Cardiovascular disease (CVD) is the number one cause of death worldwide, according to the World Health Organization (WHO). The WHO predicts that by 2030, over 28 million individuals will die from CVD annually [1
]. Over the past decade, there has been increased interest in lifestyle and dietary interventions to reduce CVD risk. Research has shown that individuals who adhere to US national guidelines for a healthful diet [2
] and physical activity [3
] have lower cardiovascular morbidity and mortality than those who do not adhere to these guidelines. Higher fruit and vegetable consumption has been suggested to be inversely associated with a decreased risk of CVD [2
]. Berry consumption has recently been reviewed and has shown to be an essential fruit group in a heart-healthy diet [4
]. This may be due in part to the abundance and variety of dietary bioactive components present in plant foods.
Anthocyanins are the red-orange to blue-violet pigments present in many fruits, vegetables, flowers, grains, and other plant-derived foods. Interest in the biological effects of anthocyanins has grown because of their noted presence in the human diet, as well as their potential use as a value-added alternative to synthetic colorants in many food products. Evidence from epidemiological studies supports potential preventative effects of these compounds toward the onset of CVD [5
] in a dose-response manner in both men and women [6
]. Animal and in vitro
cell studies support biological plausibility for these compounds to favorably improve validated and surrogate biomarkers of CVD [9
In humans, several small to medium-sized randomized controlled trials (RCTs) have assessed the effects of purified anthocyanins and anthocyanin-rich extracts on validated biomarkers of CVD in populations of both healthy and diseased adults (i.e.
, those with elevated markers). A plethora of clinical evidence and expert reviews support increased consumption of anthocyanin-rich whole foods and CVD prevention [4
]; however, to our knowledge, there is no systematic review that assesses the effect of purified anthocyanins and/or anthocyanin-rich extracts on markers of cardiovascular health among RCTs. The objective of this study was to systematically review these RCTs and to identify research gaps where additional scientific evidence is warranted. For this systematic review, we chose to evaluate validated and/or common markers used clinically as biomarkers of cardiovascular health and to diagnose cardiovascular diseases (i.e.
, lipids, triglycerides and blood pressure). Many types of inflammatory markers have also been measured across clinical studies; however, we chose not to review these markers because of their limited clinical use and high inter- and intra-assay variability.
An inverse relationship between anthocyanins and anthocyanin-rich foods and CVD outcomes (e.g., mortality) has been observed among epidemiological studies. McCullough et al.
recently observed a significant inverse dose-response relationship among 38,180 men and 60,289 women in regard to anthocyanin intake (3.8–22.2 mg/day) and age-adjusted CVD mortality [6
]. This systematic review of RCTs suggests that anthocyanins may have potential to influence CVD development and progression among individuals with elevated risk biomarkers. Although most of the potential effects seen in this review were nonsignificant, improvement of biomarkers were consistent across studies, particularly in those with elevated risk biomarkers at baseline.
CVD development and progression is slow and may span decades. Nutritional interventions often show small changes in the short term but clear effects over the lifespan. Interestingly, trials that used high doses of purified anthocyanins did not observe much more of an effect compared with those studies of anthocyanin-rich extracts containing more physiologically achievable intake. No dose-response relationships were identified among the RCTs included in this review. It is possible that other dietary bioactive components present in the anthocyanin-rich extracts may exert synergistic effects or contribute to a threshold effect.
Results from animal studies suggest that anthocyanins and other polyphenols may slow or inhibit the absorption of lipids and glucose in the intestine. It has been reported that tea catechins may improve lipid profiles by inhibiting the micelle formation by bile acid [27
]. Another possible mechanism for cholesterol-lowering effects of anthocyanins could be the inhibition of cholesterol synthesis. It has been shown that anthocyanins can activate AMP-activated protein kinase (AMPK) [28
], which is involved in the regulation of energy homeostasis and influences the activity of many enzymes. One enzyme that is inhibited by AMPK is 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase [30
]. Because HMG-CoA reductase is the limiting enzyme of cholesterol synthesis, increased AMPK activity would inhibit cholesterol synthesis and consequently lead to lower cholesterol levels. Furthermore, AMPK inhibits the activity of acetyl-CoA carboxylases ACC1 and ACC2, which leads to increased fatty acid oxidation and decreased fatty acid synthesis [30
], and, accordingly, lower triglyceride concentrations. It is possible that anthocyanins may have the ability to modulate low-grade inflammation, as consumption of anthocyanin-rich foods such as berries have been suggested to affect many inflammatory markers of CVD in vivo
]. Berry consumption has been suggested to be an effective strategy to counteract postprandial metabolic and oxidative stress associated with CVD, especially lipid oxidation [31
]. Specific berries such as freeze-dried strawberries [32
], bilberries and lingonberries [33
], blueberries [34
] and cranberry extracts [35
], among others have shown similar favorable effects on lipid profiles those with elevated markers as suggested in our review.
In regard to blood pressure, anthocyanins have been shown to lower direct measures of arterial stiffness in a cross-sectional study of 1898 women [5
]. Across the studies, most did not observe and affect of purified anthocyanins or anthocyanin-rich extracts on blood pressure.
This systematic review identified several gaps in the literature. The age range of participants in most studies was large and may contribute to the null findings of many studies, because it is likely that interventions may have a greater effect among older populations and/or those with an elevated risk of developing CVD. Compliance was also not reported in many of the included studies.
In studies that were not so heterogeneous, a meta-analysis would be carried out to assess the magnitude of effect of purified anthocyanins and anthocyanin-rich extracts on CVD biomarkers. However, we concluded from qualitative review that a meaningful summary estimate could not be obtained by meta-analysis due to high heterogeneity. The control groups included a range of different treatments (e.g., preventative diet). The duration of the studies (3–24 weeks), anthocyanin dose administered (7.35–640 mg/day), composition of the anthocyanin-rich extracts, variation in baseline status of the biomarkers, and difference in the reporting of outcome measures (e.g., mean absolute difference, or percent change) also varied.
For the purpose of developing recommended intakes, future intervention studies should be designed to assess whether a dose-response relationship of anthocyanins on markers of CVD exists. From this review, we identified gaps in the research literature that could be addressed in further studies. Data in “healthy” individuals (i.e., those with risk biomarkers in the normal range) are important in developing dietary guidance for the general population; however, these data are hard to obtain in short-term clinical studies with a small population. Because larger clinical studies spanning a decade or more are expensive and difficult to control, reliance on well-designed epidemiological studies may be useful in complementing smaller clinical trial data. It may be helpful for future trials to focus on a particular anthocyanin (e.g., Cy-3-glu the most common anthocyanin present in nature), because the type of aglycon and amount of glycosylation and/or acylation of the compounds may significantly alter their biological activity as well as their transportation across the basolateral membrane. By contrast, anthocyanins are currently solely consumed as mixtures in plant-derived foods and extracts. Thus, continued research in this area is equally important. Data on study compliance and evaluation of baseline status of flavonoid and/or polyphenol intakes may improve the consistency between small clinical interventions.