March april 2002 nutrinews

8537-layout mar25.qxd 3/26/02 10:43 AM Page 1 Recent health and nutrition information from Douglas Laboratories March/April 2002
NUTRACEUTICAL APPROACHES TO CORONARY ARTERY DISEASE
Mitchell J. Ghen, D.O., Ph.D. Outside of the medical/surgical neously. It is this concerted effort that focusing on supplemental issues, there is model for heart disease, modern practi- should prove to have maximum impact a marked importance in appropriate tioners should consider complementary on quality and quantity of life issues for dietary intervention as well.
approaches to assist their patients. The the coronary artery disease patient.
stand-out difference between the two Therefore, we will consider the issues of approaches is that the complementary inflammation, infection, hormones, lipids, One of the primary treatments applied strategy attempts to break the underlying platelet aggregation, vasodilation, for patients with coronary artery disease pathology perpetuating the disease. The antioxidants, sympathetic tone, stress, are anticoagulants. The aging process best example is arteriosclerotic cardio- insulin resistance and homocysteine. You lends itself to increased coagulability. The vascular disease, an epidemic malady of may note that several nutrients may be obvious consequence of hypercoagula- the industrialized nations. With so many mentioned or noted twice due to their bility is clot formation and subsequent products available today, it is best to multiple types of action. It is best that you artery occlusion. Increase in blood vis- approach the discussion by grouping choose at least one from each of these cosity can create a hemodymamic state nutraceuticals by their physiologic categories, utilize the proper dose, eval- of ischemia, with its own set of circum- actions. Our nutritional knowledge base uate the efficacy and then add or sub- stances. Ischemia is defined as low blood continued on page 2 today helps us to recognize key areas of tract substances depending on your concern that must be addressed simulta- patient's response. Though this article is NSIDE THIS ISSUE
• Nutraceutical Approaches to
Table 1 – Anticoagulant Activity
Coronary Artery Disease
• Anticoagulants . . . . . .page 1
Alpha-tocopherol . . . . . . . . .400-1600 I.U./day • Vasodilation . . . . . . .page 2
Arginine . . . . . . . . . . . 2000-6000 mg/day • Lipid Modulation . . . . .page 2 Ascorbic acid . . . . . . . . . .1000-4000 mg/day • Homocysteine Reduction . . page 3
Bromelain . . . . . . . . . . .500-3000 mg/day • Antioxidants and
Curcuma longa . . . . . . . . . 200-1200 mg/day Biological Enzymes . . . . page 5 E.D.T.A.-Oral or rectal suppository . . .Dose varies depending on renal fx • Inflammation and Infection . page 5 Essential Fatty Acids (EFAs) . . . . . 5000-10,000 mg/day • Sympathetic Tone . . . . .page 6
Ginger (powdered) . . . . . . . .1/2 to 1 tspn/3 times a day • Ionotropic and Chronotropic Ginkgo biloba . . . . . . . . . 40-120 mg/day Augmentation . . . . . .page 6 Inositol hexanicotinate . . . . . . .400-3000 mg/day • Gamma-Tocopherol . . . . .page 4
Magnesium . . . . . . . . . . 300-1600 mg/dayN-acetyl cysteine . . . . . . . . .500-3000 mg/day • Coenzyme Q10:
Pancreatin . . . . . . . . . . .300 mg/day A Brief Description . . . . . page 7

8537-layout mar25.qxd 3/26/02 10:43 AM Page 2 flow, which may or may not have total Table 2 – Vasodilation
obstruction associated with it. Ischemia can Arginine . . . . . . .3000-6000 mg/day lead to apoptosis and inflammation.
Garlic . . . . . . . .400-600 mg/day Evaluation of ischemic potential can be Hawthorne . . . . . . 160-250 mg of the flower (standardized) approached with a functional coagulation Horse chestnut . . . . . 600-700 mg (standardized to aecins) panel. This composite of tests includes the Capsicum (cayenne) . . . 40,000-100,000 heat units 1-6 capsules/day typical PT, PTT tests and also the more aspirin still have clot formation. In con- or by vasospasm. The natural substance, comprehensive combination of fibrino- trast EDTA (ethylene diaminetetracetic arginine, for example, is said to increase gen, prothrombin fragments one and acid), inhibits aggregation to all of the nitric oxide, a free radical (part of a two, thrombin-anti-thrombin complexes, substances above with the exception of group of compounds known as endothe- soluble fibrin monomers and platelet collagen. Acute phase reaction, particu- lial releasing factor, EDRF) that functions CD62P (Selectin) receptors. A valuable larly a high c-reactive protein, is related to as a vasodilator. Nitric oxide has a sec- test for evaluation of clotting is platelet vascular inflammation and or infection.
ondary effect to potentially reduce the aggregation testing. Platelet aggregation Substances, such as coumadin affect pro- damage created by homocysteine. It has occurs with the presence of adenosine, thrombin/thrombin activation. Natural been hypothesized that EDTA's benefit epinephrine, collagen and thrombin.
products like vitamin E and magnesium can, to a large degree, be attributed to its Most anti-platelet aggregation medica- have similar properties. Platelet hyperac- release of nitric oxide. Of course, EDTA is tions work only in the presence of adeno- tivity is minimized by aspirin and similarly an excellent anti-coagulant. sine (aspirin for example). This may by other natural products like ginkgo and explain why type A personalities using Also worthy of note, cayenne pepper ginger. Fibrinogen/fibrin monomers can has excellent effects on blood lipids, be addressed with enzymatic therapy like platelet activity, and vasodilatory action.
bromelain and pancreatin. Natural sub- As a wonderful first aid remedy, one tea- stances, that have similar reaction to spoon of cayenne in a glass of water can Publisher . Peter W. Hefele heparin, are arginine, niacin, bromelain quickly relieve the discomfort of acute Editor In Chief . Andrew D. Halpner, Ph.D.
and papain. I have found clinically that chest pain caused by angina. Assistant Editor . Michael Traficante increased fibrinogen levels of greater than Assistant Editor 400 mg respond quickly and effectively to & Research . Natalie Shamitko Curcuma longa. There are many products that effec- Nita Bishop, Clinical Herbalist tively control dyslipidemia without the Martin P. Gallagher, M.S., D.C.
side effects often associated with conven- An important component to coronary Mitchell J. Ghen, D.O., Ph.D.
tional medical drugs. For elevated cho- artery disease treatment is vasodilation.
Brad Lichtenstein, N.D.
lesterol, a combination of pantethine and Derek DeSilva Jr., M.D.
The consequence of vasodilation is inositol hexacotinate can demonstrate James Wilson, Ph.D.
improved blood flow and subsequent profound improvements in one month.
increase in tissue oxygenation. The For those patients with elevated triglyc- object of nitrates or nitrate therapy, a eride levels, L-Carnitine, as well as EFAs, Pittsburgh, PA 15205 mainstay of both acute and chronic coro- can often solve the problem. I prefer the Phone: (412) 494-0122 nary arterial disease care is to increase Fax: (412) 278-6804 inositol hexanicotinate form of niacin due blood flow to constricted blood vessels, to its absence of the troublesome side whether this stricture is created by plaque 8537-layout mar25.qxd 3/26/02 10:43 AM Page 3 B6, B12 and folic acid deficiency. Even Table 3 – Lipid Modulation
Raloxefen's benefit as seen in the Ruth Pantethine . . . . . . . . . . . . .500-1,000 mg/day Study "Raloxefen use for heart study" Inositol hexanicotinate . . . . . . . . 3000 mg/day suggested this drug's action on coronary Garlic . . . . . . . . . . . . . .400-600 mg/dayL-Carnitine . . . . . . . . . . . . .1000-3000 mg/day artery disease, may in part be due to its Essential Fatty Acids (EFAs) . . . . . . .
5000-10,000 mg/day homocysteine-lowering qualities. Regular MIC (methionine-inositol choline) . . . . . 200-400 mg/day of each supplementation with the three B vitamins Lpa (lipoprotein a) — decreasing agents (B6, B12 and folate) will control a great Inositol hexanicotinate . . . . . . . . .
majority of elevated homocysteine levels.
A simple blood test confirming the Vitamin C . . . . . . . . . . . . .1000-2000 mg/day patient's level of homocysteine should be L-Lysine . . . . . . . . . . . . . .1000-2000 mg/day performed with their annual routine effects of flush and liver irritation. Its gation used omega-6 fatty acids as well. In exam. Although laboratories suggest that mechanism of action is similar to all refractory cases of elevated lipids, which a level below 15 is normal, a level of less niacin compounds to reduce plasma have failed to respond to the above regi- than 10 is ideal and less than 7 is con- triglycerides, VLDL, LDL synthesis and men, consider the combination of methion- sidered optimal. total cholesterol. Pantethine is the active ine, inositol and choline in doses of 200- hormone of pantethenic acid. It is consid- 400 mg of each taken 3 times daily.
Insulin Resistance Reduction
ered to be one of the most important Lipoprotein a (Lpa) is an apolipoprotein, Receptor sensitivity for insulin parts of coenzyme A (CoA) that trans- i.e. an LDL particle, to which an additional decreases and the body compensates by ports fats to and from the cells. It has a protein is attached. Because of Lpa's simi- secreting increased amounts of insulin.
potent effect on cholesterol as well as larity with plasminogen, it interferes with This is known as ‘insulin resistance'.
triglycerides. L-Carnitine is synthesized fibrinolysis, and of course ultimately speeds Increased insulin levels promote lipogen- from lysine with the help of methionine. It up clot formation. Several substances as esis, increased thrombosis from increase improves triglyceride levels, total choles- shown Table 3 can be helpful. Coenzyme in plaminogen activator/inhibitor, and terol and increases HDL. The n-3-polyun- Q10 for example, can inhibit the Lpa decreases through a hepatic mechanism, saturated acids in large enough doses receptor expression. which will decrease HDL while increasing have been shown to be helpful in many Table 4 – Homocysteine Reduction
studies. The DART study and most recent- ly the GISSI study (published in The Lancet) are good examples. The role of Folate (folic acid) . . . . . . . . . . . .800 mcg-5 mg/day omega-3 fatty acids are several, but TMG (trimethylglycine) . . . . . . . . . . 250-1000 mg/day recent studies report that their most pro- found effects may be on arrhythmogene- Also helpful are: Serine, Glycine, and NAC (n-acetyl cysteine) sis as well as inflammation. The GISSI study reported a substantial decrease in triglyceride production. One of the most cardiovascular events as a result of fish There are many published studies devastating effects is the glycosylation oil supplementation. I believe the study supporting homocysteine as a risk factor process, whereby circulating glucose results, although impressive, would have for vascular disease. Homocysteine has attaches to proteins. Eventually this leads been even more dramatic had the investi- also been considered a good marker for continued on page 5

8537-layout mar25.qxd 3/26/02 10:44 AM Page 4 GAMMA-TOCOPHEROL: ITS IMPORTANCE AND UNIQUE PROPERTIES
When the term "vitamin E" is used, alpha-tocopherol is Alpha-tocopherol is generally thought of as the most pow- generally what comes to mind. However, vitamin E is actually erful antioxidant of the various tocopherols, and due to its a collective term that encompasses 3 other tocopherols (beta, structure it can more readily donate electrons compared with gamma, and delta) in addition to alpha-tocopherol. These gamma-tocopherol. Gamma-tocopherol, however, can better molecules are differentiated by the number and placement of quench certain dangerous reactive nitrogen species such as methyl groups on their structure (see figure). Recent research peroxynitrate and nitrogen dioxide, both of which have been has been revealing that gamma-tocopherol possesses some associated with a number of degenerative diseases. In fact, in unique properties that allow it to function independently from relation to alpha-tocopherol it has been reported that gamma- as well as synergistically with alpha-tocopherol. tocopherol is superior in detoxifying nitrogen dioxide to lessharmful compounds. In addition to its antioxidant properties, Alpha-tocopherol is the major form of vitamin E that gamma-tocopherol has also been shown to possess anti- can be found in blood as well as many tissues in humans. Due inflammatory properties and can inhibit the activity of to its abundance in the body research has generally focused cyclooxygenase-2 (COX-2) and production of prostaglandin on alpha-tocopherol, with less emphasis on the other isomers.
E2. Given the role that inflammation plays in the pathology of However, gamma-tocopherol is the major form of vitamin E cardiovascular disease this finding is particularly important.
consumed in the diet and is found in many plant seeds and the Some researchers have also reported that gamma but not oils made from them. It has been estimated that gamma- alpha-tocopherol levels are lower in those with cardiovascular tocopherol represents 70% of the vitamin E consumed in the disease compared with control subjects. Recent work has also typical US diet. Once in the body, the metabolism of alpha brought to light a relationship between gamma-tocopherol and gamma-tocopherol differs signifi- and prostate cancer. In a case-control study, the cantly. Alpha and gamma-tocopherol are correlation between alpha-tocopherol, gamma- absorbed similarly from the gastrointestinal tocopherol, selenium intake and prostate cancer tract and secreted into chylomicron was examined. The researchers found a signifi- particles without selective discrimination.
cant inverse correlation between the intake of However, when the chylomicron remnant gamma-tocopherol and the incidence of particles are taken up by the liver, alpha- prostate cancer (i.e., the greater the intake of tocopherol is preferentially incorporated gamma-tocopherol, the lower the risk of dis- into very low-density lipoprotein (VLDL) ease). Most intriguing was that alpha-toco- cholesterol particles. This preferential pherol and selenium intake was only protective placement of alpha compared with when gamma-tocopherol intake was also high. gamma-tocopherol into VLDL particles is aresult of the presence of a protein in the These interesting scientific findings, coupled liver called alpha-tocopherol transfer pro- with the fact that gamma-tocopherol, but not tein. This protein is able to recognize the alpha-tocopherol levels have been shown to stereochemistry of the various tocopherols and has the great- decline with age in humans give further credibility to the est affinity for the d-alpha form. Consequently, alpha-toco- importance of supplementing with a well-rounded mixed toco- pherol becomes selectively located in VLDL particles, which pherol supplement that contains significant amounts of after circulation and metabolism are transformed in to low- gamma-tocopherol. density lipoprotein (LDL) particles. An interesting note is that Helzlsouer KJ., Huang HY., Alberg AJ., et al. Association between alpha-tocopherol, supplementation with alpha-tocopherol in the absence of gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst2000;92:2018-2023.
gamma-tocopherol leads to a reduction of both tissue and Jiang Q., Christen S., Shigenaga MK., Ames BN. γ-Tocopherol, the major form of plasma levels of gamma-tocopherol. Nonetheless, given its vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001;74:714-722.
presence in chylomicrons, and presence in other lipopro- Jiang Q., Elson-Schwab I., Courtemanche C., Ames BN. γ-Tocopherol and its majormetabolite, in contrast to αtocopherol, inhibit cyclooxygenase activity in macrophages tein particles (albeit it at levels less than alpha-tocopherol) and epithelial cells. Proc Natl Acad Sci 2000;97:11494-11499.
gamma-tocopherol does reach the circulation and plays an McLaughlin PJ., Weihrauch JL., Vitamin E content of foods. J Am Diet Association important role.
8537-layout mar25.qxd 3/26/02 10:44 AM Page 5 dioprotective property. Some have Table 5 – Insulin Resistance Reduction
claimed that bromelain can not be effec- tive orally, but this has since been refuted.
Researchers report that soluble fibers (higher doses often used for short periods of time) have a positive effect on hypertension as well as serum-fasting insulin. Patients C.L.A. (conjugated linoleic acid) . . . . . . . 1-3 gm/dayEFAs . . . . . . . . . . . . . . . . 1-3 gm/day should be regularly tested for glycosylat- ed hemoglobin, fasting blood sugar and fasting insulin levels. to advanced glycosylation end products apy. Grapeseed extract alone has been Inflammation and Infection
(AGE), which can be a precursor to shown to reduce plaque size. Since most microvascular disease. The abnormal diets have poor consumption of antioxi- Presently, most recognize that there glucose/insulin metabolism augments dants and flavanoids, supplementation are several infectious agents that are formation of free radicals. Of course, with larger doses than usual for coronary associated with coronary vascular dis- oxidative stress is often responsible for artery disease (C.A.D.) patients may ease. Human herpes virus 6, nanobacte- many of the factors contributing to coro- ria, chlamydia and cytomegalo virus all nary artery disease. Other than the sub- have been implicated as part of the epi- Bromelain has been shown to have stances noted in Table 5, caloric restric- genesis of heart disease. Studies have numerous therapeutic benefits, including tion is an excellent way to decrease free even shown 89% of patients have effects on cytokines such as TNF-alpha, radical formation and improve insulin chlamydia in their hearts at the time of IL-1beta, IL-6 and IL-8. Studies also give sensitivity. Equally as important is a reg- bypass surgery. Most investigators agree evidence that bromelain may inhibit ular exercise program given that insulin that, although these infectious organisms platelet aggregation, an important car- receptors are located within muscle tissue.
may not be the primary cause of heart In addition, repletion with antioxidants is Table 6 – Antioxidants & Biological Enzymes
also imperative (see Table 6).
AntioxidantsVitamin A . . . . . . . . . . . . . .5000-10000 I.U./day Antioxidants and Biological Enzymes
Vitamin C (buffered preferred) . . . . . . .1000-4000 mg/day There are many studies that support Vitamin E (unesterified, natural alpha-tocopherol with mixed tocopherols and tocotrienols) . . . 800-1600 I.U./day the importance of adequate antioxidant Selenium . . . . . . . . . . . . . .200-1000 mcg/day levels and the occurrence of coronary artery disease. In several instances, it has SOD (superoxide dismutase) . . . . . . . 2000-3000 MF/units been postulated that antioxidant use is Catalase . . . . . . . . . . . . . . 2000-3000 MF/units more important than the control of lipid Table 7 – Inflammation and Infection
levels. It is well known that cholesterol in Bromelain (acid stable) . . . . . . . . . .500-2000 mg/day itself is not problematic, but the exposure of cholesterol to the oxidation process cer- tainly can generate plaque. Grapeseed Central fatty acids (EFAs) . . . . . . . . . 5000-10000 mg/day extract, vitamin E and vitamin C are Curcuma longa . . . . . . . . . . . . .200-1200 mg/day important components of antioxidant ther- Vitamin C (buffered) . . . . . . . . . . .1000-4000 mg/day 8537-layout mar25.qxd 3/26/02 10:44 AM Page 6 disease, they significantly contribute to a sequent increase in epinephrine/norepi- seems to reduce the heart failure associ- hypercoagulable state. The use of low- nephrine. Also, melatonin levels could ated with low coenzyme Q10. Another dose broad-spectrum antibiotics such as possibly explain why the majority of study on the usefulness on coenzyme tetracycline has been suggested along heart attacks occur in the early morning Q10 in clinical cardiology demonstrated with aggressive enzyme usage. It seems hours. Melatonin has also been found to large doses over time will reduce overall that this combination affords the best inhibit platelet aggregation. Saliva mela- cardiac medication requirements signifi- result of reducing infection and inflam- tonin sampling can be obtained from sev- cantly. (See insert on this page "Co- mation. Several studies have shown the eral laboratories throughout the country. enzyme Q10) Taurine, an amino acid overall effectiveness of enzyme use is has likewise been shown to have positive Table 9 depicts several substances greater than the non-steroidal anti- cardiac effects and diuretic properties.
with either ionotropic (increase heart Hawthorne berry has been used for years by western herbologists as a good Table 8 – Sympathetic Tone
ionotropic natural agent. contractibility) or chronotropic (rhythm The sympathetic nervous system heart stabilizing) effects on the heart.
A multiangle assertive approach (flight or fight) plays an important role in Regular use of these substances can often seems to be appropriate when treating C.A.D. Greater than usual sympathetic augment typical conventional medica- the coronary artery disease patient.
tone will increase heart rate and elevate tions of similar nature, i.e., digitalis and Hormonal issues should also be exam- blood pressure. Increased sympathetic antiarrythmics. Several studies have ined and a saliva profile may prove effi- activity has often been demonstrated in shown magnesium to be an excellent pre- cacious in determining DHEA, estrogen, patients with C.A.D. Increased levels of ventative of dysrythmias and can be progesterone, and testosterone levels.
adrenal medulla hormones, i.e., norepi- especially useful in intravenous doses of Recently, much has been written about nephrine and epinephrine damage the 2-3 gm in the early stages of heart attack hormones and their inverse relationship arterial lining, increase platelet aggrega- and for several days thereafter. Its use with coronary artery disease. By routine- tion and increase oxidized cholesterol, can prevent the serious rhythm distur- ly screening with these saliva and blood all which lead to a faster generation of bances that often accompany myocardial tests, you will be able to note lipid levels, arthrogenesis. Remember, calcium stimu- infarction. Long-term use is also suggest- coagulability, glucose/insulin levels, lates sympathetic discharge, whereas, ed since most patients are magnesium melatonin level, hormone levels, inflam- magnesium has antagonistic properties.
deficient. Other studies have determined matory status, and homocysteine levels.
Therefore, appropriate levels of magne- that the use of coenzyme Q10 in dosages A practitioner could then choose, from sium and melatonin help to control an of 300 mg/day one week prior to car- the tables provided, those nutritional sup- imbalanced sympathetic nervous system. diac surgery improves three-fold the plements that would address areas of serum levels and tissue levels in the heart concern revealed by the test results.
Researchers have demonstrated that of this nutraceutical. This improvement patients with C.A.D. have nighttime Table 9 – Ionotropic and Chronotropic Augmentation
melatonin levels that are 1/5 lower than Magnesium . . . . . . . . . . . . . . 1600-3000 mg/day healthy controls. Explanatory physiology is likely to be related to increased night- Hawthorne Berry . . . . . . . . . . . . .250-500 mg/day time sympathetic discharge and the sub- Coenzyme Q10 . . . . . . . . . . . . .200-400 mg/day 8537-layout mar25.qxd 3/26/02 10:44 AM Page 7 Abnormal tests would be noted and repeated after an appropriate length of treatment and adjustment of the treat- COENZYME Q10:
ment plan, by either increasing doses of A BRIEF DESCRIPTION
already-prescribed nutraceuticals, with or without the addition of new agents.
Coenzyme Q10, (CoQ10) also known as ubiquinone has been receiving Further adjustment in the program would an increasing amount of attention over the past 5 years for its cardioprotec- be necessary when the patient is taking concurrent medicine(s). Drugs that have tive abilities. CoQ10 is a fat-soluble molecule synthesized from cholesterol similar properties to those nutraceuticals, and located predominantly in mitochondria (the cell's powerhouse) where it that your patient is already taking, would plays a vital role in energy production. Specifically CoQ10 is crucial for the require appropriate adjustment. For example, patients taking anti-coagulants proper transfer of electrons through the mitochondrial respiratory chain.
would require lower doses of those sup- Given that heart muscle requires a tremendous amount of energy to function plements mentioned in Table 1. However, properly, it is not unusual that significant levels of CoQ10 can be found in other patients, taking lipid-lowering drugs, may require increased doses of heart muscle. Since CoQ10 levels have been found to be lower under cer- CoQ10. Remember, many coronary- tain circumstances, researchers have been investigating the effect that sup- related medications cause other nutrition- plemental CoQ10 can have on heart function. Not surprisingly, numerous al deficiencies and I suggest that you refer to a text describing drug-herbal clinical studies have demonstrated improvements in functional parameters of and drug-nutrient interactions. the heart in patients with congestive heart failure after supplementation with CoQ10. CoQ10 treatment prior to bypass procedures has also yielded The use of EDTA, although it is con- more positive outcomes when compared with patients who did not receive sidered by the conventional medical supplementation. CoQ10 levels have also been shown to be reduced in community as controversial, has revealed in many studies to have a significant patients taking statin drugs, as cholesterol is required for the synthesis of place in the treatment of coronary artery CoQ10 in the body. CoQ10 has been shown to be an effective antioxidant, disease along side the nutraceuticals pre- protecting against lipid peroxidation, DNA and protein oxidation and is also sented in this paper. Heavy metals do play a role in artherogenesis and should capable of functioning synergistically to help regenerate other antioxidants.
be studied further. Don't forget, in the The research community continues to find strong data indicating the benefits midst of this complex array of nutraceuti- from supplementation with CoQ10, especially in the area of cardiovascular cals, water itself may improve the out- comes of coronary events. Simply drink- health as it relates to congestive heart failure.
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