Review pubs.acs.org/JAFC
Cocoa, Blood Pressure, and Cardiovascular Health Claudio Ferri, Giovambattista Desideri, Livia Ferri, Ilenia Proietti, Stefania Di Agostino, Letizia Martella, Francesca Mai, Paolo Di Giosia, and Davide Grassi* Department of Life, Health & Environmental Sciences, University of L’Aquila, 67100 Coppito, L’Aquila, Italy ABSTRACT: High blood pressure is an important risk factor for cardiovascular disease and cardiovascular events worldwide. Clinical and epidemiological studies suggest that cocoa-rich products reduce the risk of cardiovascular disease. According to this, cocoa has a high content in polyphenols, especially flavanols. Flavanols have been described to exert favorable effects on endothelium-derived vasodilation via the stimulation of nitric oxide-synthase, the increased availability of L-arginine, and the decreased degradation of NO. Cocoa may also have a beneficial effect by protecting against oxidative stress alterations and via decreased platelet aggregation, decreased lipid oxidation, and insulin resistance. These effects are associated with a decrease of blood pressure and a favorable trend toward a reduction in cardiovascular events and strokes. Previous meta-analyses have shown that cocoa-rich foods may reduce blood pressure. Long-term trials investigating the effect of cocoa products are needed to determine whether or not blood pressure is reduced on a chronic basis by daily ingestion of cocoa. Furthermore, long-term trials investigating the effect of cocoa on clinical outcomes are also needed to assess whether cocoa has an effect on cardiovascular events. A 3 mmHg systolic blood pressure reduction has been estimated to decrease the risk of cardiovascular and all-cause mortality. This paper summarizes new findings concerning cocoa effects on blood pressure and cardiovascular health, focusing on putative mechanisms of action and “nutraceutical “ viewpoints. KEYWORDS: cocoa, blood pressure, cardiovascular health, polyphenols, endothelium
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There exist several mechanisms of how cocoa flavonoids may be protective against cardiovascular disease; these include antioxidant, antiplatelet, and anti-inflammatory effects, as well as possibly increasing high-density lipoprotein (HDL), decreasing BP, and improving endothelial function.6−10 These effects might be responsible for the reported substantial reduction in cardiovascular risk. In this brief review we aim to discuss the clinically relevant cardiovascular effects of cocoa, particularly focusing on the BP responses to cocoa and the potential clinical implications associated with its consumption.
INTRODUCTION Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to endothelial dysfunction, atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke, or death.1−3 Because risk of cardiovascular disease is linear throughout the entire range of blood pressure (BP), a large segment of the population, although not classically defined as “hypertensive”, may still be at risk.2 Therefore, lowering BP, even in the normal range, through dietary means may decrease the rate of end-organ damage caused by hypertension.1,2 Lifestyle modifications, including dietary habits, have substantial effects on risk factors for cardiovascular disease such as hypertension.2 Increased consumption of fruitsand vegetables has been recommended as a key component of a healthy diet for the prevention of cardiovascular diseases.4−6 The beneficial effects of fruits and vegetables have been largely ascribed to their content in flavonoids.4−6 In fact, a large body of evidence supports the dietary intake of polyphenols,particularly of flavonoids and the specific class of flavonoids named flavanols that are largely contained in cocoa beans, might be able to exert some beneficial vascular effects, reduce the risk for cardiovascular morbidity and mortality, and contribute to the prevention of other chronic diseases.6−9 Among phytochemicals, polyphenols constitute one of the most numerous and widely distributed groups of substances in the plant kingdom, with more than 8000 phenolic structures.6−10 They occur in a variety of fruits, vegetables, seeds, flowers, beverages, and even some manufactured foods as a component of the natural ingredients used. Cocoa is specifically rich in polyphenols, and the total polyphenol content of the cocoa bean has been evaluated to be 6−8% by weight of the dry bean.6−11 © XXXX American Chemical Society
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EVIDENCE FROM EPIDEMIOLOGICAL STUDIES With regard to the effects of cocoa on BP, a key study is represented by the Amerinds living on the San Blas Islands off the coast of Panama. Of note, authors have shown that these native Kuna Indians, daily drinking several servings of unprocessed cocoa, may represent the only known society with regular daily sodium intake that is free from age-related increments in BP and presents a very low incidence of hypertension [prevalence of hypertension was 2.2% and reflected minimal criteria with a mean systolic blood pressure (SBP) = 140 mmHg and diastolic blood pressure (DBP) < 85 mmHg] and BP did not rise with age. Conversely, all of these features disappeared in Kuna Indians who moved to the Special Issue: ISCHOM 1st International Congress on Chocolate and Cocoa in Medicine Received: February 26, 2015 Revised: June 30, 2015 Accepted: June 30, 2015
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DOI: 10.1021/acs.jafc.5b01064 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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lowest vegetable intake, while also having the highest chocolate intake.14 Concordantly, Cassidy et al.15 evaluated the association between habitual flavonoid intake and incident hypertension in men and women, involving a total of 87242 women from the Nurses’ Health Study (NHS) II, 46672 women from the NHS I, and 23043 men from the Health Professionals Follow-Up Study (HPFS). Mean amounts of flavan-3-ols ranged from 50.1 to 61.7 mg of flavan-3-ols/day [interquartile range (IQR), 12.0−72.0 mg of flavan-3-ols/day] across cohorts, whereas mean anthocyanin intakes ranged from 12.5 to 15.2 mg of anthocyanin/day (IQR, 4.6−19.3 mg of anthocyanin/day). During 14 years of follow-up were reported 29018 cases of hypertension in women and 5629 cases of hypertension in men. A high anthocyanin intake was associated with an 8% decreased risk of hypertension (quintile 5 compared with quintile 1, relative risk, 0.92; 95% CI 0.86, 0.98; p for trend < 0.03). The magnitude of the association was greater (12%) in participants 42 mg of epicatechin), with a trend for dosedependent effects for SBP]. With respect to control, cocoa flavonoids decreased SBP (p < 0.0001 for treatment) and DBP (p = 0.0011 for treatment). Accordingly, with respect to control, 24-h (mean difference −2.28 ± 1.22 mmHg) and daytime (mean difference −2.45 ± 1.57 mmHg) ambulatory SBP significantly decreased after active treatments, whereas no significant differences between treatments were observed for the monitored DBP levels. In addition, compared with control,
difference in the three experimental groups, demonstrating an unaffected function of vascular smooth muscle cells. These results give further support to the concept that (−)-epicatechin might modulate BP in hypertension by increasing NO levels in the vasculature. Moreover, the same group of authors18 showed that (−)-epicatechin administration prevented the 42 mmHg increase in BP associated with the inhibition of NO production in a dose-dependent manner (0.2−4.0 g/kg diet). This BP effect was associated with a reduction in L-nitro-L-argininemethyl ester (L-NAME)-mediated increase in the indices of oxidative stress (plasma TBARS and GSSG/GSH2 ratio) and with a restoration of the NO concentration. At the vascular level, none of the treatments modified NOS expression, but (−)-epicatechin administration avoided the L-NAME-mediated decrease in eNOS activity and increase in both superoxide anion production and NOX subunit p47(phox) expression. Thus, (−)-epicatechin resulted in the prevention of an increase in BP and oxidative stress and restored NO bioavailability.18 An additional experimental study by Cienfuegos-Jovellanos et al.19 showed that a single oral administration of natural flavonoid-enriched cocoa powder (procyanidins = 128.9 mg/g, especially monomers, dimers, and trimers = 54.1 mg/g, and mainly (−)-epicatechin = 19.36 mg/g) at different doses (50, 100, 300, and 600 mg/kg) decreased BP in SHRs but not in normotensive Wistar−Kyoto rats. The maximum effect in decreasing the SBP was caused by 300 mg/kg of cocoa powder. Interestingly, the antihypertensive effect was similar to that caused by 50 mg/kg captopril, a recognized antihypertensive agent inhibiting the angiotensin converting enzyme (ACE), thus supporting the hypothesis that, although the limitation of experimental data, flavanol-enriched cocoa powder might be used as a functional ingredient with antihypertensive effects.19 Accordingly, Sánchez et al.20 studied the effect of long-term intake of a soluble cocoa fiber product on the development of hypertension in SHRs. The active treatment reduced the development of hypertension, whereas the withdrawal of the cocoa intake promoted a BP increase.20 With regard to intervention trials, a number of clinical studies with cocoa and chocolate have involved different groups of subjects: normotensive (young, old, overweight, hypercholesterolemic), pre-hypertensive, and hypertensive with and without impaired glucose tolerance. Most of these trials reported an anti-hypertensive effect after cocoa/chocolate consumption. 21 Of note, we observed that a 15-day consumption of flavanol-rich but not flavanol-free chocolate was able to significantly lower both SBP and DBP in healthy subjects22 in hypertensive patients without (after dark chocolate, 24-h SBP −11.9 ± 7.7 mmHg, p < 0.0001; 24-h DBP −8.5 ± 5.0 mmHg, p < 0.0001)23 and with24 glucose intolerance. In the latter study,24 we observed that monitored as well as clinical SBP and DBP decreased (p < 0.0001) after flavanol-rich (SBP, −3.82 ± 2.40 mmHg; DBP, −3.92 ± 1.98 mmHg; 24-h SBP, −4.52 ± 3.94 mmHg; 24-h DBP, −4.17± 3.29 mmHg) but not after flavanol-free chocolate intake.24 Furthermore, the flavanol-rich chocolate administration significantly improved NO-dependent flow-mediated dilation of the brachial artery (p < 0.0001). Of clinical relevance, the decrement in BP was inversely correlated with the increase in flow-mediated dilation (SBP r = −0.547, p = 0.0004; DBP r = −0.488, p = 0.001; 24-h SBP r = −0.460, p = 0.003; 24-h DBP r = −0.457, p = 0.003). In agreement with the experimental findings, these results suggested a possible pathophysiological C
DOI: 10.1021/acs.jafc.5b01064 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry
Table 1. Mean Changes in SBP and DBP in Hypertensives, Pre-hypertensives, and Normotensives after Active Treatment or Placeboa difference in SBP/DBP at the end of treatment (active)
treatment/control groups Taubert et al. (2003)38 Grassi et al. (2005)23 Grassi et al. (2008)24 Muniyappa et al. (2008)39 Davison et al. (2010)28 Taubert et al. (2007)25 Heiss et al. (2010)40 Murphy et al. (2003)41 Engler et al. (2004)42 Fraga et al.(2005)43 Grassi et al. (2005)22 Crews et al. (2008)44 Davison et al. (2008)45 Al-Faris (2008)46 Shiina et al. (2009)47 Monagas et al. (2009)48 Njike et al. (2011)49 a
dark/white chocolate dark/white chocolate dark/white chocolate high-flavanol cocoa/low-flavanol drink
Studies in Hypertensives −4.8/−1.6 mmHg −12/−7.8 mmHg −3.8/−3.9 mmHg −2.0/−3.0 mmHg
difference in SBP/DBP at the end of treatment (control) +0.4/+0.3 mmHg −0.7/−0.6 mmHg −0.1/−0.2 mmHg −1.0/−4.0 mmHg
−4.1/−2 mmHg Studies in Pre-hypertensives dark/white chocolate −2.9/−1.9 mmHg high/low-flavanol drink −7/? Studies in Normotensives high/low-flavanol cocoa tablets +2.0/−1.0 mmHg high/low-flavanol chocolate −1.0/+0.9 mmHg dark/white chocolate −6.0/−5.0 mmHg dark/white chocolate −7.0/−4.2 mmHg dark chocolate + cocoa drink/low-flavanol −3.5/−0.5 mmHg chocolate + drink high-flavanol cocoa/low-flavanol drink −1.9/−1.8 mmHg dark/white chocolate −8.9/−5.3 mmHg dark/white chocolate +4.6/+6.6 mmHg cocoa powder in milk/milk 0.0/−2.0 mmHg
−2.1/−0.1 mmHg
high/low-flavanol chocolate
−0.1/+0.8 mmHg
high/low-flavanol cocoa drinks
+2.2/−0.5 mmHg
+0.1/0.0 mmHg −2/? +3.0/0.0 mmHg −2.8/−0.1 mmHg −2.0/−1.0 mmHg −0.5/−0.3 mmHg −3.1/−0.6 mmHg +4.2/+2.8 mmHg −1.3/−0.8 mmHg +4.0/+5.2 mmHg −3.0/−3.0 mmHg
Studies without control and without office blood pressure measures were excluded.
± standard error, SBP −3.2 ± 1.9 mmHg, p = 0.001; DBP, −2.0 ± 1.3 mmHg, p = 0.003). However, meta-analysis of subgroups suggested a significant anti-hypertensive effect only for the hypertensive or pre-hypertensive subgroups (SBP −5.0 ± 3.0 mmHg, p = 0.0009; DBP −2.7 ± 2.2 mmHg, p = 0.01), whereas BP was not significantly reduced in the normotensive subgroups (SBP −1.6 ± 2.3 mmHg, p = 0.17; DBP −1.3 ± 1.6 mmHg, p = 0.12). Of interest, nine trials used chocolate containing 50−70% cocoa compared with white chocolate or other cocoa-free controls, whereas six trials compared highwith low-flavanol cocoa products. Daily flavanol dosages ranged from 30 to 1000 mg in the active treatment groups, and interventions ran for 2−18 weeks. In addition, meta-regression analysis showed study design and type of control to be borderline significant but possibly indirect predictors for BP outcome.34 In contrast to previous meta-analyses, subgroup analyses by Ried et al.34 suggested that there was a difference in outcome dependent on baseline BP (hypertensive versus normotensive). Moreover, it seems important to remark that the relatively modest but significant BP-lowering effect of cocoa observed in the hypertensive subgroup should be considered of clinical relevance. A reduction of 5 mmHg in SBP has been shown to reduce the risk of cardiovascular events by about 20% over 5 years.1,2,35 Therefore, the effect of cocoa in hypertensive patients is comparable to other lifestyle modifications, such as moderate physical activity (30 min/day), which has been reported to decrease SBP by 4−9 mmHg.1,2,35 Thus, all of the above data confirmed that the ingestion of cocoa-rich and therefore flavonoid-rich chocolate might promote BP-lowering effects. However, not all of the results are univocal and in some case are even conflicting. Significant statistical heterogeneity across studies was observed, and considering the small number of subjects studied, the different quality assessment of trials and BP measurement method-
24-h daytime and night-time pulse pressure (PP) and nighttime heart rate significantly decreased after active treatments, but the effects did not seem to be dose-dependent.30 Consistent with our data, Shrime et al.,31 in a meta-analysis evaluating 24 short-term studies, showed that in response to flavonoid-rich chocolate consumption, SBP, but not DBP, decreased by −1.63 mmHg (p = 0.033). Finally, reviewing all of the findings regarding BP effects of cocoa and chocolate intake, an early meta-analysis32 reported that chocolate and cocoa intake was able to significantly reduce SBP (−5.88 mmHg; −9.55, −2.21; five studies) and DBP (−3.30 mmHg; −5.77, −0.83; four studies) (effects appeared greater in studies with higher doses and shorter duration), whereas chronic intake of other flavanols (with ≥3 included studies) did not show any effect on BP. In agreement with our findings on BP, Hooper et al.33 systematically reviewed 42 acute or short-term chronic (≤18 weeks) studies involving 1297 participants and recently reported chocolate and cocoa are able to reduce DBP and mean arterial pressure. In particular, we observed a decrease in office DBP (mean difference − 3.03 ± 1.07 mmHg; p < 0.001), with doses of cocoa flavonoids >500 mg and epicatechins >105 mg. Consistent with our results on DBP, the above cited metaanalysis showed significant reductions in DBP after cocoa and/ or chocolate administration (−1.60 mmHg; 95% CI −2.77, −0.43 mmHg) considering 22 trials with 918 participants. Furthermore, in line with our study on dose−responses in heathy subjects (significant effects in SBP for epicatechins >42 mg and DBP >105 mg), the meta-analysis showed (with different kinds of treatments: cocoa, chocolate, or both) that doses >50 mg of epicatechin/day reduced SBP and DBP, whereas doses
