A Comprehensive Review of the Research Behind Scores of Nutraceutical Ingredients That Help Keep a Heart Healthy and Happy
Consumers probably don’t need to hear again that heart disease is the leading cause of death in the U.S. Nor do they need to hear that the World Health Organization (WHO) estimates some 17 million people die worldwide each year from cardiovascular disease (CVD)—accounting for about one-third of all deaths. A healthy heart is critical for survival, but what many people may not realize is that nature provides a treasure chest of various nutrients to keep the heart and cardiovascular system healthy.
Last year functional foods for heart health grew nearly 250% from the year before, according to global market research firm Mintel, Chicago, IL. The Global New Products Database, which Mintel uses to track new product introductions in various product segments throughout the world, recorded almost 150 new functional food launches in the heart health category. It seems the high awareness of the importance of maintaining a healthy heart has prompted companies to act and consumers to reach into their wallets for these heart healthy concoctions, many of which contain nutraceutical ingredients proven to support some aspect of cardiovascular health.
The Anatomy of CVD
The heart is a complex machine, and its health is tied to a full-body orchestration of nerves, muscles, valves, arteries, capillaries, neurotransmitters, hormones and enzymes. The brain’s vasomotor center fires sympathetic pulses to coordinate this symphony, blending blood vessel dilation and contraction, fluid level, volume, pressure, heart rate and stroke. The signaling ligand messengers include epinephrine, norepinephrine, acetylcholine, vasopressin, renin, angiotension and aldosterone. Secondary cardiovascular ligands include cortisone, dopamine, serotonin, insulin, leptin and thyroid hormones. Receptors for primary ligands include alpha-1, alpha-2, beta-1, and beta-2 types, located throughout the anatomy, including heart muscle cells and artery epithelial cells. These receptors are responsible for regulating and balancing everything from stroke volume and heart rate to the contraction and relaxation of blood vessels. Epinephrine, for example, stimulates alpha-1 and specialized beta-2 receptors to constrict blood vessels. Meanwhile acetylcholine, working in conjunction with nitric oxide, stimulates beta-2 adrenergic receptors, initiating dilatation and increased blood flow.
The orchestration between ligands and receptors enables the homeostasis of blood pressure and flow throughout the circulatory system. Although the heart is the cardiovascular command center, cardiovascular health is directly related to the elasticity and strength of the blood vessel walls as well as the balance of ligands and receptors. This means the health of the blood and the blood vessel walls is essential. The heart’s health is intimately tied to these because healthy blood and elastic blood vessels are required to deliver nutrients and oxygen to the heart muscle, along with every other vital organ and tissue system.
The most common heart disease is ischemia, which is linked to elevated cholesterol, hypertension and atherosclerosis. Atherosclerosis is a narrowing and hardening of artery walls thought to be caused by artery wall damage from oxidized low-density lipoprotein (LDL), or “bad cholesterol,” and free radicals. This artery damage stimulates an inflammatory response resulting in plaque build-up, fibrin and thickened lumen. With increased plaque build-up comes the deadly risk of thrombosis events like stroke and myocardial infarction.
Some of the obvious causes of artery damage and plaque build-up include obesity, diabetes, a sedentary lifestyle and a diet high in saturated fats and/or fried foods. High blood pressure and fast or irregular heart rate, especially in persons over 40 years old, are strong markers. Higher levels of total cholesterol, LDL and very low-density lipoprotein (VLDL) cholesterol, and total triglycerides are also key markers. The exception appears to be in the case of the elderly, where recent studies have illustrated that moderately high total cholesterol among the elderly may be linked with lower mortality1,2. Nonetheless, a link between small LDL particle size and atherosclerosis has been made3, and the oxidation of LDL particles seems to be on center stage. There appear to be multiple causes for the LDL oxidation cascade. Hyperperoxides appear to be instigated, as they readily form oxidative radicals. The cascade toward LDL oxidation also seems to be accelerated by lipooxygenases like 15-LOX-2 along with cyclooxygenases.
Additional diagnostic markers for artery damage include increased homocysteine, fibrinogen and C-reactive protein levels4. These indicate the likelihood of inflammation and clotting events, with the eventual risk of thrombosis. Increased homocysteine levels may indicate problems with trans-methylation—the liver-regulated glutathione process of exchanging methyl groups to reduce oxidative stress. Methylation problems can be the result of a lack of bioavailable methyl groups such as vitamin B12. Damaged and cholesterol-laden artery walls also appear to block the production of nitric oxide from epithelial cells. This contributes to the constrictive hardening of arteriosclerosis and reduced blood flow.
Diet, Habits or Genetics
Most heart conditions can be linked to the lifestyle choices people make. There also appears to be genetic predispositions toward CVD. However, it is debatable how many purported genetic factors are actually due to lifestyle and dietary habits passed down through families5,6. Poor choices passed down through families include smoking and second-hand smoking; high meat and saturated fat diets; sedentary behavior; heightened stress; and drug/alcohol consumption. While the goal of preventive therapy is to reduce these behaviors, a range of nutraceutical strategies are increasingly being confirmed by research to stimulate a reversing of their effects.
It has become clear that diets high in saturated fats and fried foods tend to reduce vasodilation and LDL particle size, and increase oxidized LDL, which may lead to increases in triacylglycerol-rich lipoproteins. Foods high in saturated fats include animal meats, eggs and butter7,8. But dairy foods can also supply various vascular benefits9. Some dairy groups such as milk, cheese and yogurt, especially skim versions, contain less saturated fat. A 2002 randomized, double-blind, placebo-controlled study of 51 healthy adults showed that conjugated linoleic acid (CLA) from dairy showed significant improvement in VLDL-cholesterol and triacylglycerol-rich lipoprotein levels10.
Another natural extract from dairy has blood pressure reduction benefits. This is the lacto tripeptide sequence isoleucine-proline-proline (or IPP). Derived from cultured milk and aged cheeses, this tripeptide sequence is extracted using enzymatic hydrolysis. DSM Nutritional Products, Parsippany, NJ, has perfected the extraction process, resulting in a product called TensGuard. “DSM’s TensGuard is the highest potency lacto tripeptide commercially available to help maintain healthy blood pressure,” said Peter Willis, DSM’s senior marketing manager.
Coconut oil, historically considered a harmful saturated fat, contains medium chain fatty acids. More recently, medium chain fatty acids have been shown in human studies to lower lipoprotein-A concentrations in the blood, in addition to having fibrinolytic (plaque and clot reduction) effects11. In recent years, research on trans-fat consumption has concluded that oils having undergone commercial refining, hydrogenation or partial-hydrogenation, or lengthy frying, may contain high levels of trans-fats. These trans-fatty acids lead to oxidation of LDL, inflammation and subsequent plaque build-up12,13,14.
Food & Nutrient Therapies
Many studies have illustrated that long chain omega 3 fatty acids, such as alpha linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), work synergistically with gamma linoleic acid (GLA), and other polyunsaturates and monounsaturates to balance the body’s lipoprotein content and protect against LDL oxidation. Long chain DHA and EPA are of course found in fish oil and other marine sources, but can also be converted from ALA contained in seeds like walnuts, cruciferous vegetables, flax and chia seeds. GLA is found in green leafy vegetables, spirulina, borage and evening primrose. The optimal mix of lipids in the diet, as published in the Journal of the American Medical Association (JAMA), is about 10% saturates, and equal amounts of omega 3 to omega 6 oils. Cardiovascular-healthy omega 6 oils are typically derived from nuts, sesame and sunflower seeds, olives and canola.
A newer source of DHA comes from microalgae, Crypthecodinium cohnii, and Schizochytrium spp. According to Edward Nelson, MD, vice president of medical research for omega 3 brand life’sDHA, “life’sDHA has the advantage of being a renewable source of long chain omega 3 fatty acids without the saturated fat and mercury found in fish.” Algal DHA readily converts to EPA in the body15,16. In fact, in a randomized, placebo-controlled 2006 study published in the Journal of the American College of Nutrition, 116 coronary artery disease patients took either 1000 mg DHA alone or 1252 mg DHA+EPA for 8 weeks. The DHA group experienced reductions of nearly 22% triglycerides, while the DHA+EPA group experienced 18% triglyceride reduction17.
Coenzyme Q10 (CoQ10), manufactured in healthy cells and present in some foods, has been linked to improved heart muscle performance, improved pulmonary capacity and lower hypertension18. CoQ10 cycles between ubiquinone and ubiquinol in the body in its oxidized and reduced states. This electron-exchanging process has been specifically beneficial in preventing LDL oxidation19, along with increasing artery wall cellular efficiency.
Scott Steinford, president of ZMC USA, a subsidiary of Zhejiang Medicine Company—one of the largest CoQ10 manufacturers—notes that CoQ10 sales are still growing in the double-digit range, and stands today as by-volume the third largest supplement sold. “Statin manufacturers know that they deplete CoQ10,” he said, adding that Merck patented a statin-CoQ10 blend almost two decades ago. Indeed, Peter Langsjoen, MD, led several studies concluding “statin-induced coenzyme Q10 depletion.”
ZMC produces ubiquinone through a proprietary bacteria-production process. According to Mr. Steinford, early ubiquinone was also produced through a patented process utilizing tobacco-derived solanesol.
The other form of CoQ10, ubiquinol, is manufactured through a yeast fermentation process proprietary to Japan-based Kaneka Corporation, another leading CoQ10 manufacturer.
Speaking of statins, a novel HMG-CoA inhibitor extract from Monascus purpureus grown on rice, also known as red yeast rice, has demonstrated lipid improvement20. Although red yeast rice has been used in China for over a thousand years, an FDA and pharmaceutical industry dispute has erupted regarding its classification as a supplement. This issue goes back to 1998 when Pharmanex, who was marketing a red yeast rice supplement at the time, was prohibited from selling its product due to its high levels of lovastatin—the chief ingredient in the cholesterol-lowering drug Mevacor. According to the Natural Products Association, Washington, D.C., FDA took the position that because the Pharmanex product, Cholestin, contained elevated levels of the active ingredient lovastatin found in prescription drugs, it was an unapproved new drug. Further, Pharmanex advertised the products emphasizing their lovastatin content.
The NPA says Pharmanex eventually sued the agency, contending that the red yeast rice product was a dietary supplement and should not be subject to drug regulation. Despite an initial ruling in 1998 favoring Pharmanex, on March 30, 2001, a decision by the Court of Appeals affirmed FDA’s position and held that red yeast rice products containing significant amounts of the ingredient lovastatin are drugs subject to regulation by FDA. Pharmanex decided not to pursue the appeal.
Since the March 2001 decision, the NPA claims FDA has been reviewing red yeast rice dietary supplement products available in stores and on the Internet very carefully. As a result, numerous warning letters to companies identifying problematic levels of lovastatin and structure/function claims have been issued.
In response to FDA’s enforcement against traditional red yeast rice products and at the direct request of FDA’s chief counsel, NPA filed a position paper setting forth support for the continued sale of traditional red yeast rice, and distinguishing these products from the proprietary forms that are the subject of the Pharmanex case. FDA has not issued a final reply to that position paper, but has, in the meantime, ceased issuing warning letters to this industry.
Magnesium has been linked to reductions of angina and coronary artery events by dilating arteries, improving oxygen delivery, inhibiting platelet aggregation and inhibiting arrhythmias21. Meanwhile, micro- and macro-minerals, such as calcium, potassium, boron and zinc, have been linked to greater artery wall flexibility, improved heart muscle efficiency, and improved nerve function by stimulating receptors and ion channels, and activating enzymes. Other nutrients that have been linked to cardiovascular health include vitamin C and E; the amino acid L-carnitine; and pantethine—the bioactive form of vitamin B522. Niacin, or vitamin B3, has been shown to lower LDL and VLDL, and even raise HDL, though this effect seems to be limited to full-flush and not extended-release versions23.
Phytonutrient constituents like beta-1,4-glucan, lignans, isoflavones, sterols and tocotrienols have confirmed heart-healthy benefits24, especially when integrated with natural fibers. Whole nuts like walnuts, whole grains, various beans, seeds like sesame and flax, and various greenfoods are also known for imparting heart-healthy benefits.
Research has linked increased fiber to cholesterol modulation and vascular flexibility. Oats and oat bran, for example, contain beta-1,4-glucan and saponins. Beta-glucan traps dietary cholesterol within the intestine, while saponins bind to cholesterol and bile acids.
A recent nutraceutical launch with heart-healthy clout is salba, or Salvia hispanica L. A white grain once used for food and medicinal purposes by the Aztecs, salba appears to be a significant source of omega 3 fatty acids, with 2740 mg per 12-gram serving, calcium at 92 mg per serving, magnesium at 46 mg per serving, and a significant ORAC value. Mitch Propster, CEO of New York City-based Core Naturals, a distributor for salba in the U.S., said, “Average salba absorption is 76% as opposed to about 46-50% absorption from flax seeds. And salba’s 8:1 insoluble-to-soluble fiber content quadruples that of flax seeds.”
In a study carried out at St. Michael’s hospital in Toronto, 20 volunteers consumed salba for 12 weeks. The results showed that salba consumption lowered systolic blood pressure by 6 mmHg, C-reactive protein by 40%, and significantly decreased fibrinogen levels25. According to Michael Sanchez, former Balance Bar vice president and co-founder of ZSweet, salba makes an excellent ingredient. “It has a very neutral flavor and neutral white color. The whole seed can be used, ground or crushed into oil. It is a heart-healthy ingredient for grain snacks, flatbread, pasta, cereal, breads, muffins and energy bars,” he said.
Any discussion of preventing excess LDL oxidation and oxidative radicals would not be complete without reviewing antioxidants. Active antioxidants such as lecithin and octacosanol from whole grains; polyphenols and sterols contained in fruits and vegetables; lycopene and other phytochemicals from tomatoes; sulfur/allicin from onions and garlic; pectin, rutin and quercetin from apples; phytocyanidins and antioxidant flavonoids such as apigenin and luteolin from various greenfoods; and anthocyanins from various fruits and oats are all antioxidants known for cardiovascular benefits. Blueberries and tart cherries have also been touted for their oxygen radical absorbance capacity (ORAC). In vitro testing has also confirmed cranberry’s ability to interrupt LDL oxidation26.
One of the newest additions to the bevy of high-ORAC nutraceuticals is the Maqui Superberry. This small purplish fruit grown in Chile is about the size of an elderberry (another good antioxidant fruit), and is bursting with anthocyanins. According to Novelle International, the exclusive U.S. importer of Maqui, the juice concentrate has an ORAC value of more than 800,000 mmole TE/kg and an anthocyanin value of 22,420 mg/kg. Annie Eng, Novelle’s founder and CEO, explains that Maqui is currently undergoing a flurry of research in Chile. “Preliminary research indicates that Maqui exhibits high anti-inflammatory activity and inhibits COX-2 enzymes,” she commented.
The extract of vitis vinifera seed (grapeseed) is one of the highest sources of bound antioxidant proanthocyanidins called procyanidolic oligomers, or “PCOs.” Research has demonstrated that PCOs from grapeseed extract have a protective and strengthening effect on the lining of artery walls by increasing enzyme conjugation27; greater collagen fiber crosslinking28; decreased artery wall permeability29; increased glycoprotein and sulphated glycosaminoglycan synthesis30; inhibited hyaluronan-varicosis31; increased vascular wall strength32; reinforced vascular connective tissue33; reduced elastin-associated cholesterol34; lower risk and incidence of cerebral microvessel permeability35; and decreased proteinuria36. One clinical study on four groups of 10 varicose vein patients each showed that PCOs increase venous tone as compared to placebo and controls37. In another clinical trial, grapeseed PCOs resulted in increased plasma anti-oxidation and inhibition of LDL oxidation38.
Oxygenated carotenoids such as lutein and astaxanthin also have been shown to exhibit antioxidant activity. Astaxanthin is derived from the microalgae Haematococcus pluvialis.
When the arteries are damaged by oxidized LDL or other radicals leading to arteriosclerosis, the immune system responds by activating thrombin and fibrinogen. These stimulate the production of fibrin to scab the wound to promote the healing process. As this healing cascade matures, the body activates plasminogen, which produces the plasmin enzyme. Plasmin is called a fibrinolytic enzyme because it breaks down the fibrin after it is no longer needed on the wound. Inhibited plasmin genesis can result in excess fibrin and thrombin, which may slough into the bloodstream. This can lead to the dangerous condition of thrombosis. Freed fibrin and thrombin can close or occlude the blood vessels, causing heart attacks and strokes.
Several nutraceutical enzymes are available to assist the fibrinolytic process. The nattokinase enzyme, produced by the bacterium Bacillus natto, has been lauded for its fibrinolytic effects. Natto is a preparation of fermented soybeans, a traditional food in Japan. The resulting enzyme has fibrinolytic and proteolytic properties, delaying clotting, thrombosis and platelet aggregation39. In a randomized, placebo-controlled study of 92 high-risk deep vein thrombosis patients traveling by airplane—when acute deep vein thrombosis is more likely to occur—the nattokinase group experienced 60% less thrombosis than the control group40.
Obtaining and purifying nattokinase enzymes for supplement use has been perfected by half-century old Specialty Enzymes & Biochemicals Company, based in Chino, CA. Specialty Enzymes is also the leading global producer of another notable fibrinolytic enzyme called serratiopeptidase. Vic Rathi, MS, president of Specialty Enzymes, says that serratiopeptidase is known for its anti-inflammatory and anti-thrombotic effects. Serratiopeptidase is produced by the Serratia marcescens bacterium, a natural resident within the intestine of the silkworm. “Serratiopeptidase is the enzyme that allows the silkworm to arise from its sticky cocoon,” said Mr. Rathi.
Bromelain is another nutraceutical enzyme with fibrinolytic, proteolytic and anti-inflammatory properties. Naturally derived from pineapple, in vivo and in vitro studies have shown bromelain’s effectiveness in inhibiting thrombosis and platelet-aggregation by modulating plasmin-activator41,42,43. Papain, the enzyme contained in papaya, is also considered to have similar fibrinolytic properties.
Several products have recently been launched, featuring combinations of these enzymes. Rutozyme by Wobenzyme and Neprinol by Arthur Andrew Medical Products have both successfully combined multiple enzymes to create a full-spectrum effect. While Rutozyme contains nattokinase along with bromelain, papain and rutin, Neprinol contains nattokinase, serratiopeptidase, and a blend of bromelain, papain, and rutin. Mr. Rathi says that fibrinolytic blends combining both nattokinase and serratiopeptidase provide the body with a better chance of curtailing thrombosis, as each enzyme activates slightly different mechanisms. “Enteric coating is also important to guarantee assimilation before stomach acids destroy the enzymes,” he said.
Research has confirmed the effectiveness of a number of traditional cardiovascular botanicals. Arjuna from the bark of the Terminalia Arjuna tree is recommended in Indian Materia Medica for endocarditis, mitral regurgitation, pericarditis, angina, and as a heart tonic44. Several double-blind, placebo-controlled trials have illustrated arjuna’s effectiveness. Among 58 males with chronic stable angina, arjuna treated patients had significantly decreased frequency of angina and significantly better treadmill parameters45. Among 105 patients, total cholesterol in the arjuna group decreased from 8-13%, LDL cholesterol decreased from 16-26%, and lipid peroxide levels decreased significantly46. In a study of 12 patients with chronic congestive heart failure, arjuna treatment resulted in improvement of congestive heart failure symptoms, including stroke volume and ventricular ejection47,48. In 20 angina patients, arjuna treatment resulted in a 50% reduction of angina episodes; lower systolic blood pressure; and slight increases in HDL cholesterol and ventricular ejection49,50. Safety was demonstrated in all studies.
Elmwood Park, NJ-based Nutraceuticals International imports arjuna through a joint venture with Indian producer Amruta Herbals Pvt. Ltd. It is standardized to 25% tannins and is ethanol-extracted. “Arjuna is widely distributed in India. Now we are bringing these ancient healing techniques to the forefront of the American market,” said Deborah Vickery, Nutraceuticals International’s director of new product development.
Gugul, an oleoresin from the Comiphora mukul tree, is another Ayurvedic herb with thousands of years of usage in Asia. In a 12-week multi-center open trial of 205 patients, over 70% of patients lowered their cholesterol by an average of 24% and triglycerides by 23%51. In a double-blind, crossover study of 233 patients, subjects’ cholesterol lowered 11% and triglycerides 17% in the gugul treatment group. HDL also increased among 60% of the gugul group52. Other human and in vivo studies have also supported these findings53,54.
Hawthorn berry, or Crataegus oxyacantha, has been used traditionally for angina pectoris, valvular deficiency, endo-myo and pericarditis, tachycardia, cardiac neuralgias, palpitation and rheumatism of the heart55,56,57. Various double-blind, placebo-controlled, randomized human studies have shown hawthorn’s efficacy among heart patients: Hawthorn treatment increased arteriole tone, cardiac performance, orthostatic blood pressure58; improved diastolic blood pressure and anxiety59; increased exercise times, quality of life and improved dyspnea60; increased contraction force and force generation61; improved cardiac pressure, heart rate and quality of life62; and improved palpitation, dyspnea, resting pulse, ST depression, arrhythmias, and myocardial perfusion63.
This research has prompted hawthorn’s exponential growth in the marketplace. Antoine Dauby, marketing manager for France-based Naturex, explains that the company’s Moroccan plant—where they work with local growers to harvest the hawthorn plant’s berries, leaves and flowers—is probably the world’s largest hawthorn operation. “We experienced 25% growth in our hawthorn extract sales for 2007 versus 2006,” Mr. Dauby said. Hawthorn 5/7:1 extract from Naturex is standardized to vitexin-2”-O-rhamnoside.
Pycnogenol, an extract of the French maritime bark tree, has also been shown to have various cardiovascular benefits. A 2007 double-blind, randomized, placebo-controlled study carried out at Hiroshima University revealed that Pycnogenol stimulates the production of nitric oxide (NO), enabling increased blood flow and artery expansion64. Frank Schönlau, PhD, director of scientific communications for Horphag Research, worldwide distributors of Pycnogenol, explained, “It has already been shown in various studies that Pycnogenol makes platelets less ‘sticky’ and lowers high blood pressure by supporting better NO production. The fact that Pycnogenol acts as catalyst for more efficient NO production in healthy young men suggests that Pycnogenol allows their bodies to adapt more quickly to sudden metabolic challenges such as physical exercise.”
Garlic (Allium sativum) has been lauded for its ability to lower blood pressure, thin blood, lower cholesterol and reduce oxidative radicals. Although questioned for its blood lipid-reducing effects, it has been suggested its active constituent levels are often lost during heating and extraction techniques65. Even so, a meta-analysis of 1798 reports, 45 randomized human trials and 73 additional studies standardized to placebo-controls point to conservative yet real reductions in total cholesterol, triglycerides and LDL, along with significant reductions in platelet aggregation66. Other human and in vitro studies have concluded that garlic results in increased tissue blood flow67; platelet aggregation inhibition68,69; inhibition of thrombosis70; protection against oxidation and glycation of LDL71; lowered artery-wall adhesion via cholesterol ester transfer protein activity72; fibrinolytic activity; decreased artery wall thickening and decreased atherosclerosis effects73; and inhibition of endothelial cell injury, reduced LDL oxidation and greater artery wall cell viability74.
Ginger (Zingiber officinalis) has been shown to reduce blood pressure through endothelium calcium channel blocking effects75,76; inhibit platelet aggregation77; reduce atherosclerotic lesion areas by 44%, triglycerides by 27%, cholesterol by 29%, VLDL by 36% and 53%, LDL by 58% and 33%, oxidation of LDL by 45-60%78,79; inhibit atherosclerosis80,81; modulate artery wall contraction82; increase atrial contractile force83; and reduce blood pressure, bradycardia and aponea84.
Many other botanicals have been used in traditional therapies for cardiovascular benefits. Turmeric and its central rhizome constituent curcumin (diferuloylmethane) apparently work to inhibit cyclooxygenases and lipooxygenases that contribute to LDL oxidation85. Cayenne (Capsicum frutescens or Capsacin annum L.) has been shown to reduce blood pressure, bradycardia and aponea in vivo; increase sympathetic-parasympathetic nervous system ratio86; and be a potent antioxidant87. Cilantro (Coriandrum sativa) has been shown to lower cholesterol in vivo by decreasing lipid uptake while enhancing lipid breakdown88.
Other herbs traditionally used for cardiovascular health but probably need additional research support include fo-ti for possible lipid and circulation improvement; wild yam for potential cholesterol reduction; reishi mushroom for possible cholesterol and blood pressure benefits; ginkgo for potential antioxidant and circulatory benefits; and bilberry for potential improvement of circulation and blood pressure reduction. According to Nyvia Roman of Bellville, NJ-based Ecuadorian Rainforest, bilberry is a traditional herb native to Ecuador that is considered an effective therapy for poor circulation.
The Future for Heart-Healthy Nutraceuticals
The research for nutraceutical heart health benefits is beginning to pile up. The lack of side effects observed from the research, on top of thousands of years of traditional use assures consumers that nutraceuticals provide a margin of safety. Intelligent blends of heart-healthy nutraceuticals are beginning to take hold on the market, and nutraceutical companies are rapidly investing in research to further substantiate their benefits.
A perfect example of this is Flavoxine, a proprietary combination of an extract from the Amur cork tree (Phellodendron amurense) and a patented extract from Citrus sinensis (orange peel). Orange peel contains heart-healthy polymethoxylated flavones, or PMFs, while the Amur cork tree is known in Traditional Chinese Medicine for its anti-inflammatory properties. Deanne Dolnick, MS, of Salinas, CA-based Next Pharmaceuticals, commented on her company’s investment in clinical research. “We conducted a study on Flavoxine in which we observed statistically significant results for many cardiovascular parameters, including the lowering of LDL and triglycerides, the increase of HDL, and the lowering of C-reactive protein, which is a prime indicator of inflammation,” Ms. Dolnick said.
Next Pharmaceuticals plans to officially launch Flavoxine in the practitioner channel when this study is published—expected by the end of the second quarter this year. According to the company’s release of the double-blind, placebo-controlled trial, the obese Flavoxine-treated group experienced a 49% reduction of LDL, 12% increase in HDL, 18% reduction of triglycerides and 48% reduction in C-reactive protein levels. Blood pressure reduction was also significant. The normal weight treatment group experienced lower but significant results in these areas as well.
With this type of research and innovation being explored by nutraceutical companies, the future for heart healthy nutraceuticals appears bright indeed.
1. Onder G, et al. Serum cholesterol levels and in-hospital mortality in the elderly. Am J Med. 2003 Sept;115:265-71
2. Miller K. Cholesterol and in-hospital mortality in elderly patients. Am Family Phys. 2004 May.
3. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996 Sep 18;276(11):875-81.
4. Kullo IJ, Ballantyne CM. Conditional risk factors for atherosclerosis. Mayo Clin Proc. 2005 Feb;80(2):219-30.
5. Jensen HK. The molecular genetic basis and diagnosis of familial hypercholesterolemia in Denmark. Dan Med Bull. 2002 Nov;49(4):318-45.
6. Vauthier JM, Lluch A, Lecomte E, Artur Y, Herbeth B. Family resemblance in energy and macronutrient intakes: The Stanislas Family Study. Int J Epidemiol.1996 Oct;25(5):1030-7.
7. Keogh JB, Grieger JA, Noakes M, Clifton PM. Flow-mediated dilatation is impaired by a high-saturated fat diet but not by a high-carbohydrate diet. Arterioscler Thromb Vasc Biol. 2005 Mar:17.
8. Nestel PJ. Adulthood-prevention: Cardiovascular disease. Med J Aust. 2002 Jun 3;176(11 Suppl):S118-9.
9. Hu FB, Willett WC. Optimal diets for prevention of coronary heart disease. JAMA. 2002 Nov 27;288(20):2569-78.
10. Noone EJ, Roche HM, Nugent AP, Gibney MJ. The effect of dietary supplementation using isomeric blends of conjugated linoleic acid on lipid metabolism in healthy human subjects. Br J Nutr. 2002 Sep;88(3):243-51.
11. Muller H, Lindman AS, Blomfeldt A, Seljeflot I, Pedersen JI. A diet rich in coconut oil reduces diurnal postprandial variations in circulating tissue plasminogen activator antigen and fasting lipoprotein (a) compared with a diet rich in unsaturated fat in women. J Nutr. 2003 Nov;133(11):3422-7.
12. Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, Willett WC, Hu FB. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr. 2005 Mar;135(3):562-6.
13. Stachowska E, Dolegowska B, Chlubek D, Wesolowska T, Ciechanowski K, Gutowski P, Szumilowicz H, Turowski R. Dietary trans fatty acids and composition of human atheromatous plaques. Eur J Nutr. 2004 Oct;43(5):313-8.
14. Naruszewicz M, Daniewski M, Nowicka G, Kozlowska-Wojciechowska M. Trans-unsaturated fatty acids and acrylamide in food as potential atherosclerosis progression factors. Based on own studies. Acta Microbiol Pol. 2003;52 Suppl:75-81.
15. Innis SM, Hansen JW. Plasma 15. Innis SM, Hansen JW. Plasma fatty acid responses, metabolic effects, and safety of microalgal and fungal oils rich in arachidonic and docosahexaenoic acids in healthy adults. Am J Clin Nutr. 1996 Aug;64(2):159-67.
acid responses, metabolic e
16. Vidgren HM, Agren JJ, Schwab U, Rissanen T, Hanninen O, Uusitupa MI. Incorporation of n-3 fatty acids into plasma lipid fractions, and erythrocyte membranes and platelets during dietary supplementation with fish, fish oil, and docosahexaenoic acid-rich oil among healthy young men. Lipids. 1997 Jul;32(7):697-705.
17. Schwellenbach LJ, Olson KL. McConnell KJ, Stolepart RS, Nash JD, Merenich JA. The triglyceride-lowering effects of a modest dose of docosahexaenoic acid alone versus in combination with low dose eicosapentaenoic acid in patients with coronary artery disease and elevated triglycerides. J Am Coll Nutr. 2006;25(6):480-485.
18. Chapidze G, Kapanadze S, Dolidze N, Bachutashvili Z, Latsabidze N. Prevention of coronary atherosclerosis by the use of combination therapy with antioxidant coenzyme q10 and statins. Georgian Med News. 2005 Jan;(1):20-5.
19. Alleva R, Tomasetti M, Bompadre S, Littarru GP. Oxidation of LDL and their subfractions: kinetic aspects and CoQ10 content. Mol Aspects Med. 1997;18 Suppl:S105-12.
20. Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V. Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials. Chin Med. 2006 Nov 23;1:4.
21. Itokawa Y. Magnesium intake and cardiovascular disease. Clin Calcium. 2005 Feb;15(2):154-9.
22. Landmark K, Reikvam A. Do vitamins C and E protect against the development of carotid stenosis and cardiovascular disease? Tidsskr Nor Laegeforen. 2005 Jan 20;125(2):159-62.
23. Norris R. “Flush-free niacin”: Dietary supplement may be “benefit-free.” Prev Cardio. 2006 Winter:64.
24. Kerckhoffs DA, Brouns F, Hornstra G, Mensink RP. Effects on the human serum lipoprotein profile of beta-glucan, soy protein and isoflavones, plant sterols and stanols, garlic and tocotrienols. J Nutr. 2002 Sep;132(9):2494-505.
25. Vuksan V, Whitham D, Sievenpiper JL, Jenkins AL, Rogovik AL, Bazinet RP, Vidgen E, Hanna A. Supplementation of conventional therapy with the novel grain Salba (Salvia hispanica L.) improves major and emerging cardiovascular risk factors in type 2 diabetes: Results of a randomized controlled trial. Diabetes Care. 2007 Nov;30(11):2804-10.
26. Chu YF, Liu RH. Cranberries inhibit LDL oxidation and induce LDL receptor expression in hepatocytes. Life Sci. 2005;77(15):1892-1901.
27. Seo K, Jung S, Park M, Song Y, Choung S. Effects of leucocyanidines on activities of metabolizing enzymes and antioxidant enzymes. Biol Pharm Bull. 2001 May;24(5):592-3.
28. Robert AM, Robert L, Renard G. Protection of cornea against proteolytic damage. Experimental study of procyanidolic oligomers (PCO) on bovine cornea. J Fr Ophthalmol. 2002 Apr;25(4):351-5.
29. Robert AM, Tixier JM, Robert L, Legeais JM, Renard G. Effect of procyanidolic oligomers on the permeability of the blood-brain barrier. Pathol Biol. 2001 May;49(4):298-304.
30. Drubaix I, Robert L, Maraval M, Robert AM. Synthesis of glycoconjugates by human diseased veins: modulation by procyanidolic oligomers. Int J Exp Pathol. 1997 Apr;78(2):117-21.
31. Drubaix I, Maraval M, Robert L, Robert AM. Hyaluronic acid (hyaluronan) levels in pathological human saphenous veins. Effects of procyanidol oligomers, Pathol Biol. 1997 Jan;45(1):86-91.
32. Robert AM, Groult N, Six C, Robert L. The effect of procyanidolic oligomers on mesenchymal cells in culture II-Attachment of elastic fibers to the cells. Pathol Biol. 1990 Jun;38(6):601-7.
33. Corbe C, Boissin JP, Siou A. Light vision and chorioretinal circulation. Study of the effect of procyanidolic oligomers (Endotelon). J Fr Ophtalmol. 1988;11(5):453-60.
34. Wegrowski J, Robert AM, Moczar M. The effect of procyanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas. Biochem Pharmacol. 1984 Nov 1;33(21):3491-7.
35. Cahn J, Borzeix MG. Administration of procyanidolic oligomers in rats. Observed effects on changes in the permeability of the blood-brain barrier. Sem Hop. 1983 Jul 7;59(27-28):2031-4.
36. Melcion C, Verroust P, Baud L, Ardaillou N, Morel-Maroger L, Ardaillou R. Protective effect of procyanidolic oligomers on the heterologous phase of glomerulonephritis induced by anti-glomerular basement membrane antibodies. C R Seances Acad Sci III. 1982 Dec 6;295(12):721-6.
37. Royer RJ, Schmidt CL. Evaluation of venotropic drugs by venous gas plethysmography. A study of procyanidolic oligomers Sem Hop. 1981 Dec 18-25;57(47-48):2009-13.
38. Vinson JA, Proch J, Bose P. MegaNatural Gold grapeseed extract: In vitro antioxidant and in vivo human supplementation studies. J Med Food. 2001 Spring;4(1):17-26.
39. Suzuki Y, Kondo K, Ichise H, Tsukamoto Y, Urano T, Umemura K. Dietary supplementation with fermented soybeans suppresses intimal thickening. Nutrition. 2003 Mar;19(3):261-4.
40. Cesarone MR, Belcaro G, Nicolaides AN, Ricci A, Geroulakos G, Ippolito E, Brandolini R, Vinciguerra G, Dugall M, Griffin M, Ruffini I, Acerbi G, Corsi M, Riordan NH, Stuard S, Bavera P, Di Renzo A, Kenyon J, Errichi BM. Prevention of venous thrombosis in long-haul flights with Flite Tabs: The LONFLIT-FLITE randomized, controlled trial. Angiology. 2003 Sep-Oct;54(5):531-9.
41. Maurer HR. Bromelain: Biochemistry, pharmacology and medical use. Cell Mol Life Sci. 2001 Aug;58(9):1234-45.
42. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update. J Ethnopharmacol. 1988 Feb-Mar;22(2):191-203.
43. Felton GE. Fibrinolytic and anti-thrombotic action of bromelain may eliminate thrombosis in heart patients. Med Hypotheses. 1980 Nov;6(11):1123-33.
44. Nadkarni K, ed., Indian Materia Medica. reprinted 1989, Popular Prakashan Private, Ltd, Bombay.
45. Bharani A, Ganguli A, Mathur LK, Jamra Y, Raman PG. Efficacy of Terminalia arjuna in chronic stable angina: A double-blind, placebo-controlled, crossover study comparing Terminalia arjuna with isosorbide mononitrate. Indian Heart J. 2002 Mar-Apr; 54(2):170-5.
46. Gupta R, Singhal S, Goyle A, Sharma VN. Antioxidant and hypocholesterolaemic effects of Terminalia arjuna tree-bark powder: A randomised placebo-controlled trial. J Assoc Physicians India. 2001 Feb;49:231-5.
47. Kumar PU, Adhikari P, Pereira P, Bhat P. Safety and efficacy of Hartone in stable angina pectoris: an open comparative trial. J Assoc Physicians India. 1999 Jul;47(7):685-9.
48. Bharani A, Ganguly A, Bhargava KD. Salutary effect of Terminalia arjuna in patients with severe refractory heart failure. Int J Cardiol. 1995 May;49(3):191-9.
49. Dwivedi S, Jauhari R. Beneficial effects of Terminalia arjuna in coronary artery disease. Indian Heart J. 1997 Sep-Oct;49(5):507-10.
50. Dwivedi S, Agarwal MP. Antianginal and cardioprotective effects of Terminalia arjuna, an indigenous drug, in coronary artery disease. J Assoc Physicians India. 1994 Apr;42(4):287-9.
51. Nityanand S, Srivastava JS, Asthana OP. Clinical trials with gugulipid. A new hypolipidaemic agent. J Assoc Physicians India. 1989 May;37(5):323-8.
52. Wu J, Xia C, Meier J, Li S, Hu X, Lala D. The hypolipidemic natural product guggulsterone acts as an antagonist of the bile acid receptor. Molecular Endocrinology. 16(7):1590-1597.
53. Chander R, Khanna AK, Kapoor NK. Lipid lowering activity of guggulsterone from Commiphora mukul in hyperlipidaemic rats. Phytotherapy Res. 1996 10:508-511.
54. Lloyd J. American Materia Medica, Therapeutics and Pharmacognosy. Eclectic Medical Publications, Portland OR 1983.
55. Shahat AA, Hammouda F, Ismail SI, Azzam SA, De Bruyne T, Lasure A, Van Poel B, Pieters L, Vlietinck AJ. Anti-complementary activity of Crataegus sinaica. Planta Med. 1996 Feb;62(1):10-3.
56. Miller AL. Botanical influences on cardiovascular disease. Altern Med Rev. 1998 Dec;3(6):422-31.
57. Belz GG, Loew D. Dose-response related efficacy in orthostatic hypotension of a fixed combination of D-camphor and an extract from fresh crataegus berries and the contribution of the single components. Phytomedicine. 2003;10 Suppl 4:61-7.
58. Belz GG, Butzer R, Gaus W, Loew D. Camphor-Crataegus berry extract combination dose-dependently reduces tilt induced fall in blood pressure in orthostatic hypotension. Phytomedicine. 2002 Oct;9(7):581-8.
59. Walker AF, Marakis G, Morris AP, Robinson PA. Promising hypotensive effect of hawthorn extract: A randomized, double-blind pilot study of mild, essential hypertension. Phytother Res. 2002 Feb;16(1):48-54.
60. Rietbrock N, Hamel M, Hempel B, Mitrovic V, Schmidt T, Wolf GK. Actions of standardized extracts of Crataegus berries on exercise tolerance and quality of life in patients with congestive heart failure. Arzneimittelforschung. 2001 Oct;51(10):793-8.
61. Schwinger RH, Pietsch M, Frank K, Brixius K. Crataegus special extract WS 1442 increases force of contraction in human myocardium cAMP-independently. J Cardiovasc Pharmacol. 2000 May;35(5):700-7.
62. Weikl A, Assmus KD, Neukum-Schmidt A, Schmitz J, Zapfe G, Noh HS, Siegrist J. Crataegus special extract WS 1442. Assessment of objective effectiveness in patients with heart failure (NYHA II). Fortschr Med. 1996 Aug 30;114(24):291-6.
63. Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure. Am Heart J. 2002 May;143(5):910-5.
64. Nishioka K, Hidaka T, Nakamura S, Umemura T, Jitsuiki D, Soga J, Goto C, Chayama K, Yoshizumi M, Higashi Y. Pycnogenol, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans. Hypertens Res. 2007 Sep;30(9):775-80.
65. Bergner P. The Healing Power of Garlic. Rocklin, CA: Prima Publishing, 1996.
66. Ackermann RT, Mulrow CD, Ramirez G, Gardner CD, Morbidoni L, Lawrence VA. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med. 2001 Mar 26;161(6):813-24.
67. Anim-Nyame N, Sooranna SR, Johnson MR, Gamble J, Steer PJ. Garlic supplementation increases peripheral blood flow: a role for interleukin-6? J Nutr Biochem. 2004 Jan;15(1):30-6.
68. Chang HS, Yamato O, Sakai Y, Yamasaki M, Maede Y. Acceleration of superoxide generation in polymorphonuclear leukocytes and inhibition of platelet aggregation by alk(en)yl thiosulfates derived from onion and garlic in dogs and humans. Prostaglandins Leukot Essent Fatty Acids. 2004 Jan;70(1):77-83.
69. Benatuil L, Apitz-Castro R, Romano E. Ajoene inhibits the activation of human endothelial cells induced by porcine cells: Implications for xenotransplantation. Xenotransplantation. 2003 Jul;10(4):368-73.
70. Rahman K. Garlic and aging: New insights into an old remedy. Ageing Res Rev. 2003 Jan;2(1):39-56.
71. Ou CC, Tsao SM, Lin MC, Yin MC. Protective action on human LDL against oxidation and glycation by four organosulfur compounds derived from garlic. Lipids. 2003 Mar;38(3):219-24.
72. Kwon MJ, Song YS, Choi MS, Park SJ, Jeong KS, Song YO. Cholesteryl ester transfer protein activity and atherogenic parameters in rabbits supplemented with cholesterol and garlic powder. Life Sci. 2003 May 16;72(26):2953-64.
73. Ho SE, Ide N, Lau BH. S-allyl cysteine reduces oxidant load in cells involved in the atherogenic process. Phytomedicine. 2001 Jan;8(1):39-46.
74. Ide N, Lau BH. Garlic compounds minimize intracellular oxidative stress and inhibit nuclear factor-kappa b activation. J Nutr. 2001 Mar;131(3s):1020S-6S.
75. Ghayur MN, Gilani AH. Ginger lowers blood pressure through blockade of voltage-dependent calcium channels acting as a cardiotonic pump activator in mice, rabbit and dogs. J Cardiovasc Pharmacol. 2005 Jan;45(1):74-80.
76. Kobayashi M, Shoji N, Ohizumi Y. Gingerol, a novel cardiotonic agent, activates the Ca2+-pumping ATPase in skeletal and cardiac sarcoplasmic reticulum. Biochim Biophys Acta. 1987 Sep 18;903(1):96-102.
77. Koo KL, Ammit AJ, Tran VH, Duke CC, Roufogalis BD. Gingerols and related analogues inhibit arachidonic acid-induced human platelet serotonin release and aggregation. Thromb Res. 2001 Sep 1;103(5):387-97.
78. Fuhrman B, Rosenblat M, Hayek T, Coleman R, Aviram M. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice. J Nutr. 2000 May;130(5):1124-31.
79. Bhandari U, Sharma JN, Zafar R. The protective action of ethanolic ginger (Zingiber officinale) extract in cholesterol fed rabbits. J Ethnopharmacol. 1998 Jun;61(2):167-71.
80. Fuhrman B, Rosenblat M, Hayek T, Coleman R, Aviram M. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice. J Nutr. 2000 May;130(5):1124-31.
81. Bhandari U, Sharma JN, Zafar R. The protective action of ethanolic ginger (Zingiber officinale) extract in cholesterol fed rabbits. J Ethnopharmacol. 1998 Jun;61(2):167-71.
82. Pancho LR, Kimura I, Unno R, Kurono M, Kimura M. Reversed effects between crude and processed ginger extracts on PGF2 alpha-induced contraction in mouse mesenteric veins. Jpn J Pharmacol. 1989 Jun;50(2):243-6.
83. Suekawa M, Sone H, Sakakibara I, Ikeya Y, Aburada M, Hosoya E. Pharmacological studies on ginger. V. Pharmacological comparison between (6)-shogaol and capsaicin. Nippon Yakurigaku Zasshi. 1986 Nov;88(5):339-47.
84. Suekawa M, Ishige A, Yuasa K, Sudo K, Aburada M, Hosoya E. Pharmacological studies on ginger. I. Pharmacological actions of pungent constitutents, (6)-gingerol and (6)-shogaol. J Pharmacobiodyn. 1984 Nov;7(11):836-48.
85. Rao CV. Regulation of COX and LOX by curcumin. Adv Exp Med Biol. 2007;595:213-26.
86. Yoshioka M, Doucet E, Drapeau V, Dionne I, Tremblay A. Combined effects of red pepper and caffeine consumption on 24-hour energy balance in subjects given free access to foods. Br J Nutr. 2001 Feb;85(2):203-11.
87. Govindarajan VS, Sathyanarayana MN. Capsicum: production, technology, chemistry, and quality. Part V. Impact on physiology, pharmacology, nutrition, and metabolism; structure, pungency, pain, and desensitization sequences. Crit Rev Food Sci Nutr. 1991;29(6):435-74.
88. Lal AA, Kumar T, Murthy PB, Pillai KS. Hypolipidemic effect of Coriandrum sativum L. in triton-induced hyperlipidemic rats. Indian J Exp Biol. 2004 Sep;42(9):909-12.