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Eating the equivalent of 100 grams of blueberries for 4 weeks, twice a day is associated with systolic blood pressure lowering that is equivalent to the effect of BP-lowering medications, new research suggests.

Investigators believe anthocyanins, compounds with antioxidant effects and the pigments that give red, purple, and blue plants their color, are responsible for this beneficial effect on the vascular system, improving endothelial function in as little as 2 weeks.

“Our research is the first study directly linking blueberry anthocyanin consumption and circulating anthocyanin metabolites to improvements in vascular function in a healthy population,” principal investigator Ana Rodriguez-Mateos, PhD, Department of Nutritional Sciences, School of Life Course Sciences at King’s College London, United Kingdom, told Medscape Medical News.

“However, further longer-term clinical studies in larger populations are needed to confirm whether our findings will translate to the general public,” she added.

The research, which was a combination of four smaller studies in men and one study in animals, was published online February 16 in The Journals of Gerontology: Series A.

Polyphenols and Blueberries

Nutritional interventions are promising approaches to slowing cardiovascular aging, so understanding how certain fruit and vegetables improve vascular health is important, the investigators note.

They explored how bioactive compounds in blueberries work in healthy volunteers.

Previous research has suggested polyphenols are the bioactive compounds in food that protect the strongest individuals against neurodegeneration, cancer, and cardiovascular disease (CVD).

Blueberries contain a number of polyphenols, including anthocyanins, which the current study identifies as the most important component of the fruit for cardiovascular health benefits.

Although most previous studies focused on the cognitive benefits of blueberries, more recently the vitamin-, antioxidant- and fiber-rich fruit demonstrated improvements in cardiovascular function, as well.

In addition, a lower risk of myocardial infarction was associated with high intake of blueberries and strawberries in a recent Nurses Health Study.

However, these studies only showed associations, the current investigators note. They decided to fortify the evidence through a series of studies designed to demonstrate causality between blueberry anthocyanin intake and cardiovascular benefits.

Five New Studies

The researchers randomly assigned 20 healthy men to receive a drink of 11 g of freeze-dried wild blueberry powder in water twice daily and 20 other participants to a control powder drink matched for color and flavor. The primary outcome was any improvement from baseline in flow-mediated dilation (FMD), a measure of endothelial function, at 28 days.

This randomized controlled trial also assessed 24-hour ambulatory BPs on days 1 and 28 in a subgroup of 22 participants. Mean age was 34 years.

The investigators also drew blood to measure plasma blueberry polyphenols, their metabolites, and routine lab parameters. They performed messenger RNA and microRNA analyses from blood samples of 10 participants to evaluate potential ways blueberries could provide cardiovascular benefit.

In a separate uncontrolled, single-group pilot study with five volunteers, the researchers evaluated the chronic effects of the same wild blueberry drink regimen on FMD at baseline and on days 7, 14, 21, and 28.

To control for other potentially beneficial components of wild blueberry, they conducted a double-blind, crossover controlled study. Five volunteers consumed one of five treatments in random order, separated by 1 week of washout: a control drink, control drink with fiber, a control drink plus a mix of vitamins and minerals, 160 mg of pure anthocyanin, or the 11 g wild blueberry powder drink.

The fiber, mineral, vitamin, and anthocyanin levels were similar to amounts present in the wild blueberry drink. The investigators measured FMD in this study before and at 1, 2, and 6 hours after consumption.

An additional randomized, controlled double-blind crossover trial of 10 volunteers aimed to assess a dose-response for anthocyanin.

The participants took a control or one of five different anthocyanin capsules at 80, 160, 240, 320, or 480 mg on 6 different days 1 week apart. Researchers measured FMD before and again at 2 and 6 hours post-consumption.

A fifth study, carried out in mice, was designed to validate the bioactivity of circulating phenolic acid metabolites.

Clinically Significant?

Compared with baseline levels, 24-hour systolic BP dropped a mean 5.6 mm Hg (95% confidence interval [CI], 0.2 mm – 11.1 mm Hg decrease) at day 28 of the study compared with the control group.

In contrast, the change in 24-hour diastolic BP (mean decrease, 5.5 mm Hg (95% CI, 13.0 mm Hg -1.9 mm Hg) did not differ significantly between the blueberry-receiving and control groups.

The first consumption of wild blueberry drink containing 150 mg of anthocyanin significantly increased FMD by 1.5% (95% CI, 0.6% – 2.3%) 2 hours after ingestion vs the control group.

After 28 days of consuming the wild blueberries in a twice-daily regimen that included overnight fasting, FMD significantly increased by 2.3% (95%CI, 1.4% – 3.2%).

“According to a recent meta-analysis, an improvement in FMD of 1% is related to a decrease in CVD risk of 10%,” Rodriguez-Mateos said. “So our findings would be clinically significant as this would mean a 20% decrease in CVD risk if the effects would be sustained for long enough.”

“Interestingly, no further improvement in FMD was observed when blueberries were acutely consumed on day 28,” the researchers write. The acute-on-chronic increase was 0.3% (95% CI, -1.3% to 0.6%).

FMD increased significantly after 1 week of blueberry consumption, increased further after 2 weeks, and then plateaued.

“This suggests that at least 2 weeks of daily blueberry consumption are necessary to achieve a sustained improvement in endothelial function that persists after overnight fasting,” the investigators note.

Component of Interest

In the study comparing the five drink types, no significant changes in FMD were shown at 2 or 6 hours after consumption associated with the vehicle drink, the control with fiber, or the vitamin and mineral drink compared with the wild blueberry preparation.

“More importantly, 160 mg of pure anthocyanins was sufficient to increase FMD in a similar magnitude as blueberries containing 150 mg anthocyanins did,” the researchers write.

This validated their finding that anthocyanins are the primary component of blueberries associated with the observed improvements in vascular health. This was further reinforced by analyses that showed “a clear dose-dependent increase” in FMD with higher concentrations of pure anthocyanins.

The study in mice confirmed that circulating anthocyanin metabolites observed in the humans did in fact correlate with increases in FMD.

In fact, both acute and chronic anthocyanin metabolite measures were associated with significantly higher FMD compared to the vehicle: acute metabolites, 8.7% (95% CI, 3% – 15%) and chronic metabolites, 8.3% (95% CI, 2% – 14%).

Of 63 metabolites of interest identified in the study, the activity of one third (21 genes) significantly correlated with improvements in FMD.

A closer look at 20 genes whose activity correlated with changes in peripheral blood mononuclear cells (PBMCs) revealed 15 genes that orchestrate inflammation or development of CVD.

To determine the “nutrigenomic effect” of chronic wild blueberry consumption, the investigators also compared PBMC gene analyses from 10 participants at baseline vs day 28.

They found 608 genes expressed differentially by the end of the study. This group included 357 genes that were “up-regulated” or more active and another 251 that were “down-regulated.”

The most important genetic finding “was that in blood cells, we found significant changes in a large number of genes after 1 month of blueberry consumption,” Rodriguez-Mateos said. However, “what these changes really mean, we will have to investigate further.”

Too Early for Recommendations

Rodriguez-Mateos said it is too early to translate the findings into physician recommendations for patients, especially because they assessed healthy people and not a patient population.

Also, more clinical studies running longer term and in larger populations are needed “to be able to give dietary recommendations in terms of blueberry consumption to the general public,” she noted.

“But what we can say, based on our previous and recent work, is that even 100 grams of blueberries produced acute improvements in blood vessel function 2 hours after consumption, and 200 grams of blueberries per day did reduce systolic blood pressure in healthy men.”

Although the current study pinpoints anthocyanins for the majority of blueberry cardiovascular benefits, the researchers note the advantages “are still larger than achieved with the consumption of anthocyanins alone.”

They also acknowledge that anthocyanins do not exist in isolation and are just one component of blueberries.

“We cannot discard possible synergistic and/or antagonistic effects of components when consumed as a whole food, rather than individual compounds, as well as matrix effects affecting the liberation or absorption of anthocyanins from blueberries,” they write.

Rodriguez-Mateos reported that they are currently conducting the BLULIFE study to assess whether the effects of blueberries on vascular and cognitive function can be translated to other segments of the population, such as children and older adults.

In addition, future studies will help to further characterize the mechanisms-of-action of individual metabolites, establish general structure–function relationships, and identify relevant interactions, the researchers note.

“As the identified metabolites are common for a range of food bioactive classes, this knowledge represents an important building block necessary for the development of evidence based dietary recommendations for food bioactives in primary prevention,” they write.

“Causing a Stir”

Commenting on the findings for Medscape Medical News, Atom Sarkar, MD, PhD, Global Neurosciences Institute and Drexel Neurosciences Institute at Drexel University College of Medicine, Philadelphia, Pennsylvania, said the study “is causing a stir for blueberry aficionados.”

Sarkar, who was not associated with the research, noted that the study’s conclusions “focus on the beneficial effect of blueberry anthocyanin consumption and its positive role in contributing to lowering systolic ambulatory blood pressure recordings in 40 healthy ambulatory volunteers.” 

Anthocyanins are water-soluble pigments that confer colors such as red, purple, or blue to food plants, he explained. As such, they are not only found in blueberries, but in a variety of foods. In addition, there are hundreds of anthocyanins, of which this report looked at 63 plasma metabolites.

“Perhaps what this study most importantly points out,” noted Sarkar, “is that eating healthy and, in particular, choosing a plant-based diet rich in phytochemicals is beneficial to overall healthiness.”

“That being said, this study, however, is limited in scope — the study population was only 40 healthy individuals. How this would affect a more general population still needs to be elucidated, as does the impact of particular anthocyanins,” he added.

The study was supported by the Medical Research Committee of the University of Dusseldorf, a Susanne Bunnenberg grant to the Dusseldorf Heart Centre, and an unrestricted grant from the Wild Blueberry Association of North America. Rodriguez-Mateos and Sarkar have disclosed no relevant financial relationships.

J Gerontol: Series A. Published online February 16, 2019. Abstract

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