Course Title

Nutraceutical ingredients enhance cardiovascular health

Course Description

This course presents information found in the March 2005 cover story of Health Supplement Retailer (HSR) magazine.

Overview

Cardiovascular disease (CVD) is a host of interrelated conditions affecting the heart, blood vessels and blood cells. Degenerative conditions include atherosclerosis (hardening of the arteries), congestive heart failure (CHF), coronary heart disease (CHD) and hypertension (high blood pressure). These conditions contribute to other acute events including stroke and myocardial infarction (heart attack). More than 20 percent of Americans have one or more types of CVD, including 50 million Americans with hypertension and 13.2 million with CHD.

Basic Terminology

The continued prevalence of CVD remains a concern for Americans. "Thirty years of supposed preventive measures have failed," said Al Sears, M.D., director of the Wellness Research Foundation and author of The Doctor's Heart Cure (Dragon Door Publications, 2004). "Dietary changes have caused the modern epidemic of heart disease. However, research and experience prove nutritional strategies can both prevent and reverse existing heart disease."

A combination of factors appears to be driving the continued epidemic of CVD. Of particular note are the facts that seniors are living longer, medicine is more adept at helping people live with heart disease and survive incidents such as heart attack, and the baby boomers are reaching the prime time for diagnosis of CVD. The number of people treating heart conditions continues to increase, according to the Natural Marketing Institute. Data from its Health & Wellness Trends Database-six years of trended data from more than 2,000 consumer household respondents-found almost 46 percent of consumer households are managing or treating cholesterol, 31 percent are treating hypertension and 15 percent are treating heart disease. 

Fortunately, there are more nutritional products available for preventing and treating cardiovascular dysfunction. "Recent years have brought well-researched, pioneering products to the heart health market, particularly in the area of homocysteine reduction and cholesterol lowering," said Traci L. Kirksey, director of sales and marketing with Gematria Products Inc. "These formulas are much-desired alternatives to typical drugs, such as statins, and their potentially undesirable side effects."

The range of supplements available should provide retailers many options for serving their customers, said Doug Bibus, Ph.D., a member of the scientific advisory board for Coromega. "Many products are targeted at lowering blood cholesterol and blood pressure, but many supplement companies are now targeting causes of heart disease that go well beyond cholesterol," he said. "New emphasis is being placed on the key biochemical factors, inflammation and oxidative status, that are viewed as root causes of atherosclerosis. There is more to heart disease than just cholesterol." 

Bernard Collett, Ph.D., chief executive officer with Designing Health, agreed with the assessment. "What most people don't know or won't accept is both high cholesterol and blood pressure problems generally develop over years and can be categorized as degenerative diseases that are normalized through multiple channels of lifestyle choice," he said.

The importance of a healthy lifestyle is critical. Researchers suggest incorporating regular physical activity, avoiding smoking, maintaining a healthy body weight and consuming a diet rich in whole grains, fruits and vegetables, omega-3 essential fatty acids (EFAs) and unsaturated fats as the predominant form of dietary fats could prevent the majority of CVD in Western populations.1 In addition, there are certain specialty foods that may help in lowering the risk of CVD. For example, the American Heart Association (AHA) and National Cholesterol Education Program suggest the use of soy protein to lower cholesterol. The Food and Drug Administration (FDA) even approved a health claim linking the intake of 25 g/d of soy protein with a reduced risk of CHD. Soy consumption appears to improve plasma lipids, reduce LDL oxidation and improve vascular reactivity.2

Intervention studies have shown promising results for the use of isolated soy protein. Researchers at the University of Illinois, Urbana-Champaign, found providing 0.5 g/kg/d of isolated soy protein for 16 weeks to men with Type II diabetes significantly improved their total-to-HDL ratio and HDL cholesterol levels.3 Another study found the use of 30 g/d or 50 g/d of isolated soy protein in 130 subjects significantly reduced LDL cholesterol concentrations.4 

There is some question as to whether soy's heart healthy effects can be attributed to its protein or other compounds such as isoflavones. Tokyo researchers conducted a meta-analysis using eight studies comparing high- and low-isoflavone levels with identical soy protein intake and found higher levels of isoflavones led to greater decreases in LDL levels.5 As soy isoflavones already appear efficacious in reducing some menopausal symptoms, their heart health benefits may be an added bonus for women. In a Dutch study of more than 900 postmenopausal women, higher intake of isoflavones and lignans were associated with lower triglyceride levels, as well as a reduced cardiovascular risk factor metabolic score.6 

Supplemental dosages of isoflavones from red clover also appear
beneficial. In a 12-week, randomized study in 252 menopausal women, the use of two different red clover dietary supplements (Promensil, 82 mg total isoflavones, and Rimostil, 57.2 mg total isoflavones) significantly increased HDL levels and decreased triglyceride levels compared to women taking a placebo.7  Similarly, use of a supplement with 43.5 mg isoflavones by perimenopausal women reduced triglycerides, total cholesterol and LDL cholesterol.8

Ground flaxseed is another source of dietary phytoestrogens as lignans. A review from the University of Pennsylvania, Philadelphia, noted flaxseed may modestly reduce serum total and LDL cholesterol and decrease some markers of inflammation.9 Researchers from Oklahoma State University, Stillwater, examined the impact of 40 g/d of ground flaxseed on cholesterol levels in women not on hormone therapy and found supplementation significantly lowered serum total cholesterol and non-HDL cholesterol.10

Flaxseed is also a rich source of the omega-3 fatty acid alpha-linolenic acid (ALA), which may beneficially impact inflammation. When fed to rats, flaxseed increases the serum levels of both ALA and the longer-chain eicosapentaenoic acid (EPA), which is produced through enzymatic conversion of ALA.11 Studies have found intake of a high-ALA diet may decrease vascular inflammation and endothelial activation.12 Similarly, hypercholesterolemic men and women who received margarine enriched with ALA showed lower levels of C-reactive protein (CRP), a marker of inflammation.13

Flaxseed forms the basis of the new MegaFlax™ line of target-specific formulations from Designing Health. According to Collett, the MegaFlax Heart™ product incorporates whole foods with cardio-protective effects with special phytonutrients. "Bearing on the inflammatory aspect of heart disease, it has properly balanced essential fatty acids incorporated from organic flaxseed, which also delivers lignans that have renal protective antioxidant and anti-inflammatory properties," he said. Additional ingredients include oat bran fiber, hawthorn, garlic, lycopene and grape seed extract.

Beyond flax omega-3s, there has been a great deal of attention paid to the role of fish oil as a source of preformed EPA and docosahexaenoic acid (DHA). "Purified fish oils are becoming one of the most popular heart health supplements on the market today," Bibus said. "The data is so compelling that the American Heart Association now recommends consuming enough fish oil supplements per day to supply 1 gram of EPA and DHA if you are at risk of heart disease." 

The original link between marine omega-3 fatty acids and heart health came from observational studies of Japanese and Eskimo populations, for whom diets rich in fatty fish protected against CHD. Since that point, population studies have supported the association. For example, a cohort study of almost 80,000 women in the Nurses' Health Study found women in the highest quintile of intake of fish and long-chain omega-3s had a 28-percent reduced risk of stroke and a 33-percent reduced risk of thrombotic infarction compared with the lowest quintile.14

These have led researchers to suggest marine-source omega-3 fatty acids protect against CHD through several mechanisms of action, including antiarrhythmic, antithrombotic, antiatherosclerotic and anti-inflammatory activities, lowering blood pressure, lowering triglyceride concentrations and improving endothelial function.15 "Hundreds of papers document the life saving effects of long chain omega-3 fats for the reduction of heart disease and death related to heart disease," Bibus noted.

The best known intervention study that assessed the link between marine-source omega-3 EFAs and CVD risk was the GISSI-Prevenzione trial, in which 11,324 patients surviving recent myocardial infarction received either marine omega-3 EFAs (1 g/d), 300 mg/d vitamin E, both or neither for 3.5 years.16 Treatment with omega-3s significantly lowered the risk of overall, cardiovascular and sudden death, as well as incidence of non-fatal myocardial infarction and stroke. Studies have also shown the benefit of fish oil supplementation on reducing CRP levels17 and thrombin generation,18 and enhancing endothelial function, even in healthy subjects.19

There has been some discussion of the quality of fish oil supplements. "To be healthy, fish oils must be free of contaminants and must not be oxidized," Bibus said. "A general rule of thumb is that if a fish oil product smells fishy, it probably is. Generally, the fishy smell is a sign of oxidation and oxidized fish oil is not heart healthy." Instead, Bibus recommended retailers ask their manufacturers about the source of the fish oil and what type of quality control procedures they follow to ensure the freshness of the product. Many natural products manufacturers, including Coromega and Enzymatic Therapy (which supplies Eskimo 3), use pharmaceutical grade, molecularly distilled fish oil that is free of pesticides and heavy metals; however, it is critical to request documentation of the raw materials.

Another beneficial fat is olive oil, which contains high levels of monounsaturated fatty acids as well as a host of phytochemicals. The antioxidants in olive oil may protect against peroxidation, reduce plasma levels of LDL cholesterol and increase HDL cholesterol levels.20 Olive oil rich diets have also been shown to normalize blood pressure in hypertensive patients.21 In addition, the oleic acid in olive oil appears to interfere with the inflammatory response, decreasing the expression of pro-inflammatory proteins associated with atherosclerosis.22 And olive polyphenols, including hydroxytyrosol, appear to be effective free radical scavengers that can inhibit platelet aggregation.23

Another rich source of polyphenols is grape seed extract, which has been shown to have antioxidant activity that reduces LDL oxidation.24 In addition, phenolic-rich extracts from grape seeds have been shown to prevent the development of aortic atherosclerosis without impacting plasma antioxidant capacity.25 They further act in endothelial cells, increasing nitric oxide xynthase expression, enhancing vasorelaxation.26

In a study at Creighton University, Omaha, Neb., researchers investigated the effects of grape seed extract (as ActiVin® from San Joaquin Valley) with and without niacin-bound chromium (as ChromeMate® from InterHealth Nutraceuticals) on blood pressure in normotensive and hypertensive rats.27 The compounds, both individually and in combination, significantly lowered systolic blood pressure in both types of rats.

There are several other sources of antioxidant flavonoids. The flavonoids in tea, for example, appear to work as direct and indirect antioxidants, improving the resistance of lipoproteins to oxidation and inhibiting atherogenesis.28 Cocoa flavonoids may improve endothelial function, lower blood pressure, decrease platelet activation and serve as general antioxidants.29 And a review of studies on French maritime pine bark extract (as Pycnogenol®) noted the extract protects against oxidative stress, prevents platelet aggregation and reduces LDL cholesterol levels.30,31

Some newer research is exploring the role of citrus on cardiovascular function. Citrus contains an array of bioactive compounds, including flavonoids and limonoids.32 Animal studies have found supplementation
with the bioflavonoid naringin from grapefruit increases plasma antioxidant capacity and reduces aortic fatty streak areas in animals fed a high cholesterol diet.33 The citrus flavonoid hesperidin was found in studies using hypertensive rats to decrease blood pressure and heart rate.34 And tangeretin, a polymethoxylated flavone (PMF) from tangerine peel, was found in a study from KGK Synergize to modulate apoB-containing lipoprotein metabolism.35 A review of research on formulations containing citrus flavonoids including tangeritin, hesperedin and naringin noted supplementation in the diet appears to significantly reduce total and LDL cholesterol, with a tendency to further reduce serum triacylglycerols.36 Citrus PMFs are the primary ingredient in Sytrinol™, a branded ingredient distributed by SourceOne Global. The PMFs and tocotrienols work synergistically to improve cholesterol levels, according to Richard Staack, Ph.D., SourceOne's vice president of business development. "Sytrinol is a natural solution to the cholesterol problem that has been clinically proven to help maintain a healthy heart and encourage normal blood flow in arterial walls," he said. "Additionally, Sytrinol possesses antioxidant activity that helps inhibit lipid peroxide production and protects cells from damaging effects of free radicals."

Another hot source of polyphenols is pomegranate; its flavonoids appear to protect LDL against oxidation both through direct interaction with lipoprotein and through accumulation in arterial macrophages.37 Studies further suggest pomegranate juice supplementation can reduce the size of established atherosclerotic lesions and decrease the number of foam cells.38 A three-year study conducted in Israel involving 10 patients taking pomegranate juice daily found administration resulted in significant reductions in carotid intima-media thickness (IMT) and serum lipid peroxidation.39

Beyond the water-soluble polyphenols are the fat-soluble carotenoids, another powerful class of antioxidants. Carotenoids appear particularly adept at scavenging singlet oxygen and peroxyl radicals generated in the process of lipid peroxidation.40 The majority of the attention in the carotenoid area has centered on lycopene, which may work not only as an antioxidant, but also impact LDL degradation and particle size, as well as altering endothelial function.41 Data from 725 men participating in the Kuopio Ischaemic Heart Disease Risk Factor Study found men in the lowest quarter of serum lycopene levels had a 3.3-fold risk of acute coronary events or stroke compared with others, 42 as well as significantly higher IMT of the carotid artery.43

While there are several dietary sources of antioxidants, there has been some dispute regarding the benefits of antioxidant supplementation on cardiovascular risk factors. A systematic review of the effects of antioxidant vitamins in prevention of CVD found while observational studies showed a link between intake of antioxidant vitamins in the diet and reduced risk of CVD, randomized controlled trials have shown no beneficial effects in primary prevention of myocardial infarction and stroke.44 Another meta-analysis reviewed seven randomized trials of vitamin E (50 IU/d to 800 IU/d) and found vitamin E did not benefit mortality nor significantly decrease risk of cardiovascular death.45 However, recent clinical studies have shown some benefits of vitamin E supplementation. In two separate human studies, supplemental alpha-tocopherol (one of the eight isomers of vitamin E) decreased the susceptibility of LDL cholesterol to oxidation.46,47

Coenzyme Q10 (CoQ10) is another antioxidant compound with multiple roles to play in the heart health area. In fact, Sears called it "the single most important supplement to improve heart capacity and reduce the risks of heart disease." Among the activities he noted were CoQ10's role in improving muscular energy output, destruction of free radicals, reducing accumulation of oxidized fat in blood vessels, reducing hypertension and hypercholesterolemia, and regulating heart rate. Studies have shown CoQ10 has favorable activity on patients with CHF, including increasing cardiac output and reducing stroke volume,48 as well as reducing hypertension.49 Studies have found cosupplementation of CoQ10 with vitamin E reduces atherosclerosis progression and increases the plasma's resistance to lipid peroxidation.50

One of CoQ10's most promising applications in the heart health area is prevention of cardiomyopathy induced by the use of statin drugs. These pharmaceuticals, widely prescribed to lower cholesterol levels, work by blocking the same uptake channel used by CoQ10; studies have shown use of statins for as little as 30 days significantly decreases blood concentrations of CoQ10.51 Two citizen's petitions to FDA, in fact, request the agency require statins to carry a recommendation for CoQ10 supplementation to prevent statin-induced cardiomyopathy; as yet, there has been no response to the most recent request.

Often used concurrently with CoQ10 is L-carnitine, an amino acid that boosts mitochondrial activity by shuttling fuel into the cells. Carnitine has a relaxation effect on aortic rings in hypertensive animals, apparently by mediating endothelial production of nitric oxide,52 and, when used prior to induction of heart attack, protects heart function and improves recovery.53 Further, L-carnitine administration was found in an animal study to prevent the progression of atherosclerosis.54 Additional amino acids of interest to cardiac function are L-arginine, which is critical to nitric oxide production,55 and taurine, which inhibits inflammation.56

A newer product combination uses CoQ10 and enzymes, including proteolytic proteins and fibrinolytic enzymes. Arthur Andrew Medical offers the product, Neprinol™, which combines CoQ10 with Serratiopeptidase, which emulsifies deposits of cholesterol, and Nattokinase, which functions as a blood thinner and works to dissolve blood clots and arterial plaque. A recent study from Japan found that nattokinase administration prior to induction of endothelial injury prevented intimal thickening and development of thrombotic clots.57

"Systemic enzymes have an anti-inflammatory effect by directly consuming the pro-inflammatory cytokines, which directly addresses the primary cause of heart disease," said William Wong, Ph.D., N.D. "In addition, the enzymes lyse away at fibrin, the second cause of heart disease, which causes blood cells to glom together. The enzymes also eat away at adhesion molecules and reduce platelet aggregation. Systemic enzymes really open up the blood vessels and have been used for years in Europe for their ability to treat vascular diseases."

Another type of protein-casein protein hydrolysate (C12 Peptide from DMV International)-has also been investigated in the CVD arena, specifically for its ability to reduce hypertension. Researchers from the University of Pennsylvania, Philadelphia, conducted a placebo-controlled study in 10 hypertensive subjects to determine whether a single dose of C12 Peptide could reduce daytime blood pressure.58 Administration of C12 Peptide resulted in a significant reduction of systolic and diastolic blood pressure at six hours, suggesting the dairy peptides could reduce hypertension.

Many of the processes associated with hypertension, including arterial wall thickening and endothelial dysfunction, are influenced by magnesium levels, which impact vascular tone and cardiac function.59 Deficiencies in magnesium are also associated with CHF, arrhythmia and myocardial infarction,60 and experimentally induced low plasma levels of magnesium increase LDL concentrations and changes to more atherogenic forms.61

"Deficiency of magnesium may reduce relaxation of the heart and predispose individuals to hypertension," said Kirksey, whose company offers the product MagCardio, using chelated magnesium from Albion
Advanced Nutrition. "Sufficient delivery of a good, bioavailable magnesium for persons with cardiac conditions may be lifesaving."

While several nutrients impact endothelial function, increased levels of the amino acid homocysteine have been connected to venous dysfunction and an increased risk of CVD. The B vitamin folic acid is seen as one of the best compounds for lowering levels of homocysteine. Population studies have shown patients with lower folate intakes have a higher risk of CVD; for example, a Spanish study in 171 patients with myocardial infarction and 171 control patients found participants in the lowest quartile of folate intake had twice the risk of heart attack.62 Additional studies have shown a higher intake of folate significantly reduced the risk of peripheral arterial disease63 and the risk of ischemic stroke.64

Folate may also affect blood pressure. A recent study published in the Journal of the American Medical Association found younger women who consumed at least 1,000 mcg/d of total folate (through food and
supplements)-two and a half times the recommended daily intake-had a 46-percent decreased risk of hypertension compared to younger women consuming less than 200 mcg/d; in older women, higher folate intake
reduced the risk of hypertension by 18 percent.65

Another critical B vitamin is niacin, which is primarily used for its ability to increase levels of beneficial HDL cholesterol. It was used for treatment of dyslipidemia as early as the 1950s for its favorable impact on HDL levels, and studies have shown it raises HDL levels while increasing LDL size to less atherogenic large LDL subclasses.66 Its ability to increase HDL has led researchers to investigate concomitant use of niacin with statin drugs, prescribed for hypercholesterolemia. A double blind, placebo-controlled trial at the Walter Reed Army Medical Center in Washington, D.C., found the addition of 1,000 mg/d of extended-release niacin significantly reduced the rate of IMT progression in CHD patients taking statins.67 Another U.S. study found the combination of 40 mg/d lovastatin and 2,000 mg/d extended-release niacin significantly reduced LDL and triglyceride levels while significantly increasing HDL.68

On the botanical side, the herb garlic (Allium sativum) has a storied history of therapeutic use in heart health, possibly through antioxidant activity.69 In vitro work has focused on garlic's sulfur compounds, including diallyl sulfide, S-ethylcysteine and N-acetylcysteine, for their ability to inhibit superoxide production and protect LDL from oxidation.70 Enteric coated fresh garlic, such as Enzymatic Therapy's Garlinase 4000, is designed to keep the different allicin precursors separate until they reach the intestines. "In cooking, this is what happens when garlic is crushed," explained Cheryl Myers, director of health sciences with Enzymatic Therapy. "In our product, it happens when the internal wall melts away and the substances mix."

Instead of keeping the components separate, aged garlic extract instead is produced to stabilize sensitive organosulfur compounds such as allicin.71 A placebo controlled study at Harbor-UCLA Medical Center Research and Education Institute in Torrance, Calif., investigated whether aged garlic extract could slow the rate of atherosclerosis progression in 23 subjects, and found supplementation improved the total cholesterol-to-HDL ratio and lowered homocysteine levels.72

The botanical hawthorn (Crataegus oxyacantha L.) has been found beneficial for decreasing the pressure-heart rate and improving exercise tolerance, particularly in patients with CHF.73 Short-term studies have also shown hawthorn may reduce systolic and diastolic blood pressure,74 and lower total cholesterol in animals fed a high cholesterol diet.75

The Western world is not the only source for beneficial compounds. "Plants containing nutrients for the heart and arteries were discovered thousands of years ago and practiced in ancient Chinese and Ayurvedic medicine," said Grace Ormstein, M.D., medical director with Himalaya USA. "Today, this information is used to manufacture pure herbs and herbal formulations for the treatment and prevention of many health care concerns."

One such Ayurvedic offering is guggul, made from the resin of the Commiphora mukul tree, which has been used for more than 2,000 years and appears to decrease cholesterol levels. Based on clinical studies, the Indian Pharmacopeia included a standardized preparation of guggul for treatment of dyslipidemia type IIb and IV. The preparation has since been investigated in the United States by Sabinsa Corp. (which supplies the preparation as Gugulipid®). Data submitted to the FDA on a short-term safety and efficacy study showed 150 mg/d of guggulsterones may have an effect on dyslipidemia as well as other systemic effects.

Nature's Formulary is a supplier of Ayurvedic dietary supplements, including guggul, which company President P.K. Dave suggests has broader heart function than currently known. "Some studies have shown that guggul interferes with the mechanism that produces cholesterol by being an antagonist to the receptor chemicals that are needed by the body to synthesize cholesterol," he said. "Guggul is also believed to stimulate the thyroid, an organ that plays an important role in metabolizing fat." 

Arjuna (Terminalia arjuna), another Indian botanical, appears to benefit heart function. A study in rats found administration of arjuna extract prior to induction of heart damage increased levels of antioxidant defense systems and improved recovery.76 In a human trial, 500 mg of arjuna extract every eight hours significantly improved flow-mediated dilation in smokers, possibly improving endothelial function.77

Ormstein noted together with arjuna and guggul, Ayurvedic medicine offers other beneficial products. "Billilotan is a known heart tonic and supports healthy blood pressure," she added. "While Ashwagandha, an adaptogenic, has anti-stress properties that help the body maintain physical effort." Himalaya combines these ingredients in its HeartCare® product, which has been studied for its benefits to cardiovascular health. An eight-week study in 50 patients who took a placebo or two capsules of HeartCare twice daily found those taking HeartCare showed reductions in cholesterol, triglycerides, LDL and VLDL.78

Keeping Consumers' Interests at Heart

The increasing number of Americans hoping to avoid cardiovascular complications or help treat existing conditions creates an opportunity for retailers of dietary supplements. However, with so many new ingredients and formulas, the claims and purported benefits can be overwhelming. Most manufacturers advise retailers to carefully review the research and ask questions to stock efficacious products for interested shoppers.
 

"Retailers should recognize that many of the heart health supplements being sold today have failed to consistently deliver on claims," Staack said. "It is vitally important that independent science continue to distinguish those compounds that work from those that do not consistently deliver the results they claim to provide."

Ormstein also encouraged retailers to ask questions about the scientific substantiation behind product claims, as well as manufacturing quality. "Retailers should know how long a manufacturer has been in business and the history of its product lines," she said. "Does the company have control over all aspects of production? Does it follow GMPs, conduct primary research on its products and employ quality control techniques to ensure consistency? The more knowledgeable retailers become, the more comfortable they will be with making better choices regarding supplements and contributing to their customers' health."

Most manufacturers also suggested offering a range of well-researched products, including combination formulas to address overall cardiac function, as well as specific options for cholesterol control, hypertension and homocysteine reduction. "Retailers should have a variety of products to improve heart health available in inventory with supportive educational materials on these natural treatments," Sears said. "Sales associates should be well trained and well informed about supplements but should resist the urge to prescribe solutions. They should inform, but be respectful and respond to customers' requests." 

Therefore, it falls to retailers to get educated and pass on the relevant information. "Informing and educating the customer is the big hurdle, not the lack of product offerings," Collett said. "Retailers need to inform their customers and encourage young men and women to make healthy choices a consistent and ongoing part of their lifestyles so that their risk of cardiovascular disease is minimized."

For a complete list of references to this story, visit www.hsrmagazine.com after March 1, or e-mail hgranato@vpico.com.


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