Functional Foods and Cardiovascular Disease Clare M. Hasler, PhD, Susan Kundrat, MS, RD, and Deborah Wool, MS

Address Functional Foods for Health Program, University of Illinois, 1302 West Pennsylvania Avenue, Room 103 Agricultural Bioprocess Laboratory; M/C 640, Urbana, IL 61801, USA. E-mail: [email protected] Current Atherosclerosis Reports 2000, 2:467–475 Current Science Inc. ISSN 1523–3804 Copyright © 2000 by Current Science Inc.

Functional foods are foods that, by virtue of physiologically active food components, provide health benefits beyond basic nutrition. Many functional foods have been found to be potentially beneficial in the prevention and treatment of cardiovascular disease, the leading cause of mortality in the United States. These foods include soybeans, oats, psyllium, flaxseed, garlic, tea, fish, grapes, nuts, and stanol- and sterol ester enhanced margarine. When eaten in adequate amounts on a consistent basis, these foods may aid in decreasing the risk of cardiovascular disease by several potential mechanisms: lowering blood lipid levels, improving arterial compliance, reducing low-density lipoprotein oxidation, decreasing plaque formation, scavenging free radicals, and inhibiting platelet aggregation.

Introduction Cardiovascular disease (CVD) has been the leading cause of mortality in the United States every single year since 1918. As we embark on the 21st century, a similarly sobering outlook for this devastating disease faces us as CVD continues to claim more lives than the next 14 causes of death combined. Cardiovascular disease takes a life every 33 seconds, is responsible for 1 of every 2.4 deaths, and killed more than 960,000 people in 1997 [1]. Fortunately, people are becoming more concerned about the epidemic of heart disease and, with the advent of the “self-care” movement, are beginning to incorporate foods into their diet with the intention of lowering cholesterol and thus reducing their CVD risk. According to a recent PREVENTION magazine/Food Marketing Institute survey of 1000 shoppers, 72% stated that they purchase foods to lower cholesterol [2]. Foods that provide a health benefit beyond basic nutrition, such as lowering elevated blood total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, can be referred to as “functional foods.” According to the International Life Sciences Institute,

functional foods are foods that, by virtue of physiologically active food components, provide health benefits beyond basic nutrition [3]. The most recent position paper on functional foods by the American Dietetic Association emphasizes that functional foods have “... a potentially beneficial effect on health when consumed as part of a varied diet on a regular basis at effective levels” and can include whole, fortified, enriched, or enhanced foods [4••]. This review summarizes, with an emphasis on clinical findings, recent literature supporting the efficacy for 10 functional foods in CVD risk reduction: soybeans, oats, psyllium, flaxseed, garlic, tea, fish, grapes, nuts, and stanol- and sterol ester-enhanced margarine.

Soy Protein The efficacy of soy protein in reducing the risk of coronary heart disease (CHD) was confirmed in October of 1999 when the Food and Drug Administration (FDA) approved a health claim under the Nutrition Labeling and Education Act of 1990 (NLEA) for this diet-disease relationship [5•]. More than 40 clinical intervention trials were summarized in the health claim petition submitted to the FDA by Protein Technologies International, including a 1995 meta-analysis by Anderson et al. [6]. The daily effective level of soy protein set by the FDA is 25 g/day or 6.25 g/reference amount customarily consumed (RACC) as part of a diet low in saturated fat and cholesterol (25 divided by four eating occasions per day). More recent data suggest that even less than 25 grams of soy protein per day can effectively lower blood lipids. Washburn et al. [7] demonstrated a 7% reduction in LDL and a 6% decrease in TC after 5 weeks in 51 perimenopausal women consuming 20 g of soy protein per day. Although isoflavones, a class of plant substances functionally similar to estradiol, were proposed in the health claim petition as the physiologically active component in soy responsible for its cholesterol-lowering effect, the FDA did not agree with this hypothesis; there is very little human clinical data to support that isoflavones by themselves can lower TC or LDL cholesterol. Isolated isoflavones have been shown to be ineffective in lowering cholesterol in clinical trials [8], even at concentrations as high as 160 mg/d [9]. Although a recent clinical trial [10] found that 25 grams of isolated soy protein containing increasing levels of isoflavones (4, 27, 37, or 62 mg) had a

468

Nutrition

dose-dependent reducing effect on cholesterol lowering in subjects with high cholesterol, the results were modest— the highest level of isoflavones (62 mg) lowered TC and LDL cholesterol levels by only 4% and 6%, respectively. A higher level of isoflavones may be necessary to elicit a significant beneficial effect on blood lipids. In a recent study involving 13 healthy, normocholesterolemic women who consumed three different levels of isoflavones (10, 64.7, and 128.7 mg), only the highest intake of isoflavones significantly lowered LDL cholesterol by 7.6% to 10% (P < 0.05), with no effect on TC [11]. In addition to isoflavones, many components in soy may help mediate changes in lipid metabolism, including amino acids, saponins, phytic acid, trypsin inhibitors, fiber, and globulins [12]. Recent evidence suggests that soy isoflavones may provide a variety of heart health benefits apart from their capacity to lower blood lipids, including improved arterial compliance and reduced LDL oxidation [13]. Recently, Jenkins et al. [14] demonstrated a significant (P = 0.020) reduction (8.5%) in the proportion of conjugated dienes in the LDL cholesterol fraction in 20 hyperlipidemic men and postmenopausal women after 8 weeks of consuming self-selected low-fat, low-cholesterol NCEP step 2 diets containing 12 ± 2 g/day soy protein. Additional work is needed to clarify the role of soy isoflavones in cardiovascular health.

Oat-soluble Fiber It is well known that viscous soluble fibers, including oat bglucan, are hypocholesterolemic [14,15] . In January of 1997, the FDA awarded the first food-specific health claim for the relationship between oat-soluble fiber and reduced risk of CHD in response to a petition from the Quaker Oats Company [16••]. The petition summarized 37 human clinical intervention trials conducted between 1980 and 1995, 17 of which demonstrated a statistically significant effect of oat bran or oatmeal on lowering total and LDL cholesterol in hypercholesterolemic subjects consuming either a typical American diet or a low-fat diet. Quaker Oats determined that 3 g of b-glucan, the primary soluble fiber in oats, would be required to achieve a 5% reduction in serum cholesterol, which is equivalent to approximately 60 g of oatmeal or 40 g of oat bran (dry weight). Thus, the FDA requires that a food bearing the health claim contain 13 g of oat bran or 20 g of oatmeal, and that the whole oat product contain, without fortification, at least 1 g of b-glucan–soluble fiber per serving. A recent meta-analysis, which included 25 studies on oat products [17], found that 3 g of soluble fiber from oats (three servings of oatmeal, 28 g each) reduced TC and LDL by approximately 0.13 mmol/L (2%). The mechanism by which oat-soluble fiber lowers blood lipids is probably related to its ability to either reduce the absorption of cholesterol and bile acids or delay lipid digestion [18], although two recent studies suggest that oats may also reduce LDL oxidation due to the pres-

ence of various phenolic compounds [19]. In addition, oatmeal has been shown to prevent the constriction of arteries, an early sign of heart disease, when served with a high-fat meal [20]. Fifty healthy adults consumed a meal containing 50 g of fat in addition to 1.5 cups of oatmeal containing 3.5 g of b-glucan–soluble fiber, 800 IU of vitamin E, or a bowl of hot whole wheat cereal. Ultrasound measurements demonstrated that oatmeal mitigated the endothelial dysfunction associated with the high-fat meal.

Psyllium Seed Husk Another viscous soluble fiber that has been shown to be very effective in lowering blood lipids is derived from the husk of the blonde psyllium seed, defined as the dried seed coat (epidermis) of the seed of Plantago ovata. In February of 1998, the FDA extended the health claim for oat-soluble fiber and CHD to include fiber from psyllium seed husk in response to a petition from the Kellogg Company [21]. The FDA based its decision after a review of 21 human studies, including a meta-analysis involving 404 subjects. They concluded that, based on the totality of publicly available scientific evidence, there was significant scientific agreement to support the relationship between soluble fiber from psyllium seek husk and reduced risk of CHD. The FDA determined that the effective daily intake of soluble fiber from psyllium associated with a significant reduction in serum lipids was 7 g/day (equivalent to 10.2 g of husk) and would be expected to reduce total cholesterol 4% to 6% and LDL cholesterol, 4% to 8%. For a food manufacturer to qualify to use the psyllium health claim, a food should provide 1.7 g soluble fiber from psyllium husk per RACC. Because esophageal and gastrointestinal obstructions may occur following consumption of psyllium seed husk when not consumed with sufficient liquid, label statements alerting consumers to the need to consume adequate amounts of liquids are required on products bearing the health claim. Since the health claim was approved, two additional meta-analyses have confirmed the hypocholesterolemic effects of psyllium, with a percentage reduction in LDL ranging from 6% to 7.2%. The meta-analysis by Brown et al. [17] involving 2990 subjects investigated the hypocholesterolemic effects of several types of soluble fiber (pectin, oat bran, guar gum, and psyllium), of which 17 used psyllium as the fiber source (9.1 g average dose) and involved 757 subjects. Results indicated that 1 g of soluble fiber from psyllium resulted in decreases in total cholesterol and LDL cholesterol of -0.028 mmol/L (-1.10 mg/dL) and -0.029 mmol/L (-1.11 mg/dL), respectively. No significant effects were noted on triglycerides, but significant, minimal reductions were noted with HDL cholesterol. A second meta-analysis of eight studies by Anderson et al. [22] involving 384 subjects consuming 10.2 g of psyllium each day as an adjunct for more than 8 weeks found that TC and LDL were reduced by 4% (P < 0.0001)

Functional Foods and Cardiovascular Disease • Hasler et al.

and 7% (P < 0.0001), respectively, relative to placebo. No adverse effects on serum HDL or triglycerides were noted. The ratio of apolipoprotein (apo) B to apo A-I was also significantly reduced (P < 0.05). The efficacy of psyllium in the treatment of hypercholesterolemia, even in the treatment of individuals with mild-to-moderate hypercholesterolemia who have type 2 diabetes [23], appears clear. However, long-term studies have not been conducted. The average length of treatment in the meta-analysis by Brown et al. [17], for example, was less than 2 months (53 days). However, a recent multicenter study by Anderson et al. [24•] evaluated the safety and efficacy of 10.2 g of psyllium husk fiber (5.1 g twice per day) as an adjunct therapy for 26 weeks following 8 weeks on an American Heart Association (AHA) Step I diet. Of the 163 subjects who fully complied with the study protocol, psyllium treatment resulted in a reduction of serum total cholesterol of approximately 5% and a 7% decrease in LDL-C. Clearly, viscous fibers and other functional dietary components provide an opportunity to close the gap between diet and drug therapy.

Flaxseed Flaxseed is a unique plant food with potential benefits for cardiovascular health because it is a very significant source of two primary dietary constituents: 1) a-linolenic acid, an omega-3 fatty acid; and 2) the lignans, a primary class of phytoestrogens [25]. The a-linolenic acid content of flaxseed is the highest of any seed oil (57%), and the lignan content of flaxseed (milled) is approximately 67,000 mg/100 g—up to 800 times higher than in 66 other plant foods examined [26]. Although most research on flaxseed has been directed at its cancer chemopreventive activity because of the weak estrogenic and antiestrogenic activity of the lignans, data are also emerging on the ability of flaxseed to lower serum cholesterol levels. Flaxseed containing bread is currently being marketed in Australia, the United Kingdom, and New Zealand for women as an alternative to hormone replacement therapy. In a randomized, double-blind crossover study, Arjmandi et al. [27] demonstrated that the consumption of muffins and bread containing 38 grams of either flaxseed or sunflower seed for 6 weeks was able to significantly ( P < 0. 01 ) l owe r c h o l e s t e r o l by 6 . 9 % a n d 5 . 5 %, respectively, in 38 hypercholesterolemic postmenopausal women. Serum HDL and triglyceride concentrations were unaffected by either treatment. Only flaxseed reduced serum concentrations of Lp(a), a strong predictor of cardiovascular disease, by 7.4% (P < 0.05). It is not clear from this study, however, whether the lipid or the nonlipid components of flaxseed were responsible for the cholesterol-lowering effects. To answer this question, Jenkins et al. [28] conducted a controlled clinical intervention trial with partially defatted flaxseed in 29 hyperlipidemic

469

subjects (22 men and 7 postmenopausal women). Subjects consumed approximately 20 g of fiber per day from either partially defatted flaxseed (approximately 50 g) or wheat bran (control) during two 3-week treatment periods in a randomized crossover design while consuming selfselected NCEP Step II diets. Defatted flaxseed significantly reduced TC (4.6%, P < 0.001), LDL (7.6%, P < 0.001), apo B (5.4, P = 0.001), and apo A-I (5.8, P = 0.005) with no adverse effects on HDL. Additional clinical trials are needed to confirm the cardiovascular benefits of flaxseed and identify the physiologically-active constituent or constituents responsible.

Garlic Garlic (Allium sativum) ranked as the top herbal product used in the United States in 1999. The medicinal properties of this functional food, as well as its characteristic flavor and pungency, are due to an abundance of sulfurcontaining constituents [29]. The intact garlic bulb contains an odorless amino acid, alliin, which is converted enzymatically by allinase into allicin when the garlic cloves are crushed. This latter compound is responsible for the characteristic odor of fresh garlic. Allicin then spontaneously decomposes to form at least 100 sulfur-containing compounds. Although it is currently unclear which component in garlic is responsible for its cholesterol-lowering effect, many commercial garlic preparations are often adjusted or standardized to the “alliin yield” of allicin [30]. Two meta-analyses conducted in the early 1990s, which together summarized the results of 21 clinical trials, suggested that a standardized dose of garlic extract ranging from 800 to 900 mg/day could reduce TC from 9% to 12% [31,32]. However, several methodologic shortcomings of these two reviews, including the fact that dietary intake, weight, and exogenous garlic ingestion were not always well controlled, make the validity of these reports questionable. More recent trials have yielded conflicting results. A study conducted in 60 cardiac rehabilitation patients who received either two garlic capsules daily (each capsule contained ethyl acetate extract from 1 g peeled and crushed raw garlic) or placebo for 3 months showed a significant reduction in serum TC and triglycerides as well as an increase in HDL-cholesterol and fibrinolytic activity [33]. However, garlic has been shown to be ineffective in several other randomized, placebo-controlled trials. Garlic (900 mg/day) was ineffective as a hypocholesterolemic agent after 12 weeks in a randomized, placebo-controlled, double-blind study conducted by Isaacsohn et al. [34]. Similarly, no significant changes in TC, LDL cholesterol, HDL cholesterol, postprandial triglycerides, apo B, or lp(a) were noted in another double blind, randomized, placebocontrolled trial conducted for 3 months in 50 moderately hypercholesterolemic men that used an equal amount of garlic (300 mg garlic tablet three times daily) [35]. Negative findings were also observed by Byrne et al. [36] in

470

Nutrition

a longer-term (6 months) double blind, randomized, parallel trial in 20 hypercholesterolemic subjects consuming 900 mg Kwai garlic tablets. Furthermore, no significant effects of garlic on markers of oxidation were noted, although this particular finding conflicts with the increased LDL resistance to oxidation noted by Munday et al. [37] in subjects fed 2.4 g aged garlic for 1 week. Clearly, no consensus can be reached on the cholesterollowering effects of garlic, which can be attributed in large part to differences in study design and the fact that varying types of preparations have been used clinically.

Tea Flavonoids Made from the dried leaves of the bush plant Camellia sinensis, tea is second only to water as the most widely consumed beverage in the world. In 1996, worldwide tea production totaled 2.61 million metric tons with black, green, and oolong teas comprising 76%, 22%, and 2%, respectively [38]. Green tea is derived from fresh tea leaves by steaming or drying at elevated temperatures in a process that avoids oxidation of the polyphenolic compound. These compounds comprise up to 30% of the total dry weight of fresh tea leaves and include flavandiols, flavonoids, phenolic acids, and flavonols (commonly known as catechins). The four major green tea catechins are epigallocatechin-3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and catechin (EC) [39]. During the manufacture of black tea, fully dried tea leaves are subjected to a full fermentation process, during which the polyphenolic compounds are extensively oxidized. Thus, catechins are reduced to only 3% to 10% of the remaining solids while bisflavanols, theaflavins, other oligomers, and thearubigins are formed, the latter accounting for more than 20% of the remaining solids. Oolong tea is a partially fermented tea product [39]. Although the overwhelming majority of tea research has focused on its anticarcinogenic potential [40], there is emerging evidence that tea consumption may also reduce the risk of heart disease. This relationship was first brought to light in 1993 when results from the Zutphen Elderly Study found that the intake of several flavonoids (eg, quercetin, kaempferol, myricetin, apigenin, and luteolin) was inversely associated in a dose-dependent manner with the incidence of myocardial infarction (MI) in a population of 805 elderly men in the Netherlands [41]. After 5 years of follow-up, mortality rate incidence (1000 persons/year) for fatal and nonfatal MI was 16.2, 13.8, and 7.6 for a flavonoid intake of 0 to 19 mg/day, 19.1 to 29.9 mg/day, and more than 29.9 mg/day, respectively. Since the Zutphen Elderly Study was published, several additional epidemiologic studies have found that tea may protect against heart disease. The Boston Area Health Study found that consumption of 1 cup of tea per day or more reduced the risk of MI by 44% in 340 cases compared with age-, sex-, and community-matched non–tea-drinking

controls [42]. Similarly, the Scottish Heart Health Study, which involved more than 11,000 men and women followed for an average of 7.7 years, found a strong inverse correlation between tea consumption and all cause mortality, coronary death, or any major coronary event, including nonfatal MI or coronary artery surgery [43]. More recently, the Rotterdam study found that tea may also protect against aortic atherosclerosis [44]. This prospective study involved 3454 men and women aged 55 years or older in which dietary intakes were assessed at baseline with semiquantitative food frequency questionnaires and calcified plaques in the abdominal aorta were radiographically detected after 2 to 3 years of follow-up. Plaques were classified as “mild,” “moderate,” or “severe,” depending on the length of the calcified area. After adjustment for age, sex, body mass index, smoking, education, and intake of alcohol, coffee, vitamins, antioxidants, total fat, and total energy intake, a significant inverse association of tea consumption and severe aortic atherosclerosis was found. The odds ratio for developing severe aortic atherosclerosis decreased from 0.54 with the consumption of 1 to 2 cups of tea daily to 0.31 for the consumption 4 or more cups per day. The associations were stronger in women than in men. The beneficial effects of tea consumption on heart health may be due to several modes of action [45•], including inhibition in LDL oxidation. In clinical trials, however, evidence regarding the effects of tea consumption on LDL oxidation remain conflicting. In a recent study of 18 healthy adults who consumed green tea, black tea, black tea with milk, or water every 2 hours (8 cups/day) for 3 days in a crossover design study, LDL resistance to oxidation ex vivo was not enhanced [46]. Similarly, in a randomized, placebo-controlled study in which 26 healthy female and male smokers (aged 22 to 46 years) consumed 900 mL black and green tea or received a supplement of 3.6 g of green tea polyphenols per day (equaling 18 cups of green tea/day), no favorable effects were noted on LDL oxidation ex vivo, plasma antioxidant levels, or blood lipids [47]. These negative results may possibly be due to the difficulty of isolating LDL from polyphenolic compounds in serum. A recent study examined the acute effects of consuming 1 cup of either black or green tea on ex vivo Cu 2+-induced lipoprotein oxidation without prior isolation of lipoproteins from serum in 20 healthy men [48]. Drinks were consumed over 30 minutes, and blood samples were taken 60 minutes after the subjects finished the drink. Compared with the water control, there was a significantly greater (P = 0.05) lag time to LDL diene formation for black tea and a similar but nonsignificant trend for green tea.

Nuts It wasn’t until the early 1990s that the first published prospective cohort studies began to highlight the heart-healthy benefits of nut consumption [49]. Although walnuts were the first type of nuts investigated in this regard [50], several

Functional Foods and Cardiovascular Disease • Hasler et al.

additional studies have demonstrated that a variety of other types of nuts, including almonds, macadamia, pistachio, pecans, and hazelnuts, can significantly reduce both TC and LDL cholesterol when consumed as a part of a low saturated fat, low cholesterol diet. Five recent clinical studies have focused on nuts (mixed nuts, macadamia nuts, pecans, or walnuts) and cardiovascular disease and all have shown a protective effect of nut consumption [51–55]. The first study that involved mixed nuts (almonds, hazelnuts, or pecans) involved 12 hyperlipidemic women in a crossover design that lasted for two 4week periods. Subjects first consumed a refined-food diet and then switched to a phytochemical-rich diet primarily consisting of whole grains, legumes, fruits, vegetables, seeds, and two tablespoons of almonds, hazelnuts, or pecans per day. Compared with the refined-food diet, the phytochemical-rich diet lowered TC by 13% and LDL by 16%, with no significant changes in HDL or triglycerides [51]. A second study that focused on macadamia nuts involved 30 subjects who consumed three different diets each for 30 days. The first diet was a typical American diet (ie, high in saturated fat), the second diet was the AHA Step 1 diet, and the third diet was a macadamia-based diet high in monounsaturated fatty acids. Compared with the typical American diet, the macadamia-based diet lowered TC, LDL, and HDL each by 5% and triglycerides by 10% [52]. The AHA diet yielded similar results except that triglycerides were increased by 8%. A third randomized, controlled, parallel study involved 19 healthy adults who followed either a control diet (no nuts) or a pecan diet that included 68 g of pecans per day (with no additional nuts). After 8 weeks, those following the pecan diet had a 6% decrease in LDL compared with the baseline value. Effects on TC, HDL, and TG were not significantly modified [53]. The fourth and fifth studies involved walnut consumption [54,55]. The first of these was a randomized, crossover feeding study in which 49 adults with hypercholesterolemia consumed a Mediterranean diet emphasizing vegetable products, fish, and olive oil (no nuts), or a walnut diet that partially replaced olive oil and other fatty foods of the Mediterranean diet with 41 to 56 g of walnuts per day. Compared with baseline values, the walnut diet and Mediterranean diet lowered TC by 9% and 5% and LDL by 11% and 6%, respectively, but had no significant effect on HDL. Only the walnut diet lowered triglycerides by 8% and very low-density lipoprotein by 12%. Both diets lowered apo A1 levels by 5%; apo B levels decreased by 13% on the walnut diet and by 8% on the Mediterranean diet, while only the walnut diet lowered Lp(a) levels (by 9%) [54]. The second walnut study was a controlled, single-blind, crossover study of 40 Japanese men and women that tested the effect of adding 43 to 57 g/day of walnuts to the average Japanese diet for 4 weeks. The addition of walnuts was offset by consuming lesser amounts of fatty foods. Compared with the reference diet (the average Japanese diet), the walnut diet decreased TC by 4% in men and 5% in

471

women. LDL decreased in women by 11%. HDL and triglycerides were not significantly changed in men or women, while apoB decreased 7% in men and 9% in women [55].

Grapes and Grape Juice Over the last 20 years, numerous studies have been launched in an effort to explain the observation that the French population has a lower incidence of CHD than other Western populations despite the fact that they consume more fat. Now known as the “French paradox,” the link between wine intake and reduced heart disease risk first became apparent in 1979 when St. Leger et al. [56] found a strong negative correlation between wine intake and death from ischemic heart disease in both men and women from 18 countries. The French paradox is thought to result, in part, from the high concentrations of phenolic antioxidants in grapes, particularly red grapes, which are incorporated into wine during processing. For those who choose to avoid alcohol, research is emerging on the heart health benefits of grapes. Grapes contain a variety of antioxidants, including catechin, epicatechin, resveratrol, and proanthocyanidins. Proanthocyanidins are present primarily in the seeds, whereas resveratrol (3, 4', 5 trihydroxystilbene), a naturally occurring phytoalexin, is present mainly in grape skin at concentrations ranging from 50 to 100 mg/g. Resveratrol may contribute to the heart health benefits of grapes, including inhibition of lipid peroxidation, free radical scavenging activity, inhibition of platelet aggregation, and vasorelaxation effects [57]. To date, only a few human studies have investigated the potential of grape products to reduce CVD risk. Commercial grape juice has been shown to be effective in inhibiting LDL oxidation significantly in vitro as well as in LDL isolated from human subjects. In one study of 15 adults with angiographically documented CAD, participants ingested 7.7 ± 1.2 mL/kg/d of purple grape juice for 14 days. Short-term ingestion of purple grape juice reduced LDL susceptibility to oxidation and improved flowmediated vasodilation, which increased from 2.2 ± 2.9% to 6.4 ± 4.7% (P = 0.003) [58•]. The flavonoids in grapes have also been found to reduce platelet aggregation. A recently published study evaluated whether commercial grape, orange, and grapefruit juices, taken daily, reduce ex vivo platelet activity. In a randomized crossover design, 10 healthy human subjects (aged 26 to 58 years, five of each gender) drank 5 to 7.5 mL/kg/d of purple grape juice, orange juice, or grapefruit juice for 7 to 10 days each. Drinking purple grape juice for 1 week reduced the whole blood platelet aggregation response to 1 mg/L of collagen by 77% (from 17.9 ± 2.3 to 4.0 ± 6.8 ohms, P = 0.0002). The purple grape juice had approximately three times the total polyphenolic concentration of the citrus juices and was a potent platelet inhibitor in healthy subjects, whereas the citrus juices showed no effect [59].

472

Nutrition

In a study investigating the effect of black grapes on blood antioxidant levels, 21 healthy volunteers (aged 17 to 27 years) consumed red wine (5 mL/kg body weight) or dried black grapes (1 g/kg body weight). Red wine and black grapes both had a significant effect on serum antioxidant potential, with the highest values after 2 hours in the wine group and after 4 hours in the black grape group, in accordance with the finding that the release of polyphenols from grapes and absorption into intestinal cells takes longer than polyphenols from red wine [60]. Consuming red, purple, and black grapes and grape juice on a consistent basis may prove to be a practical recommendation as an adjunct therapy for preventing and managing heart disease.

Fish n-3 Fatty Acids The inverse relationship between fatty fish consumption and CVD was first brought to light nearly 30 years ago when it was reported that Greenland Eskimos had low rates of this disease despite consuming a diet containing approximately 7 g/day of omega-3 (n-3) fatty acids from marine fish. Fatty fish (salmon, tuna, mackerel, sardines, and herring) and its oils are the predominant sources of the n-3 fatty acids eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) [61]. Reduction of triglycerides has been suggested to be one of the main cardioprotective effects of fish oils [62]. Supplements of EPA and DHA (1 g/d) are known to reduce this blood lipid in diabetic and nondiabetic participants [63]. Fish eaters have also shown to have significantly lower levels of Lp(a), even when compared with vegetarians [64]. Fish oil fatty acids also reduce platelet aggregation. A 6-week intervention with 216 mg EPA, 140 mg DHA, 390 mg gamma linoleic acid, and 3480 mg linoleic acid on in vivo platelet survival and ex vivo markers of platelet activation was performed in a placebo-controlled double-blind study involving 26 hypercholesterolemic patients. Fish oil increased platelet survival (P < 0.05) and lowered malondialdehyde formation. Platelet activation changes were associated with significant reductions in total cholesterol (-2.9%), LDL cholesterol (-3.5%), and triglycerides (-12.4%) [65]. Consumption of moderate amounts of fish (one to two servings per week) has been associated with reduced CHD mortality in white men [66], as well as reduced death from nonsudden MI [67•]. However, fish consumption has not unequivocally been shown to reduce CVD death in healthy individuals. In a recent epidemiologic study with National Health and Nutrition Examination Survey I participants that were followed for an average of 18.8 years, white men who consumed fish one time per week had an age-adjusted risk of death only about three quarters that of men who never consumed fish [68]. However, risk of cardiovascular death was not significantly reduced in these men. Although additional confirmatory studies are needed (there are still no data on whether n-3 fatty acids from fish

can cause regression of established heart disease), the current consensus is that a modest intake of fatty fish is beneficial for heart health [69].

Plant Sterol and Stanol Esters The cholesterol-lowering effect of plant sterols was first identified in the 1950s. Early research investigated the efficacy of large amounts of plant sterols (such as b-sitosterol, campesterol, and stigmasterol), which are natural components of vegetable fats/oils and pine trees. The typical American diet provides about 250 mg of phytosterols, whereas vegetarians consume twice this amount [70]. Studies have found that plant stanols, the saturated derivatives of sterols (ie, sitostanol), result in greater cholesterol-lowering than plant sterols because of their enhanced ability to reduce intestinal cholesterol absorption while remaining virtually unabsorbed. Because dietary fat appeared to be the most effective vehicle for delivery of plant stanols to the small intestine, a process was developed such that plant stanols could be esterified and solubilized in fat-based foods without altering the sensory and physical properties of the food [71]. Structurally, plant sterols and stanols resemble cholesterol, which allows them to compete with cholesterol during its absorption in the digestive tract. No significant side effects, including gastrointestinal effects, have been observed with consumption of plant stanol or sterol esters, although they have been shown to lower serum carotenoid concentrations [72]. Margarine-containing stanol esters have been on the market in Finland since 1995. In 1995, results of a landmark clinical trial conducted in Finland demonstrated that a plant stanol ester-containing margarine could significantly reduce both total and LDL cholesterol by 10% and 14%, respectively, in mildly hypercholesterolemic patients [73]. Since that time, many additional studies have clinically documented the efficacy of both plant stanol esters [74] and sterols [75] in the management of elevated cholesterol. Because of this, the FDA announced on September 8, 2000 that they were authorizing the use of health claims for the association between plant sterol/stanol esters and reduced risk of CHD [75••] in response to petitions filed by Lipton, a subsidiary of Unilever (for plant sterol esters) and McNeil Consumer Healthcare, a division of Johnson & Johnson (for plant stanol esters). Lipton’s Take Control cholesterol lowering margarine product was cleared for marketing in the US on April 30, 1999; McNeil’s competitor product, Benecol, was given clearance by the FDA on May 17, 1999. Lipton submitted 15 scientific studies conducted between 1953 and 2000 on the ability of plant sterols to lower cholesterol. Of these, the FDA reviewed only the eight studies published from 1982 (considering older literature to be of little relevance because the nature of the substance differed from that included in the petition), in addition to two additional studies identified by a literature review. Nine of

Functional Foods and Cardiovascular Disease • Hasler et al.

these 10 total studies met the following qualifying criteria outlined by the FDA: 1) present data and adequate descriptions of the study design and methods; 2) be available in English; 3) include estimates of, or enough information to estimate intakes of, plant sterols or stanols and their esters; 4) include direct measurement of blood total cholesterol and other blood lipids related to CHD; and 5) be conducted in persons who represent the general US population (ie, adults with blood total cholesterol levels less than 300 mg/dL). McNeil submitted 21 scientific studies conducted from 1993 to 2000 on the cholesterol-lowering effects of plant stanol esters; the FDA also identified three additional studies from the literature. Of the 24 studies identified, 15 met the selection criteria outlined above. Based on the totality of publicly available evidence, the FDA has concluded that plant sterol/stanol esters may reduce the risk of CHD [75], thus enabling eligible spreads and salad dressings to bear the CHD health claim. Foods bearing a health claim for plant sterols must contain at least 0.65 g of plant sterols per RACC (1.3 g divided by two servings per day). Foods exhibiting a health claim for plant stanol esters must contain at least 1.7 g of stanol esters per RACC (3.4 g divided by two servings per day). Thus, the following health claim may now be used on food labels containing plant sterols: “Foods containing at least 0.65 grams per serving of plant sterols, eaten twice a day with meals for a daily total intake of at least 1.3 grams, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease. A serving of [name of the food] supplies ___ grams of vegetable oil sterol esters.” A similar claim may be used on foods containing the qualifying level of plant stanol esters: “Foods containing at least 1.7 grams per serving of plant stanol esters, eaten twice a day with meals for a total daily intake of at least 3.4 grams, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease. A serving of [name of the food] supplies ___ grams of plant stanol esters.”

Conclusions As CVD continues to be the leading cause of mortality in the United States, resear chers, practitioners, an d consumers are searching for alternatives and additions to traditional therapies for prevention and treatment. Consistent consumption of effective levels of functional foods, including soybeans, oats, psyllium, flaxseed, garlic, tea, fish, grapes, nuts, and stanol- and sterol ester-enhanced margarine, may provide an opportunity for many consumers and patients to decrease the risk of cardiovascular disease. These foods may potentially provide benefit alone, in combination, or in addition to cholesterol-lowering medications and other therapies. Although additional studies are needed, the research in the area of functional foods and CVD reduction has been growing significantly and will continue to uncover practical, food-based recommendations for heart health.

473

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

American Heart Association, 2000. Heart and stroke statistical update. American Heart Association, Dallas, TX. 2. Shopping for Health, 1999. The growing self-care movement. PREVENTION Magazine and the Food Marketing Institute. Data collected by Roper Starch Worldwide Inc., New York, NY, 1999. 3. International Life Sciences Institute North America Food Component Reports: Crit Rev Food Sci Nutr 1999, 39:303–316. 4.•• American Dietetic Association 1999: Position of the American Dietetic Association: phytochemicals and functional foods. J Am Dietetic Assoc 1999, 99:1278–1285. The most recent position paper on functional foods by the American Dietetic Association. 5.• Department of Health and Human Services, Food and Drug Administration, 1999: 21 CFR Part 101.Food labeling: health claims; soy protein, and coronary heart disease. Fed Reg 64:57700–57733. The final rule for the 12th health claim approved by the FDA in October 1999 for the relationship between soy protein consumption and reduced risk of CHD. The daily qualifying level is 25 grams/d or 6.25 grams per serving. 6. Anderson JW, Johnstone BM, Cook-Newell ME: Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995, 333:276–282. 7. Washburn S, Burke Gl, Morgan T, Anthony M: Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 1999, 6:7–13. 8. Hodgson JM, Puddey IB, Beilin LJ, et al.: Supplementation with isoflavonoid phytoestrogens does not alter serum lipid concentrations: A randomized controlled trial in humans. J Nutr 1998, 128:728–732. 9. Nestel PJ, Pomeroy S, Kay S, et al.: Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endo Metab 1999, 84:895–898. 10. Crouse JR, Morgan T, Terry JG, et al.: A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins. Arch Int Med 1999, 159:2070–2076. 11. Merz-Demlow BE, Duncan AM, Wangen KE, et al.: Soy isoflavones improve plasma lipids in normocholesterolemic, premenopausal women. Am J Clin Nutr 2000, 71:1462–1469. 12. Potter SM: Soy–new health benefits associated with an ancient food. Nutr Today 2000, 35:53–60. 13. Tikkanen MJ, Adlercreutz H: Dietary soy-derived isoflavone phytoestrogens: could they have a role in coronary heart disease prevention? Biochem Pharmacol 2000, 60:1–5. 14. Jenkins DJA, Kendall CYC, Vidgen E, et al.: The effect on serum lipids and oxidized low-density lipoprotein of supplementing self-selected low-fat diets with soluble-fiber, soy, and vegetable protein foods. Metabolism 2000, 49:67–72. 15. Jenkins DJA, Kendall CWC, Axelsen J, et al.: Viscous and nonviscous fibers, nonabsorbable and low glycaemic index carbohydrates, blood lipids and coronary heart disease. Current Opin Lipid 2000, 11:49–56. 16.•• Department of Health and Human Services, Food and Drug Administration, 1997. 21 CFR Part 101: food labeling: Health claims; oats and coronary heart disease. Fed. Reg. 62:3584–3601. The final rule for the first food-specific health claim approved by the FDA under the NLEA in January of 1997. This document is significant as it provides a template for future coronary heart disease health claim petitions from the food industry and outlines FDA's scientific criteria required to obtain such health claims.

474

Nutrition

Brown L, Rosner B, Willett WW, Sacks FM: Cholesterollowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 1999, 69:30–42. 18. Wood PJ, Beer MU: Functional oat products. In Functional Foods. Biochemical & Processing Aspects. Edited by Mazza G. Lancaster: Technomic Publishing Co., Inc. 1998:1–38. 19. Emmons CL, Peterson DM, Paul GL: Antioxidant capacity of oat (Avena sativa L.) Extracts: In vitro antioxidant activity and contents of phenolic and tocol antioxidants. J Agric Food Chem 1999, 47:4894–4898. 20. Anonymous: Oatmeal, vitamin E can prevent reduced blood flow after high-fat meal, study finds. Food Labeling Nutr News 1999, 7:9. 21. Department of Health and Human Services, Food and Drug Administration, 21 CFR Part 101 [Docket No 96P–0338]. Food abeling: health claims; soluble fiber from certain foods and coronary heart disease: final rule. Fed Reg 1998, 63:8103–8121. 22. Anderson JW, Allgood LD, Lawrence A, et al.: Cholesterollowering effects of psyllium intake adjunctive to diet therapy in men and women with hypercholesterolemia: meta-analysis of 8 controlled trials. Am J Clin Nutr 2000, 7:472–479. 23. Anderson JW, Allgood LD, Turner J, et al.: Effects of psyllium on glucose and serum lipid responses in men with type 2 diabetes and hypercholesterolemia. Am J Clin Nutr 2000, 0:466–473. 24.• Anderson JW, Davidson MH, Blonde L, et al.: Long-term cholesterol-lowering effects of psyllium as an adjunct to diet therapy in the treatment of hypercholesterolemia. Am J Clin Nutr 2000, 71:1433–1438. A well designed clinical trial investigating the effects of psyllium fiber on cholesterol-lowering. This study is noteworthy not only because it is a multicenter effort, but also because it is significantly longer than other published studies, with a 26-week intervention period. 25. Setchell KDR: Discovery and potential clinical importance of mammalian lignans. In Flaxseed in Human Nutrition. Edited by Cunnane S, Thompson LU. Champaign, IL, AOCS Press; 1995:82–98. 26. Thompson LU, Robb P, Serraino M, Cheung F: Mammalian lignan production from various foods. Nutr Cancer 1991, 16:43–52. 27. Arjmandi BH, Khan DA, Juma S, et al.: Whole flaxseed consumption lowers serum LDL-cholesterol and lipoprotein(a) concentrations in postmenopausal women. Nutr Res 1998, 18:1203–1214. 28. Jenkins DJA, Kendall CWC, et al.: Health aspects of partially defatted flaxseed, including effects on serum lipids, oxidative measures, and ex vivo androgen and progestin activity: a controlled crossover trial. Am J Clin Nutr 1999, 69:395–402. 29. Nagourney RA: Garlic: Medicinal food or nutritious medicine? J Medicinal Food 1998, 1:13–28. 30. Schulz V, Hänsel R, Tyler VE: Cardiovascular system. In Rational Phytotherapy: A Physicians’ Guide to Herbal Medicine. New York: Springer-Verlag; 1997:107–123. 31. Warshafsky S, Kamer RS, Sivak SL: Effect of garlic on total serum cholesterol: a meta-analysis. Ann Int Med 1993, 119:599–605. 32. Silagy C, Neil A: Garlic as a lipid-lowering agent— a meta-analysis. J Royal Coll Physicians Lond 1994, 28:39–45. 33. Bordia A, Verma SK, Srivastava KC: Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibronolytic activity in patients with coronary artery disease. Prostagland Leuk Ess Fatty Acids 1998, 58:257–263. 34. Isaacsohn JL, Moser M, Stein EA, et al.: Garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial. Arch Intl Med 1998, 158:1189–1194. 35. Superko HR, Krauss RM: Garlic powder, effect on plasma lipids, postprandial lipemia, low-density lipoprotein particle size, high density lipoprotein subclass distribution and lipoprotein(a). J Amer Coll Cardiol 2000, 35:321–326. 17.

Byrne DJ, Neil HA, Vallance DT, Winder AF: A pilot study of garlic consumption shows no significant effect on markers of oxidation or sub-fraction composition of low-density lipoprotein including lipoprotein(a) after allowance for non-compliance and the placebo effect. Clinical Chim Acta 1999, 285:21–33. 37. Munday JS, James KA, Fray LM, et al.: Daily supplementation with aged garlic extract, but not raw garlic, protects low density lipoprotein against in vitro oxidation. Atherosclerosis 1999, 143:399–404. 38. Weisburger JH: Second international scientific symposium on tea and health: an introduction. Proc Soc Exp Bio Med 1999, 220:193–194. 39. Yang CS: Tea and health. Nutrition 1999, 15:946–949. 40. Yang CS, Chung JY, Yang G, et al.: Tea and tea polyphenols in cancer prevention. J Nutr 2000, 130:472S–478S. 41. Hertog MGL, Feskens EJM, Hollman PCH, et al.: Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. The Lancet 193, 342:1007–1011. 42. Sesso HD, Gaziano JM, Buring JE, Hennekens CH: Coffee and tea intake and the risk of myocardial infarction. Amer J Epidemiol 1999, 149:162–167. 43. Woodward M, Tunstall-Pedoe H: Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortality. J Epidemiol Commun Health 1999, 53:481–487. 44. Geleijnse JM, Lenore LJ, Hofman A, et al.: Tea flavonoids may protect against atherosclerosis: the Rotterdam Study. Arch Int Med 1999, 159:2170–2174. 45.• Trevisanato SI, Kim Y-I: Tea and health. Nutr Rev 2000, 58:1–10. A current and well-written overview of the role of tea consumption in disease prevention and health promotion. 46. van het Hof KH, Wiseman SA, Yang CS, Tijburg LBM: Plasma and lipoprotein levels of tea catechins following repeated tea consumption. Proc Soc Exp Biol Med 1999, 220:203–209. 47. Princen HMG, van Duyvenvoorde W, Buytenhek R, et al.: No effect of consumption of green and black tea on plasma lipid and antioxidant levels and on LDL oxidation in smokers. Arterio Thromb Vasc Biol 1998, 18:833–841. 48. Hodgson JM, Puddey IB, Croft KD, et al.: Acute effects of ingestion of black and green tea on lipoprotein oxidation. Am J Clin Nutr 2000, 71:1103–1107. 49. Fraser G, Sabate J, Beeson W, Strahan M: A possible protective effect of nut consumption on risk of coronary heart disease. Arch Int Med 1992, 152:1416–1424. 50. Sabate’ J, Fraser GE, Burke K, et al.: Effects of walnuts on serum lipid levels and blood pressure in normal men. New Eng J Med 1993, 328:603–607. 51. Bruce B, Spiller GA, Klevay LM, Gallagher SK: A diet high in whole and unrefined foods favorably alters lipids, antioxidant defenses, and colon function. J Amer Coll Nutr 2000, 19:61–67. 52. Curb JD, Wergowske G, Dobbs JC, et al.: Serum lipid effects of a high-monounsaturated fat diet based on macadamia nuts. Arch Int Med 2000, 160:1154–1158. 53. Morgan WA, Clayshulte BJ: Pecans lower low-density lipoprotein cholesterol in people with normal lipid levels. J Amer Diet Assoc 2000, 100:312–318. 54. 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 Int Med 2000, 132:538–546. 55. Iwamoto M, Sato M, Kono M, et al.: Walnuts lower serum cholesterol in Japanese men and women. J Nutr 2000, 130(2):171–176. 56. St. Leger AS, Cochrane AL, Moore F: Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. The Lancet 1979, i:1017–1020. 36.

Functional Foods and Cardiovascular Disease • Hasler et al.

Fremont L: Biological effects of resveratrol. Life Sci 2000, 66:663–673. 58.• Stein JH, Keevil JG, Wiebe DA, et al.: Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation 1999, 100:1050–1055. One of the few existing human clinical intervention trials demonstrating that commercial purple grape juice can significantly improve flow-mediated vasodilation and reduce LDL oxidation. 59. Keevil JG, Osman HE, Reed JD, Folts JD: Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. J Nutr 2000, 130:53–56. 60. Ozturk HS, Kacmaz M, Cimen MYB, Durak I: Red wine and black grape strengthen blood antioxidant potential. Nutrition 1999, 15:954–955. 61. Kris-Etherton PM, Taylor DS, Yu-Poth S, et al.: Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 2000, 71:179–188. 62. Roche HM, Gibney MJ: Effect of long chain n-3 polyunsaturated fatty acids on fasting and postprandial triacylglycerol metabolism. Am J Clin Nutr 2000, 71:232–237. 63. Yosefy C, Viskoper JR, Laszt A, et al.: The effect of fish oil on hypertension, plasma lipids and hemostasis in hypertensive, obese, dyslipidemic patients with and without diabetes. Prostaglan Leuk Essen Fatty Acids 1999, 61:83–87. 64. Marcovina SM, Kennedy H, Bon GB, et al.: Fish intake, independent of apo(a) size, accounts for lower plasma lipoprotein(a) levels in Bantu fishermen of Tanzania—the Lugalawa study. Arterio Thromb Vasc Biol 1999, 19:1250–1256. 65. Pirich C, Gaszo A, Granegger S, Sinzinger H: Effects of fish oil supplementation on platelet survival and ex vivo platelet function in hypercholesterolemic patients. Thromb Res 1999, 96:219–227. 66. Albert CM, Hennekens CH, O’Donnell CJ, et al.: Fish consumption and risk of sudden cardiac death. JAMA 1998, 279:23–28. 67.• Daviglus ML, Stamler J, Orencia AJ, et al.: Fish consumption and the 30 year risk of fatal myocardial infarction. New Engl J Med 1997, 336:1046–1053. A report on the 30-year risk of death from myocardial infarction, coronary heart disease, cardiovascular disease, and all cause mortality in the Chicago Western Electric Study. This study involved 1822 men and 47,153 person-years of follow-up and demonstrated that men consuming 35 g or more of fish daily had one third of the risk of death from coronary heart disease. 57.

475

Gillum RF, Mussolina M, Madans JH: The relation between fish consumption, death from all causes, and incidence of coronary heart disease: the NHANES I epidemiologic follow–up study. J Clin Epidemiol 2000, 53:237–244. 69. Nestel PJ: Fish oil and cardiovascular disease: lipids and arterial function. Am J Clin Nutr 2000, 71:228S–231S. 70. Messina M: Health effects of phytosterols. Soy Connection 1999, 7:3–5. 71. Cater NB: Historical and scientific basis for the development of plant stanol ester foods ascholesterol-lowering agents. Eur Heart J 1999, 1:S36–S44. 72. Levine BS, Cooper C: Plant stanol esters: a new tool in the dietary management of cholesterol. Nutr Today 2000, 35:61–66. 73. Miettinen TA, Puska P, Gulling H, et al.: Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. New Eng J Med 1995, 333:1308–1312. 74. Hendriks HFJ, Westsrate JA, Van Vliet T, et al.: Spreads enriched with three different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr 1999, 53:319–327. 75.•• Department of Health and Human Services, Food and Drug Administration. 2000. 21 CFR Part 101: food labeling health claims; plant sterol/stanol esters and coronary heart disease, interim final rule. Fed Reg 65:54686–54739. The September 8, 2000 interim final rule for the health claim on consumption of plant sterol and stanol esters and reduced risk of CHD. This will be the 13th and most recent health claim approved by the FDA under the NLEA. 68.