Phytochemicals are chemicals found in plants. Plant sterols, flavonoids (FLAV'oh-noidz), and sulfur-containing compounds are three classes of micronutrients found in fruits and vegetables. These compounds may be important in reducing the risk of atherosclerosis (ath"er-o-skleh-RO'sis), which is the buildup of fatty deposits in artery walls. Within these categories are many possible compounds, most of which aren't well described and whose modes of action aren't established. Many other plant products may also be linked to the atherosclerotic process, such as antioxidant vitamins, phytoestrogens and trace minerals. These plant micronutrients will clearly be the topic of future research. As work continues on all these compounds, other unrecognized components in plants will be identified that may have promise in reducing risk of cardiovascular disease.

AHA Recommendation

More research on phytochemicals is needed in these areas:

• Nutritional databases must include better information on micronutrients.
• Large population-based studies with collected dietary data should then be reanalyzed to quantify intakes of plant sterols, flavonoids and sulfur-containing compounds, and to assess possible relationships with atherosclerosis and other chronic diseases.
• 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.
• A direct assessment of the influence of micronutrients on lipoprotein profiles, hemostatic factors and cardiovascular disease must be made. Some micronutrients may not act alone but in concert with other dietary components.

Until more of this information is gathered and fully understood, the American Heart Association recommends eating a balanced diet containing a wide variety of fruits, vegetables and whole-grain products. Eating a variety of foods is the most prudent way to ensure that you get the optimum amounts of both macronutrients and micronutrients. Use of foods containing plant sterols should be reserved for adults requiring lower total and LDL cholesterol levels because they are at high risk of -- or have had -- a heart attack.

Background

Large population studies have often shown links between the intake of vegetables and fruits and coronary heart disease that aren't 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 numerous possible plant components, many of these studies are based on a small sample of subjects or were poorly controlled. Further, the notion itself has led to claims of  "miracle" ingredients with supposed beneficial effects on cardiovascular diseases and other chronic diseases.

Substantial evidence exists in three areas: plant sterols, flavonoids and plant sulfur compounds. Here is a summary of the state of knowledge in these three areas and information about possible 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 major ones -- sitosterol (si"to-STEER'ol), stigmasterol (stig"mah-STEER'ol) and campesterol (kam-PES'ter-ol) -- can be present in Western diets in amounts almost equal to dietary cholesterol. The most prominent is sitosterol. In the early 1950s it was noted that adding sitosterol to the diet of cholesterol-fed chickens or rabbits lowered cholesterol levels in both species and inhibited the development of atherosclerosis in rabbits. Sitosterol or mixtures of soy sterols were studied extensively as cholesterol-lowering agents between 1950 and 1960. They lowered cholesterol by about 10 percent. This area merits reinvestigation using newer technologies.

In the 1980s it was demonstrated that sitostanol (si"to-STAN'ol), a saturated sitosterol derivative, reduced the absorption of cholesterol and blood cholesterol more effectively than sitosterol and at doses below those of sitosterol. In a recent study, sitostanol was combined or "interesterified" with margarine. The resultant product reduced plasma cholesterol an average of 10.2 percent in a population with mild hypercholesteremia. The sitostanol wasn't absorbed and didn't seem to interfere with absorption of fat-soluble vitamins. In 1999 several companies began marketing margarine and other products containing either stanol or sterol esters. Studies in Finland suggest these products can help lower cholesterol.

Squalene (SKWAH'leen), 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. 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 found in studies using these products. This may explain differences seen between various sources and degrees of refinement of olive oil. There are also cholesterol-lowering alcohols in rice bran oils. Several recent studies suggest that rice bran oil lowers plasma cholesterol levels about 7-10 percent in humans.

Finally, cafestol (KAF'es-tol) is a terpene present in coffee. Some studies have suggested that drinking coffee may be linked with changes in plasma cholesterol that may be explained by the presence of this compound. The manner of preparation may influence the effect of coffee; for example, filtering may remove some cholesterol-raising compounds.

Flavonoids

Flavonoids (FLAV'oh-noidz) are compounds with varied chemical structures present in fruits, vegetables, nuts and seeds. The major flavonoid categories are flavonols (FLAV'oh-nolz), flavones (FLAV'onz), catechins (KAT'eh-kinz), flavanones (FLAV'ah-nonz) and anthocyanins (an"tho-SI'ah-ninz). The main dietary sources of these compounds are tea, onions, soy and wine. The main flavonoid in onions is quercetin glucoside (KER'seh-tin GLU'ko-s?d) and the main flavonoid in tea is quercetin rutinoside (KER'seh-tin roo-TIN'o-syd).

Flavonoid intake has been inversely linked with coronary heart disease in the Zutphen Elderly Study, the Seven Countries Study and a cohort study in Finland. That is, people with a low intake of flavonoid had a higher death rate from coronary heart disease than did those who consumed more flavonoid (about five to six cups of tea per day). It should be pointed out that some flavonoids have toxic effects (gastrointestinal or allergic), especially if taken in large amounts. Systematic work is needed on the major classes of flavonoids to study their structure, effectiveness and potential harmful effects.

The link between flavonoids and atherosclerosis is based partly on the evidence that some flavonoids have antioxidant (an"tih-OK'sih-dant) properties. For example, the phenolic (fen-OL'ik) substances in red wine inhibit oxidation of human LDL. Flavonoids also have been shown to inhibit the aggregation and adhesion of platelets in blood, which may be another way they lower the risk of heart disease. Isoflavones (i"so-FLAV'-onz) in soy foods have been reported to lower plasma cholesterol and also to have effects similar to estrogen.

Plant sulfur compounds

Naturally occurring sulfur-containing compounds (the allium family) are found especially in garlic, onions and leeks, the most prominent of these being garlic. In 2000, the Agency for Healthcare Research and Quality (AHRQ) published an evidence-based "Report on Garlic: Effects on Cardiovascular Risks and Disease, Protective Effects Against Cancer, and Clinical Adverse Effects." Here are the main findings:

• Thirty-six randomized trials, all but one in adults, consistently showed that, compared with placebo, various garlic preparations led to small, statistically significant reductions in total cholesterol at one month (range of average pooled reductions 1.1 to 15.8 milligrams per deciliter [mg/dL]) and three months (range of 11.6 to 24.3 mg/dL). Eight trials with outcomes at six months showed no significant reductions of garlic compared with placebo. Changes in low-density lipoprotein levels (LDL) and triglycerides mirrored total cholesterol results; no significant changes in high-density lipoprotein levels (HDL) were found.
• Twenty-six small, randomized, placebo-controlled trials, all but one in adults, reported mixed, but never large, effects of various garlic preparations on blood pressure outcomes.
• Twelve small, randomized trials suggested various garlic preparations had no clinically significant effects on glucose in persons with or without diabetes. Two small short trials reported no statistically significant effects of garlic compared with placebo on serum insulin or C peptide levels.
• Ten small, short-duration trials, all but one in adults, showed effects of various garlic preparations on platelet aggregation and mixed effects on plasma viscosity (vis-KOS'ih-te) and fibrinolytic (fi-brin"o-LIT'ik) activity.
• There were insufficient data to confirm or refute garlic's effects on clinical outcomes such as myocardial infarction and claudication.
• Scant data, primarily from case-control studies, suggest, but do not prove, that dietary garlic consumption is associated with decreased odds of laryngeal, gastric, colorectal, and endometrial cancer and adenomatous (ad-eh-NOM'ah-tus) colorectal polyps.
• Adverse effects of oral ingestion of garlic are "smelly" breath and body odor. Other possible, but not proven, adverse effects include flatulence, esophageal and abdominal pain, small intestinal obstruction, dermatitis, rhinitis, asthma and bleeding.

What are the conclusions?

Trials show several promising, modest, short-term effects of garlic supplements on lipid and antithrombotic factors. Effects on clinical outcomes are not established, and effects on glucose and blood pressure are none to minimal. High dietary intake of garlic may be associated with decreased risks of multiple cancers. Our ability to interpret existing data is limited by marked variability in types of garlic preparations that have been studied and inadequate definition of active constituents in the various preparations.