[Heart Health] Vol. 17 No. 10 October 2012

Still Beating Strong

By Steve Myers, Senior Editor A great deal is asked of the heart, both abstractly and physically. A mere pump, the heart helps push nutrient- and oxygen-rich blood throughout the body and performs this primary task faithfully and rhythmically for decades. It is the very definition of a loyal worker. However, its efficiency, consistency and longevity rely on a healthy cardiovascular system, and this is where people can run into problems over time.

Aside from some genetically linked structural and functional issues, the heart is a happy, healthy pumper as long as the blood is flowing freely throughout the body's network of veins and arteries. Any number of situations along this vascular journey can reduce blood flow to the heart and result in heart damage or death. Unfortunately, such problems are common. Heart disease is the leading cause of death in the United States, despite a recent decline in heart-related deaths—cardiovascular disease (CVD) death rates declined 31 percent from 1998 to 2008.1 Still, about every 25 seconds, someone has a coronary event, and one person dies of a coronary event each minute, according to the American Heart Association (AHA). To put the disease prevalence in simple prospective, AHA has reported more than one in three adults has some form of CVD. The problem isn't just American.

"CVD kills more people worldwide than any other disease," said Stephen Moon, CEO, Provexis and Science in Sport. "Indeed, experts estimate that by the year 2020, nearly 40 percent of all deaths worldwide will be due to CVD, more than twice the percentage of deaths from cancer." The reason why heart disease is so prevalent is the same reason why the heart health product market is huge and still expanding. Dietary and lifestyle choices are the root of most CVD. AHA said 80 percent of heart disease and stroke is preventable. A healthy diet, consistent exercise and smoking cessation are among the top ways to prevent heart problems or improve risk factors such as hypertension, high cholesterol, high blood sugar and excess body weight.

Consumers are motivated by quality of life, but also spring into action when conventional treatment becomes a financial burden. "About 37 percent or nearly 125 million Americans have heart diseases," added Bryan See, regional product manager, Carotech Inc., citing AHA sources. "In the same report, health care cost for heart disease will rise from US$273 billion to US$818 billion in conjunction with the increase of heart disease cases to 41 percent by 2030." The good news, he assured, is that both drugs and supplements can help consumers fight certain heart diseases. "Those concerned with the side effects associated with pharmaceuticals, such as statin drugs for cholesterol, are looking for alternative medicines such as heart-health supplements like fish oil, phytosterols, tocotrienols, CoQ10, etc."

"The heart health market is estimated to grow by approximately 20 percent per year for the next several years," noted Heather Thompson, global marketing, communications, Stratum Nutrition. "Several factors are responsible for this growth: an aging population that demands a higher quality of life in their senior years; growing consumer awareness of heart health indicators; and the consumer trend toward maintaining a healthy lifestyle in order to minimize illness onset." www.naturalproductsinsider.com Page 1

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Pam Stauffer, marketing manager, Cargill, reported the United States makes up the largest single heart health food and drinks market, capturing around two-thirds of the overall sector ($6.8 billion in 2009) and is forecast to reach $10.5 billion by 2015. "The high prevalence of CVD and associated risk factors, such as hypertension, has created a consumer base willing to use food and drink products that are specifically designed to aid heart health," she said. " According to [the Natural Marketing Institute], nearly three-in-four consumers report usage of heart-healthy foods and beverages. This trend has remained stable since 2005." The consumer base for natural heart health products tends to be older, and this demographic may be poised to contribute some big growth to the sector. "The demographic of the elderly/baby boomers is increasing," See noted.

William Loh, vice president of marketing, Cargill, agreed consumer perception and focus on cardiovascular health increases with age, and the aging U.S. population will drive preference toward foods that promote cardiovascular health.

Moon confirmed the aging U.S. population is definitely contributing to an increase in sales of heart- healthy food, beverages and dietary supplements. "Indeed, more consumers are turning to functional products to help them stay healthy as they grow older."

As heart product companies jockey to gain a profitable share of the increased number of consumers seeking help, the market is getting a boost from public health efforts to increase awareness. "Governments, health professionals and the health-oriented media have consistently pressed the message on the importance of cardiovascular health, leading to increased consumer awareness of the consequences of CVD," Moon said. "This awareness is one of the primary factors driving market growth."

The depth of the awareness of heart health may be the next necessary focal point. "Many in the public fail to realize the interconnectedness of seemingly unrelated symptoms, such as elevated blood glucose levels, continuous high blood pressure or abdominal tissue accumulation, with future CVD," said Paul Dijkstra, CEO, InterHealth USA. He explained while awareness is the first step in supporting a healthy heart, consumers need to understand it takes a multifaceted approach to supporting heart health. "A combination of weight reduction, healthy diet, moderate and regular exercise, and science-backed dietary supplements and functional food and beverages may help maintain heart health."

Looking back, Dijkstra sees a heart-health category that has undergone somewhat of a revolutionary process during the past decade. "There is an interrelated triage of consumer interest, product activity and manufacturer intent," he said. "Along with the increased interest and awareness on the consumer and professional sides about the importance of supplementation—using nutraceuticals as well as functional foods and beverages—for maintaining a healthy cardiovascular system, manufacturers have significantly increased their research activities developing new compounds and new product forms much to the liking of consumers. This has lead to an increase in category growth."

Moon said more than half of Americans use supplements on a daily basis, according to the Centers for Disease Control and Prevention (CDC). "The United States is one of the key global markets for dietary supplements," he noted. "In terms of sub-segments, heart health is one of the most lucrative areas, with many consumers taking supplements to keep their hearts healthy." That said, he www.naturalproductsinsider.com Page 2

[Heart Health] Vol. 17 No. 10 October 2012 acknowledged fortified foods and beverages, which are easy to incorporate into daily life, are also growing in favor with health-conscious U.S. consumers. "Everyday products that feature naturally derived ingredients with proven health benefits are particularly popular," he said. "Some examples include spreads fortified with plant sterols, breads with high levels of fiber and beta-glucans and ready -to-drink beverages formulated with naturally derived, scientifically substantiated ingredients such as Fruitflow." Citing convenience as a key differentiator for busy consumers, he predicted "healthy shot" products will continue to grow in popularity. DSM, one of Provexis’ commercial partners, has used Fruitflow, a whole tomato extract designed to improve blood flow, in such a product to help prevent deep vein thrombosis on long-haul flights, according to Moon.

Thompson reported today’s consumers are actively seeking “convenient” supplementation, which most view to be in the form of food and beverages, whenever possible, rather than taking pills. "This trend has fueled innovation within the industry, and resulted in wide varieties of delivery methods," she noted. "We continually work in our application labs to test viability of new applications in supplement, food and beverage, whether that be a chewable, baked good, snack, drink sachet, gum or other 'convenient' new ways to supplement our heart-healthy fiber."

"Some heart-health shoppers love the convenience of dietary supplements, while others seek food and beverage alternatives," Stauffer said, noting this dichotomy can be positive for those businesses, like Cargill, that work with both dietary supplement manufacturers, and food and beverage manufacturers. "Products made with CoroWise® plant sterols range from dietary supplements such as Cardio Chews®, to many foods and beverages such as Smart Balance® Heart Right® milk and Corazonas™ chips and oatmeal squares."

Count Dijkstra among those seeing food and beverage applications as a key heart-health growth category, as he noted there is continuing product activity for heart-health food and beverages. Still, versatility might be the important characteristic in this dynamic health segment. "Market success for heart-health nutraceutical ingredients lies strongly in its application for dietary supplement, food and beverage markets," he reasoned.

In the growing market of natural heart-health ingredients, market success will also require differentiating a product from the crowd. "Consumers have many heart-healthy food, beverage and supplement choices," Stauffer said, noting Cargill continues to see demand for new product development with plant sterols. Working with customers on many levels can help ensure success, she suggested. "We conduct primary marketing research to enable sharing of proprietary consumer insights for consideration in developing product labels," she said. "Cargill also offers marketing support to co-brand customer partners via an extensive health care professional outreach program."

In a market segment saturated overall, one way to find a profitable niche may be focusing on a specific area of function and benefit. "Although manufacturers face increasing competition, there are definitely some emerging sub-segments, which offer much potential," Moon reported. "The market for ingredients promoting healthy blood circulation, for example, is still relatively underdeveloped, with less than a handful of technologies available."

One way Proxexis has differentiated its Fruitflow product is via regulatory clearances including health claims approval and generally recognized as safe (GRAS) status. Moon said the ingredient, which was licensed to DSM Nutritional Products in 2010, was the first to receive an Article 13(5) claim from www.naturalproductsinsider.com Page 3

[Heart Health] Vol. 17 No. 10 October 2012 the European Safety Authority (EFSA) and has gained GRAS status in the United States, enabling it to be used in foods. Opening up the options for varied applications and the ability to explain the health benefits in more direct language can help heart-health product formulators lift their finished product above the crowd.

"The ingredient is currently available in an easy-to-use syrup format for use in beverages, spreads and dairy products, with a powder format for dietary supplements currently in the final stages of development," Moon explained. "

See agreed product and formula differentiation are key to compete and ensure a particular product does well in the market. He sees the solution to the saturation dilemma is a synergistic combination with clinically proven functional ingredients for heart health. Combining ingredients that address complementary aspects of heart health is one method of differentiation, and another way may be developing ingredients that address such issues on their own. "Many of the ingredients used in heart- health products only address one or two heart-health issues such as blood pressure or cholesterol," claimed Dijkstra, who stressed it is important for manufacturers to look at the bigger picture when it comes to cardio health. "Manufacturers are increasingly interested in offering solutions to their customers that address particular health concerns from a holistic or a 'whole body' perspective that target several underlying mechanisms simultaneously and see the body in its entirety," he explained.

"Managing cholesterol levels and high blood pressure definitely helps support a well-functioning cardiovascular system, but often overlooked is the impact of blood sugar management on the heart and vascular system."

Thompson touted focused, scientific support as a top differentiator for its ARTINIA, a chitin-glucan fiber shown to target oxidation of low-density lipoprotein (LDL), an increasingly recognized precursor and predictor of CVD. "The heart-health market is ever changing, due to ongoing discoveries about our cardiovascular system and how it functions," she said. "As we discover new biomarkers that correlate to the function of our cardiovascular systems, we develop better supplements for supporting heart health."

Clinical research is a compelling part of an ingredient brand’s story, according to Stauffer. "Plant sterols are backed by more than 50 years of clinical research and eligible for an FDA health claim," she added, noting such support can help bring credibility to the value proposition of an ingredient and product.

Clinical trials combined with solid research and development (R&D) commitment is important to develop a product and formulation that works and is able to confer the health benefits to consumers, See offered.

Researched Heart Health Benefits Of the many risk factors associated with heart health and 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. www.naturalproductsinsider.com Page 4

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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 cholesterol 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.2 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,4,5 cocoa6 and chromium.7 Supplementation with chromium nicotinate (as ChromeMate®, from InterHealth USA) can help maintain healthy cholesterol levels already in the normal range.8 When combined with regular exercise, the supplement can support healthy body weight9 and composition by maintaining lean body mass,10 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.11,12 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.13

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.14 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.15

The carotenoid lycopene has been shown to decrease foam cell formation triggered by oxidized LDL.16 Other research reported lycopene can preserve myocardial antioxidant status and significantly inhibit lipid peroxidation resulting from myocardial ischemia-reperfusion injury.17 Also, a trial in healthy men found lycopene supplementation improved endothelial function by increasing activity of superoxide dismutase (SOD) and endogenous antioxidants.18 The results further linked lycopene to reduced high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, and reduced systolic blood pressure.

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Coenzyme Q10 (CoQ10), as ubiquinol, inhibited lipid peroxidation in the arterial wall in one study.19 A 2012 report detailed how CoQ10 improved antioxidant status and controlled oxidation in human umbilical cord cells subjected to oxidized LDL.20 CoQ10 also limited oxidized LDL's enzymatic reduction of NO synthesis—NO 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.21 This may also raise levels of HDL.22

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.23

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.24 Early studies showed niacin supplementation increased HDL levels and, when combined with statin drugs, inhibited atherosclerosis development.25,26 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.27 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.28 Fish oil can help lower unhealthy levels of LDL cholesterol,29 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.30

Considering other sources, docosahexaenoic acid (DHA) from algae also reduced triglycerides and increased HDL.31 Protection from LDL oxidation is another finding associated with DHA supplementation.32 Likewise, krill oil reportedly improved the HDL:triglyceride ratio compared to fish oil.33 Krill has also shown a greater effect on lipid and glucose metabolism than has fish oil.34 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).35 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.36 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. www.naturalproductsinsider.com Page 6

[Heart Health] Vol. 17 No. 10 October 2012

Soy protein has lowered blood pressure in both normotensive and hypertensive women,37 and isoflavone-rich soy powder added to a high-fat diet can limit blood pressure increases and oxidative damage and improve endothelial health.38

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,39 while grape seed extract (GSE) can lower systolic and diastolic blood pressure in pre- hypertensive adults,40 and improve endothelial function.41 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.42 A 2012 study found Pycnogenol taken by patients with stable coronary artery disease improved endothelial function and increased blood flow via arterial dilation.43 Other flavonoid-rich botanical ingredients found to offer blood pressure benefits include catechin-rich tea,44 anthocyanin-rich chokeberries45 and flavanoid-rich pomegranates.46

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.47 Used in conjunction with hypertensive therapy, vitamin C lowered systolic pressure and oxidative stress.48 Vitamin C is a heart-health juggernaut, also lowering LDL and triglycerides,49 inhibiting platelet aggregation,50 and reducing potentially damaging inflammation (as marked by CRP levels).51

Combined use of vitamins C and E by hypertensive men for eight weeks not only lowered systolic and diastolic pressure, but also increased antioxidant status.52 Another study in a similar population found this vitamin combo significantly improved arterial flexibility, flow-mediated dilation (FMD), vasodilation and oxidative stress.53 Nattokinase in fermented soy can inhibit thickening of the interior arterial wall, possibly by breaking down fibrin that contributes to clotting and plaque formation.54

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),55 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 tocotrienols— members of the vitamin E family—reversed atherosclerosis progression.56 Palm tocotrienols also reduced aortic systolic pressure57 and, as Tocomin SupraBio (from Carotech Inc.), lowered total and LDL cholesterol in hypercholestemia58 and reduced arterial stiffness in healthy adults.59

NO-mediated vasodilation can be impaired in cases of high LDL cholesterol levels.60 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.61

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.62 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.63 www.naturalproductsinsider.com Page 7

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Other vasodilators that also limit blood pressure include Pycnogenol,64 garlic,65 magnesium66 and the natural polyphenol resveratrol.67 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.68 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."69 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.70,71 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.72

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

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7. 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. 8. 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. 9. Grant KE et al. "Chromium and exercise training: effect on obese women." Med Sci Sports Exerc. 1997 Aug;29(8):992-8. 10. 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. 11. 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. 12. 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. 13. 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. 14. Tinahones FJ et al. "Green tea reduces LDL oxidability and improves vascular function." J Am Coll Nutr. 2008 Apr;27(2):209-13. 15. 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. 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. 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. 18. 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. 19. 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. 20. 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. 21. Staels B and Fruchart JC. " Therapeutic roles of peroxisome proliferator-activated receptor agonists." Diabetes. 2005 Aug;54(8):2460-70. 22. 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. 23. http://www.naturalproductsinsider.com/news/2012/08/whole-grape-extract-impacts-hdl.aspx 24. Kamanna VS and Kashyap ML. "Mechanism of action of niacin." Am J Cardiol. 2008 Apr 17;101(8A):20B-26B. www.naturalproductsinsider.com Page 9

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25. Villines TC et al. "Niacin: the evidence, clinical use, and future directions." Curr Atheroscler Rep. 2012 Feb;14(1):49-59. 26. 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. 27. 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. 28. 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. 29. 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. 30. IBID Yokoyama 31. 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. 32. Calzada C. "Subgram daily supplementation with docosahexaenoic acid protects low-density lipoproteins from oxidation in healthy men." Atherosclerosis. 2010 Feb;208(2):467-72. 33. 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. 34. 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. 35. 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. 36. Cabo J et al. "Omega-3 fatty acids and blood pressure." Br J Nutr. 2012 Jun;107 Suppl 2:S195- 200. 37. 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. 38. 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. 39. 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. 40. Kappagoda CT et al. Presented at Experimental Biology Conference, Washington DC, April 30, 2007. 41. 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.

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59. 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. 60. 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. 61. 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. 62. 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. 63. 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. 64. 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. 65. 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. 66. Yogi A et al. “Vascular biology of magnesium and its transporters in hypertension.” Magnes Res. 2010 Dec 1;23(4):207-15. 67. 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. 68. Houston M. "The role of magnesium in hypertension and cardiovascular disease." J Clin Hypertens (Greenwich). 2011 Nov;13(11):843-7. 69. Voloshyna I et al. "Resveratrol in cholesterol metabolism and atherosclerosis." J Med Food. 2012 Sep;15(9):763-73. 70. 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. 71. 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. 72. 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. [Epub ahead of print]

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