A number of natural products that effectively target heart health have recently begun to receive increased attention in the dietary supplement marketplace. Products such as plant sterols, polymethoxylated flavones, tocotrienols, and pomegranate have been the focus of clinical studies investigating their potential cardioprotective properties.

Phytosterols
    For over 50 years, plant sterols (also known as phytosterols) and their esters have been studied for a number of reasons including their effects on blood cholesterol in humans. Extensive clinical data in animals and humans indicate that these naturally occurring lipid-soluble compounds can play important roles in the maintenance of healthy cholesterol levels. Plant sterols and stanols can be found in vegetables, fruits, legumes, grains and oils, with some of the most common plant sterols being campesterol, sitosterol and stigmasterol (Fig. 1). As can be seen from their structure, these compounds are chemically similar to cholesterol; however, slight structural differences such as an ethyl group (sitosterol) or methyl group (campesterol) in the side chain differentiate them from cholesterol. Since plant sterols cannot be manufactured in the body, they must be obtained from the diet. Unfortunately, the typical Western diet does not supply enough sterols or stanols to result in significant alterations in blood lipids.

• In a randomized, controlled, single-blind study, 22 hypercholesterolaemic subjects were given a phytosterol enriched breakfast cereal, breads and margarine- like spreads to consume on a daily basis. After 12 weeks, subjects experienced a 13.6%reduction in median LDL cholesterol from the consumption of 2.4 g of sterol esters/day.

• A study in healthy volunteers evaluated the safety and efficacy of phytosterol-enriched spreads. This 12 month randomized, double-blind placebo-controlled study found that consumption of 1.6 g/day of phytosterols lowered total and LDL-cholesterol by 4 and 6%, respectively, and demonstrated that consumption of these phytosterols is both efficacious and safe for long term use.
   
• A study involving 38 children between the ages of 7 and 12 years with familial hypercholesterolemia consumed either a margarine type spread (placebo) or phytosterol-containing spread with 1.6 g of phytosterols for 8 weeks. Reductions in total cholesterol of 7.4% and LDL-cholesterol levels by 10.2% were observed. Triglycerides and HDL were unaffected in this study.

    The safety of phytosterols has also been confirmed by their achieving GRAS (Generally Recognized as Safe) status in the late 1990s. In 2000 the FDA approved the use of cardiovascular disease reduction claims for certain foods that contain plant sterols and stanols. Recently, the FDA has acknowledged extensions of these health claims to include a wider variety of foods including dietary supplements. The result has been an increase in the number of dietary supplements that now contain phytosterols.


Polymethoxylated Flavones
    Flavonoids are a large class of phytochemicals that have powerful antioxidant properties and play important roles in the support of both circulatory and immune health. While the benefits of flavonoids as a general class of compounds have been known for years, more recently a specific class of flavonoids called polymethoxylated flavones (also known as PMFs) have been receiving greater attention for their ability to lower cholesterol in both animal and human studies. The term polymethoxylated flavones is derived from the fact that these compounds consist of a flavone backbone to which additional methyl groups have been added (Fig. 2). Typical PMFs are compounds such as nobiletin, tangeritin and sinensetin, and can be found in concentrated amounts in the peel of citrus fruits, including oranges and tangerines.In vitro, as well as animal and in vivo human studies have demonstrated that PMFs possess potent cholesterollowering properties. Studies in human hepatoma HepG2 cells (a model used to study hepatic regulation of apolipoprotein B-containing lipoproteins including VLDL and LDL), involving nobiletin and tangeritin demonstrated the ability of these compounds to inhibit apo B secretion. The ability of these two compounds to inhibit apo B secretion was stronger than other flavonoids such as hesperetin and naringenin, which have also be studied for their ability to decrease apo B. In a recent study involving hamsters fed a hypercholesterolemic diet, the addition of 1% PMFs significantly reduced total serum cholesterol 27%, VLDL + LDL cholesterol by 40%, and triglycerides by 44%. No toxic effects of PMFs were observed. It is thought that PMF metabolites in the liver may be responsible in part for the hypolipidemic effects.

PMFs + Tocotrienols = Sytrinol™
    Intriguing data are now emerging from a new patented blend of PMFs and tocotrienols called Sytrinol™. Three human clinical studies investigating the effect of Sytrinol on blood lipids have yielded impressive results. In the first study, 10 subjects having an average total cholesterol >230 mg/dl, LDL-cholesterol > 155 mg/dl and total triglycerides of between 100 and 307 mg/dl received 300 mg of Sytrinol for 4 weeks. Compared with baseline values, total cholesterol decreased by 24%, LDL-cholesterol decreased by 19% and triglycerides dropped by 24%. These results were confirmed in a second study also involving 10 hypercholesterolemic subjects in whom similar reductions in lipid parameters were observed. A 21% reduction in apo B levels was also observed in this study, supporting the notion that polymethoxylated flavones inhibit apo B secretion. Given the success of the first two studies, a placebo-controlled, randomized, 3- phase, cross-over study involving 120 hypercholesterolemic subjects was initiated. During phase one subjects received either 300 mg/day of Sytrinol or a placebo for 12 weeks. Blood was drawn at baseline, 4, 8 and 12 weeks. The second phase of the study consisted of a 4 week washout period, followed by phase 3 in which the subjects were crossed over, so that those that received the placebo in phase 1 would then receive the active treatment. After 12 weeks, compared with baseline values, subjects receiving Sytrinol experienced statistically significant average reductions for total cholesterol, LDL-cholesterol and triglycerides of 27, 25, and 30%, respectively. No significant changes were reported in the placebo group. HDL-cholesterol was not significantly altered in either group. As of the time of this publication, the data from the first two human trials have been submitted for publication, and the third trial is now in its third phase. In all 3 studies, Sytrinol was well tolerated and there were no differences in adverse effects between the treatment and placebo groups. The strength of these results may be attributable to the unique combination of mechanisms of action by which Sytrinol is thought to work; inhibition of apo B secretion, inhibition of triglyceride synthesis, and inhibition of cholesterol synthesis.


Pomegranate
    Another interesting natural product that is receiving increased attention for its potential role in helping to maintain cardiovascular health is the pomegranate. In addition to the fact that the fruit tastes delicious and is fun to eat, pomegranates contain a wide array of beneficial polyphenolic compounds including anthocyanins, catechins, tannins, and ellagic and gallic acids (Fig. 4). Supplementation with pomegranate juice in animal studies has been shown to reduce macrophage lipid accumulation, cellular cholesterol accumulation as well as reduce the development of atherosclerosis. Recent human research has also reported the effect of supplementation with pomegranate juice in those with carotid artery stenosis. A report out of Israel earlier this year showed that after 1 year of pomegranate juice consumption, subjects with severe atherosclerosis experienced up to a 30% reduction in intima-media thickness compared with an increase in intima-thickness of 9% in the placebo group. The resistance of LDL to oxidation, as well as serum paraoxonase 1 activity was also increased after 1 year in the group receiving the pomegranate juice. Serum paraoxonase 1 (PON 1) is an enzyme associated with HDL-cholesterol that can reduce certain lipid peroxides found in arterial cells as well as lipoproteins. PON 1 has been shown to be reduced in those with diabetes and cardiovascular disease. Consequently, increases in paraoxonase activity is believed to be a beneficial outcome with respect to cardiovascular health. While the mechanisms of action and specific compounds responsible for these actions are not well understood, the combination of potent antioxidants present in pomegranates may in part be responsible for the findings. As more people look for alternatives to statin drugs, exciting natural products that help to lower cholesterol and help maintain cardiovascular health are quickly becoming a reality. Coupled with other nutrients that are well-known for their cardioprotective properties such as CoQ10, B vitamins, and omega-3 fatty acids, the addition of pomegranate, polymethoxylated flavones and plant sterols offer strong new weapons to help maintain optimal heart health.

References
American Heart Association: http://www.americanheart.org/downloadable/heart/1045754065601FS13CHO3.pdf Accessed August 16, 2004.

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