April 12, 2010
The circulatory system isnt usually the first thing that comes to mind in the area of heart health. The hot topics are usually cholesterol and blood pressure; but, the circulatory system is an intricate and systemic system often overlooked. Wikipedia defines it as an organ system that passes nutrients, such as amino acids and electrolytes; gases; hormones; blood cells, etc., to and from cells in the body to fight off disease, and stabilize the body temperate and pH to maintain homeostasis. The circulatory system is composed of two systems transporting two types of fluids, i.e., blood and lymph: the cardiovascular system, which includes blood, the heart and blood vessels; and the lymphatic systemlymph, lymph nodes and lymph vessels. Together, they ensure blood flow throughout the body.
Its main components are the heart, arteries, capillaries and veins. Arteries are blood vessels carrying blood away from the heart, while veins carry blood to the heart. Capillaries are tiny vessels connecting arteries to veins. These passage ways are extremely small, and blockage or narrowing of these areas can cause serious problems.
Endothelial cells line the entire circulatory system. They are a key player in its performance, including vasoconstriction (constriction of blood vessels) and vasodilation (the widening of blood vessels), both involved in controlling blood pressure; blood clotting thrombosis and fibrinolysis; and atherosclerosis, a condition in which the build-up of fatty materials cause the artery wall to thicken. Endothelial dysfunction is a precursor to atherosclerosis and vascular diseases such as coronary heart disease (CHD) or hypertension.
Dietary intervention, supplementation and numerous nutritional compounds can preclude the breakdown of the circulatory system by promoting vascular health, functional blood flow and more.
Back to Basics
As with most things, the beginning is usually a good place to start; in this case, the starting pointdiet modification (augmenting or omitting)has proven its worth. The U.S. Department of Agriculture (USDA) reported on several studies pointing to oats ability to promote healthy circulation. In 2006, researchers at Tufts University found one of the major polyphenols of oatsavenanthramide-cinhibited vascular smooth muscle cells (SMC), an important process in the initiation and development of atherosclerosis.1 The inhibitory effect warranted oats potential health benefits in the prevention of CHD beyond its known effect of lowering blood cholesterol. Again in 2008, Tufts researchers discovered oats talent, via its avenanthramides, for decreasing the expression of endothelial proinflammatory cytokines, which is vital to circulatory health, as inflammation in the arterial walls is a precursor to atherosclerosis.2
Another dietary addition that keeps the blood moving is walnuts. Yale University researchers randomized 24 subjects with type 2 diabetes to a diet including 56 g/d of walnuts or a diet without walnuts for eight weeks.3 This was the only dietary intervention and then the two groups swapped diets. After the walnut-enriched diet phase, endothelial function was significantly better compared with function after the walnut-free diet. Fasting serum glucose increased, while serum total cholesterol and low-density lipoprotein (LDL) cholesterol were lower after eight weeks of the walnut diet versus baseline. There were no changes in anthropomorphic measures and insulin sensitivity. Similarly, soy nuts improved blood pressure and lowered LDL cholesterol when substituted for non-soy protein in a therapeutic lifestyle diet in hypertensive women.4
Along the same line, nattokinase, from fermented soy beans, also has cardiovascular benefits. An eight-week, double blind, placebo-controlled trial found increased intake of nattokinase may play an important role in preventing and treating hypertension.5 A total of 86 participants ranging from 20 to 80 years of age with an initial untreated systolic blood pressure (SBP) of 130 to 159 mmHg received nattokinase (2,000 FU/capsule; as NSK-SD®, from JBSL-USA ) or a placebo capsule. Compared with the control group, net changes in SBP and diastolic blood pressure (DBP) were -5.55 mmHg and -2.84 mmHg, respectively, after the eight-week intervention. The corresponding net change in renin activity was -1.17 ng/mL/h for the nattokinase group compared with the control group (P<0.05). In an unpublished study from Japan Bio Science Laboratory (JBSL), 11 health subjects (five male, six female, aged 21 to 65) who met eligibility criteria ingested of 2,000 FU/d of nattokinase (as 100-mg softgel capsules of NSK-SD). A pharmacokinetic pattern was observed for NSK-SO between baseline and 48 hours post-dose, peaking at approximately 13.3 hrs ± 2.5 hours post-dose. Statistically significant increases in detectable serum nattokinase from baseline were seen two hours and 24 hours. In conclusion, nattokinase was found to have significant profibrinolytic and antihypertensive effects.
A Japanese study confirmed nattos role in heart health, noting, Dietary natto-extracts supplementation suppressed intimal thickening produced by endothelial injury in rat femoral artery. [Natto] showed enhanced thrombolysis near the vessel wall.6
Highly popularized for its heart-health benefits is the Mediterranean diet, which includes foods such as the nuts mentioned above, fruits, whole grains, and olive and fish oils. In 2008, the British Journal of Nutrition reported on chronic ingestion of three diets in 20 healthy men: a Western diet, rich in saturated fat; a Mediterranean diet, rich in monounsaturated fatty acid (MUFA); and a low-fat diet enriched in alpha-linolenic acid (ALA).7 Researchers found, chronic ingestion of a Mediterranean diet avoids the postprandial deterioration of endothelial function associated with Westernized diets in healthy individuals. Although, a meta-analysis published in the American Journal of Clinical Nutrition showed no significant evidence for concluding dietary saturated fat is associated with an increased risk of heart conditions, such as CHD and cardiovascular disease (CVD).8 In the March 1, 2010 issue of Circulation, a two-year Dietary Intervention Randomized Controlled TrialCarotid (DIRECT-Carotid) study, randomized participants to low-fat, Mediterranean or low-carbohydrate diets and were monitored for changes in carotid artery intima-media thickness.9 After two years of dietary intervention, a significant 5 percent regression in mean carotid vessel wall volume (VWV) was observed, with no differences in the low-fat, Mediterranean or low-carb groups. Mean change in intima-media thickness was 1.1 percent (P=0.18). A reduction in the ratio of apolipoprotein B100 to apolipoprotein A1 was observed in the low-carb compared with the low-fat group (P=0.001). Participants who exhibited carotid VWV regression compared with participants who exhibited progression achieved greater weight loss, greater decreases in systolic blood pressure and total homocysteine, and a higher increase of apolipoprotein A1. In multivariate regression models, only the decrease in systolic blood pressure remained a significant independent modifiable predictor of subsequent greater regression in both carotid VWV and intima-media thickness levels. Researchers concluded two-year weight loss diets can induce a significant regression of measurable carotid VWV; and the effect is similar in low-fat, Mediterranean or low-carb strategies, and appears to be mediated mainly by the weight lossinduced decline in blood pressure.
Fish is another key component in the Mediterranean diet, due to its content of omega-3 essential fatty acids (EFAs). In January 2010, a study from the University of Guelph reported high intake of omega-3 EFAs may reduce the bodys ability to remove blood clots in the short term.10 Eight 45-year-old men with metabolic syndrome consumed either water or a high-saturated fat beverage with either a high or low content of omega-3 longchain polyunsaturated fatty acids (LCPUFA). Both fat loads resulted in a significant increase in whole-blood TAG concentration, plasma PAI-1 and t-PA concentrations and PAI-1 activity, as well as a significant decrease in t-PA activity after consuming the beverage. PAI-1 concentration and activity increased following high-LCPUFA consumption compared with the low-LCPUFA beverage (P<0.05). Furthermore, the high-LCPUFA beverage resulted in a lower t-PA activity (P<0.05), signifying a lower capacity for fibrinolysis (the process wherein a fibrin clot, the product of coagulation, is broken down). The effects of the two fat loads on the plasma t-PA concentration and platelet aggregation did not differ. Additionally, when 9 g of fish oil were added to a meal, endothelial nitric oxide synthase (eNOS) expression increased in endothelial cells and vascular reactivity improved.11
Red wine is another inclusion in the Mediterranean diet, with its natural polyphenolresveratroldemonstrating heart-healthy advantages such as possibly preventing the development of chronic degenerative diseases such as CVD.12 In obese Zucker rats, high plasma concentrations of triglycerides, total cholesterol, free fatty acids, insulin and leptin were reduced in obese rats that received resveratrol.13 The elevated hepatic lipid content was significantly lower in obese rats treated with resveratrol, and chronic intake of resveratrol enhanced visceral adipose tissue (VAT) eNOS expression. Additionally, the raised systolic blood pressure and reduced aortic eNOS expression found in obese Zucker rats were significantly improved in the resveratrol-treated obese rats.
At the 4th International Conference on Polyphenols and Health (ICPH) in Yorkshire, England, in 2009, DSM Nutritional Products presented data from two analyses of the first human study of resVida® trans-resveratrol. Study participants included 19 overweight or obese untreated hypertensive men and post-menopausal women randomly assigned to consume placebo and three single doses of resVida trans-resveratrol (30, 90, 270 mg) at weekly intervals. Both study analyses found a significant effect of trans-resveratrol supplementation on flow-mediated dilation (FMD; P=0.006) with FMD increasing from 3.9 +/- 0.8 after placebo to 7.6 +/- 1.6 percent at 270 mg. FMD was also linearly related to plasma trans-resveratrol concentration. The preliminary data suggests resVida trans-resveratrol is an active mediator of the purported cardiovascular health benefits of red wine and grape consumption. The second study also reported a resVida did not demonstrate a treatment effect on the blood pressure response to exercise.
And, a review published in the Annals of the New York Academy of Science noted, studies with rabbits fed a high cholesterol-diet show grape seed procyanidins are strongly protective not only in terms of reducing plasma lipid peroxides, but they also markedly inhibit lipid-laden foam-cell deposition. Drinking wine at meals provides this kind of protection, and the final benefits are realized by the prevention of the development of atheromatous lesions even under conditions of hypercholesterolemia.14
Green tea is lauded for its benefits on many aspects of health, including the heart. Brief treatment with green tea, or more specifically, epigallocatechin gallate (EGCG), significantly reduced serum levels of prostate-specific antigen (PSA), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in men with prostate cancer with no elevation of liver enzymes.15
Researchers at the Boston University School of Medicine found EGCG acutely improved endothelial function in humans with coronary artery disease, and said EGCG may account for a portion of the beneficial effects of flavonoid-rich food on endothelial function.16 The double blind, placebo-controlled, crossover study examined the effects of EGCG (as Teavigo®, from DSM) on endothelial function in 42 subjects. The brachial artery flow-mediated dilation was measured at six time points: prior to treatment with EGCG or placebo, two hours after an initial dose of EGCG (300 mg) or placebo, and after two weeks of treatment with EGCG (150 mg twice daily) or placebo. The order of treatments (EGCG or placebo) was randomized and there was a one-week washout period between treatments. Brachial artery flow-mediated dilation two hours after the first dose of 300 mg of EGCG (P=0.01), but was similar to baseline (P=0.12) after two weeks of treatment with the final measurements made approximately 14 hours after the last dose. Placebo treatment had no significant effect, and there were no changes in reactive hyperemia or the response to sublingual nitroglycerin. The changes in vascular function paralleled plasma EGCG concentrations, but were unchanged from baseline after two weeks of treatment.
And again in 2009, researchers in Poland provided evidence that EGCG, along with other tea polyphenolic compounds (theaflavins and black tea extract), offers protective effects against oxidative stress formation in endothelial cells.17
Augmenting the diet with color from carotenoids can be advantageous, and that includes lycopenethe carotenoid that gives tomatoes their vibrant red color. Italian researchers explored the relationship between plasma levels of some lipid-soluble antioxidants (gamma-tocopherol, alpha-tocopherol, lycopene, beta-carotene and ubiquinone) with carotid maximum intima-media thickness, an index of atherosclerotic severity.18 The inverse relationship of plasma lycopene with intima-media thickness was compatible with a protective role of lycopene in atherosclerosis, although the mechanism of protection did not apparently involve a decrease in endothelial activation measured through soluble adhesion molecules.
A Japanese study confirmed lycopenes ability to ameliorate atherosclerosis after researchers randomized 31 healthy Japanese female students to three treatment groupscontrol group, 480 g of a control drink; low group, 160 g of tomato juice plus 320 g of the control drink; high group, 480 g of tomato juiceproviding 0, 15 and 45 mg of lycopene for one menstrual cycle.19 As a result of alpha-tocopherol and lycopenes ability to protect LD from oxidation, researchers concluded, Oral intake of lycopene might be beneficial for ameliorating atherosclerosis.
And a 2009 Chinese study contributed to the supportive research on lycopene, reporting it decreased the oxidative injury of endothelial cells induced by H(2)O(2) injury and displayed protective effects on endothelial cells; it attenuate the expression of p53 and caspase-3 mRNA in injured cells, and diminish the apoptosis of injured cells, leading to a possible explanation as to why lycopene can prevent atherosclerotic CVDs.20
Collectively, many of these ingredients work in concert as a nutrigenomics cocktail. An intervention with dietary products, including resveratrol, green tea extract, alpha-tocopherol, vitamin C, omega-3 fatty acids and tomato extract affected inflammatory processes, oxidative stress and metabolism in humans.21 Healthy overweight men (n=36) with mildly elevated plasma C-reactive protein concentrations received the combination dietary supplement in a double blind, placebo-controlled, crossover study with treatment periods of five weeks. Plasma adiponectin concentrations increased by 7 percent, whereas C-reactive protein (principal inflammation marker) was unchanged. However, a multitude of subtle changes were detected by an integrated analysis of the "omics" data, which indicated modulated inflammation of adipose tissue, improved endothelial function, affected oxidative stress and increased liver fatty acid oxidation.
Although vitamin E is found in vegetables such as asparagus and avocado, it may not be the easiest vitamin to add via diet; but supplementing with vitamin E may be worth it, as found in the study above. An in vitro Japanese study published in Atherosclerosis offers additional support. It found a model compound 25-hydroxycholesterol can enhance the interaction between monocytes and human aortic endothelial cells; and tocotrienols provide an inhibitory effect on monocytic cell adherence to human aortic endothelial cells relative to alpha-tocopherol by inhibiting the vascular cell adhesion molecule expression.22 And, in February 2010, Taiwanese scientists found rutin in combination with vitamin E attenuated vascular endothelial growth factor expression in HL-60 cells.23 They noted the effect was mediated by a decreased binding activity of the nuclear factor-activator protein-1 through downregulation of protein expression of the IGF1-R/IRS-1, while the antioxidant activity of rutin and vitamin E appeared to play a minor role.
Similarly, vitamin C deserves some attention in the circulatory arena. Synergistically, vitamin C and vitamin E (2 g and 400 IU, respectively) lend preventive effects against FMD reduction and endothelial dysfunction in open sea air divers.24 Researchers at the University of Colorado, Boulder, found vitamin C favorably affected the capacity of the endothelium to release t-PA in overweight/obese adults, and daily supplementation was noted as an effective lifestyle intervention strategy for improving endothelial fibrinolytic regulation.25
Vitamin K is a vital vitamin for vascular health. Vitamin Kdependent proteins, including matrix Gla-protein (MGP), have been shown to inhibit vascular calcification. The activation of these proteins is dependent on the availability of vitamin K. The Rotterdam study examined whether dietary intake of phylloquinone (vitamin K1) and menaquinone (vitamin K2) were related to aortic calcification and CHD.26 A total of 4,807 subjects with dietary data and no history of myocardial infarction were included at baseline and followed for 10 years. The relative risk of CHD mortality was reduced in the mid and upper tertiles of dietary menaquinone compared to the lower tertile. Intake of menaquinone was also inversely related to all-cause mortality and severe aortic calcification. However, phylloquinone intake was not related to any of the outcomes. Another study found rats with arterial calcification, inhibited by MGP, and the resulting decrease in arterial distensibility, were reversible by high-vitamin K intake.27 Rats received a calcification-inducing diet containing both vitamin K and warfarin. During a second six-week period, animals were randomly assigned to receive either 3 mg/g of vitamin K and 1.5 mg/g, of warfarin, a diet containing a normal (5 µg/g) or high (100 µg/g) amount of vitamin K (either K1 or K2). Increased aortic calcium concentration was observed in the group that continued to receive vitamin K and warfarin, and also in the group changed to the normal dose of vitamin K and arterial calcification progressed. Both vitamin K-rich diets decreased the arterial calcium content by 50 percent. In addition, arterial distensibility was restored by the vitamin K-rich diet. Using MGP antibodies, local vitamin K deficiency was demonstrated at sites of calcification.
And to sweeten the dietary deal, a recent study published in the International Journal of Obesity found stevia was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the vascular wall, which inhibited atherosclerotic plaque development and induced plaque stabilization.28 In the study, 12-week-old mice were treated with stevioside (10mgkg1, n=14) or placebo (n=20) for 12 weeks. Stevioside had no effect on weight and triglycerides, but lowered glucose and insulin. Stevioside treatment improved adipose tissue maturation and increased glucose transport, insulin signaling and antioxidant defense in white visceral adipose tissues. Together, these increases were associated with a two-fold increase of adiponectin. In addition, stevioside reduced plaque volume in the aortic arch by decreasing the macrophage, lipid and oxidized LDL content of the plaque. The higher smooth muscle cell-to-macrophage ratio was indicative for a more stable plaque phenotype. Circulating adiponectin was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the aorta of stevioside-treated mice.
What about dessert? Well chocolate is a great circulatory booster. Solid dark chocolate and liquid cocoa improved endothelial function and lowered blood pressure in overweight adults, according to a 2008 study at Yale University.29
Another Step in the Right Direction
Ginkgo biloba is popular for its effects on cognition, but many studies are supporting its ability to boost circulatory health. In 2009, Chinese researchers explored the effect of ginkgo leaf extract on vascular endothelial function in patients with early stage diabetic nephropathy.30 A total of 64 patients were randomized into two groups: conventional therapy for diabetes (control) or conventional therapy for diabetes plus ginkgo leaf extract tablets for eight weeks. The brachial arterial endothelium dependent dilating function in the treated group increased after treatment, while the level of von Willebrand factor (vWF) decreased, as well as an increase in nitric oxide (NO). These indexes were not significantly changed in the control group after treatment, leaving researchers to conclude ginkgo leaf extract could improve the endothelium dependent vascular dilating function in diabetic patients. Another study with diabetic subjects found Ginkgo biloba may act as a potent therapeutic adjuvant in respect to ischemic myocardial injury, and may contribute to preventing late complications in diabetic cardiopathy.31
Interestingly, ginkgo may fight against the deleterious effects of cigarette smokingspecifically the increase in oxidative stress and numbers of apoptotic endothelial cells in the lungs, two common side effects of smoking. After researchers investigated the cytoprotective effects and therapeutic mechanisms of ginkgo against oxidative stress and apoptosis induced by cigarette smoke extract in human pulmonary artery endothelial cells (HPAECs), they found ginkgo conferred protection from oxidative stress-related apoptosis induced by cigarette smoke extract in HPAECs and its therapeutic effects depend on transcriptional upregulation of HO-1 by ginkgo via the three major mitogen-activated protein kinases/ nuclear factor erythroid-2-related factor 2 pathway.32
Similarly, French maritime pine bark works wonders on the heart of smokers. An study published in Thombrosis Research assessed the effects of Pycnogenol® (from Natural Health Science) on platelet function in humans.33 Cigarette smoking increased heart rate and blood pressure, but these increases were not influenced by oral consumption of Pycnogenol or aspirin just before smoking. However, increased platelet reactivity yielding aggregation two hours after smoking was prevented by 500 mg of aspirin or 100 mg of Pycnogenol in 22 German heavy smokers. In a group of 16 American smokers, blood pressure increased after smoking. It was unchanged after intake of 500 mg aspirin or 125 mg Pycnogenol. In another group of 19 American smokers, increased platelet aggregation was more significantly reduced by 200 mg than either 150 mg or 100 mg Pycnogenol supplementation. The study showed a single, high dose of 200 mg Pycnogenol remained effective for more than six days against smoking-induced platelet aggregation. Also, aspirin significantly (P<0.001) increased bleeding time from 167 to 236 seconds while Pycnogenol did not.
A separate double blind, randomized, placebo and active drug study evaluated forearm blood flow (FBF) responses to acetylcholine, an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, in healthy young men before and after two weeks of 180 mg/d of Pycnogenol (n=8) or placebo (n=8).34 Pycnogenol, but not placebo, augmented FBF response to acetylcholine. SNP-stimulated vasodilation was similar before and after two weeks of treatment in the control and Pycnogenol groups. Administration of N(G)-monomethyl-L-arginine, an NO synthase inhibitor, completely abolished Pycnogenol-induced augmentation of the FBF response to acetylcholine, suggesting Pycnogenol augments endothelium-dependent vasodilation by increasing in NO production.
Policosanol, a mixture of fatty alcohols derived from natural sources, including beeswax, a waxy extract of sugarcane and rice bran, has been studied for its role in circulation. An article published in NutraCos cited several studies confirming Policosanols (from Sabinsa) ability to inhibit platelet aggregation, which in turn is helpful in maintaining cardiovascular health; its benefit over the statin drug Lovastatin in subjects suffering from intermittent claudication; its ability to prevent LDL oxidation and the related detrimental actions of metalloproteinase enzymes, which promote blood vessel destruction, partly by interfering with high-density lipoproteins (HDL) protective effect; its ability to lower foam cells in treated rats, reflecting modulated inflammatory response and higher blood vessel integrity; its ability to reduce the proliferation of cells in the lining of the arteries and stop cell overgrowth; its ability to work synergistically with aspirin to inhibit the formation of blood clots; and significantly reduce the level of thromboxane, a blood-vessel constricting agent that contributes to abnormal platelet aggregation, after two weeks of supplementation.35
D-ribose, a naturally occurring pentose sugar, is also another good-for-the-heart ingredient. Patients with stable coronary artery disease or patients presenting an acute myocardial infarction may undergo revascularization using an "off" cardiopulmonary bypass procedure. Ribose was investigated in a patient population undergoing revascularization.36 A total of 44 adult patients with ischemic coronary artery disease were enrolled. A least one-third of the patients had sustained an acute myocardial infarction prior to presentation and pre-operative ejection fractions ranged between 30 percent and 72 percent. All patients underwent "off" bypass coronary revascularization with 20 patients consuming no pre-operative metabolic substrate and the remaining 24 patients were supplied with oral D-ribose (from Bioenergy) pre-operatively. The ribose-treated patients demonstrated a 49-percent greater increase in cardiac indices compared to controls (P<0.028). The data implied when using an "off" cardiopulmonary bypass coronary artery revascularization procedure, the pre-loading of oral D-ribose may improve cardiac function post-operatively.
Niacin (vitamin B3) is popular for its benefits on cholesterol; however, studies are supporting its positive effects on atherosclerosis. A meta-analysis of niacin, alone or in combination with other lipid-lowering drugs, found in primary analysis, niacin significantly reduced major coronary events, stroke and any cardiovascular events.37 Except for stroke, the pooled between-group difference remained significant in sensitivity analysis excluding the largest trial. In comparison with the non-niacin group, more patients in the niacin group had regression of coronary atherosclerosis, whereas the rate of patients with progression decreased by 41 percent. Similar effects of niacin were found on carotid intima thickness with a weighted mean difference in annual change of -17mum/year. Researchers concluded: Although the studies were conducted before statin therapy become standard care, and mostly in patients in secondary prevention, with various dosages of nicotinic acid 1 g/d to 3 g/d, this meta-analysis found positive effects of niacin alone or in combination on all cardiovascular events and on atherosclerosis evolution. In a 2009 double blind, randomized, placebo-controlled study, 2 g/d of modified-release nicotinic acid was added to statin therapy in 71 patients with low HDL cholesterol and either: 1) type 2 diabetes with CHD; or 2) carotid/peripheral atherosclerosis for one year.38 Nicotinic acid increased HDL cholesterol by 23 percent and decreased LDL cholesterol by 19 percent. At 12 months, nicotinic acid significantly reduced carotid wall area compared with placebo. Mean change in carotid wall area was -1.1 +/- 2.6 mm(2) for nicotinic acid versus +1.2 +/- 3.0 mm(2) for placebo. In both the treatment and placebo groups, larger plaques were more prone to changes in size.
The good news is, an unending amount of research supports natural compounds and dietary intervention for vascular health; and new clinical support is continually surfacing as researchers further investigate the effects of these natural compounds. In fact, Italian researchers stated in a 2010 study published in Circulation: Even if clinical investigation of more potent anti-platelet drugs represents an important future objective to improve the prevention of cardiovascular disease, a non-pharmacological approach to lower platelet function may be another intriguing prospective.39 So fortunately, there are many ingredient options with the scientific backing needed to validate their inclusion in functional foods and beverages, and other natural products.
References are on the next page...
References for "Circulation: The Other Side of Heart Health"
1. Lin Nie et al. Mechanism by which avenanthramide-c, a polyphenol of oats, blocks cell cycle progression in vascular smooth muscle cells Free Radical Biology and Medicine 2006; 41(5):702-708
2. Weimin Guo et al. Avenanthramides, polyphenols from oats, inhibit IL-1-induced NF-B activation in endothelial cells Free Radical Biology and Medicine 2008;44(3):415-29.
3. Yingying Ma et al. Effects of Walnut Consumption on Endothelial Function in Type 2 Diabetic Subjects Diabetes Care 2010;33(2):227-232
4. Francine K et al. Effect of Soy Nuts on Blood Pressure and Lipid Levels in Hypertensive, Prehypertensive, and Normotensive Postmenopausal Women Archives of Internal Medicine 2007;167(10):1060-1067
5. Kim JY et al. Effects of nattokinase on blood pressure: a randomized, controlled trial Hypertens Res. 2008 Aug;31(8):1583-8
6. Suzuki Y et al. Dietary supplementation of fermented soybean, natto, suppresses intimal thickening and modulates the lysis of mural thrombi after endothelial injury in rat femoral artery Life Sci. 2003 Jul 25;73(10):1289-98
7. Fuentes F et al. Chronic effects of a high-fat diet enriched with virgin olive oil and a low-fat diet enriched with alpha-linolenic acid on postprandial endothelial function in healthy men Br J Nutr. 2008 Jul;100(1):159-65
8. Patty W Siri-Tarino, Qi Sun, Frank B Hu and Ronald M Krauss Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease Am J Clin Nutr 2010;91:35-546
9. Iris Shai, RD, PhD et al. Dietary Intervention to Reverse Carotid Atherosclerosis Circulation. 2010;121:1200-1208
10. Camilla Montegaard et al. Acute Ingestion of Long-Chain (n-3) Polyunsaturated Fatty Acids Decreases Fibrinolysis in Men with Metabolic Syndrome J Nutr. 2010 Jan;140(1):38-43
11. Demaison L, Moreau D. Dietary n-3 polyunsaturated fatty acids and coronary heart disease-related mortality: a possible mechanism of action. Cell Mol Life Sci. 2002 Mar;59(3):463-77.
12. Wayne R. Leifert and Mahinda Y. Abeywardenaa et al. Cardioprotective actions of grape polyphenols Nutr Res.2008;28(11):729-737
13. Rivera L, et al. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol. 2009 Mar 15;77(6):1053-63
14. Ursini F, Sevanian A. Wine polyphenols and optimal nutrition Ann N Y Acad Sci. 2002 May;957:200-9
15. Jerry McLarty et al. Tea Polyphenols Decrease Serum Levels of Prostate-Specific Antigen, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor in Prostate Cancer Patients and Inhibit Production of Hepatocyte Growth Factor and Vascular Endothelial Growth Factor In vitro Cancer Prev Res July 2009 2:673-682
16. Widlansky ME et al. Acute EGCG supplementation reverses endothelial dysfunction in patients with coronary artery disease J Am Coll Nutr. 2007 Apr;26(2):95-102
17. uczaj W et al. Polyphenols action against oxidative stress formation in endothelial cells Acta Pol Pharm. 2009 Nov-Dec;66(6):617-24
18. Gianetti J et al. Inverse association between carotid intima-media thickness and the antioxidant lycopene in atherosclerosis Am Heart J. 2002 Mar;143(3):467-74.
19. Maruyama C et al. Effects of tomato juice consumption on plasma and lipoprotein carotenoid concentrations and the susceptibility of low density lipoprotein to oxidative modification J Nutr Sci Vitaminol (Tokyo). 2001 Jun;47(3):213-21
20. Tang X et al. Protective effects of lycopene against H2O2-induced oxidative injury and apoptosis in human endothelial cells Cardiovasc Drugs Ther. 2009 Dec;23(6):439-48
21. Gertruud CM Bakker et al. An anti-inflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach Am J Clin Nutr Feb. 24, 2010
22. Yuji, Naito et al. Tocotrienols reduce 25-hydroxycholesterol-induced monocyteendothelial cell interaction by inhibiting the surface expression of adhesion molecules Atherosclerosis. 2005;180(1):19-25
23. Chuang CH, Huang CS, Hu ML Vitamin E and rutin synergistically inhibit expression of vascular endothelial growth factor through down-regulation of binding activity of activator protein-1 in human promyelocytic leukemia (HL-60) cells Chem Biol Interact. 2010 Feb 12;183(3):434-41
24. Obad A et al. Antioxidant pretreatment and reduced arterial endothelial dysfunction after diving. Aviat Space Environ Med. 2007 Dec;78(12):1114-20.
25. Van Guilder GP et al. Acute and chronic effects of vitamin C on endothelial fibrinolytic function in overweight and obese adult humans J Physiol. 2008 Jul 15;586(14):3525-35
26. Geleijnse JM et al. Dietary intake of menquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study. J Nutr. 2004;134:3100-05.
27. Schurgers LJ et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood. 2007;109:2823-31.
28. B Geeraert et al. Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice International Journal of Obesity (2010) 34, 569577
29. Faridi Z et al. Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial Am J Clin Nutr. 2008 Jul;88(1):58-63
30. Li XS et al. Effect of Ginkgo leaf extract on vascular endothelial function in patients with early stage diabetic nephropathy Chin J Integr Med. 2009 Feb;15(1):26-9
31. Schneider R, Welt K, Aust W, Löster H, Fitzl G Cardiac ischemia and reperfusion in spontaneously diabetic rats with and without application of EGb 761: II. Interstitium and microvasculature Histol Histopathol. 2009 May;24(5):587-98
32. Hsu, CL et al. Ginkgo biloba extract confers protection from cigarette smoke extract-induced apoptosis in human lung endothelial cells: Role of heme oxygenase-1 Pulm Pharmacol Ther. 2009 Aug;22(4):286-96
33. Pütter M et al. Inhibition of smoking-induced platelet aggregation by aspirin and pycnogenol Thromb Res. 1999 Aug 15;95(4):155-61
34. Nishioka K et al. Pycnogenol, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans Hypertens Res. 2007 Sep;30(9):775-80
35. NutraCos July/August 2007 A double-blind study to evaluate the safety and efficacy of policosanol vs. Latorvastatin in the treatment of hyperlipidaemia
36. D. Perkowski et al. Pre-Surgical Loading of Oral D-Ribose Improves Cardiac Index in Patients Undergoing "Off" Pump Coronary Artery Revascularization FASEB J (Part 1) 2005; 19 (4): A 695
37. Bruckert E, Labreuche J, Amarenco P Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis Atherosclerosis. 2009 Dec 21.
38. Lee JM et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study J Am Coll Cardiol. 2009 Nov 3;54(19):1787-94
39. Francesco Violi, MD; Pasquale Pignatelli, MD; Stefania Basili, MD Nutrition, Supplements, and Vitamins in Platelet Function and Bleeding Circulation. 2010;121:1033-1044
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