Take Heart

The heart health market is steadily growing, showing no signs of slowing down.

By Yousry Naguib, Ph.D.
Contributing Editor, Nutraceuticals World magazine (October 2006)

This article in a nutshell
• The bright side?
• Heart health food and supplement sales: what the market says…
• Heart health ingredient round-up: what the research says…
• Research profiles on omega 3’s, CoQ10, phytosterols and more…

It is not always a good thing to be number one, especially in the case of cardiovascular disease (CVD), which is still the leading cause of death among Americans. According to the American Heart Association’s “Heart Disease and Stroke Statistics” 2004 report, diseases of the heart continue to claim more lives than all major causes of death.
Perhaps some figures will help put the urgency of heart-related conditions in perspective: Over seven million Americans have suffered a heart attack in their lifetime; CVD killed nearly one million Americans in 2001; and from 1979 to 2001, the number of cardiovascular operations and procedures increased four-fold. Heart disease also kills more women than men, accounting for one in five female deaths. Possibly even more startling, however, is heart disease claims responsibility for more deaths in women than all forms of cancer combined.

The Bright Side?

Surprisingly, there is some good news. Heart disease is one of the most preventable health conditions. In fact, people have the power to reduce some of their risks by avoiding smoking, limiting alcohol consumption, eating a diet rich in fruits, vegetables and whole-grain products, and exercising regularly.

Consumers also need to take control of health conditions that may put a strain on the heart, such as high cholesterol, high low density lipoprotein (LDL, bad cholesterol) and low high density lipoprotein (HDL, good cholesterol), high blood pressure, and stress. The risk for heart disease increases as the total amount of cholesterol (TC) increases. The TC goal should be less than 200 mg/dl; HDL should be higher than 40 mg/dl; and LDL should be less than 130 mg/dl in healthy adults.

Normally, the liver makes all the cholesterol the body needs. But cholesterol also enters the body from dietary sources, such as animal-based foods like milk, eggs and meat. When there is too much cholesterol in the blood, it builds up in the artery walls. Over time, this buildup causes the arteries to harden—a process called atherosclerosis. The arteries become narrowed and blood flow to the heart muscle slows or becomes blocked. If the blood supply to a portion of the heart is completely cut off by a blockage, the unfortunate result is a heart attack.

Cholesterol-lowering drugs include: statins, niacin, bile-acid sequestrants, and fibric acid derivatives. Statins block the production of cholesterol in the liver itself. These drugs are the first line of treatment for most people with high cholesterol. The side effects of statin drugs, however, include: muscle aches, abnormal liver function, allergic reaction (skin rashes), and decreased sexual desire.

High blood pressure (hypertension) is another common heart disease risk factor, which affects almost 60 million people in the U.S. Nearly one in three adults has systolic blood pressure (the top number) over 140, and/or diastolic blood pressure (the bottom number) over 90, which puts them in the category of hypertension. High blood pressure is dangerous because it makes the heart work harder to pump blood to the body. It also contributes to hardening of the arteries, or atherosclerosis.

Hypertension can be controlled through diet, exercise, weight management, and if needed, medications, which include: diuretics, beta-blockers, ACE (angiotensin converting enzyme) inhibitors, calcium channel blockers, and vasodilators.

There are a variety of supplements that may help support healthy cholesterol levels and prevent high blood pressure. Given the staggering statistics mentioned previously, it is clear the pharmaceutical industry has its hands full, and it cannot carry out the very important job of managing heart health all by itself. It could use some help in the form of legitimate supplement and food ingredients backed by substantial clinical evidence to make the enormous job of managing heart health at least feasible in the years to come.

Heart Health Food & Supplements Salys: What the Market Says…

According to Nutrition Business Journal’s (San Diego, CA) annual condition-specific supplement and functional food analysis, heart health supplement sales in the U.S. were $1 billion in 2005 out of total supplement sales of $21.3 billion. “Overall heart health supplement sales were up 7% in 2005, and leading contributors were essential fatty acids, or EFAs (both fish and plant-derived oils), and CoQ10,” said Grant Ferrier, editor, NBJ. “Other products with significant sales volume included potassium, vitamin E (in spite of negative publicity) and hawthorne.”

Mr. Ferrier added, “Meanwhile, more growth has been seen in heart health functional foods, where sales were up 14% in 2005 to $2.5 billion out of $26.6 billion in total functional foods. The largest contributor to the category is breads & grains (including cereal), mostly as a result of qualified health claims related to oats and soluble oat fiber.”

Plant sterols, Mr. Ferrier pointed out, is also a contributor in spreads, juices and other applications, and the ingredients mirroring the supplement category, especially EFAs, are increasingly showing up in foods.

“While heart health products contribute $3.5 billion in sales to what NBJ calls the nutrition industry, this is still an order of magnitude less than the $36 billion spent on heart health drugs last year,” Mr. Ferrier commented.

Heart Health Ingredient Round-Up: What the Research Says…

The mounting evidence surrounding coenzyme Q10 (CoQ10), phytosterols and omega 3 fatty acids cannot be overlooked. In fact, a recent report highlighted the latter ingredient as having the potential to save more lives than cardiac defibrillators. The study, published in the American Journal of Preventive Medicine, claims that if fish oil is as effective against fatal heart arrhythmias as evidence suggests, the researchers conclude, it would have more widespread benefits than either automated external defibrillators (AEDs) or implanted defibrillators. And there’s more…much more.

Omega 3 Fatty Acids: This is a type of fat found in fatty fish like mackerel and salmon, as well as plant sources like flaxseed, walnuts and canola oil.

Both epidemiologic and interventional studies have demonstrated beneficial effects of omega 3 fatty acids from fish and fish oil on cardiovascular disease. A recent systematic review of the literature on the effects of omega 3 fatty acids (consumed as fish or fish oil rich in eicosapentaenoic acid, EPA, and docosahexaenoic acid, DHA, or as alpha-linolenic acid, ALA) on cardiovascular disease revealed that increased consumption of omega 3 fatty acids from fish or fish oil supplements, but not of alpha-linolenic acid (ALA), reduced the rates of all-cause mortality, cardiac and sudden death, and possibly stroke 1.

Flaxseed has been part of human diets for thousands of years in Asia, Europe and Africa. Flaxseed is very high in omega 3 essential fatty acids, fibers, and lignans. Flaxseed has recently become a popular dietary supplement due to its apparent benefits for a host of health conditions, including cardiovascular-related issues.

In a recent clinical study on mildly hyperlipidemic patients with plasma total cholesterol greater than 240 mg/dL, a low-fat diet plus supplementation with 20 grams of ground flaxseeds per day for 60 days was associated with significant reductions in TC (-17.2%), LDL (-3.9%), triglycerides, TG, (-36.3%) and TC/HDL ratio (-33.5%). The study concluded that dietary flaxseed can significantly improve lipid profiles in hyperlipidemic patients and may favorably modify cardiovascular risk factors 2.

Policosanol: This unique natural product comes from sugar-cane wax, honeybee’s wax, or rice bran. It is made up of octacosanol and several other long chain fatty alcohols. Research indicates that policosanol from sugar cane is effective at reducing cholesterol levels.

A 2002 study published in the American Heart Journal (February issue) reviewed the literature on placebo-controlled lipid-lowering studies using policosanol, and found that at doses of 10 to 20 mg per day, policosanol lowered cholesterol by 17% and 21%, respectively; LDL 21% and 29%, respectively; and raised HDL by 8% and 15%, respectively. The study concluded that policosanol is “a very promising phytochemical alternative to classic lipid-lowering agents such as statins. 3”

However, these same authors conducted a 12-week dose dependency trial, involving up to 80 mg per day of policosanol from sugar cane, (note: the clinical trial was held from September 29, 2000, to May 10, 2001—before the date of the above mentioned study) on 143 patients with hypercholesterolemia. This study, published in the May 2006 issue of JAMA, found no statistically significant difference between policosanol and placebo in their effect on lipid levels (LDL, TC, HDL, and TG) 4.

In a more recent study (2005), researchers at Purdue University conducted a meta-analysis of 52 randomized controlled trials involving over 4500 hyperlipidemia patients. The analysis showed that policosanol is more effective than plant sterols and stanols for LDL level reduction and more favorably alters the lipid profile: TC, HDL, and TG levels. The net LDL reduction in the treatment groups minus that in the placebo groups was greater with policosanol than plant sterols and stanols (-24% versus -10%) 5.

Phytosterols (plant sterols): These substances are the counterparts of the animal product cholesterol. Structurally, phytosterols resemble cholesterol, but they differ markedly in their intestinal absorption, and metabolic fate. Unlike cholesterol, phytosterols are either not absorbed or minimally absorbed in the digestive tract of humans 6.

The National Cholesterol Educational Panel issued a recommendation in 2001 that phytosterols be added to cholesterol-lowering regimens, along with the more traditional cholesterol-fighting measures, such as regular exercise, weight loss, and a low-fat diet.

Clinical trials have demontrated that intake of 2 grams per day of plant sterols and stanols reduces serum LDL concentrations by approximately 10% 7. Phytosterol/stanols have also been found to lower cholesterol in familial hypercholesterolemic (FH) people (very high low-density lipoprotein cholesterol), which is responsible for the high incidence of premature coronary heart disease. A meta-analysis of clinical trials found that fat spreads enriched with 2.3±0.5 grams phytosterols/stanols per day significantly reduced TC between 7% and 11%, and LDL between 10% and 15% in 6.5±1.9 weeks compared to control treatment, without any adverse effects. TG and HDL concentrations were not affected 8.

Plant sterols also reduced serum TC (by 6.5%) and LDL (by 10.4%) when added to low fat dairy products (yoghurt, low-fat hard cheese and low-fat fresh cheese) in subjects with mild or moderate hypercholesterolemia. The targeted plant sterol intake was 2 grams per day in the sterol group. There was no change during the trial in serum HDL or TG concentrations 9.

Guggul: Herbal extracts from Guggul (Commiphora mukul) come from the mukul myrrh tree native to Arabia and India, and has been widely used in Asia as a cholesterol-lowering agent.
A 1994 study of 61 patients (31 in the guggulipid group and 30 in the placebo group) found that guggulipid taken at a dose of 50 mg twice daily for 24 weeks, decreased TC by nearly 12%, LDL by 12.5%, TG by 12%, and the ratio of the TC to HDL by over 11%, whereas the cholesterol levels were unchanged in the placebo group 10.

A 2005 study evaluated the scientific evidence on guggul for hyperlipidemia and found that most scientific evidence reported before 2003 suggested that guggulipid elicits significant reductions in serum total cholesterol, LDL, and TG, as well as elevations in HDL 11.

However, a 2003 study published in JAMA found small significant increases in serum LDL levels associated with the use of guggul compared to placebo. No significant changes in TC, HDL, or TG were measured. The study concluded that the effects of guggulipid in patients with high cholesterol are not clear, with some studies finding cholesterol-lowering effects, and other research suggesting no benefits at all 12.

CoQ10: Patients suffering from congestive heart failure exhibit impaired myocardial energy production, and increased oxidative stress. Nutritional factors known to be important for myocardial energy production and the reduction of oxidative stress, such as L-carnitine, D-Ribose, and CoQ10, are reduced in this patient population. Studies in animals and limited trials in humans have shown that dietary replacement of some of these compounds in heart failure can significantly restore depleted levels and may result in improvement in myocardial structure and function 13.

CoQ10 is found in virtually all cells of human body, including the heart, liver and skeletal muscles. CoQ10 functions as a carrier to transfer electrons across the membrane of mitochondria (the energy generator in the body’s cell) to drive the production of adenosine triphosphate (ATP), the fuel that energizes cells in our body. Heart muscle cells have the greatest concentration of mitochondria at 5000 per cell.

Both cholesterol and CoQ10 share a common biosynthetic pathway, which involves the formation of mevalonate compound with the aid of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase. Inhibition of HMG-CoA reductase by statin drugs at the mevalonate level will inevitably decrease the levels of both cholesterol and CoQ10.

Several studies have already revealed a possible dose-related and significant decrease in CoQ10 serum levels as a result of HMG-CoA reductase inhibitor treatment. In a double blind, randomized clinical trial of hypercholesterolemic patients, one group received Lovastatin while the other took Pravastatin over a period of 18 weeks. At the end of the study period, the total serum level of CoQ10 declined by about 25% in the Lovastatin and Pravastatin groups 14.

Research in patients with hypertension indicates that treatment with CoQ10 decreases blood pressure possibly by decreasing oxidative stress. In one randomized, double-blind, placebo-controlled trial on 46 men and women with systolic hypertension who received 60 mg of CoQ10 twice daily, a reduction of 17.8 mmHg in systolic blood pressure was reported 15.

L-Carnitine. Several experimental studies have shown that L-carnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism SUPERSCRIPT 16. Studies also show that administration of L-carnitine (1.5g-6g per day) for up to one year to patients with myocardial infarction results in a beneficial effect of less death and less heart failure 17.

D-Ribose. D-Ribose is a naturally occurring sugar. It is the sugar moiety of adenosine triphosphate (ATP), the energy currency of the cell, and it provides the power all cells need to function. To date, it has been investigated, both in animal and clinical studies, as a metabolic supplement for the heart.

In a feasibility clinical study involving 15 patients with chronic coronary artery disease, D-Ribose supplementation improved heart function, and increased exercise tolerance and quality of life in heart patients 18.

In a recent international conference of the American Thoracic Society in San Diego, CA, Dr. Perkowski, chief of cardiothoracic surgery at Saddleback Memorial in Laguna Hills, CA, presented to the Federation of American Societies for Experimental Biology (FASEB) the results of a controlled study on the effects of D-Ribose (CORvalen) supplementation in 44 patients with ischemic coronary heart disease that were undergoing coronary bypass surgery without the use of a heart-lung machine. Cardiac function was measured before and after surgery. The patients treated with D-Ribose prior to their revascularization showed a 49% greater increase in cardiac indices after surgery.

Beta-Glucans. These substances belong to a group of biopolymers known as polysaccharides, made up of many smaller sugar molecules. Various beta-glucans have been isolated from mushrooms, yeast, oats and barley. Several studies have indicated that consumption of oat bran lowers blood cholesterol, and this effect has been attributed specifically to oat bran’s soluble fiber, beta-glucan.

Researchers at Maastricht University, in Netherlands examined the effects of a beta-glucan on serum lipids in healthy subjects. Subjects consumed daily a fruit drink providing 5 grams of rice starch (control group) or beta-glucan from oats for 5 weeks. At the end of the treatment, differences between the control and beta-glucan groups in the change in serum concentrations of TC and LDL cholesterol were -4.8% and -7.7%, respectively. The researchers also showed that beta-glucan lowers serum concentrations of TC and LDL cholesterol by reducing cholesterol absorption without affecting plasma concentrations of lipid-soluble antioxidants 19.

Tocotrienol. A vitamin E analogue of tocopherols, tocotrienols are found in abundance in palm and rice bran oils. They have been shown in various studies to be effective in lowering serum TC and LDL cholesterol levels. Tocotrienols suppress the production of the hepatic enzyme beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase, which results in less cholesterol being manufactured by liver cells. This mechanism differs from that of statins, the most popular anti-cholesterol drugs, which work as inhibitors of HMG-CoA reductase.

In a recent review by Dr. Tan, a mixture of delta- and gamma-tocotrienols (9:1) was reported to lower TC and LDL by 13%, TG by 23%, while increasing HDL by 6% after 2 months of supplementation 20.

Citrus polymethoxylated flavones (PMF). High dietary intake of citrus juice (orange or grapefruit) has been shown to reduce hypercholesterolemia, an effect attributed to the flavanone glycosides hesperetin from oranges and naringenin from grapefruit 21. In addition to these flavanones, citrus also contain PMF; the most common ones are tangeretin and nobiletin. PMF have also found to lower cholesterol and TG in hamsters with diet-induced hypercholesterolemia 22.

A patented formulation, termed Sytrinol, comprising both PMF and tocotrienols, developed by KGK Synergize in Canada, has been shown in clinical trials to lower TC by 20%, LDL by 22%, and TG by 28%. PMF modulate lipoprotein and lipid metabolism directly in the liver, by decreasing apoprotein B needed for endogenous synthesis of LDL cholesterol, and inducing the suppression of diacylglycerol acyltransferase, an enzyme required for TG synthesis.

Cocoa. Cocoa and chocolate have recently been added to the heart health story because they are rich plant-derived antioxidant flavonoids, which have beneficial cardiovascular properties. Researchers at Harvard University reviewed publications from 1966 through 2005 for experimental, observational, and clinical studies of relations between cocoa, cacao, chocolate and flavonoids and the risk of cardiovascular disease. The data from short-term randomized trials suggest cocoa and chocolate may exert beneficial effects on cardiovascular risk via effects on lowering blood pressure, anti-platelet function, higher HDL, and decreased LDL oxidation. Researchers suggest conducting larger randomized trials to definitively investigate the impact of chocolate consumption on long-term cardiovascular outcomes 23. In a pre-clinical trial, soluble cocoa fiber (from Nutraceutical Group Marketing Team) was shown to lower cholesterol levels, especially bad cholesterol, by as much as 54%.

Soy protein’s potential benefits for lowering heart disease risk have received mainstream attention in recent years. Research studies indicate that soy proteins can help maintain healthy blood pressure. For example, results of a 12-week study published in the Annals of Internal Medicine (2005) suggest that consuming soy protein can lower blood pressure when compared to a complex carbohydrate 24. Research published in Journal of NutritionITAL (2002) also showed that soymilk was able to decrease blood pressure when compared to a cow milk control 25.

Garlic. This herb has been widely recognized for its prevention and treatment of cardiovascular and other diseases. While earlier trials suggest that garlic might mildly lower TC and TG levels in the blood 26, more recent trials found garlic to have minimal success in lowering TC and TG 27. In a four-year clinical trial on people aged 50 to 80 years old, with atherosclerosis, consumption of 900 mg of a standardized garlic supplement was found to reduce arterial plaque formation by 5-18% 28.

Bioactive Peptides. Bioactive peptides that inhibit angiotensin I converting enzyme (ACE) in the cardiovascular system can contribute to the prevention and treatment of hypertension. These peptides are produced in the enzymatic hydrolysate of food material such as milk 29, sardine protein 30, bonito fish 31, maize, wheat, and soybeans, and also from microbe-fermented products.

Researchers at University of Pennsylvania reported that the hydrolysate of bovine milk protein, either alone or in combination with algenic acid, significantly reduced day time blood pressure by 9.2 mmHg in (systolic) and 6.0 mmHg in (diastolic) 32.

Nattokinase. This pro-fibrinolytic enzyme can be found in the vegetable cheese natto, a popular fermented soybean food in the Japanese diet. Natto is prepared by fermenting boiled soybeans with Bacillus sppITAL (e.g. Bacillus subtilis, Bacillus nattoITAL).

Nattokinase has been found to have blood clot dissolving abilities. In an in vitro study, researchers at University of Southern California showed that nattokinase incubated with blood samples for 30 minutes at 37 degrees C. significantly decreased red blood cell aggregation and whole blood viscosity. These data suggest its potential role as a therapeutic agent in preventing vascular disease such as heart attack, stroke, hypertension, and deep vein thrombosis 33.

SIDE BAR
Now Milk Chocolate can be Heart Healthy Too!
In mid-September, Mars, Incorporated, Hackettstown, NJ, extended its brand of CocoaVia bars. This time around the bars contain milk chocolate, while still maintaining the heart healthy benefits of dark chocolate. In fact, like all CocoaVia heart-healthy snacks, this new range of products delivers the unique combination of cocoa flavanols, the heart-healthy compounds naturally in cocoa beans, and plant sterols, in three varieties: CocoaVia Milk Chocolate Bars, CocoaVia Milk Chocolate Bars with Almonds and CocoaVia Milk Chocolate-Covered Raisins.

Mars also has plans to introduce the line's first beverage—CocoaVia Rich Chocolate Indulgence. Each serving is guaranteed to contain at least 100 milligrams of cocoa flavanols—the same amount in the original dark chocolate varieties of CocoaVia.

To make these new products possible, Mars pioneered a new technology to retain more cocoa flavanols, resulting in milk chocolate with the same level of cocoa flavanols as its CocoaVia Dark Chocolate products. CocoaVia also is the only line to guarantee a significant level of cocoa flavanols through the use of a proprietary process called Mars Cocoapro, which retains much of the natural cocoa flavanols. Additionally, CocoaVia is fortified with calcium and a mix of heart-healthy nutrients including folic acid, vitamins B-6, B-12, C and E.

References
1. Wang C., et al. n-3 Fatty acids from fish or fish oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 2006; 84:5
2. Mandasescu S., et al. Flaxseed supplementation in hyperlipidemic patients. Rev Med Chir Soc Med Nat Iasi. 2005; 109:502
3. Gouni-Berthold I, Berthold HK. Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am Heart J. 2002 Feb; 143:356
4. Berthold HK., et al. Effect of policosanol on lipid levels among patients with hypercholesterolemia or combined hyperlipidemia: a randomized controlled trial. JAMA 2006; 295:2262
5. Chen JT., et al. Meta-analysis of natural therapies for hyperlipidemia: plant sterols and stanols versus policosanol. Pharmacotherapy 2005; 25:171
6. Heinemann T., et al. Comparison of intestinal absorption of cholesterol with different plant sterols in man. Eur J Clin Invest 1993; 23:827
7. Tikkanen MJ. Plant sterols and stanols. Handb Exp Pharmacol. 2005; 170:215
8. Moruisi KG., et al. Phytosterols/stanols lower cholesterol concentration in familial hypercholesterolemic subjects: a systematic review with meta-analysis. J Am Coll Nutr 2006; 25:41
9. Korpela R., et.al. Safety aspects and cholesterol-lowering efficacy of low fat dairy products containing plant sterols. Eur J Clin Nutr. 2006; 60:633
10. Singh RB., et al. Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 1994; 8:659
11. Ulbricht C., et al. Guggul for hyperlipidemia: a review by the Natural Standard Research Collaboration. Complement Ther Med 2005;13:279
12. Szapary PO., et al. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. JAMA 2003; 290:765
13. Allard ML., Jeejeebhoy KN, Sole MJ. The management of conditioned nutritional requirements in heart failure. Heart Fail Rev. 2006; 11:75
14. Mortensen SA., et al. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 1997; 18:S137
15. Burke BE., et al. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J 2001; 94:1112
16. Ferrari R., et al. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann N.Y. Acad Sci. 2004; 1033:79
17. Pauly D.F., et al. The role of carnitine in myocardial dysfunction. Am J Kidney Dis 2003; 41(4 Suppl 4):S35-43
18. Omran H., et al. D-Ribose improves diastolic function and quality of life in congestive heart failure patients: a prospective feasibility study. Eur J Heart Fail. 2003; 5:615
19. Naumann E., et al. Beta-glucan incorporated into a fruit drink effectively lowers serum LDL-cholesterol concentrations. Am J Clin Nutr 2006; 83:601
20. Tan, B. Appropriate spectrum vitamin E and new perspectives on deomethyl tocopherols and tocotrienols. J Am Nutr Assoc. 2005; 8:35
21. Manthey JA., et al. Biological properties of citrus favonoids pertaining to cancer and inflammation. Curr Med Chem. 2001; 8:135
22. Kurowska EM, Manthey JA. Hypolipidemic effects and absorption of citrus polymethoxylated flavones in Hamsters with diet-induced hypercholesterolemia. J Agric Food Chem 2004; 52:2879
23. Ding EL., et al. Chocolate and prevention of cardiovascular disease: a systematic review. Nutr Metab (Lond) 2006; 3:2
24. He J., et al. Effect of soybean protein on blood pressure: a randomized, controlled trial. Ann Intern Med 2005; 143:1
25. Rivas M., et al. Soy milk lowers blood pressure in men and women with mild to moderate essential hypertension. J Nutr 2002; 132:1900
26. Neil HA., et al. Garlic powder in the treatment of moderate hyperlipidemia: A controlled trial and a meta-analysis. J R Coll Phys 1996; 30:329
27. Berthold HK., et al. Effect of garlic oil preparation on serum lipoproteins and cholesterol metabolism. JAMA 1998; 279:1900
28. Koscielny J. The anti-atherosclerosis effect of Allium sativum. Atherosclerosis 1999; 144:237
29. Seppo L., et al. Effect of ingesting sour milk fermented using Lactobacillus helveticus bacteria producing tripeptides on blood pressure in subjects with mild hypertension. J Hum Hypertens. 2004; 18:795
30. Kawasaki T., et al. Antihypertensive effect and safety evaluation of vegetable drink with peptides derived from sardine protein hydrolysates on mild hypertensive, high-normal and normal blood pressure subjects. Fukuoka Igaku Zasshi. 2002; 93:208
31. Fujita H., et al. Effect of an ace-inhibitory agent, katsuobushi oligopeptide, in the spontaneously hypertensive rat and in borderline and mildly hypertensive subjects. Nutrition Research 2001; 21:1149
32. Townsend RR., et al. A randomized, double-blind, placebo-controlled trial of casein protein hydrolysate (C12 peptide) in human essential hypertension. Am J Hypertens 2004; 17:1056
33. Holsworth RE Jr., et al. Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell aggregation and whole blood viscosity. Clin Hemorheol Microcirc. 2006; 35:139.