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July/August 2014 Issue
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A New Era for Nutraceuticals in Cardiovascular Disease Prevention



Heart disease used to mean a weak heart and nutraceuticals used to be bystanders among clinical heart disease solutions. Times have changed.



By Casey Adams



Published November 1, 2009

Heart disease is still the number one killer in the U.S., and it is anticipated to keep that rank through at least 2020. The American Heart Association (AHA) reported on September 30 that one-third of Americans—about 80 million—have some form of cardiovascular disease, and almost half of Americans (about 49%) have cholesterol levels in the range of being at risk for heart disease.

No wonder a report by Business Insights predicts that heart healthy foods and drinks will hit nearly $8 billion in Europe and the U.S. by 2010—representing 6% growth over the period between 2006 and 2010. The U.S. heart health market alone was estimated to be $5 billion in 2007.

Vascular Disease Mechanisms & Markers



As medical researchers continue to trace the mechanisms of most heart disease pathologies, the prominent factor is vascular disease. Whether it is heart attack/ischemia, stroke, coronary artery disease, cor pulmonale, hypertension or deep vein thrombosis—most heart diseases are linked with the progression of damaged and inflamed arteries: vascular disease.

Atherosclerosis is the most common, but fibromuscular dysplasia (FMD) is now suspected in a growing percentage of vascular disease etiologies. Dr. Thom Rooke, a vascular expert at the Mayo Clinic, concluded recently that 10 million Americans may have FMD—a swelling of arteries not even covered in many medical schools1.

Atherosclerosis occurs as the artery walls are damaged from oxidized low-density lipoproteins (LDL), initiating an inflammatory response. Lipoproteins transport cholesterol and triglycerides through the bloodstream as either very-low density (VLDL), low-density, intermediate-density or high-density lipoproteins (HDL).

Intestinal cholesterol comes from our diet and from liver synthesis, which is sent with bile into the intestines. Here it is absorbed into the blood through the intestinal wall and transported via lipoproteins. VLDL-c typically hydrolyzes its lipids through lipoprotein lipase to LDL, and LDL’s density and small particle size make it the perfect candidate for oxidation.

As LDL-c particles enter artery walls, they can become oxidized by free radicals. The oxidation process results in OxLDL-c and metabolites, and of course, artery damage. Monocytes reduce OxLDL-c to form foam cells. Dead foam cells become the foundation for artery plaque. The subsequent inflammation pile-up of plasmin, fibrin and adhesion proteins such as ICAM and VCAM combine to harden the artery wall, narrowing and restricting blood flow and elasticity. Should parts of the pile-up detach, the clogging of infarction or thrombosis could result.

Prominent vascular disease markers include cholesterol and triglyceride titers, along with inflammation markers such as homocysteine, fibrinogen and C-reactive protein. Emerging markers include arterial compliance—the measurement of artery stiffness measured by pulse wave velocity—and ischemia-modified albumin (IMA). IMA is a combined diagnostic measurement now associated with abnormal lipids, microvascular damage, inflammation, hypertension and hyperglycemia2.

The Nutraceutical Triple-Play



Averting vascular disease is now a central calling for the nutraceuticals industry. This is because the mechanisms of vascular damage have increasingly indicated a major culprit: a lack of nutrition hygiene.

There are three strategies nutraceuticals can offer to prevent and reverse vascular disease. The first is to reduce circulating levels of LDL-cholesterol. This is achieved by modulating cholesterol production in the liver, binding cholesterol within the intestines and/or increasing LDL-c receptor uptake in the liver. In a 2003 research review from the UK’s Peninsula Medical School, 11 nutraceuticals were found among 25 clinical studies to reduce cholesterol3.

The second strategy is to reduce the possibility of oxidation by neutralizing radicals with antioxidants. The third is to reduce artery plaque through fibrinolytic activity. Nutraceuticals can execute all three strategies.

Sterols, Stanols, Phenols & Flavones



The National Heart, Lung and Blood Institute’s most recent NCE report described plant sterols as “therapeutic options to enhance LDL-c lowering.”

Plant-derived sterols and stanols compete with cholesterol to form micelles with bile salts. This reduces cholesterol’s absorption into the bloodstream. In a 2009 meta-analysis of 76 clinical studies, sterols and stanols reduced LDL-c by an average of 13.65 mg/dL—with 2 grams per day producing therapeutic effects4.

All plants contain sterols such as stimasterol, beta-sitosterol and campesterol. Significant amounts appear in vegetables, nuts and seeds. Key plant stanols are saponins. They include 24-alpha-ethylcholestanol, 3-beta, 5-alpha-stigmastan-3-ol, beta-sitostanol, fucostanol and stigmastanol. Significant stanol content is found in pecans, avocados, pumpkin seeds, cashews, rice bran, sea buckthorn and others. Plants favored for sterol and stanol extraction include corn, soybeans and wheat.

Furostanol, for example, is derived from fenugreek. A study published in the Journal of the Association of Physicians of India reported significant triglyceride reductions and increased HDL-c from fenugreek in a study of 20 diabetic patients5.

A unique commercial form of sterols is Microphyte. “Microphyte is produced by a patented milling technology called vortex milling, allowing us to produce a small phytosterol particle with higher dispersability in liquids and spreads,” said David Fondots, a vice president at Extracts & Ingredients, Ltd, Union, NJ, producer of Microphyte.

Phenols have been shown to reduce cholesterol levels and LDL oxidation. Green tea (Camellia sinensis) polyphenols reduced LDL-c by 9 mg/dL in a study of 111 healthy adults6. Pomegranate polyphenols reduced oxidized LDL levels by 39% in a study of 10 diabetic patients at Israel’s Rambam Medical Center7. “Pomegranate polyphenols can protect LDL-c against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages,” said the study’s authors8.

Apple polyphenols have also been shown to reduce LDL-c oxidation. A study of 27 volunteers at the University of California showed that 375 ml of apple juice per day significantly reduced LDL-c oxidation9. Similar results have been found with purple grape juice and grape seeds, as we know from “French paradox” research. “Polyphenols and their subclass flavonoids from plant sources have been well documented to significantly prevent vascular damage,” said Jeff Wuagneux, CEO of RFI Ingredients, Blauvelt, NY. RFI manufactures a line of polyphenolic extracts of green tea, apple, pomegranate and red grape called OxyPhyte.

Forty-four healthy adult males took a placebo or a combination of prune, pomegranate, apple, grape, raspberry, blueberry, white cherry and strawberry for four weeks at Russia’s Center of Modern Medicine. The fruit group’s average LDL-c levels fell from 195 mg/dL to 169 mg/dL10.

Other superfruits like the wolfberry (or goji) (Lycium barbarum or L. chinense) have attracted attention for their phytosterol content. Goji is also one of the few fruits containing heart-healthy omega 3 alpha-linolenic acid. Goji also contains antioxidant carotenoids such as zeaxanthin and prebiotic fibers known to lower cholesterol levels11.

Campbell’s and Minute Maid brand managers have caught on, adding goji juice to recent offerings. Greg Kaiser, president of Encore Fruit Marketing, San Dimas, CA, said that goji is a small but growing part of his company’s sales. “This market is still relatively small, but we are expecting to see more product launches.”

Mr. Kaiser added that sea buckthorn (Hippophae rhamnoides L.) is positioned to be on the next wave of heart-healthy superfruits. “Sea buckthorn berry has been under study for a while and is poised to see increased attention in the next couple of years,” said Mr. Kaiser. True to form, sea buckthorn research has revealed more than 190 compounds, including vitamins A, C, B1, B2, K and E, 64 fatty acids and lipids (including EFAs), amino acids, flavonoids, phenols (including tocopherols), terpenes, tannins, and 20 minerals. Two recent in vivo studies have shown sea buckthorn’s ability to reduce cholesterol and triglycerides12.

The oxygenated sterols from reishi mushroom (Ganoderma lucidum) such as ganoderol and ganoderic acid have been shown to inhibit cholesterol synthesis within liver cells13. Other medicinal mushrooms like cordyceps also show vascular protection. “Cordyceps and reishi provide a perfect balance of medicinal mushrooms for the cardiovascular system. Cordyceps increases blood flow and the reishi reduces cholesterol production,” said Paul Stamets of Fungi Perfecti, LLC, Olympia, WA—producers of the CordyChi combination of cordyceps and reishi.

Bound antioxidant proanthocyanidin flavones called procyanidolic oligomers or “PCOs” are found in grape seed extract. Research has demonstrated PCOs have a protective and strengthening effect on artery walls through increased enzyme conjugation14; greater collagen fiber crosslinking15; decreased artery wall permeability16; increased glycoprotein and sulphated glycosaminoglycan synthesis17; inhibited hyaluronan-varicosis18; increased vascular wall strength19; reinforced vascular connective tissue20; reduced elastin-associated cholesterol21; lower risk and incidence of cerebral microvessel permeability22; and decreased proteinuria23. A clinical study of four groups of 10 varicose vein patients showed that PCOs increase venous tone compared to placebo24. In another clinical trial, grape seed PCOs resulted in the inhibition of LDL-c oxidation25.

The flavonoid-rich extract from French maritime pine bark (Pinus pinaster) has been the subject of numerous studies showing antioxidant and vascular-protective effects. In a 2008 clinical study from the University of Arizona, 48 hypertensive diabetic subjects took either Pycnogenol (Pinus pinaster extract) or placebo for 12 weeks. The Pycnogenol group experienced an average of 12.7 mg/dL reduction in LDL-c, and a significant decrease in blood pressure. Plasma endothelin-1 also fell by 3.9 pg/mL in the Pycnogenol group26. “Pycnogenol improves the synthesis of endothelial nitric oxide. Pycnogenol makes platelets less sticky and lowers high blood pressure by supporting better NO production,” said Frank Schönlau, PhD, director of scientific communications for Horphag Research, worldwide distributors of Pycnogenol.

Polymethoxylated Flavones (PMFs)



Sytrinol is a new combination of polymethoxylated flavones (PMFs) and several palm tocotrienols (alpha, delta and gamma). A series of three clinical studies have confirmed Sytrinol’s ability to reduce LDL-cholesterol and triglycerides. In the first study, 60 hypercholestemic volunteers took 300 mg of Sytrinol daily for four weeks. LDL-c was reduced by 19%, and triglycerides by 24%. In another study, after four weeks of Sytrinol use, 10 hypercholestemic patients experienced reductions of 22% in LDL-c, 21% in apolipoprotein B, and 28% in triglycerides—with a 5% increase in anti-inflammatory apolipoprotein A1. In a 12-week study, 120 moderately hypercholestemic volunteers taking Sytrinol experienced reductions of 27% in LDL-c and 34% in triglycerides27.

Another unique PMF is Flavoxine, a combination of extracts from the Phellodendron amurense (Amur cork tree) and Citrus sinensis (orange peel). Eighty overweight and normal weight human subjects were given either Flavoxine or placebo in a 2008 study published in Nutrition Journal. After eight weeks, overweight subjects in the Flavoxine group experienced a 44.6% reduction in LDL-c, an 11.8% increase in HDL-c, and an 18% decrease in triglycerides. Normal-weight subjects also had significant improvement (-16.8%, +4% and -14.5%, respectively)28. “We found significant results for several cardiovascular parameters, including a reduction in blood pressure,” said Deanne Dolnick of Flavoxine supplier Next Pharmaceuticals, Salinas, CA, one of the study’s authors.

Super Fibers



Certain fibers also bind cholesterol in the digestive tract. The leading cholesterol-reducing fibers include Plantago psyllium seed husks; fruit pectin; galactomannan (guar gum) from the Cyamopsis tetragonolobus tree; fenugreek fiber; and beta-D-glucans from the cell walls of oats and barley grains.

A 2007, University of Teesside Cochrane review of clinical studies concluded that oats lowered LDL-c an average of 7 mg/dL29. Barley beta-D-glucans have illustrated similar results. A University of Minnesota Medical School study of 155 volunteers showed that 5 grams of high molecular weight beta-D-glucans resulted in a 15% reduction of LDL-c30.

A study from Venezuela’s University of Zulia reported that 6 grams of beta-D-glucans per day for eight weeks led to an average increase of 28% in HDL-c levels and decreases in LDL-c, VLDL-c and triglycerides31.

A number of condensed oat and barley fiber offerings are available now. GTC Nutrition’s OatVantage bran concentrate avails as much as 54% beta-glucans. Cevena Bioproducts’ ViscoFiber offers 45% beta-glucans with natural viscosity. Cargill’s Barliv is an extract of barley beta-glucan fiber that can be used in a number of formulations—even clear beverages. “Barliv’s lower molecular weight has enabled successful development of low-viscosity beverages such as juice drinks and near waters,” said Wade Schmelzer, Cargill’s principal food scientist.

Chia seed is another “super fiber” source. Chia contains 40 grams of fiber per 100 grams (5 grams soluble). One 25-gram serving also contains 5 grams of omega 3 ALA, 179 mg of calcium, 81 mg of magnesium and maintains an antioxidant 2060 um/TE ORAC value. Sandra Gillot, general manager with Functional Products Trading S.A.—the Chile-based supplier of Benexia—commented that chia seed “increases 14 times more in weight than wheat bran and 16 times more than linseed.” Benexia supplies black chia, white chia, organic, chia bran, chia oil, chia protein and chia ALA powder—a patent-pending water-soluble omega 3 microencapsulated powder.

Fats for Vascular Health



The cardiovascular benefits of omega 3 oils are no secret. Marine, plant and algal sources of omega 3 fatty acids such as alpha linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have all been shown to improve cardiovascular markers. In a 2007 Oxford University review of 23 clinical studies between 1966 and 2006, omega 3 polyunsaturated fats reduced triglycerides by 25%, VLDL-c by 36% and VLDL-triaglycerol by 39.7%. LDL-c levels slightly increased, by 5.7%, however32. Omega 3 consumption appears to reduce the risk of LDL-c oxidation by reducing diacylglycerol acyltransferase (DGAT) activity in the liver.

Diets high in saturated fats, trans-fats and fried foods tend to increase VLDL-c and LDL-c levels. This is not necessarily applicable to dairy, however. Dairy is high in conjugated linoleic acid (CLA). A study of 51 healthy adults published in the British Journal of Nutrition found that CLA significantly lowered VLDL-c and triglycerides33.

Furthermore, dairy tripeptides such as valine-prolyl-proline (VPP) and isoleucine-proline-proline (IPP) from cultured dairy products have been shown to be vascular-healthy. A review of 12 clinical trials of 623 patients showed both IPP and VPP decreased systolic and diastolic blood pressure an average of 4.8 mmHg and 2.2 mmHg, respectively34. DSM Nutritional Products supplies IPP in a product called TensGuard.

Another “good” saturated fat is coconut oil. A recent study of 40 adult women published in this year’s Lipids journal resulted in a significant increase in HDL and reduction of the LDL:HDL ratio35. Other studies have shown coconut oil reduces lipoprotein-A levels and artery plaque36. “Coconut oil has shown to be cardiovascular protective because of its mid-length fatty acid chains,” said Hans Friese, CEO of Ciranda, Inc., a supplier of organic coconut oils to the U.S. market.

Soy’s Mechanism of Action



Soy’s heart-health benefits have been shown in multiple studies over two decades. Yet its mechanism has puzzled researchers. In a 2007 study led by Alfredo Galvez, PhD, from the University of California-Davis, the bioactive soy peptide Lunasin was found to be responsible for much of soy’s cholesterol-lowering effects. In cell culture HepG2 liver cells, Lunasin significantly reduced HMG-coA reductase expression by 50% through histone H3 acetylation. HMG-coA reductase is the enzyme responsible for cholesterol biosynthesis. Lunasin also up-regulated SP1 expression by 60%, stimulating LDL-c receptors that clear plasma cholesterol37. “The effect of Lunasin on histone H3 acetylation provides a plausible and testable mechanism of action to explain the LDL-c and total cholesterol-lowering effect attributed to soy proteins,” said Dr. Galvez. Lunasin is produced by Soy Labs, LLC, Fairfield, CA.

Tocotrienols



Controversial meta-analyses and a large 2008 clinical study38 have put tocopherol in question as a significant vascular agent. Its lesser-known cousin tocotrienol has fared better in clinical studies. A 2008 study from Malaysia’s Kota Bharu School of Medicine gave placebo or tocotrienols to 36 healthy males. After two months, their arterial compliance significantly improved39. In another placebo-controlled clinical trial of 40 subjects at Tokyo’s Medical and Dental University, triglyceride levels were reduced by 17% after eight weeks of 120 mg tocotrienol supplementation40. “Tocotrienol is a rapidly emerging natural compound with huge potential, distinct from the more widely known tocopherol,” said Dr. Lee Smith, CEO of tocotrienol-producer Davos Life Science Pte, Ltd.

Vitamin D



A new study presented in late September at the American Heart Association’s High Blood Pressure Research Conference followed 559 women ages 24 to 44. Vitamin D deficient women had triple the likelihood of developing hypertension 15 years later. In a study of 3488 people led by Adit Ginde, MD, from the University of Colorado School of Medicine, found that deficiency in vitamin D triples the risk of dying from heart disease41. Dr. Ginde commented, “It’s likely that more than one-third of older adults now have vitamin D levels associated with higher risks of death and few have levels associated with optimum survival.”

Pantethine



The biologically active co-enzyme similar to vitamin B5 is the precursor for coenzyme A. In a study of 16 diabetic patients, high cholesterol and high beta-thromboglobulin levels, pantethine significantly reduced beta-thromboglobulin, triglycerides, total cholesterol and apo levels with 600 mg for three months and 1200 mg for six months42.

Garlic



Allium sativum has shown consistent vascular-protective benefits. In a review of 1798 reports and 118 clinical trials, one month of garlic use significantly reduced LDL-cholesterol and triglycerides, each by an average of between 1.2-17.3 mg/dL. At three months, this reduction went up to 12.3-25.4 mg/dL. The authors also reported significant inhibition of platelet aggregation among patients in the studies43. A multitude of other studies have confirmed garlic’s antioxidant and vascular-protective qualities.

Inhibiting Oxidation & Inflammation



When it comes to staving off the LDL-c oxidation process, there is no shortage of antioxidants among nutraceuticals. Larry Robinson, PhD, put it succinctly: “Oxidized LDL-c cholesterol becomes a pro-inflammatory substance the body is trying to remove. Any product that increases the antioxidant capacity of the blood should act to reduce this artery inflammation.” Dr. Robinson was among a team of researchers that confirmed the significant anti-inflammatory, antioxidant effects of the nutraceutical, EpiCor, developed by Embria Health Sciences, Ankeny, IA, from the fermentation medium of the Saccharomyces cerevisiae yeast. In vitro, in vivo and clinical studies have shown Epicor to be a significant anti-inflammatory and antioxidant agent44.

Fibrinolytic Enzymes



Should LDL-c oxidation occur, making thrombin, plasmin and fibrinogen release possible, nutraceutical enzymes are available with proven fibrinolytic effects. Nattokinase produced through soybean fermentation with Bacillus natto has shown significant fibrinolytic effects45. In a study of 92 deep vein thrombosis patients, the nattokinase group experienced 60% less thrombosis than the control group46. Another fibrinolytic enzyme is serratiopeptidase, known for its anti-inflammatory and anti-thrombosis effects. Serratiopeptidase is produced by the bacterium Serratia marcescens. Bromelain and papain, derived from pineapple and papaya, respectively, are natural enzymes with proven fibrinolytic, proteolytic and anti-inflammatory properties47,48,49.

The Bottom Line



The list goes on. Probiotics, hawthorn (Crataegus oxyacantha) turmeric (Curcuma longa), guggul (Comiphora mukul), artichoke (Cynara cardunculus), arguna (Terminalia Arjuna) cayenne (Capsicum annum), cilantro (Coriandrum sativa), Ginkgo biloba, knotweed (Polygonum multiflorum), wild yam (Dioscorea villosa), bilberry (Vaccinum myrtillus), ginger (Zingiber officinale) and others have also shown positive vascular effects in one respect or another.

This credible array of research on nutraceuticals promises to change the landscape of vascular disease in the decade to come. The continued focus on clinical research will be the key to executing the nutraceutical industry’s vascular disease “triple-play.”

About the Author: Dr. Adams has more than two decades of natural foods and nutraceuticals industry experience. He also has an alternative health practice in Watsonville, CA. He is president of Realnatural, Inc., an industry consulting firm, and the author of several books on natural health. He can be reached at cadams@realnaturalhealth.com.­­

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