Researched Heart Health Benefits

Of the many risk factors associated with heart health and cardiovascular disease (CVD), the primary targets of natural products are cholesterol, triglycerides, blood pressure, blood flow, endothelial function, atherosclerotic plaque formation and heart rate/rhythm. The broader view considers the effects of natural ingredients on various cardiac events, in preventing and limiting damage, as well as aiding recovery.

Cholesterol is one of the most common risk factors for heart disease and is the focus of many consumers. The body needs cholesterol for many important tasks, and naturally gets only the it needs from the liver. However, excess cholesterol from the diet can contribute to the formation of atherosclerotic plaque, which a deposit of cholesterol, fibrin, calcium and other substances in the blood. Under certain conditions, these plaques can narrow arteries and possibly break off to become a clot (thrombus), which can result in the heart (and other vital organs) not receiving enough blood and oxygen, causing a heart attack.

Consumers trying to lower levels of bad cholesterol, or LDL, have responded to studies showing intake of plant sterols, which are structurally similar to endogenous cholesterol, can reduce absorption of cholesterol, possibly by competing with LDL for absorption in the intestines.¹ The evidence on plant sterols in cholesterol reduction convinced FDA to authorize a health claim that plant sterols may reduce the risk of heart disease when combined with a diet low in cholesterol and saturated fats.

Other compounds studied for LDL-lowering effects include aged garlic extract (AGE),² olive oil phenols,³ phytoestrogens,⁴ cocoa⁵ and chromium.⁶ Supplementation with chromium nicotinate (as ChromeMate®, from InterHealth USA) can help maintain healthy cholesterol levels already in the normal range.⁷ When combined with regular exercise, the supplement can support healthy body weight⁸ and composition by maintaining lean body mass,⁹ thereby improving an important lifestyle factor in heart health.

Beta-glucans also have an FDA-approved health claim for lowering cholesterol, based on studies showing beta-glucan intake can lower LDL in cases of high cholesterol or mild hypercholestemia.^10,11 A combination of beta-glucan and chitin-glucan (as ARTINIA) may reduce oxidized LDL by as much as 26 percent in people with normal cholesterol levels.¹²

Oxidized LDL contains free radicals that contribute to atherosclerosis plaque formation. Oxidized LDL can wreak havoc in the endothelium (blood vessel lining), triggering inflammation, increasing foam cell production (atheroma cells) and  reduced nitric oxide (NO) production. NO helps blood vessels relax and dilate, which improves blood flow.

A number of antioxidant ingredients have been studied for possible inhibition of the oxidation of LDL and other lipids. Green tea polyphenols have reduced oxidized LDL concentration and improved brachial artery blood flow in healthy women.¹³ Similarly, cocoa polyphenols have demonstrated a protective effect against LDL oxidation and may increase high-density lipoprotein (HDL) cholesterol, often called good cholesterol, because it shuttles LDL cholesterol back to the liver.¹⁴

The carotenoid lycopene has been shown to decrease foam cell formation triggered by oxidized LDL.¹⁵ Other research reported lycopene can preserve myocardial antioxidant status and significantly inhibit lipid peroxidation resulting from myocardial ischemia-reperfusion injury.¹⁶ Also, a trial in healthy men found lycopene supplementation improved endothelial function by increasing activity of superoxide dismutase (SOD) and endogenous antioxidants.¹⁷ The results  further linked lycopene to reduced high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, and reduced systolic blood pressure.

Coenzyme Q10 (CoQ10), as ubiquinol, inhibited lipid peroxidation in the arterial wall in one study.¹⁸ A 2012 report detailed how CoQ10 improved antioxidant status and controlled oxidation in human umbilical cord cells subjected to oxidized LDL.¹⁹ CoQ10 also limited oxidized LDL's enzymatic reduction of NO synthesisNO signals the endothelium to relax, triggering vasodilation and improved blood flow.

Lipoproteins contain cholesterol, triglycerides and protein. Very low-density lipoprotein (VLDL) has the highest concentration of triglycerides among the lipoproteins, and is also associated with heightened risk of atherosclerosis. Pterostilbene, a compound found in blueberries and grapes, can help regulate cholesterol and lower the body's production of VLDL and triglycerides by acting on transcription factor PPAR-alpha.²⁰ This may also raise levels of HDL.²¹

People with controlled LDL levels may still have increased heart disease risks if their HDL levels are too low. A number of ingredients increase HDL levels. Recent research showed supplementation with whole grape extract (as Vincare, from Ethical Naturals) increased HDL and the ratio of HDL to total cholesterol.²²

B vitamin niacin (nicotinic acid) improved HDL levels by limiting the breakdown of HDL; it also inhibited an enzyme required for synthesis of triglycerides, which resulted in decreased production of VLDL and LDL.²³ Early studies showed niacin supplementation increased HDL levels and, when combined with statin drugs, inhibited atherosclerosis development.^24,25 However, a recent National Institutes of Health (NIH) large clinical trial (AIM-HIGH) investigating combined high-dose niacin (extended release) and statin therapy on low HDL and high triglycerides in metabolic syndrome patients was halted early after researchers found no additional benefit from the high-dose niacin on cardiac events.²⁶ The niacin treatment increased HDL by 20 percent and reduced triglycerides by 25 percent.

Long-chain omega-3 essential fatty acids (EFAs) from fish oil raised HDL and decreased triglycerides as part of a roster of benefits for heart health.²⁷  Fish oil can help lower unhealthy levels of LDL cholesterol,²⁸ and EPA (eicosapentaenoic acid) from fish oil taken with statins by patients with a history of coronary artery disease reduced major coronary events by 19 percent compared to stain treatment alone.²⁹

Considering other sources, docosahexaenoic acid (DHA) from algae also reduced triglycerides and increased HDL.³⁰ Protection from LDL oxidation is another finding associated with DHA supplementation.³¹ Likewise, krill oil reportedly improved the HDL:triglyceride ratio compared to fish oil.³² Krill has also shown a greater effect on lipid and glucose metabolism than has fish oil.³³

The net effect of these fatty acids on heart health has been varied. EPA and DHA in tandem have been linked to lower risk of fatal cardiac events, as has the combination of DHA with docosapentaenoic acid (DPA).³⁴ This research review further revealed DHA can positively impact atrial fibrillation, and EPA plus DPA correlated with lower risk of non-fatal CVD endpoints.

High doses of polyunsaturated fats may cause a slight decrease in blood pressure, especially systolic pressure.³⁵ Chronic hypertension can weaken blood vessels by exerting damaging pressure on the vessel walls and can contribute to heart attacks and other CVD events related to thrombosis and blocked arteries. Several natural ingredients can help manage blood pressure.

Soy protein has lowered blood pressure in both normotensive and hypertensive women,³⁶ and isoflavone-rich soy powder added to a high-fat diet can limit blood pressure increases and oxidative damage and improve endothelial health.³⁷

Botanicals rich in phytonutrients such as flavonoids have turned in consistent results on blood pressure. Grapes can address inflammatory contributors to hypertension and endothelial dysfunction,³⁸ while grape seed extract (GSE) can lower systolic and diastolic blood pressure in pre-hypertensive adults,³⁹ and improve endothelial function.⁴⁰ The key may be GSE's antioxidant phtyochemicals, including oliomeric proanthocyanidin complexes (OPCs).

Pine bark is also rich in OPCs and has shown promising results against hypertension. Pycnogenol, a branded French maritime pine bark extract from Horphag Research, reduced systolic, but not diastolic, pressure.⁴¹ A 2012 study found Pycnogenol taken by patients with stable coronary artery disease improved endothelial function and increased blood flow via arterial dilation.⁴²

Other flavonoid-rich botanical ingredients found to offer blood pressure benefits include catechin-rich tea,⁴³ anthocyanin-rich chokeberries⁴⁴ and flavanoid-rich pomegranates.⁴⁵

Vitamin C aids in collagen production and vascular flexibility, and supplementation with the nutrient has reduced both systolic and diastolic blood pressure in hypertension patients.⁴⁶ Used in conjunction with hypertensive therapy, vitamin C lowered systolic pressure and oxidative stress.⁴⁷ Vitamin C is a heart-health juggernaut, also lowering LDL and triglycerides,⁴⁸ inhibiting platelet aggregation,⁴⁹ and reducing potentially damaging inflammation (as marked by CRP levels).^{50Combined use of vitamins C and E by hypertensive men for eight weeks not only lowered systolic and diastolic pressure, but also increased antioxidant status.51 Another study in a similar population found this vitamin combo significantly improved arterial flexibility, flow-mediated dilation (FMD), vasodilation and oxidative stress.52 Nattokinase in fermented soy can inhibit thickening of the interior arterial wall, possibly by breaking down fibrin that contributes to clotting and plaque formation.53}

Vasodilation, which expands the vessel and  improves blood flow, is a common benefit among ingredients that help attenuate blood pressure. In fact, research suggested vitamin E (as gamma-tocotrienols) may lower blood pressure by supporting endothelial nitric oxide synthase (eNOS),⁵⁴ an enzyme involved in production of NO, which is needed for vasodilation. In patients with narrowing of the carotid artery (main vessel to the brain), supplementation with a complex of palm tocotrienolsmembers of the vitamin E familyreversed atherosclerosis progression.⁵⁵ Palm tocotrienols also reduced aortic systolic pressure⁵⁶ and, as Tocomin SupraBio (from Carotech Inc.), lowered total and LDL cholesterol in hypercholestemia⁵⁷ and reduced arterial stiffness in healthy adults.⁵⁸

NO-mediated vasodilation can be impaired in cases of high LDL cholesterol levels.⁵⁹ A component of NO production is the amino acid L-arginine, which has been shown to reduce arterial pressure and improve endothelial function people with hypercholesterolemia and atherosclerosis.⁶⁰

Ginkgo biloba supports vasodilation through the NO pathway and may also help in blood pressure management. In hypertensive subjects, ginkgo extract administration restored vasodilatory function and significantly improved systolic blood pressure.⁶¹ Standardized ginkgo extract (as EGb 761, from Schwabe Pharma) can suppress age-related increases in blood pressure, in addition to proving strong anti-thrombotic and antioxidant effects in stroke-prone hypertension.⁶²

Other vasodilators that also limit blood pressure include Pycnogenol,⁶³ garlic,⁶⁴ magnesium⁶⁵ and the natural polyphenol resveratrol.⁶⁶ A 2011 review of magnesium in heart health noted the mineral is effective at blood pressure reduction, but is more effective in this regard when combined with potassium.⁶⁷ The review further found magnesium is as effective as one antihypertensive drug and can increase the effectiveness of all antihypertensive medications. Overall, increased magnesium intake can improve insulin sensitivity, hyperglycemia, diabetes mellitus, left ventricular hypertrophy, dyslipidemia, NO production, endothelial function and vasodilation.

Resveratrol's actions in heart health were spelled out in a 2012 review article, which reported the polyphenol "reduces platelet aggregation, induces vasorelaxation, limits endothelial activation, and modulates lipid and lipoprotein metabolism."⁶⁸ The underlying mechanisms behind these actions is not fully known, but reviewers noted pathways utilized by resveratrol include oxidative stress reduction and eNOS activation.

The NO pathway is just one of the targets of the lycopene-free Fruitfow tomato extract, which also interacts with cGMP signaling, Ca2+ flux and tissue factor (TF, pro-coagulant). A pair of studies demonstrated Fruitflow modulates platelet function to help limit aggregation and improve blood flow as soon as three hours after supplementation and lasting for at least 12 hours.^69,70 A proprietary whey-derived bioactive peptide ingredient (as CVH47, from Glanbia Nutritionals) taken by men and women with impaired brachial artery flow-mediated dilation (FMD) improved FMD, but not via the NO pathway.⁷¹

The many approaches to heart health and the many ingredients in the heart health marketplace can be overwhelming, but scientific results and R&D progress can shine a light on the best products. Whether focusing on one specific aspect of heart health, such as NO-mediated vasodilation or oxidized LDL, or favoring ingredients or products that act on multiple risk factors, including obesity and diabetes, the growing heart health market appears to have room for new and improved formulations. Ability to work in the increasingly popular convenient functional food and beverage formats is a plus, although supplements are still a popular format in the United States and should not be ignored.

References listed on the next page.

For more on Heart Health ingredients and the market, visit INSIDER's Heart Health Content Library.

References:

1. Heinemann T, Axtmann G, von Bergmann K. Comparison of intestinal absorption of cholesterol with different plant sterols in man." Eur J Clin Invest. 1993 Dec;23(12):827-31.

2. Seo DY et al. "Independent beneficial effects of aged garlic extract intake with regular exercise on cardiovascular risk in postmenopausal women." Nutr Res Pract. 2012 Jun;6(3):226-31.

3. Castaner O Et al. "The effect of olive oil polyphenols on antibodies against oxidized LDL. A randomized clinical trial." Clin Nutr. Mar. 2. Published online ahead of print.

4. Lukaczer D, et al. Effect of a low glycemic index diet with soy protein and phytosterols on CVD risk factors in postmenopausal women." Nutrition. 2006 Feb;22(2):104-13.

5. Jia L., et al Short-term effect of cocoa product consumption on lipid profile: a meta-analysis of randomized controlled trials." Am J Clin Nutr. 2010 Jul;92(1):218-25.

6. Sharma S et al. "Beneficial effect of chromium supplementation on glucose, HbA1C and lipid variables in individuals with newly onset type-2 diabetes." J Trace Elem Med Biol. 2011 Jul;25(3):149-53.

7. Preuss HG et al. "Effects of niacin-bound chromium and grape seed proanthocyanidin extract on the lipid profile of hypercholesterolemic subjects: a pilot study." J Med. 2000;31(5-6):227-46.

8. Grant KE et al. "Chromium and exercise training: effect on obese women." Med Sci Sports Exerc. 1997 Aug;29(8):992-8.

9. Crawford V et al. "Effects of niacin-bound chromium supplementation on body composition in overweight African-American women." Diabetes Obes Metab. 1999 Nov;1(6):331-7.

10. Wolever TM, et al. Physicochemical properties of oat β-glucan influence its ability to reduce serum LDL cholesterol in humans: a randomized clinical trial." Am J Clin Nutr. 2010 Oct;92(4):723-32.

11. Onning G, et al. Consumption of oat milk for 5 weeks lowers serum cholesterol and LDL cholesterol in free-living men with moderate hypercholesterolemia." Ann Nutr Metab. 1999;43(5):301-9.

12. McIntosh GH, et al. Barley and wheat foods: influence on plasma cholesterol concentrations in hypercholesterolemic men." Am J Clin Nutr. 1991 May;53(5):1205-9.

13. Tinahones FJ et al. "Green tea reduces LDL oxidability and improves vascular function." J Am Coll Nutr. 2008 Apr;27(2):209-13.

14. Baba S et al. "Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans." Am J Clin Nutr. 2007 Mar;85(3):709-17.

15. Napolitano M. et al. " Effects of lycopene on the induction of foam cell formation by modified LDL." Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1820-7.

16. Napolitano M et al. "Effects of lycopene on the induction of foam cell formation by modified LDL." Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1820-7.

17. Kim JY et al. "Effects of lycopene supplementation on oxidative stress and markers of endothelial function in healthy men." Atherosclerosis. 2011 Mar;215(1):189-95.

18. Mohr D, Bowry VW, Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation." Biochim Biophys Acta. 1992 Jun 26;1126(3):247-54.

19. Tsai KL et al. "A novel mechanism of coenzyme Q10 protects against human endothelial cells from oxidative stress-induced injury by modulating NO-related pathways." J Nutr Biochem. 2012 May;23(5):458-68.

20. Staels B and Fruchart JC. " Therapeutic roles of peroxisome proliferator-activated receptor agonists." Diabetes. 2005 Aug;54(8):2460-70.

21. Rimando AM et al. "Pterostilbene, a new agonist for the peroxisome proliferatoractivated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters." J. Agric. Food Chem. 2005;53: 3403.

22.  http://www.naturalproductsinsider.com/news/2012/08/whole-grape-extract-impacts-hdl.aspx

23. Kamanna VS and Kashyap ML. "Mechanism of action of niacin." Am J Cardiol. 2008 Apr 17;101(8A):20B-26B.

24. Villines TC et al. "Niacin: the evidence, clinical use, and future directions." Curr Atheroscler Rep. 2012 Feb;14(1):49-59.

25. Insull W Jr et al. "Efficacy of extended-release niacin with lovastatin for hypercholesterolemia: assessing all reasonable doses with innovative surface graph analysis." Arch Intern Med. 2004 May 24;164(10):1121-7.

26. Boden WE et al. "Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy." N Engl J Med. 2011 Dec 15;365(24):2255-67.

27. Saito Y et al. "Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS)." Atherosclerosis. 2008 Sep;200(1):135-40.

28. Yokoyama M et al. "Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis." Lancet. 2007 Mar 31;369(9567):1090-8.

29. IBID Yokoyama

30. Bernstein AM et al. " A Meta-Analysis Shows That Docosahexaenoic Acid from Algal Oil Reduces Serum Triglycerides and Increases HDL-Cholesterol and LDL-Cholesterol in Persons without Coronary Heart Disease." J Nutr. 2012 Jan;142(1):99-104.

31. Calzada C. "Subgram daily supplementation with docosahexaenoic acid protects low-density lipoproteins from oxidation in healthy men." Atherosclerosis. 2010 Feb;208(2):467-72.

32. Ulven SM, et al. Metabolic Effects of Krill Oil are Essentially Similar to Those of Fish Oil but at Lower Dose of EPA and DHA, in Healthy Volunteers." Lipids. 2010 Nov 2.

33. Burri L et al. " Differential effects of krill oil and fish oil on the hepatic transcriptome in mice." (Front. Gene.2011 June 25;(2)45.

34. Mozaffarian D and Wu JH. "(n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary?" J Nutr. 2012 Mar;142(3):614S-625S.

35. Cabo J et al. "Omega-3 fatty acids and blood pressure." Br J Nutr. 2012 Jun;107 Suppl 2:S195-200.

36. Nasca MM, Zhou JR, Welty FK. Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women." Am J Cardiol. 2008 Jul 1;102(1):84-6.

37. Park E et al. Soy isoflavone supplementation alleviates oxidative stress and improves systolic blood pressure in male spontaneously hypertensive rats." J Nutr Sci Vitaminol (Tokyo). 2005 Aug;51(4):254-9.

38. López-Sepúlveda R et al. Wine polyphenols improve endothelial function in large vessels of female spontaneously hypertensive rats." Hypertension. 2008 Apr;51(4):1088-95.

39. Kappagoda CT et al. Presented at Experimental Biology Conference, Washington DC, April 30, 2007.

40. Edirisinghe I, Burton-Freeman B, Kappagoda CT. Mechanism of the endothelium-dependent relaxation evoked by a grape seed extract." Clin Sci. 2008;114:331-7.

41. Hosseini S et al. "A randomized, double-blind, placebo-controlled, prospective, 16 week crossover study to determine the role of Pycnogenol in modifying blood pressure in mildly hypertensive patients." 2001; 21(9): 1251-1260.

42. Enseleit F et al. " Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study." Euro Heart J. 2012;33(3): 1589-1597.

43. Kim JA. Mechanisms underlying beneficial health effects of tea catechins to improve insulin resistance and endothelial dysfunction." Endocr Metab Immune Disord Drug Targets. 2008 Jun;8(2):82-8.

44. Broncel M et al. [Effect of anthocyanins from Aronia melanocarpa on blood pressure, concentration of endothelin-1 and lipids in patients with metabolic syndrome.][Article in Polish]" Pol Merkur Lekarski. 2007 Aug;23(134):116-9.

45. Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure." Atherosclerosis. 2001 Sep;158(1):195-8.

46. Juraschek SP et al. "Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials." Am J Clin Nutr. 2012 May;95(5):1079-88.

47. Mahajan AS et al. Antihypertensive and antioxidant action of amlodipine and vitamin C in patients of essential hypertension." J Clin Biochem Nutr. 2007 Mar;40(2):141-7.

48. McRae MP. " Vitamin C supplementation lowers serum low-density lipoprotein cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials." J Chiro Med. 2008 June;7(2):48-58.

49. Wilkinson IB et al. "Oral vitamin C reduces arterial stiffness and platelet aggregation in humans." J Cardiovasc Pharmacol. 1999 Nov;34(5):690-3.

50. Block G et al. "Vitamin C treatment reduces elevated C-reactive protein." Free Radic Biol Med. 2009 Jan 1;46(1):70-7.

51. Rodrigo R et al. Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension." Clin Sci (Lond). 2008 May;114(10):625-34.

52. Plantinga Y et al. Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients." Am J Hypertens. 2007 Apr;20(4):392-7.

53. 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.

54. Miyazawa T et al. "Anti-angiogenic function of tocotrienol." Asia Pac J Clin Nutr. 2008;17 Suppl 1:253-6.

55. Kooyenga DK, et al. Palm oil antioxidant effects in patients with hyperlipidaemia and carotid stenosis-2 year experience." Asia Pacific J Clin Nutr 6, no. 1 (1997): 72-75.

56. Rasool AHG, et al. Dose dependent elevation of plasma tocotrienol levels and its effect on arterial compliance, plasma total antioxidant status, and lipid profile in healthy humans supplemented with tocotrienol rich vitamin E." J. Nutr Sci Vitaminol 5, no. 6 (2006): 473-478.

57. KH Yuen et al. Effect of Mixed-Tocotrienols in Hypercholesterolemic Subjects." Functional Foods in Health and Disease 3 (2011): 106-117.

58. Rasool, AHG et al. Arterial compliance and vitamin E blood levels with a self emulsifying preparation of tocotrienol rich vitamin E." Arch Pharm Res Vol 31, no. 9 (2008): 1212-1217.

59. Diehl KJ et al. "Nitric oxide-mediated endothlium-dependent vasodilation is impaired with borderline high-LDL cholesterol." Clin Transl Sci. 2012 Feb;5(1):21-6.

60. Lin PH et al. Rheolytic pharmacomechanical thrombectomy in experimental chronic deep vein thrombosis: effect of L-arginine on thrombogenicity and endothelial vasomotor function." World J Surg. 2007 Apr;31(4):664-75.

61. Kubota Y et al. Effects of Ginkgo biloba extract feeding on salt-induced hypertensive Dahl rats." Biol Pharm Bull. 2006 Feb;29(2):266-9.

62. Sasaki Y et al. Effects of Ginkgo biloba extract (EGb 761) on cerebral thrombosis and blood pressure in stroke-prone spontaneously hypertensive rats." Clin Exp Pharmacol Physiol. 2002 Nov;29(11):963-7.

63. Hosseini S et al. "A randomized, double-blind, placebo-controlled, prospective, 16 week crossover study to determine the role of Pycnogenol in modifying blood pressure in mildly hypertensive patients." 2001; 21(9): 1251-1260.

64. Steiner M et al. A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids." Am J Clin Nutr. 1996;64(6):866-70.

65. Yogi A et al. Vascular biology of magnesium and its transporters in hypertension." Magnes Res. 2010 Dec 1;23(4):207-15.

66. Milanovic G et al. "Resveratrol Reduces Blood Pressure, Changes of Antioxidant Enzyme Activity and Histological Parameters in Experimental Model of Malignant Hypertension: Pp.29.171." J Hypertension. 2012; 28:e500.

67. Houston M. "The role of magnesium in hypertension and cardiovascular disease." J Clin Hypertens (Greenwich). 2011 Nov;13(11):843-7.

68. Voloshyna I et al. "Resveratrol in cholesterol metabolism and atherosclerosis." J Med Food. 2012 Sep;15(9):763-73.

69. O'Kennedy N et al. "Effects of antiplatelet components of tomato extract on platelet function in vitro and ex vivo: a time-course cannulation study in healthy humans." Am J Clin Nutr. 2006 Sep;84(3):570-9.

70. O'Kennedy N et al. "Effects of tomato extract on platelet function: a double-blinded crossover study in healthy humans." Am J Clin Nutr. 2006 Sep;84(3):561-9.

71. Ballard KD et al. "Acute effects of ingestion of a novel whey-derived extract on vascular endothelial function in overweight, middle-aged men and women." Br J Nutr. 2012 Jun 13:1-12.