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Study  with 25096 men over 10 years 2000 to 2010

FIVE SOURCE OF Flavanoids  from Berries, Apple/pears & Citrus

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Cocoa Flavanols Linked to Vascular Protection in ESRD

Sanjeet Bagcchi, MBBS

January 07, 2016

Ingestion of cocoa flavanols (CF) can attenuate hemodialysis (HD)-induced and chronic endothelial dysfunction in patients with end-stage renal disease (ESRD) and improve vascular function in high-risk patients, according to a new study published online December 17 in the Clinical Journal of the American Society of Nephrology.

Cocoa flavanols are plant-derived polyphenols that are present in cocoa.

Tienush Rassaf, MD, from the Department of Cardiology, West German Heart and Vascular Center, Essen, Germany, and colleagues note that ESRD is regarded as an important cardiovascular risk factor. "This leads to a dramatic increase in morbidity and mortality in this population, which is eight times greater than in the general population," the researchers write. In ESRD, vascular dysfunctions are linked with heart failure and sudden cardiac deaths.

"Elevated cardiac troponin levels reflect this, an important predictor of all-cause mortality in ESRD," the researchers note. They also point out that in patients with ESRD, impaired bioavailability of nitric oxide further perpetuates vascular dysfunctions. "Importantly, HD acutely impairs endothelial function through reduction of [nitric oxide] bioactivity," they explain.

Dietary supplements rich in CF could lead to improvement in vascular function; however, studies assessing the effect on vascular dysfunction in patients with ESRD are "sparse." Therefore, the researchers conducted a randomized, double-blind, placebo-controlled trial during 2012 to 2013 to assess "the impact of flavanol-rich bioactive food ingredients on acute and chronic HD-induced vascular dysfunction in ESRD." They enrolled 57 participants undergoing HD for underlying renal diseases, including hypertensive and diabetic nephropathy, glomerulonephritis, and polycystic kidney disease.

Of the 57 participants, the researchers randomly assigned 52 to a chronic parallel group trial. They provided 26 participants with beverages rich in CF (900 mg CF per study day) and 26 participants with a nutrient-matched, CF-free placebo. In the study, "[p]rimary and secondary outcome measures included changes in [flow-mediated dilation (FMD)] and hemodynamics," Dr Rassaf and colleagues explain.

The patients tolerated ingestion of CF well, and acute ingestion led to an FMD improvement by 53% (3.2% ± 0.6% to 4.8% ± 0.9% vs placebo, 3.2% ± 0.7% to 3.3% ± 0.8%; P < .001), without affecting heart rate and blood pressure.

Compared with placebo, after a 30-day ingestion of CF, the researchers noted an increase in baseline FMD of 18% (3.4% ± 0.9% to 3.9% ± 0.8% vs placebo, 3.5% ± 0.7% to 3.5% ± 0.7%; P < .001); this was associated with a decrease in diastolic blood pressure (73 ± 12 to 69 ± 11 mm Hg vs placebo, 70 ± 11 to 73 ± 13 mm Hg; P = .03) and an increase in heart rate (70 ± 12 to 74 ± 13 bpm vs placebo, 75 ± 15 to 74 ± 13 bpm; P = .01).

The researchers also note that during HD, acute ingestion of CF led to an alleviation of HD-induced vascular dysfunction (3.4% ± 0.9% to 2.7% ± 0.6% vs placebo, 3.5% ± 0.7% to 2.0% ± 0.6%; P < .001), and the effect was sustained "throughout the study" (acute-on-chronic, 3.9% ± 0.9% to 3.0% ± 0.7% vs placebo, 3.5% ± 0.7% to 2.2% ± 0.6%; P = .01).

According to Dr Rassaf and colleagues, the study yields four major findings: in patients with ESRD, ingestion of CF (at 900 mg per day) is well tolerated, endothelial dysfunction is partly reversed by acute and chronic ingestion of CF, chronic ingestion of CF leads to decrease in diastolic blood pressure without "affecting markers of aortic stiffness," and CF ingestion mitigates vascular dysfunction induced by HD.

"The exact mechanisms through which CF exert putative cardioprotective effects still remain incompletely elucidated," the authors write. "Impacts on [nitric oxide] homeostasis with increased nitrosothiol plasma levels, cellular signal cascades, altered gene-expression and enzyme activity are considered potential pathways. In the present study we did not observe differences in plasma nitrite or nitrate levels possibly due to small sample size or due to activation of [inducible nitric oxide synthase] as suggested for ESRD patients," the researchers explain.

In an accompanying editorial, Carmine Zoccali, MD, and Francesca Mallamaci, MD, from the Ospedali Riuniti, Reggio Calabria, Italy, write, "While the evidence that flavonoids exert favorable effects on the cardiovascular system in studies based on surrogates like FMD or pulse wave velocity and may lower [blood pressure] in human hypertension seems robust and credible, until now there is no large trial based on clinical end-points showing a benefit by these compounds. Thus, although likely, the therapeutic benefit of flavonoids for the prevention and treatment of cardiovascular disease remains an open question."

However, in the last 2 decades, no meaningful cardiovascular prognosis has been noted in patients with ESRD, they point out. The nephrology community needs to be attentive to a "promising intervention" such as CF, considering the serious burden of cardiovascular disease among patients receiving HD, they write. The findings of this study might be a turning point in the battle against cardiovascular disease in patients undergoing HD, provided other studies (based on same surrogates) and a trial based on clinical end-points confirm the findings, they conclude.

This work was funded in part by the European Commission. MARS Symbioscience provided the CF test products and analytical standards. The authors and editorialists have disclosed no relevant financial relationships.

CJASN. Published online December 17, 2015. Abstract

Largest Research Trial of Cocoa Flavanols and Heart Health Launched


JoAnn Manson


You don't have to be a chocolate lover to have heard of the cocoa bean, which is where the popular treat comes from. What you might not know is that the cocoa bean contains naturally occurring bioactive compounds called cocoa flavanols, which have been associated with health benefits.


In a novel collaboration, BWH will conduct the largest research trial to date to investigate the heart health benefits of cocoa flavanols by administering the concentrated nutrients in capsule form.

These nutrients are often destroyed during processing but will be preserved in this study using a special technique. Once initiated, this large-scale nutritional intervention will evaluate the role of flavanols in reducing the risk of heart attack, stroke and death from cardiovascular disease in 18,000 women and men nationwide.

The Seattle-based Fred Hutchinson Cancer Research Center, the National Institutes of Health (NIH) and Mars, Incorporated are partners in the trial.


The study will also explore the effect of a daily multivitamin compared to a placebo, as a follow-up to previous research conducted only in men that suggested that multivitamins may lower the risk of cancer.

This five-year nationwide study will be the first large-scale randomized trial of multivitamins that includes women.


"Cocoa flavanols and multivitamins are two of the most promising and exciting nutritional interventions available, and this new trial is the natural next step in advancing our understanding of their potential benefits," said JoAnn Manson, MD, D.Ph., chief of the Division of Preventive Medicine at BWH and the Michael and Lee Bell Professor of Women's Health at Harvard Medical School.

"In smaller studies, cocoa flavanols have been linked to improvements in risk factors for heart disease, such as reductions in blood pressure and cholesterol levels, improvements in the body's sensitivity to insulin and improved ability of blood vessels to dilate."


Manson will co-lead the trial with Howard Sesso, ScD, MPH, also of BWH Preventive Medicine.


The proposed placebo-controlled trial uses an innovative and cost-efficient approach to recruitment by including interested individuals who have participated in other research studies. This allows for a rapid recruitment process and avoids the delays and high costs of recruiting new research participants.


Recruitment of women will be done through the Women's Health Initiative, and men will be recruited from other large population-based studies. This trial substantially increases the number of women included in randomized trials of interventions for prevention of cardiovascular disease and cancer, areas where inclusion of women has lagged.

The recruitment process had begun in fall 2014 and continue into 2015 and 2016.


Mars, Incorporated will provide cocoa flavanol-containing capsules for use in this study. Study infrastructure support will be provided by both the NIH's National Heart, Lung, and Blood Institute and Mars, Incorporated

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Dietary cocoa flavanols improve blood vessel function in patients with kidney dysfunction

  • Date:
  • December 18, 2015
  • Source:
  • American Society of Nephrology (ASN)
  • Summary:
  • Individuals with failing kidneys are at increased risk of developing heart problems, and they're more likely to die from cardiovascular causes than from any other cause. Now investigators suggest that ingesting a drink rich in cocoa flavanols improved blood vessel function and reduced diastolic blood pressure in patients with kidney failure.


Cocoa flavanols lower blood pressure and increase blood vessel function in healthy people

Cocoa flavanols could help maintain cardiovascular health as we age

  • Date:
  • September 10, 2015
  • Source:
  • University Hospital Düsseldorf
  • Summary:
  • Consuming cocoa flavanols lowers blood pressure, increases flow-mediated vasodilation and improves blood cholesterol profile. Applying the Framingham risk score suggests that cocoa flavanols might therefore be able to reduce age-related risk of developing cardiovascular diseases.

    Two recently published studies in the journals Age and the British Journal of Nutrition (BJN) demonstrate that consuming cocoa flavanols improves cardiovascular function and lessens the burden on the heart that comes with the aging and stiffening of arteries. The studies also provide novel data to indicate that intake of cocoa flavanols reduces the risk of developing cardiovascular disease (CVD).

    As we age, our blood vessels become less flexible and less able to expand to let blood flow and circulate normally, and the risk of hypertension also increases. Arterial stiffness and blood vessel dysfunction are linked with cardiovascular disease -- the number one cause of deaths worldwide. "With the world population getting older, the incidence of cardiovascular disease, heart attacks and stroke will only increase," says Professor Malte Kelm, Professor of Cardiology, Pulmonary Diseases and Vascular Medicine at University Hospital Düsseldorf and Scientific Director of FLAVIOLA. "It is therefore pivotal that we understand the positive impact diet can have on cardiovascular disease risk. As part of this, we want to know what role flavanol-containing foods could play in maintaining the health of the heart and blood vessels."

    Cocoa flavanols are plant-derived bioactives from the cacao bean. Dietary intake of flavanols has been shown to have a beneficial effect on cardiovascular health but the compounds are often destroyed during normal food processing. Earlier studies have demonstrated that cocoa flavanol intake improves the elasticity of blood vessels and lowers blood pressure -- but, for the most part, these investigations have focused on high-risk individuals like smokers and people that have already been diagnosed with conditions like hypertension and coronary heart disease. These two studies in Age and BJN are the first to look at the different effects dietary cocoa flavanols can have on the blood vessels of healthy, low-risk individuals with no signs or symptoms of cardiovascular disease.

    Cocoa flavanols increase blood vessel flexibility and lower blood pressure

    In the study published in Age, two groups of 22 young (<35 years of age) and 20 older (50-80 years of age) healthy men consumed either a flavanol-containing drink, or a flavanol-free control drink, twice a day for two weeks. The researchers then measured the effect of flavanols on hallmarks of cardiovascular aging, such as arterial stiffness (as measured by pulse wave velocity), blood pressure and flow-mediated vasodilation (the extent to which blood vessels dilate in response to nitric oxide).

    They found that vasodilation was significantly improved in both age groups that consumed flavanols over the course of the study (by 33% in the younger age group and 32% in the older age group over the control intervention). In the older age group, a statistically and clinically significant decrease in systolic blood pressure of 4 mmHg over control was also seen.

    Improving cardiovascular health and lowering the risk of CVD

    In the second study, published in BJN, the researchers extended their investigations to a larger group (100) of healthy middle-aged men and women (35-60 years) with low risk of CVD. The participants were randomly and blindly assigned into groups that consumed either a flavanol-containing drink or a flavanol-free control drink, twice a day for four weeks. The researchers also measured cholesterol levels in the study groups, in addition to vasodilation, arterial stiffness and blood pressure.

    "We found that intake of flavanols significantly improves several of the hallmarks of cardiovascular health," says Professor Kelm. In particular, the researchers found that consuming flavanols for four weeks significantly increased flow-mediated vasodilation by 21%. Increased flow-mediated vasodilation is a sign of improved endothelial function and has been shown by some studies to be associated with decreased risk of developing CVD. In addition, taking flavanols decreased blood pressure (systolic by 4.4 mmHg, diastolic by 3.9 mmHg), and improved the blood cholesterol profile by decreasing total cholesterol (by 0.2 mmol/L), decreasing LDL cholesterol (by 0.17 mmol/L), and increasing HDL cholesterol (by 0.1 mmol/L).

    The researchers also calculated the Framingham Risk Score -- a widely used model to estimate the 10-year cardiovascular risk of an individual -- and found that flavanol intake reduced the risk of CVD. "Our results indicate that dietary flavanol intake reduces the 10-year risk of being diagnosed with CVD by 22% and the 10-year risk of suffering a heart attack by 31%," says Professor Kelm.

    The combined results of these studies demonstrate that flavanols are effective at mitigating age-related changes in blood vessels, and could thereby reduce the risk of CVD in healthy individuals. The application of 10-year Framingham Risk Scores should be interpreted with caution as the duration of the BJN study was weeks not years and the number of participants was around 100, not reaching the scale of the Framingham studies. That being said, Professor Kelm comments that "the reduction seen in risk scores suggests that flavanols may have primary preventive potential for CVD." Other longer-term studies, such as the 5-year COcoa Supplement and Multivitamin Outcomes Study (COSMOS) of 18,000 men and women, are now underway to investigate the health potential of flavanols on a much larger scale.


    Story Source:

    The above post is reprinted from materials provided by University Hospital Düsseldorf. Note: Materials may be edited for content and length.

    Journal Reference:

  • Roberto Sansone, Ana Rodriguez-Mateos, Jan Heuel, David Falk, Dominik Schuler, Rabea Wagstaff, Gunter G. C. Kuhnle, Jeremy P. E. Spencer, Hagen Schroeter, Marc W. Merx, Malte Kelm, Christian Heiss. Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study. British Journal of Nutrition, 2015; 1 DOI: 10.1017/S0007114515002822


Flavanols in cocoa may offer benefits to the brain

Scientists unveil new findings that suggest compounds in special cocoa may enhance brain blood flow and improve cognitive health

A special cocoa made to retain naturally occurring compounds called flavanols may have the potential to help maintain healthy brain function and chart the course for future research that could lead to new solutions for preventing cognitive decline and dementia, according to a panel of scientists who presented new data at the annual meeting of the American Association for the Advancement of Science (AAAS).

Several studies suggest that consumption of a special cocoa made to be rich in flavanols, a naturally occurring nutrient abundant in fresh cocoa, may improve blood vessel function. Now, scientists believe the potential blood flow benefits associated with consumption of this flavanol-rich cocoa may extend to the brain -- which could have important implications for learning and memory.

“This research is impressive in that multiple laboratories are coming to the same conclusion about this flavanol-rich cocoa, and the findings give us completely new insights into how this flavanol-rich cocoa may impact health in a variety of ways not previously known,” said symposium organizer Harold H. Schmitz, Ph.D., chief science officer at Mars, Incorporated, which helped sponsor today’s symposium and has supported research on cocoa flavanols for more than 15 years. “The findings raise the possibility that products utilizing this cocoa could be developed to help maintain healthy brain function throughout several life stages. More research examining the potential of this cocoa in this important area of public health need is clearly warranted.”

During the session entitled “The Neurobiology of Chocolate: A Mind-Altering Experience?,” a panel of scientists presented evidence from several recent studies that demonstrated the enhanced brain blood flow after study participants consumed a specially formulated flavanol-rich cocoa beverage that was supplied by Mars, Incorporated. One study, conducted by Ian A. Macdonald, PhD, from the University of Nottingham Medical School in the United Kingdom, found that the consumption of this cocoa resulted in regional changes in blood flow in study participants, suggesting that cocoa flavanols may have therapeutic potential for the treatment of vascular impairments within the brain itself.

“Our study showed that acute consumption of this particular flavanol-rich cocoa beverage was associated with increased blood flow to grey matter for 2 to 3 hours,” Macdonald said. “This raises the possibility that certain food components like cocoa flavanols may be beneficial in increasing brain blood flow and enhancing brain function among older adults or for others in situations where they may be cognitively impaired, such as fatigue or sleep deprivation.”


Norman K. Hollenberg, MD, PhD, of Harvard Medical School and Brigham and Women’s Hospital, presented new findings based on his ongoing work with the Kuna Indians of Panama, who are heavy consumers of cocoa. The indigenous population still living on the Islands near Panama consume a type of cocoa rich in flavanols on a daily basis and experience unusually low rates of hypertension and cardiovascular disease. Hollenberg’s latest findings, which are published this month in the International Journal of Medical Sciences, used death certificates to compare cause-specific deaths of island-dwelling Kuna to those who live on mainland Panama -- who do not drink the flavanol-rich cocoa that is so prominent on the islands.

Hollenberg and colleagues found the Kuna Indians living on the islands had significantly lower rates of heart disease and cancer compared to those on the mainland. The relative risk of death from heart disease on the Panama mainland was 1,280 percent higher than on the islands and death from cancer was 630 percent higher. In his AAAS presentation, Hollenberg suggested that the same mechanism resulting in improved blood vessel function that he and others have observed following consumption of Mars’ special cocoa could also be responsible for the enhanced brain blood flow he and Professor Macdonald have independently reported in previously published research. Specifically, Hollenberg and others have observed that these improvements in blood vessel function following flavanol rich cocoa consumption are paralleled by an increase in the circulating pool of nitric oxide, a critical molecule in the circulatory system that helps dilate blood vessels and keeps them pliable.

Hollenberg fed flavanol-rich cocoa to healthy volunteers who were over age 50 and observed a “striking blood flow response” that evolved over several weeks. “Since this cocoa preparation is so well tolerated, it raises hope that the brain blood flow response it stimulates can result in maintenance of healthy brain function and cognition, which is an issue that unfortunately plagues many older adults today,” Hollenberg said. This advancement in science related to brain health is especially exciting at a time when the nation’s 78 million baby boomers are aging. The need to impact cognitive function and brain health will only continue to grow with this aging population.


Bayard V, Chamorro F, Motta J, Hollenberg NK. Does flavanol intake influence mortality from nitric oxide-dependent processes? Ischemic heart disease, stroke, diabetes mellitus, and cancer in Panama. International Journal of Medical Sciences. 2007;4:53-58.

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