Heart-healthy Ingredients: The Beat Goes On
Cardiovascular disease (CVD) remains the leading cause of mortality in the U.S., killing nearly one million Americans each year. This staggering situation created an economic tidal wave estimated at over $368 billion in 2004, according to the American Heart Association (Dallas). Traditional approaches to treatment remain focused on prescription drugs and surgery. But the high costs and undesirable side effects of many standard protocols have forced the medical community to reassess the status quo in dealing with the nation's number one health menace.
Bruce Holub, professor at the University of Guelph (Ontario, Canada) suggests that a proactive, preventive model of health care holds the key to a workable solution for CVD and other chronic diseases appearing at younger ages today than ever before. Holub hypothesizes that such a model--which might include the early introduction of nutraceuticals and functional foods well researched for cardiovascular benefits--could save a minimum of $300 billion dollars annually in health-care costs in North America.
Food, beverage and dietary supplement products making heart health claims are now a multi-billion dollar category in the U.S., with comparable markets in Europe, Japan and Australia. (See the "Now Introducing" chart.) The introduction in May 2005 of One-A-Day Cholesterol Plus by Bayer Health Care's Consumer Care division (Morristown, N.J.), billed as the first multivitamin "specially formulated with heart-health supporting ingredients,"? is one indication that the pharmaceutical industry is scrambling to reposition itself in this profitable marketplace. However, for non-pharmaceutical manufacturers, in spite of prolific new product research and applications development, some marketing hurdles stand in the way of new product introductions. Labeling claims permitted by FDA remain limited for dietary supplement nutraceutical ingredients, although convincing scientific evidence has paved the way for a number of new food ingredient health claims.
Black, oolong, white and green teas (all derived from the leaves of Camellia sinensis) support cardiovascular health through a variety of mechanisms. Some studies indicate a moderate but consistent cholesterol-lowering effect in moderate-to-heavy tea drinkers, and other research suggests additional benefits via lowered blood pressure and cholesterol and even improved blood vessel functioning. A study published in 2004 in the American Journal of Cardiology demonstrates that flavonoids in tea directly improve blood vessel health and blood circulation.1 Findings published in the Journal of Nutrition showed that five servings of black tea per day reduced low-density lipoprotein (LDL) cholesterol by over 11% and total cholesterol by 6.5% in mildly hypercholesterolemic adult study participants.2 Another study, which involved more than 3,400 Saudi men and women, found that people who drank more than six cups of black tea daily lowered their risk of coronary heart disease (CHD) by more than half, compared to those who were not regular tea drinkers.3
A study from the U.K. Institute of Child Health (London) in 2005 suggests that tea is a healthy drink for stroke patients, and that green tea, in particular, can act as a shield against damage caused by a heart attack or a stroke. The laboratory study, headed by Dr. Anastasis Stephanou, shed light on the mechanism that may be responsible for tea's cardio-protective benefits. The team discovered that epigallocatechin-3-gallate (EGCG)--a major chemical component of green tea--reduces cell death that occurs in the absence of oxygen (ischemia). A heart attack causes a drastic reduction in the amount of oxygen and nutrients able to reach the brain and heart, which can lead to cell death and irreparable harm. In such a situation, EGCG blocks the action of a protein that induces cell death and accelerates the recovery of heart cells and tissues, further alleviating organ damage. "We're extremely encouraged by these findings and hope to implement them in the clinical setting," said Dr. Stephanou.4
One long-term study suggests that consumption of dietary fiber, especially water-soluble fiber, is inversely associated with CHD risk.5 The Food and Drug Administration (FDA) has authorized as final rule, without change, a health claim acknowledging the relationship between beta-glucan soluble fiber from whole oat sources and reduced risk of CHD.6 Large epidemiologic studies that link dietary fiber with prevention of CHD have formed the basis for recommendations from the National Academy of Science for fiber intake: 38g and 25g/day for young men and women, respectively, based on an intake of 14g of fiber per 1,000 calories.7
The specific mechanisms by which fiber may protect against CHD include lowering blood cholesterol (soluble fiber), attenuating blood triglyceride levels (primarily soluble fiber), decreasing hypertension (all fiber), and normalizing postprandial blood glucose levels (all fiber).7 This diversity of benefits provided by both soluble and insoluble fibers underscores the importance of taking into account the total amount of fiber consumed from various sources. Thus, nutrition experts counsel that individuals should increase their consumption of both types of fiber, not solely soluble fiber.
Omega-3 Fatty Acids
The evidence supporting the cardio-protective benefits of omega-3 fatty acids is so robust that in September 2003, the FDA approved a qualified health claim for products containing the omega-3 compounds eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Such products may now state that "consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease," based on "supportive but not conclusive research." Clinical trials demonstrate that omega-3s reduce the risk of heart attacks and strokes, and consumption of 200mg/day DHA is associated with a 50% reduction in risk of sudden cardiac death.8 Ongoing clinical investigation has led some international expert panels and health organizations to recommend even higher daily intakes of EPA and DHA--at least 450mg for people without CHD and up to 1,000mg for those with CHD.9
A number of mechanisms may be responsible for the cardiovascular benefits of omega-3 fatty acids. Omega-3s improve the ratio of high-density lipoprotein (HDL) to LDL, lower levels of triglycerides, and have antiplatelet and anti-arrhythmic effects.10-14 A new study suggests an additional mechanism of action. The randomized, double-blind, placebo-controlled, multi-center study demonstrated modest improvements in a number of cardiovascular parameters in mildly hypercholesterolemic subjects receiving 1g/day of DHA derived from microalgae, including lowered triglyceride and LDL levels and a slight increase in HDL, according to preliminary results announced in May, 2005 by a Columbia, Md.-based manufacturer of DHA. These results are consistent with previous studies that used similar low doses of fish oil containing DHA and EPA. In addition, participants who took 200mg or 1g/day of the microalgae-produced DHA had a statistically significant reduction in C-reactive protein (CRP) at 26 weeks, compared with the placebo group. Emerging research indicates that high levels of CRP are associated with vascular inflammation and, thereby, an elevated risk of CVD, suggesting that lowering CRP levels may be yet another way that omega-3 fatty acids promote cardiovascular health.15
Phytonutrients in Nuts, Grains and Plants
Epidemiological studies assessing the relationship between diet and heart disease have repeatedly demonstrated the benefits of plant-based diets. More recent studies have focused on determining which specific plant foods are responsible for preventing CVD. For vegetarians, nuts may exert some of the most powerful protective effects. This finding surprised researchers, who had anticipated that the absence of meat in the diet would be the main factor.16 Other population studies have reached similar conclusions about the cardio-protective effects of nut consumption. In 2000, a well-controlled clinical study concluded that substituting walnuts for part of the monounsaturated fat provided by a cholesterol-lowering "Mediterranean diet" further reduced total and LDL cholesterol levels for people with elevated cholesterol.17 Based on this and other convincing evidence, in December, 2003, the FDA approved a qualified health claim for walnuts that allows packaging to state that walnuts can reduce the risk of heart disease. Manufacturers may now claim, "Supportive but not conclusive research shows that eating 1.5oz. per day of walnuts, as part of a low saturated fat and low cholesterol diet and not resulting in increased caloric intake, may reduce the risk of coronary heart disease."
Interestingly, many nuts are exceptionally rich in individual phytonutrients currently being researched and positively linked with heart health, including arginine, vitamin E, folate, fiber, potassium, magnesium, tannins and polyphenols. Polyphenols (phenolic compounds, including the subcategory known as flavonoids) are found in all plants and have been extensively researched in tea, vegetables, fruits, legumes, nuts, olive oil, cereals, red wine and many cardio-protective herbs, including hawthorn (Crataegus laevigata), which is approved for the treatment of cardiovascular disease in Europe. Some epidemiologic studies have reported protective associations between flavonoids and CVD, while others have been inconclusive. Various phytoestrogens are abundant in soy, flaxseed oil, whole grains, fruits and vegetables, and most afford antioxidant properties with favorable effects on cardiovascular health.18 Resveratrol, prevalent in red wine and nuts, has antioxidant, antithrombotic and anti-inflammatory effects.18 Solid science-based research has demonstrated that consumption of plant sterols, soybean proteins, various fibers and nuts favorably modulate the risk of CVD through cholesterol-lowering properties.18,19 Epidemiologic studies have consistently demonstrated that nuts have beneficial effects on CHD-related morbidity and mortality in different population groups, and clinical studies show that regular consumption of nuts or legumes lowers total and LDL cholesterol levels and LDL particle size.19,20 Dietary fiber, essential fatty acids and other bioactive constituents in nuts all contribute to their cardio-protective effects.20
New evidence shows that garlic (Allium sativum) cannot only prevent but may also reverse some aspects of arteriosclerosis, according to a study presented in 2005 at the 6th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology in Washington.21 Based on this and other compelling research, various dietary supplement companies are formally requesting the FDA allow a specific health claim for garlic. "Garlic not only reduces the buildup of arterial plaque, but also reverses existing plaque,"? according to Joerg Gruenwald, Ph.D., president of Berlin's Phytopharm Consulting and author of The Physician's Desk Reference for Herbal Medicine. "FDA should look at our data and give garlic a real health claim for reduction of risk of coronary heart disease," he said. Dr. Gunter Siegel, director of the Department of Physiology at Charit© University of Medicine (Berlin), found that a low dose of a specific branded garlic inhibits by 15% the formation of nanoplaque--the substance that develops in the earliest stages of arteriosclerosis and eventually clogs arterial walls--even when all the factors normally responsible for such blockage are present. "With a higher concentration—it goes to 30%," Siegel said. He added, "Normally, HDL helps to hinder nanoplaque in the same way garlic acts—so garlic can be called a 'phyto-HDL.'"
Traditional and Emerging Applications
Barry Titlow, CEO of an Escondido, Calif.-based distributor of nutraceutical ingredients, notes that interest in products formulated to combat CVD is at an all-time high. "We're seeing a number of first time entrants--including pharmaceutical companies--stepping into the arena of functional foods and dietary supplements products targeted specifically at CVD and CHD. Many of these products are multi-component formulations using nutrients investigated rigorously for their cardio-supportive benefits." Titlow notes that coenzyme Q 10 and the amino acids carnitine, arginine and citrulline are among the more popular ingredients being incorporated in functional foods, beverages and dietary supplements designed for heart health.
Close scrutiny of decades of research suggests adequate evidence is available to link a growing number of food groups, nutrients and dietary patterns with decreased risks of CVD. New generations of consumers and their health care practitioners appear receptive to the potential for life and lifestyles free from these devastating health burdens. While efficacy, safety and regulatory boundaries remain nagging barriers to marketplace entry for some cardio-healthy ingredients, the drive to seek out viable alternatives to synthetic drugs--and their potential side effects--is increasing, as a beleaguered pharmaceutical industry remains productively challenged to market safer products. NS
Brian Keating is the founder of Sage Group International (Seattle, Wash.), a natural products industry consultancy providing market and product development services to natural foods, nutraceutical and specialty beverage companies worldwide.
Evelyn Leigh is a natural products industry consultant and writer based in Boulder, Colo. She is co-author of the Herb Research Foundation's Encyclopedia of Popular Herbs (Prima Publishing, 2000).
1. Hirata K, Shimata K, Watnabe H, et al. Black tea increases coronary flow velocity reserve in healthy male subjects. American Journal of Cardiology 2004; 93(11): 1384-1388.
2. Davies MJ, Judd JT, Baer DJ, et al. Black tea consumption reduces total and LDL cholesterol in mildly hypercholesterolemic adults. J Nutr 2003; 133(10):3298S-3302S.
3. Hakim IA, Alsaif MA, Alduwaihy M, et al. Tea consumption and the prevalence of coronary heart disease in Saudi adults: Results from a Saudi national study. Preventive Medicine 2003; 36(1): 64-70.
4. Townsend PA, Scarabelli TM, Pasini E, et al. Epigallocatechin-3-gallate inhibits STAT-1 activation and protects cardiac myocytes from ischemia/reperfusion-induced apoptosis. FASEB J 2004; 18(13): 1621-3.
5. Bazzano LA, He J, Ogden LG, et al. Dietary fiber intake and reduced risk of coronary heart disease in US men and women: The National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Arch Intern Med 2003; 163(16):1897-904.
6. Food and Drug Administration, HHS. Food labeling: health claims; soluble dietary fiber from certain foods and coronary heart disease. Final rule. Fed Regist 2003; 68(144):44207-9.
7. Lupton JR, Turner ND. Dietary fiber and coronary disease: does the evidence support an association? Curr Atheroscler Res 2003; 5(6):500-5.
8. Horrocks LA, Yeo YK. Health benefits of docosahexaenoic acid (DHA). Pharmacol Res 1999; 40(3): 211-225.
9. Harris WS. Are omega-3 fatty acids the most important nutritional modulators of coronary heart disease risk? Curr Arterioscler Res 2004; 6(6): 447-52.
10. Oh R. Practical applications of fish oil (Omega-3 fatty acids) in primary care. J Am Board Fam Pract 2005; 18(1): 28-36.\
11. Iso H, Rexrode KM, Stampfer MJ, et al. Intake of fish and omega-3 fatty acids and risk of stroke in women. Journal of the American Medical Association 2001; 285: 304-312.
12. Ismail HM. The role of omega-3 fatty acids in cardiac protection: an overview. Front Biosci 2005; 10: 1079-88.13. Harper CR, Jacobsen TA. The fats of life: the role of omega-3 fatty acids in the prevention of coronary heart disease. Arch Intern Med 2001; 161(18) 2185-92.
14. De Lorgeril M. Nutritional trials for the prevention of coronary heart disease. Asia Pac J Clin Nutr 2004; 13(suppl):S2.
15. Unpublished study results released May 12, 2005 by Martex Biosciences.
16. Strahan TM. Nuts for cardiovascular protection. Asia Pac J Clin Nutr 2004;13(Suppl):S33.
17. Zambon D, Sabate J, Munoz S, et al. Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men and women. A randomized crossover trial. Ann Intern Med 2000; 132(7):538-46.
18. Kris-Etherton PM, Hecker KD, Bonanome A, et al. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med 2002; 113(suppl 9B):71S-88S.
19. Lamarche B, Desroches S, Jenkins DJ, et al. Combined effects of a dietary portfolio of plant sterols, vegetable protein, viscous fiber and almonds on LDL particle size. Br J Nutr 2004;92(4):657-63.
20. Kris-Etherton PM, Zhao G, Binkoski AE, et al. The effects of nuts on coronary heart disease risk. Nutr Rev 2001;59(4):103-11.
21. Siegel G, Malmsten M, Pietzsch J, et al. The effect of garlic on arteriosclerotic nanoplaque formation and size. Phytomedicine 2004; 11(1): 24-35.
Sidebar 1: Studying up on Proteins
Although soy has been thought to possess heart health benefits for nearly a century, a meta-analysis study published in 1995 of 38 clinical studies involving more than 700 subjects showed that, in comparison to control diets, soy protein significantly reduced LDL-cholesterol (~13%) and triglycerides (~10%) while increasing HDL-cholesterol (although by an insignificant 2.4%).1 This research helped lead to the FDA heart health claim for certain foods that contained 6.25g soy protein per serving, which was based on dividing the daily qualifying level (25g) by four to represent the four eating occasions of breakfast, lunch, dinner and snack. Researchers continue to investigate the soy protein's cardiovascular benefits. For example, articles by Jenkins DJ et al. in JAMA and elsewhere compared a diet of cholesterol-lowering foods with plant sterols, soy protein, viscous fibers and almonds and concluded that it could reduce the heart risk factor--C-reactive protein--to a similar extent as 20mg of the prescription drug lovastatin.2
The dairy industry is not to be left out as research has focused more closely on cholesterol-lowering and hypertension-reducing peptides and bioactives found in dairy products. A monograph by Dairy Management Inc. (http://doitwithdairy.com/infolib/monographs/pdf/I_11CARDIO.pdf) provides an overview. Interest has gone beyond theoretical research as suppliers now provide dairy peptides, either as ingredients with labels such as "hydrolyzed whey protein isolate"? or as specially fermented milk proteins in milk-based products for consumers. For example, Calpis USA (Torrance, Calif.) just launched Ameal S into the U.S. market. The first ingredient listed is whey protein and the product notes the presence of 6mg lactotripeptide and states that it is "clinically proven to help maintain a healthy blood pressure level."
Sidebar 2: Caring about Cations
The Nurses' Health Study that began in 1980 with 85,764 middle-aged female nurses showed that intakes of calcium, potassium, and magnesium were each associated with reduced risk of hypertension and of ischemic stroke. Clinical trials generally have found that potassium has the strongest effect and that the association with calcium intake was stronger for dairy than for non-dairy calcium intake (http://stroke.ahajournals. org/cgi/content/full/30/9/1772).
The DASH diet (Dietary Approaches to Stop Hypertension) also encourages the consumption of fruits, vegetables, and low- or non-fat dairy products to provide a high intake of potassium, as well as magnesium and calcium.
Marketers have yet to rush in mass to provide products touting either reduced-risk of hypertension or cardiovascular disease due to their calcium, potassium and magnesium content, but some have taken advantage of the solid nutritional science. For example, Bayer's (Morristown, N.J.) One A Day Cholesterol Plus Multivitamin/Multimineral Supplement "contains folic acid and calcium to support healthy blood pressure." Its first four ingredients are forms of calcium, potassium and magnesium minerals. And, Kellogg's (Battle Creek, Mich.) new Healthy Heart variety of Smart Start Cereal notes that it contains oat bran and potassium, and is low in sodium to help lower cholesterol and blood pressure.
--Claudia D. O'Donnell, Chief Editor