While used traditionally in a number of cultures, one of the best examples of its medicinal use is from the Kuna Indians who have lived for centuries on remote islands off of the Caribbean coast of Panama. This group of indigenous people is famous the lack of hypertension, an infrequent prevalence of CVD, diabetes, and cancer, and a longer lifespan, compared to Panamanians living on the mainland. However, when these people migrate to an urban environment, the incidence of hypertension and vascular diseases increased significantly. Nutritional assessments showed that the consumption of total fruit, fish, and cocoa-containing beverages were significantly higher among Kuna Indians living on the island compared to those residing in Panama City, even though the overall dietary intake of added sugars and salt was higher in the indigenous group. Scientists hypothesized that cocoa may be an influencing factor in the low prevalence of CVD in this population, due to its high concentration of flavonoids. The primary flavonoids in cocoa are flavanols, including monomeric catechins, epicatechin, and polymeric procyanidins. Cocoa also contains methylxanthines, i.e., theobromine and caffeine, large plastic growing pots which remain in flavanol-poor cocoa butter and cocoa solids after pressing. The effect of cocoa flavanols on vascular function was first reported more than two decades ago.
Extending the observations about cocoa flavanols to broader dietary patters, studies exploring the association between the intake of flavonoids and the risk of CVD have yielded inconsistent results, suggesting that certain sub-classes may be more effective than others in terms of cardio-protection. Some observational studies have shown that the dietary intake of flavanols was associated with a decreased risk of CVD and ischemic heart diseases. Epidemiological studies have reported that a moderate amount of chocolate consumption was associated with a decreased risk of CVD. A Cochrane meta-analysis concluded that the consumption of flavanol-rich chocolate and cocoa products had a small but statistically significant effect on reducing systolic and diastolic blood pressure, both by 1.76 mmHg. Similarly, another systematic review and meta-analysis included 42 acute and short- term randomized controlled trials concluded that chocolate, cocoa, and flavanol intake significantly improved vasodilation function as measured by flow-mediated dilatation , reduced diastolic blood pressure by 1.6 mmHg, and marginally improved the serum cholesterol profile. However, these results were strongest among individuals with moderately elevated blood pressure and untreated hypertension. The vasodilation function in healthy males, measured by FMD, was significantly increased one to four hours after taking a cocoa drink containing 917 mg of cocoa flavanols, compared to baseline values and to those consuming a control beverage with 37 mg of flavanols.
The pattern of improvement in FMD from the flavanol-rich cocoa beverage was closely mirrored when participants also consumed 1 or 2 mg/kg of body weight of -epicatechin dissolved in water, suggesting -epicatechin and its metabolites were the main contributors of the vascular effects. Additional research from the same study found that while -epicatechin is a primary contributor to the vasodilation function, dimeric and oligomeric procyanidins that are metabolized by the gut microbiome may also contribute to the vasculo-protection. In healthy young men, daily intake of a cocoa extract containing 130 mg of -epicatechin and 560 mg of procyanidins for 30 days significantly improved FMD and reduced blood pressure and arterial stiffness as measured by pulse wave velocity , while 20 mg of -epicatechin and 540 mg procyanidins, or a control capsule, did not. However, total cholesterol was decreased after in both groups consuming cocoa, suggesting synergistic effects of -epicatechin and procyanidins, possibly through gut microbiome-mediated catabolism. Cocoa also contains methylxanthines, which are biologically active. While the intake of theobromine and caffeine alone did not result in a significant change in vascular endothelial function measures, interestingly, the combination of methylxanthines plus a high cocoa flavanol drink induced a significant improvement in FMD response than the beverage only. In addition, plasma metabolites of -epicatechin were higher after consuming the flavanol-rich cocoa drink with methylxanthines than when the flavanols were consumed alone, indicating a likely interaction between theobromine, caffeine, and cocoa flavanols on vascular function. Several molecular mechanisms regarding the effects of flavanols on blood pressure and vasodilation have been proposed. Flavanols such as -epicatechin can increase nitric oxide production directly by increasing endothelial nitric oxide synthase expression. The release of NO consequently increases intracellular cGMP which then induces a relaxation of vascular smooth muscle cells. The increased eNOS activation may also be modulated by flavanols through a calcium/calmodulin pathway by increasing the intracellular calcium concentration, or by phosphatidylinositol 3-kinase/protein kinase B -dependent eNOS phosphorylation. In addition, -epicatechin has been shown to down-regulate the expression of nicotinamide adenine dinucleotide phosphate oxidase by inhibiting the synthesis of vasoconstrictors such as endothelin-1, and therefore increase the utilization of NO.
Flavanols may also directly inhibit angiotensin-converting enzyme activity, which increases NO production. Apart from modulating NO production, flavanols may also induce the release of endothelium-derived relaxing factors such as hydrogen peroxide and prostacyclin. Cocoa flavanols also benefit cardiovascular health by inhibiting platelet activation and adhesion. In healthy individuals, platelet aggregation induced by collagen and adenosine diphosphate, and the expression of P-selectin, was significantly decreased compared to a placebo group after the daily intake of 234 mg of cocoa flavanols and procyanidins for 28 days. Some studies have reported that the reduction in platelet aggregation was not different between flavanol-rich darkchocolate or low-flavanol dark chocolate mixed with white chocolate, suggesting potential antiadhesive effects from methylxanthines. While the exact mechanisms to explain the interaction between flavanols and platelets are still under investigation, proposed mechanisms from in vitro and ex vivo models include an inhibition in the expression of endothelial adhesion molecules , and the down-regulation of pro-inflammatory factors such as interleukin -6 and tumor necrosis factor-α, large plastic pots which also decrease the recruitment of other proinflammatory compounds. Mango originated from the Indian subcontinent and has been cultivated for thousands of years. The bark, leaves, roots, and flowers of the tree, and the peel, kernel, and pulp of the fruit, have been used in traditional medicine in tropical and sub-tropical regions throughout the world. The bark and leaves have been used for treating diarrhea and diabetes in Bangladesh, and Ghana, with the pulp and kernel used for hemorrhaging in the lungs and intestines in India.54 Mango fruit is a rich source of fiber, vitamins C and E, folate, potassium, β-carotene, and phenolic compounds. Dietary intake of vitamins C and E, and β-carotene, are associated with reduced risks for CVD. Major phenolic compounds reported in mango pulp include mangiferin, quercetin, kaempferol, myricetin, catechin, gallic acid, ferulic acid, protocatechuic acid, and chlorogenic acid. One study observed that a higher mango intake was associated with improved nutrient intakes, diet quality, and body mass index , factors known to reduce the risk of CVD. Clinical trials also suggest that mango fruit may have protective effects against the development of CVD. Daily intake of 200g of fresh-cut Ataulfo mango for 30 days decreased blood lipids and increased the plasma antioxidant capacity in healthy adults. In obese men and women aged 20-50 years, supplementation of 10 g/d freeze-dried mango pulp for 12 weeks decreased blood glucose levels but not inflammatory or any cholesterol markers. Another study reported that the daily intake of 400 g of fresh frozen mango pulp significantly decreased systolic blood pressure only in individuals with a BMI of 18-26.2 kg/m2 . In contrast, plasminogen activator inhibitor 1, IL-8, and mitochondrial pyruvate carrier-1 were significantly reduced in individuals when the BMI was partitioned as > 28.9 kg/m2 . In addition, in participants with impaired glucose sensitivity, the supplementation of 100 or 300 mg/d of mango fruit powder with 250 ml water daily for four weeks significantly increased the vasodilation of arteries as measured by the reactive hyperemia index compared to a placebo group.
Mangiferin is a unique compound in mango that has been studied for its vasculo protective effects . A mango bark extract with a high concentration of mangiferin decreased cholesterol in plasma and liver, and reduced oxidative stress in mice. A subsequent human study showed that the daily intake of 900 mg of Vimang® for 90 days reduced a measure of serum oxidative stress compared to a control group among older individuals. In both the animal and human studies, the marker of oxidative stress, while considered valid at the time of the study, is now viewed with limitations. In overweight hyperlipidemic individuals, the daily intake of 150 mg of mangiferin for 12 weeks significantly improved lipid profiles and glucose homeostasis. In hyperuricemic rats, mangiferin intake significantly reduced SBP, serum uric acid and inflammatory markers, and increased the expression of eNOS. One potential mechanism to help explain the vasodilatory effect of mangiferin may be due to the increased expression of eNOS, and therefore enhanced the production of NO. Reports have shown that the composition of phenolic compounds in mango varied significantly among different varieties. Mango varieties with high polyphenol content, such as Ataulfo, may play a more prominent role in cardiovascular health, but the interaction between the polyphenols, carotenoids and other bio-active compounds in mango must be considered. Further studies may also focus on the potential effects of mango by-products on metabolic health, since the total concentration of phenolic compounds is higher in the kernel, peel, leaves, and bark compared to the edible fruit. Such explorations may be useful in processing what is considered as agricultural waste into useful extracts. Low-bush blueberry and high-bush blueberry are two common species originally grown in North America. Native Americans have a long folklore history of using both types of blueberry plants to treat rheumatism and infection. Anthocyanins are responsible for the red, blue, and purple color in ripe berries. Blueberries are one of the most abundant sources of anthocyanins in commonly consumed fruits. The total anthocyanin level in fresh blueberries is significant, reaching up to 487 mg/100g. Blueberries also contain appreciable amounts of proanthocyanidins and hydroxycinnamic acids , along with vitamins and minerals, fiber, and small quantities of flavonols and flavanols. Epidemiological studies suggest that a higher dietary anthocyanin intake is associated with a lower risk of hypertension, and reduced arterial stiffness in women, though these studies do not specify blueberries as the sole source of these bio-actives. A meta-analysis of 19 cohort studies reported that the dietary intake of anthocyanins was associated with a decreased risk of coronary heart disease and CVD mortality, but not myocardial infarction, stroke, or total CVD risk. The effects of blueberries on markers of CVD risk have been studied. In obese postmenopausal women with pre- and stage I-hypertension, daily consumption of 22 g of freeze-dried blueberry powder containing 469 mg of anthocyanins for eight weeks significantly reduced systolic and diastolic blood pressure by 7 mmHg and 5 mmHg, respectively, and arterial stiffness measured by brachial-ankle PWV, compared to their baseline values or to a placebo group. In healthy males, FMD was significantly increased one, two, and six hours after the intake of 34, 57, and 80 g of blueberry powder mixed in water , compared to a control drink. However, no changes were seen in arterial stiffness measures. In addition, the increase in polyphenol metabolites and decrease in neutrophil NADPH oxidase in plasma were correlated to FMD, suggesting that the phenolic metabolites after blueberry powder consumption effectively improved vasodilation functions by elevating the bio-availability of NO through inhibition of NADPH oxidase. Later the research group identified that the FMD improvements were mainly due to anthocyanin metabolites. The blood pressures of overweight and obese smokers who consumed 250 g of blueberries for three weeks showed no significant changes from baseline values . Among mid-aged women who were at risk for type II diabetes, daily consumption of 240 ml of wild blueberry juice with 314 mg of anthocyanins for seven days significantly improved serum nitrates and nitrites, but no change were noted for in glucose metabolism parameters, cholesterols, inflammatory markers, platelet adhesion molecules, vasodilation, or blood pressure, compared to baseline and the placebo group. Taken together, the above results suggest that clinical trials with blueberries may need require a few weeks or longer of regular intake in order to observe clinically significant changes. Similar to blueberries, the American-cranberry is also a plant that is native to North America and has a long history of botanical uses by indigenous people, such as for urinary tract disorders and diarrhea.