Klaus W.Lange

Department of Experimental Psychology, University of Regensburg, Regensburg 93040, Germany

Keywords:

Tea

Cardiovascular diseases

Health

Prevention

Treatment

A B S T R A C T

The findings of various epidemiological studies, interventions using randomized controlled trials and mechanistic experiments have suggested a protective role of tea and its bioactive components in cardiovascular health.The potential of tea in the prevention of cardiovascular diseases (CVDs) has therefore attracted increasing research interest.Polyphenols, in particular flavonoids, found in both green and black tea, have been suggested to play a primary role in the reduction of CVD risk.While promising results regarding the effects of tea on blood pressure and other CVD-related biomarkers have been found in preclinical experiments, the effects demonstrated in human studies are modest and less satisfactory.This discrepancy may be explained, at least in part, by different research strategies used in human and animal research.However, since tea is globally one of the most commonly consumed beverages, even small beneficial effects in humans may shift the population distribution of CVD risk, with major implications for public health.However, research conducted to date does not yield sufficiently robust evidence to allow a recommendation as to an optimal level of tea consumption as an element of health policies seeking to prevent hypertension and improve cardiovascular health.

1.Introduction

The three most popular types of tea consumed worldwide,unfermented green tea, fully fermented black tea and partially fermented oolong tea, are manufactured from the leaves of the plantCamellia sinensis.While green tea is consumed primarily in East Asia and oolong tea in Southeastern China, black tea is favored in Europe,Western Asia and North America [1].Since antiquity, tea has been believed in China to possess health promoting effects [2].In recent decades, beneficial health effects of tea have been extensively studied bothin vitroandin vivo, and tea and its bioactive components appear to have potential in the management of cardiovascular, metabolic and neurodegenerative diseases as well as cancer [3].

Numerous meta-analyses have examined associations between tea consumption and a wide range of health outcomes [4].In regard to total mortality risk, tea consumption has been reported to be associated with a marked reduction, by 41% (risk ratio: 0.59, 95%confidence interval: 0.40-0.97) [5], with an increment in the intake of tea by three cups per day associated with a decrease in total mortality by 24% (risk ratio: 0.76, 95% confidence interval: 0.63–0.91) [5].Consumption of both green tea and black tea were associated with decreased total mortality, with an increase of one cup of green or black tea daily reducing the risk by 4% and 3%, respectively [6].Long-term health benefits of tea consumption in the prevention of cancer [7],cardiovascular diseases (CVDs) [8-10], type-2 diabetes [11,12],cognitive decline and dementia [13-15]as well as depression [16-18]have been suggested.

2.CVDs

CVDs are pathological conditions affecting the heart and/or blood vessels and include coronary artery diseases, heart failure, stroke and cardiomyopathy [19,20].These conditions are globally the leading causes of morbidity, disability and mortality [21].The pathogenetic mechanisms involved in CVDs vary depending on the disease.For example, coronary artery disease, stroke and peripheral artery disease involve arteriosclerosis, which may be caused by hypertension,smoking, dietary factors, obesity, diabetes mellitus, lack of physical exercise or other factors [22].

Hypertension is a major cause of cardiovascular events and mortality [23-25].The risk of CVDs has been found to double for each increment of 20/10 mm Hg in blood pressure starting from 115/75 mm Hg [23].Hypertension has been linked to almost 50% of cases of ischemic heart disease and 60% of stroke cases [26].Even modest reductions in blood pressure have been shown to be associated with a decrease in the risks of coronary heart disease and stroke [27].Lifestyle interventions, such as healthy dietary patterns, management of body weight, regular physical exercise and adequate sleep, are increasingly recognized as important factors in the prevention and therapy of hypertension [28].

While hypertension as a risk factor of CVDs is undisputed, the role of lipids, i.e.high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) as well as triglycerides,in CVDs is less clear [29].Clinical studies have focused on the effects of a reduction in LDL-C and triglycerides and the potential for raising HDL-C.Lifelong exposure to elevated levels of LDL-C has been found to increase the rates of cardiovascular events, while LDL-C reduction can decrease the risk of myocardial infarction, stroke and vascular death [30].Negative results of randomized controlled trials (RCTs) do not support the hypothesis that low HDL-C causes CVDs, and the concept that interventions raising the levels of HDL-C are capable of reducing cardiovascular risk is questionable [31].Furthermore, RCTs demonstrating cardiovascular benefits of triglyceride reduction are scarce [32].However, harmful effects,including inflammation and calcification of arterial cells, which are known risk factors of heart disease, are an established result of transfatty acid intake [33].

3.Evidence of tea effects in CVDs

Dietary factors are believed to be involved in the development of CVDs.For example, modifications of diet have been found to be effective in regulating blood pressure [34].The suggestion that regular tea intake, as part of a healthy dietary pattern, may play a role in maintaining cardiovascular health, reducing risk of CVDs and decreasing all-cause mortality in adult populations has led to the development of a field of research investigating potential health benefits of tea [35-37].Consumption of tea is thought to improve endothelial functions and to reduce blood pressure [38], and the findings of various studies support a role of tea in CVDs [39,40].Several cohort studies have demonstrated that increased tea intake is associated with a reduced risk of major cardiovascular outcomes [41-45].

Various scientific approaches may be employed in establishing the efficacy of therapies and other interventions, including the potential health benefits of foods and nutraceuticals.The primary methods used are observational (epidemiological or population-based) studies,interventional studies (clinical trials) and mechanistic (laboratorybased) studies [46].

3.1 Epidemiological evidence

The findings of epidemiological studies have pointed to an association between high consumption of both green and black tea and a decrease in the risk of CVDs [45,47].For example, a large population-based study comprising 40 000 middle-aged adults in Japan found that, compared to no tea consumption, habitual tea intake (daily average of two cups or approximately 17 oz.for 10 years) was associated with a reduced risk of death from CVDs [47].Another epidemiological survey from Japan, comprising 76 979 individuals, found that mortality from CVDs was reduced when more than 6 cups of tea per day were consumed [48].Studies conducted in North America and Europe also showed that consumption of black tea reduced the risk of CVDs [49].In the Netherlands, a decrease in CVD mortality was linked to a daily intake of 3–6 cups of black tea in a study of 37 514 healthy adults who had been followed up for 13 years [45].Epidemiological findings have suggested that green and black tea may decrease the risk of coronary heart disease and stroke by 10%–20% [50].In China, green tea consumption has been found to be associated with a reduced risk of mortality from all CVDs, with an increase of one cup of green tea per day linearly decreasing the risk by 5% [6].An increase in the intake of tea by three cups daily was associated with a decrease in the risk of cardiac death by 26% [5].In comparison with low or no tea consumption, high intake of green tea has been reported to be related to a decrease in the risk of CVDs [51], coronary artery disease [5], myocardial infarction and stroke [51].An association between intake of green tea and hypertension was examined in a cohort study comprising 1 507 individuals [52].In comparison with non-habitual tea drinkers, the risk of developing hypertension was reduced by 46% or 65% in those who consumed 120–599 mL/day and 600 mL/day or more, respectively [52].The findings of meta-analyses of some observational studies are summarized in Table 1.

Table 1Reviews and meta-analyses examining the effect of tea on CVDs andrelated outcomes.

3.2 Interventional evidence

Various RCTs examining the effects of tea on CVD-related parameters, such as blood pressure and lipids, have been conducted.The results of systematic reviews and meta-analyses of these studies can be found in Table 1.For example, a Cochrane review on the role of tea in the primary prevention of cardiovascular diseases concluded that both green and black tea, the type and dosage of which differed between the trials included, have beneficial effects on lipid levels and blood pressure, but these findings were based on a small number of trials which were at risk of bias [53].In another meta-analysis of RCTs,no effects of short-term intake of green or black tea on systolic or diastolic blood pressure were observed, while following long-term tea consumption of at least 12 weeks, pooled mean systolic and diastolic blood pressure was significantly reduced by 1.8 and 1.4 mm Hg,respectively [54].In the meta-analysis published most recently, black tea supplementation significantly reduced mean systolic and diastolic blood pressure by 1.04 and 0.59 mm Hg, respectively, compared to control [55].At present, the results of the available studies suggest some benefits of green and black tea on blood pressure and lipid levels.However, more longer-term trials at low risk of bias are required to confirm this.

3.3 Mechanistic evidence

The reduction of CVD risk associated with tea consumption has been suggested to be due in large part to the high concentrations of polyphenols, in particular flavonoids, in both green and black tea [62].Green tea and black tea contain similar amounts of total polyphenols,but different types of flavonoids result from the different degree of oxidation during processing [63].Catechins contained in tea include epigallocatechin gallate, catechin, epicatechin, gallocatechin,gallocatechin gallate, epigallocatechin and epicatechin gallate [64].Widespread consumption of tea provides a major source of flavonoid intake in humans and may provide more than half of total intake [65].Various experimental studies performedin vitroandin vivohave investigated the mechanisms underlying cardiovascular protective effects of tea and its bioactive compounds.

Tea flavonoids can modulate enzymes involved in oxidative and inflammatory stress, improve endothelial function and enhance nitric oxide status, which may contribute, at least to some degree,to potential benefits on cardiovascular health [66].The findings ofin vitrostudies suggest that the cardioprotective efficacy of green tea catechins may be mediated through multiple mechanisms,including inhibitory effects on oxidation, vascular inflammation and thrombogenesis [67,68].Studies in rodents have demonstrated that green tea catechins influence the production of nitric oxide and vasodilation and thus improve endothelial dysfunction and hypertension [68].

Several biological activities of catechins may possibly be capable of providing antihypertensive benefits.These activities include an elevation in the levels of plasma nitric oxide, which can inhibit proinflammatory cytokines and platelet aggregation and improve endothelial dysfunction [69].Furthermore, catechins may have antiinflammatory effects through the suppression of inflammatory factors,such as cytokines and adhesion molecules [70,71].They may also exert vasodilating effects through the suppression of contractile responses by inhibiting mRNA expression of endothelial nitric oxide synthase and endothelin-1 [72,73].

Numerous studies using preclinical animal modelshave found that the administration of tea attenuated increases in blood pressure,decreased the formation of vascular reactive oxygen species and improved endothelium-dependent relaxation in the aorta [74-78].Furthermore, tea intake has been shown to lead to increments in brachial artery flow-mediated dilation and improved endothelial function [79,80].However, the findings of human intervention studies do not support the hypothesis that a decrease in the formation of reactive oxygen species contributes to the beneficial effects of tea on vascular function [81,82].

In addition to flavonoids, other active substances contained in tea may improve vascular function.For example, the administration ofL-theaninein vitrohas been shown to enhance the production of nitric oxide and arterial vasodilation [83], suggesting thatL-theanine may also play a role in the vascular benefits of tea.

In regard to lipid metabolism, green tea catechins have been shown to increase cholesterol 7α-hydroxylase gene expression in HepG2 cells [84,85], which may stimulate bile acid production and reduce cholesterol levels in hepatocytes.Green tea extracts have been found to inhibit the intestinal absorption of lipids and to upregulate LDL receptors in the liver [86-88], which leads to improved blood lipid profiles.

Taken together, the observations of experimental studies performedin vitroandin vivoevidence cardioprotective effects of tea bioactives including a reduction of oxidative stress, alleviation of inflammation, protection of endothelial and cardiomyocyte functions,amelioration of ischemia and reperfusion injury and a reduction in blood lipids.The relevant mechanisms involved have been discussed in more detail elsewhere [89].

4.Appraisal of the evidence

4.1 Differences in research strategies

Several lines of evidence, including the findings of epidemiological studies, intervention trials and mechanistic experiments, support the hypothesis that tea and its bioactive components play a role in cardiovascular health and disease.However, one should bear in mind that the significance and quality of these approaches varies.

In observational or epidemiological studies, i.e.cohort, case control and cross-sectional studies, the effect of a risk factor or intervention is observed, and no attempt is made to influence which participants are exposed to the risk.Observational studies are subject to confounding and selection bias, since unmeasured or unmeasurable factors may affect treatment effects and cannot be accounted for by statistical methods [90].For example, the health effects of foods, as assessed in epidemiological studies, may be influenced by numerous other known or unknown lifestyle factors.Although a cohort can be defined by one common exposure, they may also share other characteristics that could affect the outcome.Thus, observational studies cannot establish causal relationships between intervention and outcome.

In experimental studies, an intervention is introduced and its effects are studied.Experimental studies are usually randomized, i.e.,the participants are assigned by chance to the (experimental/treatment and control) groups.The (well designed and conducted) RCT, and especially the systematic review and meta-analysis of several RCTs,has become the gold standard for producing reliable evidence of the efficacy of a treatment [46].With the exception of the treatment being tested, all factors should be kept constant.RCTs are therefore able to establish cause-and-effect relationships between an intervention and a particular health outcome.However, many research questions cannot be investigated using this approach, for example when the potentially delayed appearance of an outcome necessitates a trial over an extended time period, as in the case of some food and nutrition studies.

Neither observation nor intervention studies are able to provide any information on the way in which particular nutraceuticals exert health effects.The mechanisms of action of nutraceuticals are usually investigated usingin vitrotests, cell cultures and animal models.These studies can provide insights into the possible mode of action and potentially harmful effects of nutraceuticals, but they may not reflect the complexity of human physiology, and the translational relevance of their findings is therefore uncertain.

4.2 Surrogate markers and clinically meaningful outcomes

The use of RCTs in the investigation of the effects of dietary interventions on long-term outcomes of chronic diseases poses major challenges [91].Consequently, RCTs examining the effects of foods frequently assess intermediate or surrogate outcomes of chronic disease.

In clinical trials investigating CVDs, meaningful outcome measures include the incidence of heart attacks, cardiac deaths or strokes.However, such endpoints are undesired, the number of events is small and a clinical trial examining such outcomes would need to be conducted over long periods of time.Since this is not feasible,surrogate markers (or endpoints), i.e.biomarkers as substitutes for a clinically relevant endpoint, are commonly used to assess the effect of a specific intervention.A surrogate marker may correlate with a real clinical endpoint but the relationship is not guaranteed [92,93].Therapeutically induced changes in a surrogate endpoint are expected to reflect changes in a clinically relevant endpoint [94].In several cases, studies employing surrogate markers found beneficial effects of a particular treatment, while replication studies using clinical endpoints were unable to demonstrate a benefit or even showed harmful effects[95].

In regard to CVDs, surrogate endpoints including physiological and biochemical biomarkers, such as blood pressure and lipid levels,can be obtained using laboratory measurements.A common example is cholesterol, since elevated cholesterol has been found to be associated with, but not necessarily causative in, an increased likelihood of heart disease [29].Another possible surrogate biomarker is blood pressure.Hypertension has been estimated to be a comorbid factor in 69% of individuals with a first heart attack and in 75% of those with chronic heart failure [96].A reduction in blood pressure by 5 mm Hg has been shown to decrease the risk of ischemic heart disease and stroke by 21% and 34%, respectively [97,98].Therefore, the small reductions in blood pressure, as reported in meta-analyses of RCTs examining the effect of tea [54,57], may have a significant impact on the risk of CVDs.However, the meta-analysis by Liu et al.[54]found that only long-term consumption of green or black tea (> 12 weeks) resulted in a significant decrease in systolic and diastolic blood pressure.In the meta-analysis by Khalesi et al.[57], some studies included individuals with high baseline blood pressure or diabetes,while others included only healthy participants.Furthermore, most studies did not control for the effects of a change in dietary habits on their results [57].These limitations make it difficult to generalize the meta-analytic findings to the population level.

4.3 Discrepancy between animal and human studies

The summary of the available findings above shows generally good results in preclinical studies investigating the effects of tea on blood pressure and other CVD-related parameters.Human studies have also yielded positive results, but the value of these findings appears to be qualified by several caveats (see limitations in Table 1).A number of factors may account for the discrepancy between animal and human trials.Differences in biochemical and physiological metabolism between humans and animals offer an obvious explanation as to why findings in animals cannot necessarily be translated and generalized to humans.However, several other explanations are possible in the case of tea and CVDs.

In animal research, the general living conditions, including housing, feeding and wake-sleep cycle can be controlled and kept constant, and diseased animals are excluded from studies.In contrast,the findings of epidemiological studies on tea and CVDs in humans are likely to have been confounded by various factors, such as socioeconomic status and lifestyle [49], which may have influenced or masked possible effects and may thus reduce the power for detecting preventive effects.Cardiovascular health can be affected by many lifestyle factors, such as smoking, diet, alcohol intake, stressinducing environments and work conditions, physical activity and sleep patterns [22].These habits differ between cultures, and the findings from one country are therefore not globally representative and should not be generalized.For example, certain “healthy” dietary patterns in East Asia or Mediterranean Europe versus Western-style diets may be more relevant in regard to cardiovascular health than the (additional) consumption of tea.The effect of tea polyphenols on blood pressure is likely to depend on dietary polyphenol status prior to the intervention and, thus, on their ability to provide any additional benefit below a possible ceiling effect of polyphenol supplementation.Differences in lifestyles could also result in differential tea effects in men and women.Furthermore, prevalent medical conditions, such as hypertension, obesity and diabetes, can also affect potential effects of tea.Some of the available human trials included people with high baseline blood pressure or diabetes, while others included only healthy individuals [57].

Different results in preclinical and clinical studies are also likely to be due to lower amounts of tea consumed in humans compared to the doses administered in animals.In animal research, the dosages of tea are chosen to maximize the likelihood of revealing the hypothesized effect.The doses of tea polyphenols administered in animals are much higher, by a factor of 10 to over 100, than their concentrations in blood and organs of humans following tea intake.While the concentration of tea polyphenols in animal experiments is usually in the range of 20–100 μmol/L, their concentration in human blood is often found to be approximately 0.5 μmol/L [3].Furthermore,the poor bioavailablity of tea polyphenols, especially epigallocatechin gallate, needs to be considered [99,100].In addition, the tea polyphenols epigallocatechin gallate, epicatechin, epigallocatechin and epicatechin gallate are metabolized and excreted via different routes [101,102].

Animal experiments usually apply a reductionist approach, i.e.,the behavior and interactions of complex systems are investigated and explained in terms of their individual parts and mechanisms.A complex real life system is explained in terms of its constituent units,which can be more easily analyzed and comprehended.For example,in the case of tea effects on health, the impact of tea bioactives is investigated on single biochemical pathways and physiological outcomes rather than on the entire organism.While the reductionist approach is successful in explaining various mechanistic details of biological processes, it is unable to account for the complexity and dynamics of biochemical interactions in different body systems.In contrast, the approach of systems biology attempts to investigate the network of interactions between different biological systems and to describe complex outcomes, which are difficult to predict on the basis of individual mechanisms.Food bioactives can interact with and influence numerous organismic components and may have additive,synergistic or antagonistic effects.Thus, while the effects of tea and its compounds may demonstrate positive effects on various physiological mechanisms involved in blood pressure control, the net effect on hypertension in humans may be less pronounced than expected.

It therefore seems apparent that different research strategies may explain different sizes of tea effects observed in human and animal research.Ethical considerations preclude the use of some experimental designs of animal studies in humans.However, several issues related to the choice of outcome markers, dose-response relationships and potential adverse events deserve further investigation.

5.Future directions

Various aspects of the effects of tea consumption on cardiovascular health warrant further elucidation.This includes the role of different types of tea, dose-response relationships, possible adverse effects, methodological issues, the funding of clinical trials and potential implications for introducing tea consumption into clinical practice.

5.1 Type of tea

Due to different methods of harvesting, storing and processing,different teas derived from the plantC.sinensiscontain different types and amounts of bioactive compounds, such as natural antioxidants.Green tea and black tea contain similar amounts of total polyphenols,but the degree of oxidation during processing results in different types of flavonoids [63].Systematic trials comparing different types of tea are lacking.

The levels of flavonoids in prepared tea depends on various factors, including their concentration in tea leaves, the quantity of leaves used to prepare the infusion, the volume, temperature and pH of the water used, the brewing time, the duration between preparation and consumption of tea, the volume of the infusion consumed and the type of tea [103].

5.2 Dose-response relationships

The quantity of tea consumed appears to be an important factor in the prevention of CVDs.The Women’s Health Study, in which tea intake was relatively low, with only a small proportion of participants drinking more than four cups of black tea per day, revealed only a statistically non-significant trend regarding CVD prevention [104].

The optimal amount of daily tea intake providing benefits for cardiovascular health is unknown.A daily dosage of epigallocatechin gallate with a range of 69-657 mg (approximately equivalent to 2–6 cups of tea) has been estimated to provide beneficial effects regarding CVDs [105].However, the wide range of catechin dosages administered in the available studies (208–1 344 mg/day [61]) do not allow any conclusions as to the dose-response relationship between tea intake and blood pressure-reducing effects.The findings of observational studies may help determine potential effective doses for testing in RCTs, which are frequently initiated before sufficient evidence of an effective dose is available [106].

5.3 Adverse effects of tea

In the absence of reports of toxicity associated with tea consumption, tea is considered to be a safe beverage.Side effects observed in tea intervention trials examining CVDs include rash and gastrointestinal disturbances such as vomiting and diarrhea, but no serious adverse effects were reported [58].

Concerns have been raised concerning the safety of high-dose supplementation of green tea catechins.For example, hepatotoxic effects and liver disease following dietary supplementation with green tea extracts have been reported [107-109].Hepatotoxicity of green tea catechins has also been observed in animal studies [110-112].Even with a maximum tea intake (13 g/day) and a maximum brewing rate of green tea catechins with the highest extracting rate (20%), the highest figure of catechins consumed was calculated as 2.6 g [113].This amount is approximately 10-60 times lower than the safe dose of a maximum daily intake of 150 g of green tea extracts [114]or 30 g of epigallocatechin gallate [115].Therefore, liver damage in humans seems unlikely under the conditions of traditional tea consumption.

Human trials have indicated that green tea was the major dietary source of oxalate in some individuals with kidney oxalate stones [116].Associations of tea consumption with esophageal [117]and gastric [118]cancers may be due to thermal injury following the intake of very hot tea [119,120].

In future trials, the safety of tea and its compounds should be assessed systematically, with larger quantities consumed over extended periods of time.

5.4 Methodological issues

The intervention trials included in the meta-analyses examining tea and CVD markers vary markedly in catechin dose, intervention type, duration, participants, blinding procedures, ethnic group,baseline health status and overall quality.These variations may contribute substantially to the heterogeneity of studies, which limit the validity of the pooled results.The short duration of most trials (3–16 weeks) provides no information on the long-term effects of tea intake on blood pressure, which is of crucial importance in cardiovascular protection.The sample sizes of many of the RCTs investigating tea effects are small, which may lead to an overestimation of treatment effects and publication bias [121,122].Several meta-analyses have used subgroup analyses, with multiple statistical testing increasing the risk of type I statistical errors (“false positive”).Since the primary purpose of these meta-analyses is the generation of hypotheses, their results should be interpreted with caution.

5.5 Funding of studies

Findings published on tea and CVDs may have been subject to influence by funding sources.For example, in regard to the 20 RCTs included in the meta-analysis by Onakpoya et al.[58], 8 studies were funded exclusively by industries manufacturing green tea, 5 studies received funding from government or public institutions and 1 trial was supported by both government and a manufacturer of green tea.The remaining 6 RCTs received no funding, but the authors of 5 of these studies had affiliations to tea manufacturers, while the authors of the 6thstudy were affiliated to a public institution [58].Interestingly,the results reported in manufacturer-sponsored trials differed from those revealed by government-funded studies.While the meta-analysis of 12 trials (with 1 010 participants) receiving financial support from manufacturers or with authors affiliated to tea manufacturers reported a slight, statistically significant decrease in systolic blood pressure linked to green tea, the 6 studies (comprising 332 participants) funded by public institutions or with authors working at public organizations found a non-significant difference [58].No multiple testing correction was performed.

The discrepancy between trials sponsored by the tea industry and those funded by public institutions might be explained by vested interests of the researchers involved in the studies or by a bias of the publication towards positive findings, resulting in the underreporting of less favorable results.Subtle mechanisms through which sponsorship may influence the effect of interventions on outcomes have been shown [123]and overestimation of benefits and underestimation of harm may result from vested interests alone [123].More independent RCTs are therefore required.

5.6 Clinical implications

Large-scale, well-controlled clinical trials are required to establish the health promoting effects of tea consumption and to provide recommendations for human populations.Some evidence suggests that a daily intake of 5–6 cups of green tea may decrease systolic blood pressure, total cholesterol and LDL-C.While the effects of tea on these surrogate biomarkers of CVDs appear to be modest at best,even small reductions in blood pressure due to dietary changes may significantly impact the prevalence of hypertension and the risk of CVD [23].Community-wide preventive measures may be capable of shifting the population distribution of CVD risk [124].Contaminants in tea and tea infusions that could pose potential health hazards should be considered [125].In order to provide high-quality evidence of the role of tea in CVDs, well-designed long-term RCTs, conducted in large and representative samples and using different types and doses of tea and its components, are needed.

6.Conclusion

The findings of numerous epidemiological studies have indicated that tea consumption is inversely associated with CVD risks, especially in habitual tea drinkers.Furthermore, a variety of experimental studies conductedin vitroandin vivohave revealed an array of mechanisms of action that may underlie the protective effects of tea and its bioactive compounds against CVDs.However, the level of evidence provided from observational research was in general only low.Further evidence derived from long-term, high-quality RCTs is needed to determine whether these observational associations are causal.No adverse effects of tea have been reported at normal levels of consumption.However, the safety of tea and its compounds should be assessed systematically, with larger quantities consumed over extended periods of time.

Although the effects of tea on CVD risk and its surrogate biomarkers, such as blood pressure, are limited, in view of the widespread consumption of tea and the high global prevalence of hypertension, such effects may nevertheless be important for cardiovascular health at the population level.Even small beneficial effects in humans may shift the population distribution of CVD risk, with major implications for public health.However, while the inclusion of tea in health policies seeking to prevent hypertension and improve cardiovascular health may be desirable, a recommendation as to the optimal level of tea consumption cannot be made on the basis of currently available evidence.

Conflict of interest

The author declared that there is no conflict of interest.