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Heinrich Heine University Düsseldorf

1. Overview

The partnership between Mars, Incorporated and the Heinrich Heine University in Düsseldorf, Germany dates back several years. One project by Mars, Heinrich Heine University and the University of California, Davis resulted in a paper in the journal PNAS in 2006 that is still one of the most highly cited papers in the field ( Both Mars and Heinrich Heine University were also members of the pan-European, EU-funded flavanol research consortium called FLAVIOLA between 2009 and 2013, along with the University of Reading and five other members. Mars works closely with the university’s cardiology division, whose cardiology experts run one of the largest heart clinics in Europe. The two partners are currently working together to establish how flavanols affect blood vessel function, cardiovascular health and aging. They are also concerned with establishing biomarkers of cardiovascular health and aging. A biomarker is a sort of test that scientists and medical professionals can perform to give an indication of what is happening inside the body.

2. Partnership outcomes

During their years of collaboration, Mars and Heinrich Heine University have conducted research that has brought many new insights to the field of flavanol research. Below are some recent outcomes from the partnership.

Dietary intake of flavanols in the EU

Several studies have shown that flavanol intake can improve blood vessel function, blood pressure and cholesterol. A team of researchers from Mars, the University of Reading, the University of Cambridge and Heinrich Heine University Düsseldorf conducted a study that was published in the British Journal of Nutrition in 2014 whose aim was to understand how much of these beneficial compounds people in the European Union were consuming on a daily basis. Using the EFSA Comprehensive European Food Consumption Database and a recently developed flavanol food composition database, we managed to establish average intake amounts across fourteen EU countries. Overall, mean habitual intake of flavanols was 369 mg/d. However, intake varied considerably. In Ireland, the mean habitual intake was 793 mg/d while, in Czechia, it was only 181 mg/d. We found that tea was the largest source of dietary flavanols in the EU, accounting for 62% of flavanol intake. Pome fruits (e.g., apples and pears), berries, cocoa products and stone fruits were also notable sources of dietary flavanols. The intake of flavanol monomers and theaflavins was particularly high in the British Isles and Central Europe, where consuming tea is common. Intake of proanthocyanidins, on the other hand, was highest in Spain, Italy and France due to a large amount of fruit in the diet.

At 368 mg/d, the mean habitual intake of dietary flavanols is well below the amount used in various dietary intervention studies that have shown improved blood vessel function and cardiovascular risk after flavanol consumption. It is therefore possible that residents in EU countries are not consuming adequate amounts of flavanols to exploit the full cardioprotective benefit of these compounds. Thanks to this study, scientists are in a better position to investigate the impact of different flavanol intake amounts on public health.

Image: Heat maps showing mean habitual intake of total flavanols, flavanol monomers, proanthocyanidins and theaflavins in 14 countries across the EU. The consumption of total flavanols, flavanol monomers and theaflavins is higher in the British Isles and central Europe, where the consumption of tea is common. In southern Europe, the intake of proanthocyanidins is higher due to the consumption of fruit, in particular pome fruit.

Read more about this study: Vogiatzoglou, A., et al., Assessment of the dietary intake of total flavan-3-ols, monomeric flavan-3-ols, proanthocyanidins and theaflavins in the European Union. Br J Nutr, 2014

Cocoa flavanols decrease age-related vascular stiffness

Research by Mars, Incorporated and Heinrich Heine University Düsseldorf published in the journal Age showed that intake of cocoa flavanols improved several hallmarks of cardiovascular aging. A group of 20 older men (aged 50-80) volunteered for the study. They had no signs of cardiovascular disease but, when compared to a group of 22 younger men (aged



Read more about this study: Heiss, C., et al., Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial. Age (Dordr), 2015

Prospective cohort study indicates flavanol intake not sufficient to reduce CVD risk

A team from Mars, Incorporated, the University of Reading, the University of Cambridge and Heinrich Heine University Düsseldorf conducted an investigation into the association between flavanol consumption and cardiovascular disease risk, which was published in the journal Free Radical Biology and Medicine in 2015. The research team had access to detailed dietary information from almost 25,000 participants from the EPIC-Norfolk cohort who had completed a 7-day food diary. The study found no association between flavanol intake and blood pressure and cardiovascular disease risk. This result is corroborated by earlier epidemiological studies, however it contradicts the findings of dietary intervention studies, which have shown previously that individuals consuming a diet high in flavanols see improvements in vascular function measures (which are markers of cardiovascular disease risk) when compared to placebo controls. The reason for this discrepancy could lie in the types of flavanols being consumed by the EPIC-Norfolk cohort. Using food composition tables, we estimated that only 10% of the EPIC-Norfolk population were consuming more than 50 mg/d of (−)-epicatechin, which is the threshold beyond which improvements in blood pressure have been observed in the past. The flavanol (−)-epicatechin is also the only member of the flavanol group to have been directly and causally linked to improvements in blood vessel function.

Read more about this study: Vogiatzoglou, A., et al., Associations between flavan-3-ol intake and CVD risk in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk). Free Radic Biol Med, 2015

Age has little impact on the absorption, distribution, metabolism and excretion of cocoa flavanols

A paper published in the journal Molecular Nutrition & Food Research in 2015 by researchers from Mars, the University of Reading and Heinrich Heine University Düsseldorf showed that there are only small differences in the way cocoa flavanols are absorbed, metabolized and excreted by young people and old people. The group of younger people in the study (aged 18-35) and the group of older people (aged 65-80) consumed two cocoa-flavanol-containing drinks in this placebo-controlled crossover study, one drink had a cocoa-flavanol concentration of 5.3 mg/kg body weight and the other with a concentration of 10.7 mg/kg body weight. At the low concentration, there were no significant differences in absorption, metabolism and excretion between young and old. At the higher concentration, there was a small but significant difference in the concentration of certain metabolites in the blood and urine. Since there are few differences in the way cocoa flavanols and cocoa-flavanol metabolites are behaving inside the body between young and old, it is expected that the beneficial effect of these compounds on vascular function will translate between different age groups. These results also support the potential of developing dietary guidelines for flavanols in the long term.

Read more about this study: Rodriguez-Mateos, A., et al., Influence of age on the absorption, metabolism, and excretion of cocoa flavanols in healthy subjects. Mol Nutr Food Res, 2015

CVD risk in healthy people lowered by cocoa flavanols in dietary intervention study

Mars, Incorporated and Heinrich Heine University in Düsseldorf, Germany conducted a randomized, placebo-controlled and double blind clinical study to test the effects of cocoa flavanols on cardiovascular risk. The study, published in the British Journal of Nutrition in 2015, showed that the people consuming flavanols had a lower risk of heart attacks and other cardiovascular diseases after one month than the group consuming a placebo. 100 healthy men and women aged 35-60 were randomly assigned into groups who would receive either 450 mg of cocoa flavanols twice a day or a nutrient-matched, flavanol-free placebo. Tests showed improvements in the ability of the blood vessels to dilate in the group who were consuming the flavanol drinks. There were also improvements in plasma lipids (cholesterol) and blood pressure. We were able to use these scores to calculate cardiovascular disease risk using a scoring system called the Framingham Risk Score. The group consuming the flavanol drink saw a drop in the risk of being diagnosed with cardiovascular disease by 22% and the risk of dying from cardiovascular disease by 30%. Flow-mediated dilation, blood pressure and blood lipids are accredited surrogate markers of cardiovascular disease risk and the improvements seen in this study demonstrate the potential of flavanols to maintain cardiovascular health — even in healthy people.

Video: Cardiologist Prof. Marc Merx from Heinrich Heine University Düsseldorf explains the details of the 2015 British Journal of Nutrition study and the 2015 Age study

Read more about this study: Sansone, R., et al., 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. Br J Nutr, 2015

Methylxanthines enhance the effects of cocoa flavanols on the cardiovascular system

A team from Mars, Heinrich Heine University, the University of Reading and the University of California, Davis published research in 2017 in the American Journal of Clinical Nutrition that demonstrated an interesting effect of compounds called methylxanthines when consumed together with flavanols. Methylxanthines are compounds such as caffeine and theobromine that can be found in flavanol-containing foods, such as tea and cocoa. In tea, caffeine is the main methylxanthine whereas, in cocoa, it is theobromine. In a series of four clinical studies reported together in the paper, we established that methylxanthines enhanced the ability of cocoa flavanols to improve markers of cardiovascular function. When the participants in the study consumed only cocoa flavanols, there was an increase in flow-mediated dilation, a measure of the elasticity of the blood vessels. There was also an increase in circulating angiogenic cells and a drop in pulse-wave velocity and diastolic blood pressure — all of which are established markers of improved blood-vessel function. When the participants consumed a drink containing flavanols plus methylxanthines, the vascular effects were enhanced. Consuming cocoa flavanols with methylxanthines also caused a higher concentration of flavanol metabolites in the blood compared to flavanols alone. This increase in flavanol metabolites in the blood may be behind the enhanced vascular effects.

Image: tea and cocoa are two plants that contain flavan-3-ols as well as methylxanthine compounds. The predominant methylxanthine in tea is caffeine. In cocoa, it is theobromine.

Read more about this study: Sansone, R., et al., Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies. Am J Clin Nutr, 2017