are needed to determine whether acute effects of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone are sustained over time. Third, coffee is a rich source of chlorogenic acids, which have strong anti-inflammatory properties [
13,
14]. Inflammation also plays a critical role in endothelial dysfunction [
44,
45]. In the present study, there were no significant differences in serum levels of high-sensitivity C-reactive protein between beverage A and beverage B (Table
3). It is unlikely that inflammation contributes to high content of chlorogenic acid-induced improvement in postprandial vascular injury. Fourth, we had no information on the participants’ coffee consumption background. Although we confirmed that the concentrations of plasma chlorogenic acids at baseline were low, we cannot deny the possibility that the participants’ coffee consumption background affected the results of the study. Finally, coffee contains hundreds of compounds that might affect endothelial function. We cannot rule out the possibility that compounds other than chlorogenic acids and hydroxyhydroquinone have a greater influence on endothelial function.
In conclusion, a single intake of coffee with a high content of chlorogenic acids and low hydroxyhydroquinone is effective for improving postprandial endothelial dysfunction. Further studies are needed to assess the long-term effects of drinking coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone on vascular function, onset of cardiovascular disease, and cardiovascular events.
Acknowledgements
We thank Miki Kumiji, Megumi Wakisaka, Ki-ichiro Kawano, and Satoko Michiyama of Hiroshima University, Research Institute for Radiation Biology and Medicine, for their excellent secretarial assistance.