The most documented cardiovascular activity of flavan- 3-ols is their positive effects on vasculature. For example, biomarker-estimated flavan-3-ol intake was inversely associated with reduced systolic and diastolic blood pressure in the EPIC Norfolk study . Additionally, flavan-3-ols have also been shown to reduce arterial stiffness . The exact mechanisms behind these improvements likely include the enhanced bio availability of endothelial-derived nitric oxide, decreasing superoxide-mediated nitric oxide breakdown, and improvement in serum lipids. To put this in perspective, just a 1% increase in FMD has been shown to reduce CVD risk by 8% and 13% in asymptomatic and diseased populations, respectively . Lastly, animal and in vitro studies provide emerging evidence that flavan-3- ols improve inflammatory status via the interference of prooxidant enzyme-signaling cascades and adhesion molecule expression ; however, fluctuations in background cytokine production contribute to difficulty in detecting subtle changes in inflammatory status. More recent evidence supporting the cardiovascular benefits derived from flavan-3-olswas published from the COSMOS randomized clinical trial evaluating a cocoa extract supplement in ∼21,000 older adults . Following a median treatment and follow-up period of 3.6 y, a significant 27% reduction in CVD deaths was observed as well as a significant 16% reduction in major cardiovascular events .

Although it is critical to extend mortality follow-up, current results support long-term cardiovascular benefits through the provision of a flavan-3- ol–rich intervention. Additionally,seedling starter pot a recent meta-analysis of cohort studies investigating the relation between flavonoid consumption and cardiovascular outcomes builds upon findings from Raman et al. . Individuals with the highest intake of flavan-3-ols, catechins, and proanthocyanidins had a 15%, 25%, and 17% significantly lower RR, respectively, of CVD compared with individuals with the lowest intake . Although Raman et al. found moderate evidence in prospective cohort studies that flavan-3-ol intake was associated with a reduced risk of CVD mortality, CHD, stroke, and type 2 diabetes mellitus, no association was shown for incidence of hypertension . However, a notable limitation in evaluation of these prospective cohort studies is the tool for assessing risk-of-bias. This tool did not include an “ascertainment of exposure” question, which is one of the unique challenges that should be considered in nutrition-related systematic reviews . Additionally, the majority of included prospective cohort studies within Raman et al. included only a single dietary assessment and, therefore, the data did not likely constitute moderate level evidence . Several other challenges/limitations arise regarding intake of flavan-3-ols using data from prospective cohort studies. First, if a substantial portion of the diet is replaced by a food high in flavan-3-ols, then total energy intake and other nutrients associated with plant food intake likely also improve. This can lead to the conclusion that a wide variety of flavan- 3-ol sources and amounts can provide a detectable health benefit.

It remains unclear, however, how much of that benefit is directly attributable to the effects of flavan-3-ols compared with elimination of less healthy components from the diet, a reduced caloric intake, or increased consumption of other healthy dietary constituents. Additionally, it should be noted that confounding factors including potential effect modifiers and multi collinearity along with lack of adjustment for covariates might affect any observed association. These phenomena can also occur to a lesser extent in clinical trials of flavan-3-ol–rich foods. Despite challenges that arise from use of data from prospective cohort studies, the consistency among these investigations considered for this guideline support the Expert Panel recommendation of 400–600 mg/d flavan-3-ol intake for cardiometabolic health. Future prospective cohort studies would benefit from using omics technologies to identify and validate novel biomarkers of exposure to assist researchers in overcoming measurement error from assessing flavan-3-ol intake via FFQs. Additionally, although genetic instrumental variable analysis, commonly known as Mendelian randomization, cannot establish causality, it does have the potential to eliminate reverse-causation that is prevalent in traditional nutrition epidemiology. Of interest, a genetically predicted extra daily cup of tea consumption was associated with a decrease in small vessel stroke in a recent Mendelian randomization analysis of UK Biobank participants .The potential risks of increasing flavan-3-ol intake through supplementation are of concern and warrant elaboration. Concentrated green tea extracts and purified catechins, including the well-known epigallocatechin gallate , have been implicated in both benefits and harms from green tea.

Liver injury and gastrointestinal distress are the most widely reported adverse effects associated with flavan- 3-ol consumption, mainly arising from supplementation with concentrated green tea extracts in a fasted state. Because intake recommendations should draw heavily upon toxicology tenets, the Expert Panel considered evidence from 3 high-quality systematic reviews and risk assessments when developing the guideline . The systematic reviews highlight numerous reports of potential green tea extract–mediated hepatotoxicity that suggest liver damage can occur after ingestion of bolus doses in high quantities for extended periods of time. Liver injury due to green tea supplements typically manifests within 3 mo of chronic ingestion; however, the latency to onset of symptoms can range from 10 d to 7 mo . Most cases present symptoms of acute hepatitis accompanied by marked hepatocellular enzyme elevations. Under specific conditions such as fasting, higher doses and repeated administration of green tea extract result in systemic plasma catechin concentrations that are substantially higher than when ingested under fed conditions and/or low single doses. Damage to the liver can occur through the first- and second-phase metabolism of catechins when saturation of drug metabolizing enzymes occurs. In several animal toxicity studies, EGCG has been shown to accumulate in the liver causing dose-dependent liver necrosis resulting in the primary cause-of-death in test animals . Toxicity worsened when EGCG was administered as a high-dose supplement to animals under fasting conditions. Other reported adverse effects of flavan-3- ol preparations include gastrointestinal distress , dizziness, and muscle fatigue . In animal models, absorbed EGCG damaged the gastrointestinal tract in a dose-dependent manner . The Expert Panel also considered several assessments and opinions by authoritative scientific bodies that provided guidance around the safety of green tea extracts or EGCG including the US Pharmacopeia , Health Canada , EFSA , and Norwegian Institute of Public Health . Each has provided cautionary guidance around the use of high-dose supplemental green tea extracts or EGCG. For example, the recent scientific opinion from EFSA regarding the safety of green tea catechins concluded that there is evidence from clinical trials that intake of doses ≥800 mg EGCG/d taken in supplemental form can increase serum transaminases.

Similarly, the Chinese Nutrition Society has proposed a 800 mg/d tolerable upper intake level for proanthocyanidins . As such, foods including tea, cocoa,cinnamon, apples, and berries should be prioritized over supplementation when seeking potential cardiometabolic benefits from flavan-3-ols.In order to assess the health equity of the guideline, it must be acknowledged that mean dietary intake of flavan- 3-ols varies greatly among the general adult population. For example, in the United States, the mean intake is 223 mg/d compared with 793 mg/d in Ireland . Across the globe,round nursery pots the greatest food sources of flavan-3-ols include tea, apples, pears, berries, and chocolate/cocoa products . Despite the variety of flavan-3-ol sources, intake analysis from the NHANES 2007–2016 shows tea accounting for 35– 94% of dietary flavan-3-ol intake in the United States . Among tea consumers, consumption was highest in older adults, non-Hispanic Whites, Asians, and individuals with higher education and socioeconomic status . Thus, these results suggest that the equity of health benefits derived from flavan-3-ols might not be achieved equally across all populations. Regarding acceptability and feasibility, the key question is how stakeholders accept or agree with the conferred effects including benefits or harms as well as cost associated with adopting the guideline. First, given the pervasiveness of cardiometabolic diseases in the general adult population, individual awareness of these diseases has increased, especially among women . Thus, practical approaches to reduce risk are warranted. Acknowledging the high benefit-to-risk ratio when flavan-3-ols are consumed in the recommended range of 400–600 mg/d, it is advantageous that foods rich in flavan-3-ols are among the most highly consumed flavonoids by the general population .

Further, the fact that each can be consumed in many forms at a variety of cost points extends the feasibility of the guideline. To highlight feasibility, estimated flavan-3-ol contents of primary food sources are provided in Table 4 along with standard serving sizes . Practically speaking, a combination of foods listed allows for intake in the range of the guideline recommendation for cardiometabolic health benefits. Finally, it should be noted that foods in this list with greatest alignment to the Dietary Guidelines for Americans 2020–2025 should comprise the majority of sources for bolstering flavan-3-ol intake .The health efficacy of this bio-active guideline recommendation is dependent upon the bio activity of flavan-3-ols. Thus, special populations such as those with autoimmune, cancer, and kidney or liver diseases can have altered absorption, distribution, metabolism, and excretion, thus affecting the bio availability and subsequent effectiveness of phenolic compounds in food . Similarly, specific life stages, such as pregnancy, can also affect the bio activity of phenolic compounds. For example, some clinical trials evaluating flavan-3-ol intake from berries and cocoa/chocolate products on health outcomes in pregnancy showed improvement in maternal weight gain, glycemic control, inflammation, and placental function .Although this bio-active can be consumed in supplement form, it should be noted that a supplement is intended to complement or enhance the diet. By the very definition, a supplement is defined as a dietary substance to supplement the diet by increasing the total dietary intake . Because toxicity is more commonly associated with high-dose single nutrient supplementation than with foods , a food first approach to flavan-3-ol intake could capitalize on the potential synergy of this bio-active with other nutrients in the food matrix while also minimizing risks associated with intake of supraphysiological doses of individual compounds from extracts or supplements. Furthermore, this guideline is a food-based guideline and not a recommendation for flavan- 3-ol supplements. Lastly, as foods provide an assortment of nutrients and bio-active compounds with benefits for health, the Dietary Guidelines for Americans 2020–2025 and Canada’s Dietary Guidelines recognize that nutrition requirements should be met primarily through foods .A guideline recommendation for a plant bio-active such as flavan-3-ols is a departure from previous recommendations as it is not based on deficiencies but rather improvement in health outcomes. The Expert Panel found moderate evidence supporting cardiometabolic protection resulting from flavan-3-ol intake such that we are proposing the first dietary recommendation for a bio-active compound. The recommendation of 400–600 mg/d for flavan-3-ols to improve cardiometabolic health is based on beneficial effects observed across a range of disease biomarkers and endpoints. This recommendation is higher than the recent health claim of 200 mg/d for cocoa-flavanols by EFSA . The main reason for this discrepancy is that the EFSA health claim is only based on vasodilation as an endpoint and no other cardiometabolic disease markers. Regarding upper intake limits for flavan-3-ols, risk assessments of green tea catechins by EFSA concluded that no adverse effects are expected for intakes <800 mg/d . It must be acknowledged that challenges were encountered in establishing this guideline, such as limitations from lack of homogeneity in protocols. For example, studies included in the Raman et al. systematic review/meta-analysis reported large discrepancies in quality as well as lack of consensus in population description, duration of supplementation, form of bio-active/food/extract, and statistical methods . Implementing methodological consensus in executing and describing randomized clinical trials would allow for more rigorous assessment of study findings for comparison and pooling of data. Other limitations include the following: inclusion of more men than women in randomized clinical trials, different biomarkers used to assess prevention and development of cardiometabolic disease, and heterogeneity in dosages examined along with metabolism and assessment of circulating concentrations, which was not routinely evaluated. Additionally, it should be noted that cohort studies often relied on self-reported dietary intake, often at one time point, to assess benefit, which could contribute to information bias compromising internal validity; furthermore, the estimates of flavan-3-ol exposure were calculated from different food composition databases, which could preclude precise comparability. Although FFQ data can clearly differentiate between extremes of intake, this assessment method does not account for the extensive inter individual metabolism that these compounds undergo after ingestion, which could impact effectiveness. As such, future studies should integrate biomarker, genetic, and dietary assessment methods to assess the effect of flavan-3-ols and their metabolites on cardiometabolic health.