We probably don’t
need to hear again that heart disease is the leading cause of death in the
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 notable in their ability to regulate and balance 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 Anatomy of CVD
This 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 and 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 LDL and other oxidative 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.
Obvious signs for 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, low-density lipoprotein (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 mortality(1,2). Nonetheless, a link between small LDL particle size and atherosclerosis has been made(3), and the oxidation of LDL particles seems to be on center stage. There appear to be multiple causes for LDL oxidation cascade. Hyperperoxides appear to be instigated, as they readily form oxidative radicals. The cascade towards 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 levels(4). 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 bio-available methyl groups such as vitamin B-12. 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 we make. There also appears to be genetic predispositions toward CVD. However, it is debatable how many purported genetic factors are actually lifestyle and dietary habits being passed down through families(5,6). 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, 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, reduce LDL particle size, and increase oxidized LDL, seemingly related to increases in triacylglycerol-rich lipoproteins. Foods high in saturated fats include animal meats, eggs, and butter(7,8). Other dairy such as milk, cheese and yogurt, especially skim versions, contain less saturated fat. Dairy foods can also supply various vascular benefits. A 2002 randomized double-blind placebo study of 51 healthy adults showed that conjugated linoleic acid from dairy showed significant improvement in VLDL-cholesterol and triacylglycerol-rich lipoprotein levels(9).
Another natural extract from dairy has reputed blood pressure reduction benefit. 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 has perfected the extraction process with 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, however, medium chain fatty acids have been shown in human studies to lower lipoprotein-A concentrations in the blood while having fibrinolytic (plaque and clot reduction) effects(10). 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 oxidative LDL, inflammation and subsequent plaque build-up(11,12,13).
Food and Nutrient Therapies
Many studies have illustrated
long chain omega-3 fatty acids such as alpha
linolenic acid (
An newer source of DHA comes from micro-algae Crypthecodinium cohnii, and Schizochytrium spp.. According to Edward B. Nelson, M.D., Vice President of Medical Research for Life’s DHA, “Life’s DHA 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 body(15,16). 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 1000mg DHA alone or 1252mg DHA+EPA for eight weeks. The DHA group experienced reductions of 21.8% triglycerides, while the DHA+EPA group experienced 18.3% triglyceride reduction(17).
CoQ10, manufactured in healthy cells and present in some foods, has been linked to improved heart muscle performance, improved pulmonary capacity, and lower hypertension(18). 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 oxidation(19), 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 statins deplete CoQ10,” he adds. Mr. Steinford reminds us that Merck patented a statin-CoQ10 blend almost two decades ago. Peter H. Langsjoen, MD, led several studies concluding “statin-induced coenzyme Q10 depletion.”
Zhejiang Medicine Company produces ubiquinone through a proprietary bacteria-production process. The other form of CoQ10, ubiquinol, is manufacturered through a yeast-process proprietary to Kanaka. According to Mr. Steinford, early ubiquinone was also produced through a patented process utilizing tobacco-derived solanesol.
Speaking of statins, a novel HMG-CoA inhibitor extract from Monascus
purpureus grown on rice, also known as red yeast rice, has demonstrated lipid improvement(20).
Though red yeast rice has been used in
Magnesium has been linked to reductions of angina and coronary artery events by dilating arteries, improving oxygen delivery, inhibiting platelet aggregation and inhibiting arrhythmias(21). 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 been linked to cardiovascular health include vitamin C and E; the amino acid L-Carnitine; and pantethine—the bioactive form of B5(22). Niacin has been shown to lower decrease LDL and VLDL, and even raise HDL, though this effect seems to be limited to full-flush and not extended-release versions(23).
Phytonutrient constituents like beta-1,4-glucan, lignans, isoflavones, sterols and tocotrienols have confirmed heart-healthy benefit(24), 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 stimulating 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-3s with 2740mg per 12gm
serving, calcium at 92mg per serving, magnesium at 46mg per serving, and a
significant ORAC value. Mitch Propster, CEO of Core Naturals, LLC, the
exclusive distributor for salba in the
Antioxidants
Any discussion of preventing excess LDL oxidation and oxidative radicals cannot be complete without reviewing antioxidants. Active antioxidants such as lecithin and octacosanol from whole grains; polyphenols and sterols contained in vegetables; lycopene and other phytochemicals from tomatoes; quercetin and sulfur/allicin from onions and peppers; pectin, rutin and quercitin from apples; phytocyanidins and antioxidant flavinoids such as apigenin and luteolin from various greenfoods; and anthocyanins from various fruits and even oats; are all antioxidants known for cardiovascular benefits. Blueberries and tart cherries have been touted for their oxygen radical absorbance capacity (ORAC). In vitro testing has also confirmed cranberry’s ability to interrupt LDL oxidation(26).
One of the newest additions to
the bevy of high-ORAC nutraceuticals is the Maqui Superberry. This is small purplish fruit grown in
The extract of vitis vinifera seed (grapeseed) is one of the highest sources of bound antioxidant proanthrocyanidins 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 conjugation(27); greater collagen fiber crosslinking(28); decreased artery wall permeability(28); increased glycoprotein and sulphated glycosaminoglycan synthesis(30); inhibited hyaluronan-varicosis(31); increased vacular wall strength(32); reinforced vascular connective tissue(33); reduced elastin-associated cholesterol(34); lower risk and incidence of cerebral microvessel permeability(35); and decreased proteinuria(36). One clinical study on four groups of 10 varicose vein patients each showed that PCOs increase venous tone as compared to placebo and controls(37). In another clinical trial, grapeseed PCOs resulted in increased plasma anti-oxidation and inhibition of LDL oxidation(38).
Oxygenated carotenoids such as lutein and astaxanthin also have been shown to exhibit antioxidant activity as well. Astaxanthin is derived from microalga Haematococcus pluvialis.
Fibrinolytic Enzymes
When the arteries are damaged by oxidative 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 and 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 form 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
soybeans, a traditional food in
Obtaining and purifying nattokinase enzymes for supplement use has been perfected by half-century old Specialty Enzymes & Biochemicals Company. Specialty Enzymes is also the leading global producer of another notable fibrinolytic enzyme called serratiopeptidase. Vic Rathi, M.S., President of Specialty Enzymes, says that serratiopeptidase is known for its anti-inflammatory and anti-thrombosis 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," says 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-activator(41,42,43). Papain, the enzyme contained in papaya, is considered to have similar fibrinolytic properties.
Several products have come out with 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," says Mr. Rathi.
Botanical Therapies
Research has confirmed the effectiveness of a number of traditional cardiovascular botanicals as well.
Arguna from the bark of the Terminalia Arjuna tree is recommended in Indian Materia Medica for endocarditis, mitral regurgitation, pericarditis, angina, and as a heart tonic(44). 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 parameters (45). Among 105 patients, total cholesterol in the arguna group decreased from 9.7-12.7%, LDL cholesterol decreased from 15.8-25.6%, and lipid peroxide levels decreased significantly(46). In a study of twelve patients with chronic congestive heart failure, patients, arjuna treatment resulted in improvement of congestive heart failure symptoms including stroke volume and ventricular ejection(47,48). In twenty angina patients, arjuna treatment resulted in a 50% reduction of angina episodes; lowered systolic blood pressure; and slight increases in HDL-cholesterol and ventricular ejection(49,50). Safety was demonstrated in all studies.
Nutraceuticals International,
LLC imports arjuna in a joint venture with Indian
producer Amruta Herbals Pvt. Ltd., standardized to 25% tannins, and
ethanol-extracted. “Arjuna is widely distributed in
Gugul, an oleoresin from the Comiphora
mukul tree, is another ayurvedic
herb with thousands of years of usage in
Hawthorn
This research is translating to hawthorn’s exponential growth in the marketplace. Antoine Dauby, Marketing Manager of the New Jersey-based nutraceutical giant 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 reveals. Naturex’ hawthorn 5/7:1 extract 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 study done at the
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-reduction effects, it has been suggested its active constituent levels are often lost during heating and extraction techniques(65). Even so, in a meta-study of 1798 reports, 45 randomized human trials and 73 additional studies standardized to placebo-controls, conservative yet real reductions in total cholesterol, triglycerides, and LDL were confirmed, along with significant reductions in platelet aggregation(66). Other human and in vitro studies have concluded that garlic results in increased tissue blood flow(67); platelet aggregation inhibition(68,69); inhibition of thrombosis(70); protection against oxidation and glycation of LDL(71); lowered artery-wall adhesion via cholesterol ester transfer protein activity(72); fibrinolytic activity; decreased artery wall thickening and decreased atherosclerosis effects(73); and inhibition of endothelial cell injury, reduced LDL oxidation and greater artery wall cell viability(74).
Ginger, (Zingiber officinalis) has been shown to reduce blood pressure through endothelium calcium channel blocking effects(75,76); inhibit platelet aggregation(77); 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 LDL oxidation and inhibit atherosclerosis(80,81); modulate artery wall contraction(82); increase atrial contractile force(83); and reduce blood pressure, bradycardia and aponea(84).
Many other botanicals have
been used in traditional therapies for CV benefits. Turmeric and its central rhizome constituent curcumin (diferuloylmethane) hassn apparently works to inhibit
cyclooxyenases and
lipooxenases that contribute to LDL oxidation(85).
Other herbs traditionally used
for cardiovascular health and probably needing additional research include fo-ti for possible lipid and
circulation improvement; wild yam
for potential cholesterol reduction; reishi
mushroom for possible cholesterol and blood pressure benefits; gingko for potential antioxidant and
circulatory benefits; and bilberry
for potential improvement upon circulation and blood pressure reduction.
According to Nyvia Roman of Equadorian Rainforest, LLC, bilberry is a
traditional herb and native of
A Bright Future for Heart-Healthy
Nutraceuticals
The research for nutraceutical heart-healthy benefits is beginning to pile up. The lack of side effects observed from the research and with thousands of years of traditional treatment 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 investing into research.
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, M.S. of Next Pharmaceuticals, commented on their company’s investment into double blind research. “We conducted a study on Flavoxine in which we observed statistically significant results for many cardiovascular parameters, including the lowering of LDL & triglycerides, the increase of HDL and the lowering of C-Reactive Protein, a prime indicator of inflammation,” Ms. Dolnick says. Next Pharmaceuticals plans to officially launch Flavoxine through the practitioner channel when this study is published, expected by the end of Q2 2008. 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 by nutraceutical companies, the
future for heart healthy nutraceuticals appears bright indeed.
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