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(Circulation. 1997;95:2591.)
© 1997 American Heart Association, Inc.

Articles

Phytochemicals and Cardiovascular Disease

A Statement for Healthcare Professionals From the American Heart Association

Barbara V. Howard, PhD; David Kritchevsky, PhD

, For the Nutrition Committee

Key Words: AHA Medical/Scientific Statements • cholesterol • atherosclerosis • lipoproteins

Epidemiological studies have often shown relationships between vegetable/fruit intake and coronary heart disease that are not clearly attributable to major macronutrients or known vitamins and minerals. This suggests that other components of plants may be important in lowering risk of cardiovascular disease. Although the literature contains studies of a myriad of possible plant components, many of these studies are small or poorly controlled. Further, the supposition itself has led to claims of "miracle" ingredients with supposed mitigating effects on cardiovascular as well as other chronic diseases. A substantial body of evidence has accumulated in three areas: plant sterols, flavonoids, and plant sulfur compounds. This review summarizes the state of knowledge in these three areas and explores possibilities for future work.

Plant Sterols

The plant kingdom contains a number of sterols that differ from cholesterol by having ethyl or methyl groups or unsaturation in the side chain. The predominant ones—sitosterol, stigmasterol, and campesterol—can be present in Western diets in amounts almost equal to dietary cholesterol.¹ The most prominent is ß-sitosterol, which differs from cholesterol in that it has an ethyl group at carbon 24 of the side chain. In the early 1950s it was noted that the addition of sitosterol to the diet of cholesterol-fed chickens or rabbits lowered cholesterol levels in both species and inhibited atherogenesis in the latter.² Sitosterol or mixtures of soy sterols were studied extensively as cholesterol-lowering agents between 1950 and 1960.³ The preparations achieved cholesterol lowering of approximately 10%.⁴ The mode of action appears to involve inhibition of cholesterol absorption, although the plant sterols themselves are absorbed very poorly.⁵ The mechanism of inhibition of cholesterol absorption is believed to be through crystallization and co-precipitation. Ingestion of 1 g of ß-sitosterol reduced absorption of cholesterol by 42% in a meal containing 500 mg of cholesterol.⁶ The decrease in plasma cholesterol is probably due to an increase in LDL receptor activity. However, the decline in plasma cholesterol is relatively less than the decrease in absorption, presumably because of a compensatory increase in cholesterol synthesis. This area merits reinvestigation using newer technologies.

In the 1980s it was demonstrated that sitostanol, a 5- saturated sitosterol derivative, reduced the intestinal absorption of cholesterol and serum cholesterol more effectively than sitosterol and at doses below those of sitosterol.⁷ In a recent study⁸ sitostanol was interesterified with margarine, and the resultant product (1.9 to 2.6 g sitosterol per day) exhibited a hypocholesterolemic effect in a population with mild hypercholesteremia. The mean 1-year reduction in plasma cholesterol was 10.2%. The sitostanol was not absorbed and did not appear to interfere with absorption of fat-soluble vitamins.

Squalene, a sterol precursor also found in plant products, was originally suggested to have a cholesterol-lowering effect, but earlier studies in animals showed that it had no positive influence on atherosclerosis.² Sitosterols and squalene are present in both monounsaturated and polyunsaturated vegetable oils and thus may be responsible for some of the variable cholesterol-lowering effects observed in studies using these products; this may explain differences observed between various sources and degrees of refinement of olive oil. Other cholesterol-lowering alcohols in rice bran oils include esters of triterpene alcohols that inhibit hepatic cholesterol esterase and tocotrienols that inhibit HMG Co-A reductase.⁹ However, there is conflicting evidence as to whether rice bran oil decreases plasma cholesterol levels in humans.¹⁰

Finally, cafestol is a terpene present in coffee. Some studies but not others have suggested that coffee intake may be associated with changes in plasma cholesterol that may be explained by the presence of this compound. Suggestions have been made that the manner of preparation may influence the effect of coffee; filtering may remove some cholesterol-raising compounds.

Flavonoids

Flavonoids are derivatives of 2-phenyl-1-benzopyran-4-one with varied chemical structures present in fruits, vegetables, nuts, and seeds.^{11 12} The major flavonoid categories are flavonols, flavones, catechins, flavanones, and anthocyanins. The main dietary sources of these compounds are tea, onions, soy, and wine. The main flavonoid in onions is quercetin glucoside and the main flavonoid in tea is quercetin rutinoside. Flavonoid intake has been inversely associated with coronary heart disease in the Zutphen Elderly Study,¹³ the Seven Countries Study,¹⁴ and a cohort study in Finland.¹⁵ In the Zutphen Elderly Study,¹³ for example, a flavonoid intake of 0 to 19.0 mg/d was associated with a coronary heart disease mortality rate of 18.5 per 1000 person-years, compared with a mortality rate of 7.8 among those who consumed more than 29.9 mg/d (30 mg/d represents approximately five to six cups of tea per day). It should be pointed out that some flavonoids exert toxic effects (gastrointestinal or allergic), especially if taken in large amounts. Systematic work is needed on the major classes of flavonoids to categorize their structure, efficacy, and potential adverse effects. The link between flavonoids and atherosclerosis is based partly on the evidence that some flavonoids possess antioxidant properties and have been shown to be potent inhibitors of LDL oxidation in vitro. For example, the phenolic substances in red wine inhibit oxidation of human LDL.¹⁶ Flavonoids have also been shown to inhibit platelet aggregation and adhesion,¹⁷ which may be another way they lower the risk of heart disease. Isoflavones in soy foods have been reported to lower plasma cholesterol and also to have estrogenlike effects.¹⁸

Plant Sulfur Compounds

Naturally occurring sulfur-containing compounds (the allium family) may influence plasma cholesterol and atherosclerosis. These substances are found especially in garlic, onions, and leeks, the most prominent of these being garlic. Garlic oil was in the pharmacopeia of the Babylonians and other ancient peoples.¹⁹ Garlic oil or garlic has been shown to be hypolipidemic in humans, with a recent meta-analysis suggesting that one half clove of garlic per day lowered serum cholesterol by approximately 9%.²⁰ The same amount of garlic was shown to reduce cholesterol levels and severity of atherosclerosis in cholesterol-fed rabbits.²¹ Garlic contains a number of compounds, but those thought to be the most active are diallyl disulfide and its mono S oxide (allicim). The mechanism of hypocholesterolemia may be the inhibition of cholesterol synthesis.²² Garlic has also been reported to inhibit platelet aggregation,²³ decrease coagulation time,²⁴ and lower blood pressure.²⁵ Garlic in large quantities, however, can actually have significant side effects, such as anemia or allergic manifestations.¹⁹ Much more work is needed in the chemistry and pharmacology of the sulfur-containing compounds in plants.

Conclusions

Plant sterols, flavonoids, and sulfur-containing compounds represent three classes of compounds found in fruits and vegetables that may be important in reducing risk of atherosclerosis. Within these categories are multiple possible compounds, most of which are not well characterized and whose modes of action are not established. In addition, many other plant products (ie, antioxidant vitamins, phytoestrogens, and trace minerals) may also be linked to the atherosclerotic process. These plant micronutrients will clearly be the topic of future research. As work continues on all of these compounds, other unrecognized components will be identified.

Nutritional databases must be further developed to include better information on micronutrients, and large population-based studies that contain collected dietary data should be reanalyzed using improved nutritional databases to quantify consumption of plant sterols, flavonoids, and sulfur-containing compounds and to assess possible relationships with atherosclerosis and other chronic diseases. In addition, careful metabolic studies using newer techniques to measure cholesterol absorption and lipoprotein metabolism must be conducted to define the mechanism of action of each of these micronutrients. Finally, a direct assessment of the influence of micronutrients on lipoprotein profiles, hemostatic factors, and cardiovascular disease must be made. It should be recognized that some micronutrients may not act alone but in concert with other dietary components. Thus, benefits may come from the integration of several dietary components.

Until more of this information is gathered and fully understood, consumption of a balanced diet containing a wide variety of fruits, vegetables, and whole-grain products is recommended as the most prudent way to ensure optimum consumption of macronutrients and micronutrients.

Footnotes

"Phytochemicals and Cardiovascular Disease" was approved by the American Heart Association Science Advisory and Coordinating Committee in November 1996.

A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Avenue, Dallas, TX 75231-4596. Ask for reprint No. 71-0115. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or . To make photocopies for personal or educational use, call the Copyright Clearance Center, 508-750-8400.

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