Berry (Poly)phenols and Cardiovascular Health - Journal of

Review pubs.acs.org/JAFC

Berry (Poly)phenols and Cardiovascular Health Ana Rodriguez-Mateos,*,† Christian Heiss,† Gina Borges,§ and Alan Crozier§ †

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany § Plant Products and Human Nutrition Group, School of Medicine, College of Medical, Veterinary and Life Sciences, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom ABSTRACT: Berries are a rich source of (poly)phenols, including anthocyanins, flavan-3-ols, procyanidins, flavonols, ellagitannins, and hydroxycinnamates. Epidemiological evidence indicates that the cardiovascular health benefits of diets rich in berries are related to their (poly)phenol content. These findings are supported by small-scale randomized controlled studies (RCTs) that have shown improvements in several surrogate markers of cardiovascular risk such as blood pressure, endothelial function, arterial stiffness, and blood lipids after acute and short-term consumption of blueberries, strawberries, cranberries, or purified anthocyanin extracts in healthy or diseased individuals. However, firm conclusions regarding the preventive value of berry (poly)phenols cannot be drawn due to the small number of existing studies and limitations that apply to the available data, such as lack of controls or failure to assess the absorption and metabolism of (poly)phenols. Although the current evidence is promising, more long-term RCTs are needed to establish the role of berry (poly)phenols to support cardiovascular health. KEYWORDS: berries, (poly)phenols, flavonoids, tannins, cardiovascular disease

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INTRODUCTION Diet has been recognized as an important determinant of cardiovascular risk. Epidemiological evidence has indicated that the consumption of diets rich in fruits and vegetables is associated with a decrease in the risk of cardiovascular disease (CVD).1−3 The cardioprotective effects of such diets are often attributed to their (poly)phenol content. Indeed, epidemiological evidence also indicates that there is an association between high dietary intake of (poly)phenols and the decreased risk of CVD.4−7 In recent years, berry fruits have generated a lot of interest due to their low calories and high content of potential bioactive compounds, such as (poly)phenols, fiber, minerals, and vitamins. In vitro and animal studies designed to investigate their potential bioactivities have been conducted. However, the results obtained should be interpreted with care due to the inherent limitations of such models. For example, many in vitro studies have not taken account of the extensive metabolism of flavonoids that occurs in vivo or the very different bioavailability profiles of the various flavonoid subclasses.8 As a consequence, such studies have failed to assess the bioactivity of the relevant human (poly)phenol metabolites at biologically relevant concentrations. In addition, investigations have not taken account of the differing bioavailability and metabolism of (poly)phenols between animals and humans. Taken together, this means that, by far, the most effective way of assessing the efficacy of (poly)phenols in the human vascular system are randomized controlled trials (RCTs) that are sufficiently powered using relevant endpoints over relevant timeframes. This review will attempt to highlight the best-controlled and most physiologically relevant evidence supporting the link between berry (poly)phenol intake and cardiovascular health. In particular, we will focus on well-controlled, randomized, human intervention studies examining the protective effects of © XXXX American Chemical Society

berry (poly)phenols on accredited clinically relevant risk markers.

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CLASSIFICATION OF BERRY (POLY)PHENOLS (Poly)phenols are plant secondary metabolites that are present in many fruits and vegetables. The major class of (poly)phenols is the flavonoids, comprising six main subclasses: anthocyanins, flavan-3-ols, flavonols, flavanones, flavones, and isoflavones.8 In berries, the most abundant class of flavonoids is the anthocyanins. The most common anthocyanidin aglycones are pelargonidin, cyanidin, delphinidin, peonidin, petunidin, and malvidin (Figure 1), which form conjugates with sugars and organic acids to generate numerous anthocyanins. Berries have different types of anthocyanins; for example, strawberries have only pelargonidin conjugates, whereas blueberries contain cyanidin, delphinidin, malvidin, petunidin, and peonidin conjugates.9 Significant amounts of other flavonoids such as flavan-3-ols and quercetin-based flavonols are also present, together with nonflavonoid (poly)phenols including chlorogenic acids, phenolic acids, hydroxycinnamates, ellagitannins, and stilbenes (Figure 2). Flavan-3-ols are the most complex subclass of flavonoids, ranging from simple monomers to oligomeric and polymeric procyanidins, which are also known as condensed or nonhydrolyzable tannins. The two chiral centers at C-2 and C-3 of the monomeric flavan-3-ol produce four isomers for each level of B-ring hydroxylation, two of which, (+)-catechin and (−)-epicatechin, are found in berries such as blueberries.10 Special Issue: 2013 Berry Health Benefits Symposium Received: August 23, 2013 Revised: September 19, 2013 Accepted: September 23, 2013

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dx.doi.org/10.1021/jf403757g | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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hydroxycinnamates include ferulic acid and p-coumaric acid.10 Berries can also contain phenolic acids, including gallic acid, whereas ellagic acid-based ellagitannins, such as sanguiin H-6 (Figure 2), have a much more widespread occurrence, being found in a diversity of berries including raspberries, strawberries, and blackberries. Stilbenes, such a resveratrol-3O-glucoside (Figure 2), occur in some berries but typically in relatively small amounts.

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EVIDENCE FROM EPIDEMIOLOGICAL STUDIES

Epidemiological studies suggest that the daily intake of berry flavonoids, in particular, anthocyanins, may have cardioprotective effects in humans.4−7,12 The Iowa Women’s Health prospective study followed nearly 35,000 postmenopausal women for 16 years and estimated the intake of seven flavonoid subclasses using the USDA database. The intake of anthocyanins was associated with a reduced risk of coronary heart disease (CHD) and CVD-related mortality.7 This study also highlighted bran, apple, pear, chocolate, red wine, and strawberries as being the foods most likely to contribute significantly to reductions in disease risk. A more recent prospective study has found an inverse correlation between flavonoid intake and risk of death from CVD in a population of nearly 100,000 men and women of around 70 years of age.6 In this study, a higher intake of flavonoids (512 vs 94 mg/day) was associated with an 18% lower risk of CVD death. In addition, anthocyanins, flavan-3-ols, flavonols, proanthocyanidins, and flavones were also associated with a 14−17% lower risk of CVD death. Some data have been obtained with even younger populations, in particular, women, whose CVD risk increases significantly after menopause. A 2013 study found an association between higher anthocyanin intake and a 32% decrease in the risk of myocardial infarction (MI) in nearly 100,000 women 25−45 years of age, after a follow up period of 18 years.4 For every 15 mg increase of anthocyanins in their diet, a 17% decrease in the risk of MI was observed. Strawberry

Figure 1. Structures of the major berry anthocyanidins.

Oligomeric and polymeric proanthocyanidins have an additional chiral center at C-4 in the “upper” and “lower” units. Type B proanthocyanidins are formed from (+)-catechin and (−)-epicatechin by oxidative coupling between the C-4 of the “upper” monomer and the C-6 or C-8 of the adjacent “lower” or “extension” unit to create oligomers or polymers, and they are present in blueberries, for example. Type A proanthocyanidins have an additional ether bond between C-2 in the B-ring of one monomer and C-7 in the A-ring of the other monomer (Figure 2), and they are found in cranberries. Proanthocyanidins can occur as polymers of up to 50 units. Proanthocyanidins that consist exclusively of (epi)catechin units are called procyanidins and are the most abundant type of proanthocyanidins in plants.9 The nonflavonoids present in berries include hydroxycinnamates, such as the chlorogenic acids, of which 5-Ocaffeoylquinic acid is the most widely distributed and which has been found in substantial amounts in blueberries.11 Other

Figure 2. Structures of (poly)phenolic compounds occurring in berries. B


C

healthy healthy smokers CVDd risk obese MSg obese dyslipidemic hyperchole hyperchole prehypertensj prehypertensj MIf obese MSg T2Dk healthy T2Dk CADc obese MSg healthy healthy postmeni healthy CVDd risk

blueberries, freeze-dried blueberries, frozen blueberries, fresh blueberries, freeze-dried blueberries, freeze-dried blueberries, freeze-dried bilberry/black currant ACNa bilberry/black currant ACNa bilberry/black currant ACNa bilberry/black currant ACNa bilberry/black currant ACNa chokeberry extract cranberry juice cranberry juice cranberry extract cranberry juice cranberry extract cranberry juice strawberries, freeze-dried strawberries, freeze-dried elderberry extract elderberry extract 1 56

1 1 21 42 56 45 84 90 168 28 28 45 28 56 84 14 84 28 21 28 14 56

days

= +

=

= = =

= =

= = = = + = = + = = = +

BP

= +

= + = = = + + = =

+ =

= = = + + +

+

=

=

=

arterial lipids stiffness

=

=

+

=

+ =

endothelial function

= =

=

=

= =

+ =

= = = = =

+

=

glucose platelet

750 mL 240 mL 480 mL 320 g 500 g 5 mL 25 g 250 mL 160 g

204 mg TP,l 50 mg ACNa 835 mg TP,l 515 mg ACNa

500 mL 480 mL

100−560 g 300 g 250 g 148 g 350 g ≈280 g

+ +

+ + − − − − − + − − + − − − − − − − − − + +

fresh fruit or juice absorption

319−1791 mg TP,l 129−724 mg ACN,a 14−637 mg CAb 727 mg TP,l 348 mg ACN,a 90 mg CAb ndh 375 mg ACN,a 127 mg CAb 1624 mg TP,l 742 mg ACNa 1462 mg TP,l 668 mg ACNa 160 mg ACNa 320 mg ACNa 320 mg ACNa 640 mg ACNa 640 mg ACNa 215 mg TP,l 64 mg ACNa 400 mg TP,l 21 mg ACNa 458 mg TP,l 25 mg ACNa ndh 2.1 mg ACNa ndh 835 mg TP,l 94 mg ACNa ndh 200 mg TP,l 154 mg ACNa 40 mg ACNa 500 mg ACNa

(poly)phenol content

+ −

+ + + + − + + + + + + + + + + + + + + − + +

double blind

33 34

24 21 22 23 20 19 36 37 47 35 52 25 29 26 28 49 48 27 31 30 38 32

ref

a ACN, anthocyanins. bCA, chlorogenic acid. cCAD, coronary artery disease. dCVD, cardiovascular disease. ehyperchol, hypercholesterolemic. fMI, myocardial infarction. gMS, metabolic syndrome. hnd, not determined. ipostmen, postmenopausal. jprehypertens, prehypertensive. kT2D, type 2 diabetes. lTP, total (poly)phenols.

black currant juice mixed berries, frozen

population

type of berry

Table 1. Summary of Randomized Controlled Trials Investigating the Effect of Berry (Poly)phenols on Surrogate Markers of Cardiovascular Disease Risk

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surrogate markers of CVD risk, including hypertension, endothelial dysfunction, arterial stiffness, lipid metabolism, and platelet activation. In this section, we will discuss the most relevant human RCTs, in which at least one of these markers has been assessed. Effects on Blood Pressure. Hypertension is a major risk factor for CVD and has been associated with the development of atherosclerosis and the progression of the disease.18 Several studies have investigated changes in blood pressure after intake of blueberries,19−24 chokeberries,25 cranberries,26−29 strawberries,30,31 elderberries,32 black currants,33 mixed berries,34 or purified anthocyanins35−37 (Table 1). The length of these studies ranged from 1 to 90 days, and the study populations consisted mainly of people at risk or with CVD, but in a few studies healthy individuals were also tested.21,24,32,33,38 From these investigations, only two double-blind RCTs, conducted with MI survivors and hypercholesterolemics, have shown improvements in blood pressure after berry consumption.25,37 A 6 week supplementation with a chokeberry extract containing 64 mg of anthocyanins, 128 mg of procyanidins, and 23 mg of phenolic acids showed decreases in both systolic (SBP) and diastolic (DBP) blood pressure by 11 and 7.2 mmHg, respectively, in 44 MI survivors receiving statin therapy.25 In another double-blind RCT, a decrease in SBP of 6.7 mmHg was observed in hypercholesteromic individuals after 12 weeks of daily consumption of 320 mg of berry anthocyanins in comparison to baseline values. However, when compared with the placebo group, the change in SBP was not significant.37 In addition, two single-blinded RCTs have reported changes in blood pressure.20,34 Decreases in SBP of 6% and in DBP of 4% were observed after a 56 day supplementation with freezedried blueberries containing 1624 mg of total (poly)phenols and 742 mg of anthocyanins (equivalent to 350 g of fresh berries) by individuals with metabolic syndrome (MS).20 Although smaller, significant reductions in blood pressure were also observed in the control group (decreases of 1.5 and 1.2% in SBP and DBP, respectively). The control intervention consisted of 950 mL of water per day, which was the same amount of water taken with the blueberry drink by the volunteers on the blueberry intervention arm. Another singleblinded study has shown a modest decrease in systolic blood pressure (1.2%) after an 8 week consumption of a mixture of bilberries, lingonberries, black currants, strawberry puree, and chokeberry and raspberry juice (837 mg of total (poly)phenols, 515 mg of anthocyanins) by a middle-aged population at risk of CVD.34 The control used in this study was a mix of porridge, sugar water, and marmalade sweets. The results of those two studies should be interpreted with caution as these studies were not double-blinded, and controls were not macro- and micronutrient-matched to the berry intervention. In most of the investigations mentioned above, blood pressure was not the primary outcome of the study. Furthermore, with one exception, none of the studies used 24 h ambulatory blood pressure, which is the gold standard technique for the measurement of blood pressure. In a doubleblind crossover RCT, Hassellund and colleagues35 investigated the effects of a 4 week supplementation of purified berry anthocyanins (2 × 320 mg) on sitting, supine, and 24 h ambulatory blood pressure in 27 healthy men with blood pressure >140/90 mmHg. No changes in sitting systolic blood pressure (primary end point), supine, or ambulatory blood

and blueberry intake also tended to be associated with a decrease in risk. Cardiovascular health is determined by not only the absence of CVD but also the function of the cardiovascular system. A cross-sectional study investigated nearly 2000 women between 18 and 75 years old for 11 years and found an inverse correlation between a higher anthocyanin intake and lower arterial stiffness and central blood pressure.12 An increase in the diet of 44 mg of anthocyanins/day was associated with a decrease in systolic BP of 3 mmHg and a decrease in pulse wave velocity (PWV) of 0.4 m/s. Interestingly, berries and red wine were also associated with a decrease in PWV. Furthermore, a large prospective study in men and women under 60 years of age that were followed up for 14 years also showed an association between a higher anthocyanin intake in their diets, mainly from strawberries and blueberries, and an 8% reduced risk of incident hypertension.5 Despite these encouraging data sets, there are several epidemiological studies that have found no relationship between berry flavonoid intake and cardiovascular risk.13−17 Discrepancies between studies of this nature may be due to inadequacies in the ability of commonly used dietary intake questionnaires and food composition tables to accurately assess flavonoid intake in human populations or may even result from issues surrounding the nature of the human population studied with, for example, populations with a high baseline flavonoid intake showing no effect. To avoid such discrepancies, future observational studies must attempt to assess flavonoid intake via the analysis of reliable biomarkers of their intake in plasma, urine, or stool samples.

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EVIDENCE FROM RANDOMIZED CONTROLLED TRIALS Although epidemiological investigations are showing promising results regarding the potential role of berry (poly)phenols in cardiovascular health, as described in the previous section, to confirm if such observations are genuine and to build potential cause-and-effect relationships between berry (poly)phenols and clinically relevant end points of CVD risk, RCTs are necessary, as they are the most reliable method to investigate cause-andeffect relationships. In recent years, several such trials have been conducted, although many exhibit profound limitations. The most important limitations include lack of blinding, absence of proper controls, and lack of detailed compositional analysis of the foods that were tested. For example, to make inferences related to potential causal relationships between (poly)phenol intake and the clinical outcomes being assessed, a suitable control intervention is essential. Ideally, controls should be indistinguishable in taste and appearance from the intervention tested and accurately matched for micro- and macronutrient composition, including other potential bioactive compounds. So far, the basic understanding of berry (poly)phenol pharmacokinetics is incomplete, and to date the absorption and metabolism of many berry (poly)phenols have not been investigated. It is an important prerequisite to assess whether (poly)phenols, or more likely their metabolites, are indeed entering the circulatory system and may only then qualify for mediating the observed effects. To date, no RCTs have investigated the effects of berry (poly)phenols on hard CVD end points, such as MI, or CVD mortality. However, there have been a number of short-term, small-scale, human intervention studies designed to test the effect of (poly)phenol-rich berries on prognostically validated D



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in endoPAT were observed after a 6 week supplementation with a blueberry drink (375 mg of anthocyanins, 127 mg of 5O-caffeoylquinic acid) by men at risk of CVD.23 In another study, laser-Doppler iontophoresis was used to measure cutaneous perfusion microvascular function, with no improvements observed 2 h postconsumption of black currant juice by healthy volunteers.33 More studies are needed to confirm that (poly)phenol-rich berries can improve endothelial function, in particular, over longer periods of time with healthy populations. Effects on Arterial Stiffness. Arterial stiffness has been associated with the risk of CVD, and increased arterial stiffness is a recognized cardiovascular risk factor.42−44 PWV, in particular, carotid−femoral PWV, is considered the most robust and reproducible method for measuring arterial stiffness.43 A crossover RCT involving volunteers with coronary artery disease (CAD) showed a decrease in carotid−femoral PWV of 0.5 m/s after consumption of cranberry juice (835 mg of total (poly)phenols, 94 mg of anthocyanins) for 4 weeks.27 In contrast, acute supplementation of a blueberry drink (766− 1791 mg of total (poly)phenols, 310−724 mg of anthocyanins, 137−20 mg of procyanidins, 273−637 mg of 5-O-caffeoylquinic acid) had no effect on carotid−femoral PWV in healthy men.24 Arguably, this suggests that chronic berry supplementation may be necessary to induce improvements in arterial stiffness in healthy young men. Augmentation index (AI), another marker of arterial stiffness, has also been correlated with cardiovascular risk.43,44 RCTs have found no changes in AI after a 4 week supplementation with cranberry juice (400 mg of total (poly)phenols, 21 mg of anthocyanins) by obese volunteers 23 and a 6 week supplementation with a blueberry drink (375 mg of anthocyanins, 127 mg of 5-O-caffeoylquinic acid) by subjects at risk of CVD.29 To date, insufficient evidence exists to correlate berry (poly)phenol intake and improvements in arterial stiffness, although data from a well-conducted doubleblind RCT with cranberry juice described above12 and a crosssectional study described in the epidemiology section,27 in which a decrease in PWV was reported to be associated with a higher intake of anthocyanins in the diet and with berry intake, are promising. Effects on Blood Lipids. Hypercholesterolemia is one of the major risk factors for the development of CVD. In particular, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and total serum cholesterol levels (LDL-C, HDL-C, TC, respectively) have been related to cardiovascular risk.45,46 The strongest evidence regarding the effect of berry (poly)phenols on blood lipids comes from studies conducted in dyslipidemic populations using purified bilberry and black currant anthocyanin extracts (Table 1). A 12 week study with bilberry and black currant anthocyanins (160 mg/day) involving 120 dyslipidemic subjects reported an increase of 14% in HDL-C and a decrease in LDL-C of 14%, with no changes in TC or triglycerides (TAG).36 In a parallel study with a similar population of hypercholesterolemics, daily consumption of 320 mg of bilberry and black currant anthocyanins resulted in a 12% increase in HDL-C, a 10% decrease in LDL-C, and no changes in TC or TAG.37 The same investigators also reported a 14% increase in HDL-C and a 10% decrease in LDL-C when the daily 320 mg anthocyanin intake by the same or similar populations was extended to 24 weeks.47 This suggests that long-term berry consumption leads to sustained and clinically relevant improvement in blood lipids.

pressure after anthocyanin supplementation were observed in this study. In summary, there is not enough evidence to support the involvement of berry (poly)phenols in lowering blood pressure. More controlled intervention studies in relevant populations over adequate time scales are required. Effects on Endothelial Function. In the context of prognosis, endothelial dysfunction is an important process underlying the development and progression of atherosclerosis.39 It is characterized by decreased bioactivity of nitric oxide and impaired flow-mediated vasodilation (FMD). Measurement of FMD of the brachial artery using highresolution ultrasound is the most widely used validated method to assess endothelial function in humans.40 Several studies have tested the effect of (poly)phenol-rich foods on FMD. The strongest evidence is the positive effects of flavan-3-ol-rich foods, such as cocoa or tea, on endothelial function after acute or short-term supplementation.8,41 However, limited data exist regarding the effects of berry consumption on endothelial function (Table 1),21,23,24,27,33,37 with only four RCT studies having investigated the effects of berry (poly)phenols on FMD.24,27,37 A recent double-blind crossover RCT conducted with healthy young men has shown significant improvements in FMD at 1, 2, and 6 h postconsumption of a wild blueberry drink containing 766−1791 mg of total (poly)phenols (310− 724 mg of anthocyanins, 137−320 mg of procyanidins, and 273−637 mg of 5-O-caffeoylquinic acid).24 The effects observed at 1−2 h were correlated with increases in plasma metabolites possibly derived from the metabolism and/or breakdown of anthocyanins and 5-O-caffeoylquinic acid, whereas the effects observed at 6 h were linked to gut microbial metabolites. A second crossover RCT, with a very similar population, investigated the intake dependency of blueberry (poly)phenols on FMD. This revealed that FMD increased with increasing intake from 319 to 766 mg of total (poly)phenols (129−310 mg of anthocyanins, 57−137 mg of procyanidins, 114−273 mg of 5-O-caffeoylquinic acid, equivalent to 100−240 g of fresh blueberries), after which FMD plateaued.24 The effects on FMD observed are likely to be at least in part related to the anthocyanin content of blueberries, as in a crossover study with 12 hypercholesterolemic individuals, 1 and 2 h after acute consumption of a purified bilberry and black currant anthocyanin extract (320 mg of anthocyanins), FMD improved, by 2.7 and 1.8%, respectively, in parallel with the increases in plasma anthocyanin levels.37 The magnitude of the changes in FMD were very similar to those obtained after consumption of blueberries (2.4 and 1.5% at 1 and 2 h, respectively). The short-term effects of anthocyanin consumption were also investigated in a parallel study with 150 hypercholesterolemic individuals, with a 2.8% increase in FMD observed after a 12 week supplementation.37 Another study with cranberry juice failed to show an improvement on FMD after a 4 week supplementation by 44 CHD patients. However, an uncontrolled pilot study with 15 of these patients showed a 1% improvement in FMD 4 h after cranberry juice consumption.27 Some studies have used alternative techniques, such as peripheral artery tonometry (PAT) of the fingertips, to measure endothelial function. No changes were observed in acute endoPAT vascular function in healthy volunteers after consumption of 300 g of blueberries containing 348 mg of anthocyanins (1 h postconsumption).21 Similarly, no changes E



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reactivity in response to stimulation to ADP and collagen after daily consumption of 500 mg of elderberry anthocyanins by healthy postmenopausal women.32 In contrast, a single-blinded study has shown a decrease in platelet aggregation after consumption of mixed berries (837 mg of total (poly)phenols, 515 mg of anthocyanins) for 8 weeks by a middle-aged population at risk of CVD.34 Berry consumption inhibited platelet function by 11% as measured with a platelet function analyzer using collagen and ADP as platelet activators. Doubleblind RCTs are needed to confirm these interesting observations. Effect on Blood Glucose Levels and Insulin Resistance. Most of the RCTs conducted with berries have reported no changes in serum glucose levels after cranberry, blueberry, strawberry, elderberry, chokeberry, or pure anthocyanin interventions (Table 1),19,23,25,28,31,32,36,37,48 except for one study with 31 prehypertensive men who received a daily supplement of 640 mg of purified bilberry and black currant anthocyanins for a period of 1 month.52 One RCT produced an improvement in insulin sensitivity after consumption of a blueberry smoothie for 6 weeks (1462 mg of total (poly)phenols, 668 mg of anthocyanins) by obese, nondiabetic insulin-resistant individuals.19 This study used the gold standard technique for the measurement of insulin sensitivity, the hyperinsulinemic−euglycemic clamp, and observed a 22% improvement in the blueberry group as compared with 5% in the control group. Two studies investigating insulin resistance in type 2 diabetics and dyslipidemics in a cranberry and purified anthocyanin intervention detected no changes in the homeostatic model of assessment of insulin resistance (HOMA-IR).28,37 This is a less invasive, cheaper, and less labor intensive model for assessing insulin sensitivity, but it has certain limitations. More work is needed to investigate whether berry (poly)phenols can lower blood sugar and improve insulin resistance, with the potential of being therapeutic agents for the treatment of diabetes.

In addition to these studies with pure anthocyanins, several studies have shown that similar effects on blood lipids can be observed following berry supplementation (Table 1). A 3 week RCT with freeze-dried strawberries (equivalent to 320 g fresh weight) produced a decrease in TC of about 4% in obese individuals, with no changes in HDL-C, LDL-C, or TAG.31 Unfortunately, the (poly)phenol content of the freeze-dried strawberries was not determined. The authors speculated that the 8 g of fiber in the intervention may have been partly responsible for the observed effects, as the control was matched for sugars, flavor, and color but not for fiber. A strength of this study is that the background diet was strictly controlled over the intervention, with all subjects following a controlled diet starting 1 week before initiation of the intervention and maintained during the 7 week supplementation period. However, no washout period between the intervention and the control arm was included, which may have confounding effects on the outcomes of the study due to potential carry-over effects. Another 4 week study with freeze-dried strawberry powder (equivalent to 500 g of fresh weight, 200 mg of total (poly)phenols, 154 mg of anthocyanins) in MS subjects produced 10 and 11% decreases in TC and LDL-C, respectively.30 This RCT was single blinded as the control arm consisted of four cups of water, which was the amount of liquid ingested with the strawberry intervention. Thus, the control was not matched to the strawberry intervention for macro- and micronutrients. With cranberry, decreases in LDL-C and TC were observed in 32 type 2 diabetics after daily consumption of 3 × 500 mg of an encapsulated cranberry extract over 12 weeks.28 HDL-C and TAG did not differ between the intervention and control arms. Unfortunately, the (poly)phenol content of the intervention was not reported, so it is difficult to draw conclusions on the cause and effect relationship between the effects observed and the (poly)phenol amount ingested. In contrast to these findings, no changes were observed in three RCTs with cranberry interventions involving MS, type 2 diabetes, and healthy individuals,26,48,49 or after black currant, blueberry, chokeberry, and elderberry supplementation in healthy individuals, subjects with CVD risk factors, and MI survivors (Table 1).19,25,32,33,38 In a single-blinded study, a 5% increase in HDL-C was reported after 8 weeks’ consumption of mixed berries (837 mg of total (poly)phenols, 515 mg of anthocyanins) by a middle-aged population at risk of CVD,34 with no changes in TAG, TC, and LDL-C being observed. Taken together, there is consistent evidence on the favorable effects of 12−24 week daily intake of 160−320 mg of anthocyanins on blood lipids in dyslipidemic individuals, and some evidence exists regarding improvements in obese/MS subjects after strawberry supplementation for 3−4 weeks. The potential beneficial effects of other berry (poly)phenols on blood lipids is at present unclear. Effects on Platelet Aggregation. Another significant effect that has been attributed to (poly)phenols is the ability to inhibit platelet activation and, thus, the formation of blood clots, a key mechanism implicated in the pathophysiology of atherosclerosis. Platelets play an important role in the early stages of atherosclerosis and coronary thrombosis, and several studies have reported an inhibition of platelet activation after consumption of cocoa flavan-3-ols.50,51 Only two RCTs have investigated the effect of berry (poly)phenol consumption on platelet activation and aggregation (Table 1). In a 12 week double-blind RCT, no changes were reported in platelet

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MECHANISMS OF ACTION As well as providing evidence on the efficacy of berry (poly)phenols to improve cardiovascular risk surrogates, several RCTs have attempted to supply evidence for potential mechanisms of action. For example, Zhu et al.37 reported an increase in serum cGMP in hypercholesterolemics after a 12 week supplementation with 320 mg of purified anthocyanins, and this was paralleled by increases in FMD (r = 0.428, p < 0.05). Importantly, when an intravenous infusion of L-Nmonomethylarginine (L-NMMA), a competitive nitric oxide synthase (NOS) inhibitor, was given to six participants, the beneficial effects of the anthocyanins on FMD were abolished, and significant changes in hyperemic blood flow and blood pressure were observed between the anthocyanin and LNMMA/anthocyanin interventions. This suggests that the mechanism of action of anthocyanins in the vasculature involves the nitric oxide/cGMP signaling pathway. It has recently been shown with healthy volunteers, 1, 2, and 6 h postconsumption, that blueberry-related increases in FMD were correlated with plasma levels of blueberry (poly)phenol metabolites and decreases in neutrophil NADPH oxidase activity.24 The phenolic metabolites have a structure similar to the NADPH oxidase inhibitor apocynin (acetovanillone), and it has been proposed that in an in vitro model of endothelial cells they act as potent NAPDH oxidase inhibitors.53 A decrease in F



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molecular pathways such as cholesterol metabolism, inflammatory process and cell adhesion, oxidative stress, inflammation, angiogenesis, and transendothelial migration.59,60 Another study with apoE deficient mice fed a 1% freeze-dried blueberry diet for 20 weeks reported that the supplement attenuated foam cell formation, which is an early stage of the development of atherosclerosis, by down-regulating the scavenger receptors SRA and CD36, which are the major receptors responsible for the binding and uptake of modified LDL in macrophages.61 (Poly)phenol colonic catabolites found in the serum of mice after blueberry consumption were also shown to inhibit mRNA expression and protein levels of pro-inflammatory cytokines TNF-α and IL-6, by reducing phosphorylation levels of MAPK JNK, p38, and Erk 1/2 in a murine macrophage cell line.62 In a study using diabetic apoE deficient mice, supplementation with 0.2% cyanidin-3-O-glucoside for 6 weeks lowered the aortic lesion area by 45%, improved endothelium-dependent vasorelaxation, and increased the capacity of in vitro adhesion to fibronectin, migration, and tube formation of endothelial progenitor cells (EPCs).63 The mechanism for these improvements involved higher phosphorylation levels of AMP-activated protein kinase Thr 172 and endothelial nitric oxide synthase Ser1177 in EPCs derived from the cyanidin-3-O-glucosidetreated diabetic mice compared with those in nondiabetic mice. Physiologically relevant berry supplementations in different animal models, such as rats, Syrian golden hamsters, or pigs, have shown an array of beneficial effects such as reduced mortality after induced MI, inhibition of aortic lipid deposition, lowering of blood pressure, improvements in endotheliumdependent vasorelaxation, and decreases in plasma TC and LDL-C.57,64−70 More efforts are needed to confirm the mechanisms that have been proposed to mediate the observed effects, using relevant in vivo models or in vitro models with circulating metabolites and microbial catabolites at biological concentrations.

NADPH oxidase activity has previously been linked to alterations in nitric oxide levels via inhibition of superoxide production,53,54 and the inhibition of NADPH oxidase activity has been proposed as the main mechanism mediating the shortterm improvements in FMD observed after consumption of (−)-epicatechin.55 These findings suggest that blueberry (poly)phenol metabolites may mediate improvements in endothelial function by increasing the bioavailability of nitric oxide via their potential to inhibit NAPDH-oxidase. However, further work is needed to confirm whether this is indeed the case. In another study with purified berry anthocyanins in dyslipidemics, anthocyanins were shown to decrease the mass and activity of plasma cholesteryl ester transfer protein (CETP), a plasma protein that mediates the removal of cholesteryl ester HDL in exchange for a triglyceride molecule derived primarily from LDL, VLDL, or chylomicrons. The decreased levels of this protein have been suggested as a possible mechanism for the increase in HDL-C and decrease in LDL-C.36 It was also found that changes in HDL-C correlated with the changes in CETP activity and that changes in LDL-C correlated with changes in CETP mass, whereas changes in cellular cholesterol efflux to serum positively correlated with changes in HDL-C. Thus, it is feasible to hypothesize that anthocyanins may act as CETP inhibitors.36 Numerous in vitro and animal studies have been conducted to investigate the mechanisms of action of berry (poly)phenols. Of note, many of these investigations using cell lines have made extensive use of berry extracts, (poly)phenolic aglycones, or sugar conjugates, at concentrations in the low micromolar to millimolar range. However, following ingestion, most berry (poly)phenolics appear in plasma not as the parent compound but as phase II metabolites, and their presence in the circulation after dietary intake rarely exceeds nanomolar concentrations. With in vivo studies, the same issues apply. When animal studies, such as human RCTs, are conducted, experimental design is of importance and should take into account factors such as a suitable control, characterized intervention, and blinding. Much of the in vivo mechanistic evidence comes from studies conducted with apoE deficient mice, a widely used animal model of accelerated atherosclerosis. Using this model, after a 20 week supplementation with a diet containing 1% freeze-dried blueberries, fewer atherosclerotic lesions were observed, with a decrease of 39% in the lesion area of the aortic sinus and a 58% decrease in the descending aorta.56 These effects were independent of the blood lipid profile and the total plasma antioxidant capacity. Furthermore, four major antioxidant enzymes were up-regulated in blueberry-fed mice (superoxide dismutase (SOD) 1 and 2, glutathione reductase (GSR), and thioredoxin reductase 1), with the activities of SOD and GSR being higher in the liver and serum. An increase in hepatic SOD and GSR has also been reported together with an increase in plasma paraoxonase activity after intake of raspberry juice for 12 weeks by Syrian golden hamsters fed an atherogenic diet.57 These studies suggest a potential mechanism of action for berries against atherosclerosis by inhibition of lipid peroxidation and enhancement of antioxidant defenses. Similarly, supplementation of apoE deficient mice with a 0.02% bilberry extract for 16 weeks inhibited plaque development.58 Microarray analysis of the liver and the aorta of the animals after a 2 week supplementation with the bilberry extract indicated modulated gene expression, with respective changes in 2289 and 1261 genes involved in various cellular and

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SUMMARY Although evidence for the cardiovascular benefits of berry (poly)phenols in humans is accumulating, their role in the prevention of CVD is, at present, unclear. Recent epidemiological studies have shown associations between higher berry flavonoid intake and lower risk of CVD, and a number of smallscale, human intervention studies have shed some light on the beneficial effects of various berry (poly)phenol-rich foods on surrogate markers of CVD risk. Whereas there is some evidence to suggest that acute and/or short-term consumption of berry (poly)phenols can have a positive effect on blood lipids or vascular function, the long-term effects of berry interventions are currently unknown, and RCTs with hard clinical end points are lacking. As a consequence, uncertainty remains regarding which specific (poly)phenols are directly responsible for beneficial actions in vivo, as berries contain not only anthocyanins but a diversity of (poly)phenolic compounds.9 Investigations using pure anthocyanins are encouraging, suggesting that anthocyanins may be at least mediating part of the observed beneficial effects. Few studies have assessed the absorption and metabolism of berry (poly)phenols, which is a critical factor in establishing potential cause-and-effect relationships. More short- and long-term double-blind randomized studies, using well-characterized interventions and adequate controls and clinically relevant end points, are needed before conclusions can be drawn regarding their efficacy. The outcomes of such studies may help to elucidate the role of G



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(10) Taruscio, T. G.; Barney, D. L.; Exon, J. Content and profile of flavanoid and phenolic acid compounds in conjunction with the antioxidant capacity for a variety of northwest Vaccinium berries. J. Agric. Food Chem. 2004, 52, 3169−3176. (11) Rodriguez-Mateos, A.; Cifuentes-Gomez, T.; Tabatabaee, S.; Lecras, C.; Spencer, J. P. Procyanidin, anthocyanin, and chlorogenic acid contents of highbush and lowbush blueberries. J. Agric. Food Chem. 2012, 60, 5772−5778. (12) Jennings, A.; Welch, A. A.; Fairweather-Tait, S. J.; Kay, C.; Minihane, A. M.; Chowienczyk, P.; Jiang, B.; Cecelja, M.; Spector, T.; Macgregor, A.; Cassidy, A. Higher anthocyanin intake is associated with lower arterial stiffness and central blood pressure in women. Am. J. Clin. Nutr. 2012, 96, 781−788. (13) Hertog, M. G.; Feskens, E. J.; Kromhout, D. Antioxidant flavonols and coronary heart disease risk. Lancet 1997, 349, 699. (14) Lin, J.; Rexrode, K. M.; Hu, F.; Albert, C. M.; Chae, C. U.; Rimm, E. B.; Stampfer, M. J.; Manson, J. E. Dietary intakes of flavonols and flavones and coronary heart disease in US women. Am. J. Epidemiol. 2007, 165, 1305−1313. (15) Rimm, E. B.; Katan, M. B.; Ascherio, A.; Stampfer, M. J.; Willett, W. C. Relation between intake of flavonoids and risk for coronary heart disease in male health professionals. Ann. Intern. Med. 1996, 125, 384−389. (16) Sesso, H. D.; Gaziano, J. M.; Liu, S.; Buring, J. E. Flavonoid intake and the risk of cardiovascular disease in women. Am. J. Clin. Nutr. 2003, 77, 1400−1408. (17) Cassidy, A.; Rimm, E. B.; O’Reilly, E. J.; Logroscino, G.; Kay, C.; Chiuve, S. E.; Rexrode, K. M. Dietary flavonoids and risk of stroke in women. Stroke 2012, 43, 946−951. (18) Lenfant, C.; Chobanian, A. V.; Jones, D. W.; Roccella, E. J. Seventh report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7): resetting the hypertension sails. Hypertension 2003, 41, 1178− 1179. (19) Stull, A. J.; Cash, K. C.; Johnson, W. D.; Champagne, C. M.; Cefalu, W. T. Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. J. Nutr. 2010, 140, 1764− 1768. (20) Basu, A.; Du, M.; Leyva, M. J.; Sanchez, K.; Betts, N. M.; Wu, M.; Aston, C. E.; Lyons, T. J. Blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome. J. Nutr. 2010, 140, 1582−1587. (21) Del Bo, C.; Riso, P.; Campolo, J.; Moller, P.; Loft, S.; KlimisZacas, D.; Brambilla, A.; Rizzolo, A.; Porrini, M. A single portion of blueberry (Vaccinium corymbosum L.) improves protection against DNA damage but not vascular function in healthy male volunteers. Nutr. Res. (N.Y.) 2013, 33, 220−227. (22) McAnulty, S. R.; McAnulty, L. S.; Morrow, J. D.; Khardouni, D.; Shooter, L.; Monk, J.; Gross, S.; Brown, V. Effect of daily fruit ingestion on angiotensin converting enzyme activity, blood pressure, and oxidative stress in chronic smokers. Free Radical Res. 2005, 39, 1241−1248. (23) Riso, P.; Klimis-Zacas, D.; Del Bo, C.; Martini, D.; Campolo, J.; Vendrame, S.; Moller, P.; Loft, S.; De Maria, R.; Porrini, M. Effect of a wild blueberry (Vaccinium angustifolium) drink intervention on markers of oxidative stress, inflammation and endothelial function in humans with cardiovascular risk factors. Eur. J. Nutr. 2013, 52, 949− 961. (24) Rodriguez-Mateos, A.; Rendeiro, C.; Bergillos-Meca, T.; Tabatabaee, S.; George, T.; Heiss, C.; Spencer, J. P. Intake and time dependence of blueberry flavonoid-induced improvements in vascular function: a randomized, controlled, double-blind, crossover intervention study with mechanistic insights into biological activity Am. J. Clin. Nutr. 2013, DOI: 10.3945/ajcn.113.066639, (25) Naruszewicz, M.; Laniewska, I.; Millo, B.; Dluzniewski, M. Combination therapy of statin with flavonoids rich extract from chokeberry fruits enhanced reduction in cardiovascular risk markers in patients after myocardial infraction (MI). Atherosclerosis 2007, 194, e179−184.

berry (poly)phenols in the prevention of CVD risk and may be used to make specific dietary recommendations regarding berry consumption to the general population.

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AUTHOR INFORMATION

Corresponding Author

*(A.R.-M.) Phone: +49-211-811-5893. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED AI, augmentation index; BP, blood pressure; CETP, cholesteryl ester transfer protein; cGMP, cyclic guanosine monophosphate; CHD, coronary heart disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; FMD, flow-mediated dilation; GSR, glutathione reductase; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model of assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; L-NMMA, NG-monomethyl-L-arginine acetate; MI, myocardial infarction; MS, metabolic syndrome; PAT, peripheral arterial tonometry; PWV, pulse wave velocity; RCTs, randomized controlled trials; SBP, systolic blood pressure; SOD, superoxide dismutase; TAG, triacylglycerol; TC, total cholesterol; VLDL, very low density lipoproteins

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REFERENCES

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Berry (Poly)phenols and Cardiovascular Health - Journal of

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