Are Bioactives the New Magic Treatment for Cardiovascular Disease?

Are Bioactives the New Magic Treatment for Cardiovascular Disease?

What is responsible for the multiple benefits of a largely plant based diet?

The benefits of a largely plant-based diet have been implicated in primary disease prevention, disease-risk reduction, as well as healthy aging. The most well known example of a largely plant-based diet is the traditional Mediterranean diet. A series of observational and epidemiological studies have concluded that higher adherence to this type of diet is positively associated with better cognitive function and reduced risk of several chronic often comorbid diseases, including cardiovascular disease, depression, Parkinson’s, and Alzheimer’s disease.

The regular consumption of a Mediterranean diet has also been shown to be associated with reduced microvascular brain damage. This suggests a possible role of diet-related impairments in cerebral blood flow to brain regions involved in different aspects of memory such as the hippocampus and the prefrontal cortex. Several variants of the Mediterranean diet such as the DASH diet (Dietary Approaches to Stop Hypertension) and the MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay) have been shown to reduce several cardiovascular risk factors, and are associated with better cognitive function, slower cognitive decline, lower depressive symptoms, decreased risk of dementia and larger total brain volumes. In summary, these epidemiological studies strongly suggest benefits of these largely plant-based dietary patterns both on brain and cardiovascular health, with considerable evidence for a mediating role of improvements in cerebral vascular function.

The unique family of polyphenol molecules.

Polyphenols are bioactive compounds (referred to as “bioactives”, “phytochemicals” or “botanicals) found in plants, consisting of a large, diverse group of molecules, serving two major beneficial roles in plants: One, as defense mechanisms to respond to perturbations of homeostasis, such as drought, UV light, pests, and diseases and two as part of a signaling code between soil microbes living in close proximity of the root system and the plant. While many polyphenols are natural antioxidants when evaluated in a test tube, able to scavenge harmful free radicals that would otherwise damage the cell, only a very small proportion of their beneficial effects when ingested by humans is related to their antioxidant effects.

Polyphenols are found in fruits and vegetables, with tea, pome fruits and some berries being among the foods richest in polyphenols. More than 8,000 polyphenol compounds have been discovered in various plant species, which can be classified into four subclasses: phenolic acids (~30% of all polyphenols), stilbenes, lignans, and flavonoids (~60% of all polyphenols). Flavonoids, the largest family of polyphenols, can be broken down into 6 further subclasses: flavanols (also known as flavan-3-ols), flavonols, flavanones, flavones, anthocyanins, and isoflavones.

Bioavailability studies in humans indicate that due to their large size, flavonoid polyphenols are poorly absorbed in the small intestine (5-10%), reaching very low, transient plasma levels after consumption. This lack of bioavailability has led the FDA several years ago to remove a comprehensive website listing polyphenols based on their antioxidant capacity. (Antioxidant capacity is the ability for a compound or compounds to reduce the concentration of free radicals in a given system, a test almost exclusively determined in an in vitro system). This assessment is very different from what happens to these molecules when consumed by a person. Most of polyphenols will reach the ileum and colon intact where they interact with the gut microbiota resulting in an extensive chemical modification of the ingested compound into small phenolic, absorbable metabolites

“…beneficial effects of polyphenol consumption on brain and cardiovascular health have been supported by a growing number of randomized controlled trials…”

Even though epidemiological studies demonstrating a beneficial effect of polyphenol consumption on brain and cardiovascular health have been supported by a growing number of randomized controlled trials, conflicting results have been reported, with considerable divergence in study designs and poor characterization of the tested products (e.g., whole fruit powders, polyphenol-rich berry extract, fruit juices, effect of extensive processing of the original compound), impeding the progress to conclusively demonstrate a causative role of polyphenol containing foods on brain health.

The idea that dietary bioactives, food constituents not essential to human life, may play an important role in disease risk reduction, primary disease prevention, and healthy aging, has had significant developments in the last decade. For example, there are a considerable number of dietary intervention studies which found that the flavanol epicatechin (contained in green tea, red wine, and cocoa beans) plays a role in the prevention of cardiovascular disease, as well as the secondary prevention of diabetes.

Dietary flavonoids are a structurally diverse set of naturally occurring polyphenolic compounds in plant-based foods, and flavan-3-ols are derivatives of flavanols, a major subclass of flavonoids, that include complex, bioactive molecules found in cocoa beans, tea leaves, grapes, red wine, and other foods.

The rediscovered healing power of the cocoa bean.

Cocoa is made from the bean of the cacao tree, Theobroma cacao, and has a long history of medicinal use and potential health benefits based upon its flavanol and procyanidin content. Cocoa extract also contains methylxanthines such as theobromine and caffeine, which may enhance the vascular and central nervous system effects of cocoa flavanols.

Numerous short term, small-scale dietary intervention studies have examined the cardiovascular effects of flavanols and procyanidins, which have included well-characterized cocoa and cocoa product test materials linked to cardiovascular benefits. These trials have provided broader insights on the absorption, metabolism, and excretion of flavanols in humans with those focused on cocoa flavanol intake (as beverages, supplements, or chocolate) at up to 2000 mg/d and up to 1 y of treatment. Data have shown improvements in several biological mechanisms involved in cardiovascular disease, such as the ability of blood vessels to widen (“endothelium-dependent vasodilation”), blood pressure, inflammation, and platelet activation and provide insight into cocoa’s potential vascular effects due to intake of the flavanol (−)- epicatechin. Even though meta-analyses of such studies support benefits for flavanols on cardiometabolic biomarkers, prospective studies examining cocoa products restricted to chocolate intake or to usual levels of dietary flavanol intake with risk of cardiovascular disease (CVD) have been inconsistent, likely due to uncertainty of cocoa flavanol content and measurement error.

“COSMOS is the first trial testing how these individual or combined cardiovascular mechanisms may translate into longer-term reductions in clinical cardiovascular events.”

However, until recently, no large-scale trials have evaluated flavanol-rich cocoa extract containing all potential bioactive components of the cocoa bean on clinical cardiovascular outcomes. To address this question, Howard Sesso and a team of investigators from the Brigham and Women’s Hospital and Harvard Medical School, Boston, MA initiated the Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), a large-scale randomized double blind, placebo controlled trial supported by the company Mars Edge and the National Institutes of Health. The COSMOS study aimed to test a supplement prepared from cocoa bean extract and a typical multivitamin in the prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major cardiovascular disease and recently diagnosed cancer. Participants were randomly assigned to the cocoa bean extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction, stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.

After a median of 3.6 years of treatment, the investigators found that among older women and men with high compliance, flavanol supplementation significantly reduced cardiovascular death by 27%, whereas the risk for individual cardiovascular outcomes (such as myocardial infarction, stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina), or for the number of total cardiovascular events were not significantly reduced compared to the placebo arm. Finally, cocoa extract had no effect on the secondary outcomes of total invasive cancer and major site-specific cancers.

Does a piece of chocolate a day keep the doctor away?

As discussed in a recent podcast with Hagen Schroeter, Chief Science Officer of Mars Edge, the cosponsor of the COSMOS study, the answer is a definite no. Even though this large-scale study was originally designed to demonstrate the health benefit of eating chocolate, the main commercial product of the parent company Mars, any such claim had to be publicly withdrawn for several reasons. Any health benefits from consuming flavanols from commercial, tasty chocolate products would be negated by the simultaneous consumption of excessive calories in the form of sugar, fat and emulsifiers contained in these products. Moreover, while the raw material from which chocolate is made is the flavonoid rich cocoa bean, the extensive processing of the bean extract results in a depletion of the end product of any health promoting flavanols. Finally, the metabolism of the ingested flavonoid is highly dependent on the composition of the gut microbiome, breaking the nonabsorbable parent compound into the smaller metabolites, including the compound gamma valerolactone which can be detected in the blood.

Not every individual has the right composition of such microbes to effectively generate the absorbable compound, a situation that was reflected in significant interindividual variation of clinical benefits. Based on these caveats and the impressive findings of the COSMOS study, is it beneficial to take a daily supplement of 1,000 mg of Cocoa flavanols? The evidence for such a recommendation is definitely a lot stronger than for most other supplements or multivitamins on the market, and may be worth the cost associated with the chronic intake of this supplement. If the primary mechanism underlying the flavanols’ benefit on the heart and on the brain (evidence not discussed in this post) is indeed the combination of beneficial effects on the blood vessels supplying these organs, it is a prudent investment in overall health when combined with other health promoting lifestyle changes such as exercise and healthy diet. And for the chocolate lovers out there: Continue to indulge in a piece of delicious chocolate after a healthy dinner, but don’t expect it will protect your heart!


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.