Reducing the risk of coronary heart disease is still the top priority for health agencies the world over. Researchers have identified a solid handful of nutritional ingredients that addresses CHD by either lowering LDL cholesterol or raising HDL. Vijaya Juturu, PhD, investigates
Coronary heart disease (CHD) is one of the leading causes of death among men and women in the US and worldwide.1,2 The prevalence of risk factors—such as obesity and diabetes—that predispose individuals and populations to CHD is rising rapidly. Several clinical and epidemiological studies have shown that elevated blood cholesterol levels are associated with the development of CHD.3,4,5 In particular, these studies have demonstrated that low-density lipoprotein cholesterol (LDL-C) was the primary lipoprotein mediating atherosclerosis.
Population studies such as the Framingham Heart Study, the Lipid Research Clinics Trial and the Multiple Risk Factor Intervention Trial reported a direct relationship between levels of LDL-C (as well as total cholesterol) and the rate of new-onset CHD.4,5,6 In particular, LDL-C above 100mg/dL appears to be atherogenic. LDL-C circulating in the blood sticks to the walls of the arteries together with other complex substances and forms plaque. The plaque becomes a thick, hard deposit and blocks the arteries, causing atherosclerosis.
In addition, it is known that inflammation in the blood-vessel wall plays an essential part in both the development of atherosclerosis and the rupture of atherosclerotic plaques. Certain markers in the blood such as C-reactive protein, cytokines, interleukin, fibrinogen, serum amyloid A (SAA), serum viscosity, plasminogen activator inhibitor-1 and von Willebrand factor are known to rise when inflammation is present. Researchers are investigating whether these markers are raised in people with coronary heart disease. However, these inflammatory markers further stratify the risk of coronary heart disease. The inflammatory cycle continues and enhances the lesion to form an atherosclerotic plaque and a disruption of coronary blood flow in the arteries.
Other risk factors such as cigarette smoking, hypertension, diabetes and a low level of high-density lipoprotein (HDL) cholesterol also enhance CHD risk.7
Several clinical trials suggested that lowering of coronary risk lipids and lipoproteins reduces the risk of CHD and associated diseases.8,9,10 Risk stratification continues for LDL-C-lowering therapy and to increase HDL cholesterol. Nutritional therapy remains the first step of treatment, with drug therapy reserved for use in patients at high risk for CHD or patients who do not respond to diet and exercise alone. (See Table 1)
The American Heart Association earlier this year recommended four goals for preventing cardiovascular disease: Achieve a healthy overall diet, achieve a healthy weight, promote desirable blood lipid levels, and promote desirable blood pressure. Improving diet quality by incorporating fruits and vegetables, whole legumes, whole cereals and reduced fatty acids, including dairy products, is essential for preventing cardiovascular disease.11
Treating hypercholesterolemia begins with lifestyle changes. Losing weight, stopping smoking, exercising more, and reducing the amount of fat and cholesterol in the diet helps to bring cholesterol levels down to normal levels. However, some people need to use cholesterol-reducing therapy to reduce their risk of CHD problems.
Table 2 summarises the beneficial effects of the active functional nutrients to reduce the risk of CHD through cholesterol modulation. The purpose of this article is to review the clinical significance of the biological active components such as policosanol, plant stanols and sterols, soy peptides, soy esters, soy protein, isoflavones, and vitamins and minerals on improving cholesterol levels in humans. Also addressed is the possible mechanisms by which these components may affect lipids and lipoprotein metabolism.
Essential Alcohols: Policosanol
For the past couple of decades, research focus has been on the role of biological active dietary components in the control of lipids and lipoprotein metabolism. Policosanol is a mixture of essential alcohols isolated from sugar cane wax (Saccharum officinarum L). It consists of octacosanol (66 per cent), hexacosanol (7 per cent), triacontanol (12 per cent) and 15 per cent eicosanol, tetracosanol, nonacosanol, dotriacontanol, tetratriacontanol and heptacosanol.
Both human and animal studies strongly support the cholesterol-lowering effect of policosanol. Short-term (eight weeks) and long-term (12 months and two years) double-blind clinical trials in patients with type II hypercholesterolemia have a significant decrease of total cholesterol (17 to 18 per cent) and LDL-C (25 per cent) and a very significant increase of HDL-C (21 to 28 per cent).12,13,14
A recent study reported that after 24 weeks, policosanol at 20 and 40 mg/day significantly lowered LDL cholesterol by 27.4 per cent and 28.1 per cent, total cholesterol by 15.6 per cent and 17.3 per cent, and LDL/HDL cholesterol ratio by 37.2 per cent and 36.5 per cent, respectively.15 The ratio of total cholesterol/HDL cholesterol was lowered by 27.1 per cent and 27.5 per cent, while HDL cholesterol levels increased by 17.6 per cent and 17.0 per cent, respectively.
Policosanol at 20mg/day lowered triglycerides by 12.7 per cent and further lowered these levels by 15.6 per cent at a dose of 40mg/day, meaning that higher doses of policosanol show greater effects of lowering coronary risk lipids and lipoproteins. In 179 older patients, after 6 weeks on a lipid-lowering diet, 5 and 10mg/day policosanol for 12 weeks significantly decreased the ratios of LDL-C to HDL-C (29.1 per cent) and TC to HDL-C (28 per cent), although the triglycerides remained unchanged. In addition, numerous recent studies have reported that the policosanol cholesterol-lowering effect was better than that of statins. 15,16,17,18,19,20 Intermittent claudication, 16,21 platelet aggregation 22,23 and dyslipidemia in diabetes risk 15,24 were reduced with policosanol. Also, the sugar-derived ingredient shows positive effects against cerebrovascular disorders. 25
Overall, policosanol has been well tolerated in numerous clinical trials on more than 1,200 people, with doses up to 40mg/day, and more effective than cholesterol-lowering drugs tested in the reported studies in reducing coronary risk lipids and lipoproteins.
Plant Stanols/Sterol Esters
Plant sterols and stanols are present naturally in small quantities in many fruits, vegetables, nuts, seeds, cereals, legumes, vegetable oils and other plant sources. Dietary plant stanols and sterols inhibit the absorption of cholesterol in the small intestine by up to 50 per cent and decrease LDL-C by 14 per cent. The major antiatherogenic effects of plant sterols are the inhibition of intestinal cholesterol absorption, biological activities of phytosterols were lecithin: cholesterol acyltransferase activity, bile acid synthesis, oxidation and uptake of lipoproteins, hepatic and lipoprotein lipase activities and normalisation of the coagulation system.26 These have been linked to their anti-atherogenic properties. Plant stanols and sterols combined with statins further enhances the cholesterol-lowering effects by 20 per cent.27
Stanols and sterols have been tolerated in at least 14 clinical trials with doses up to about 2 to 3g/day. In these studies, it was reported that total cholesterol was decreased by 10 to 12 per cent, LDL-C by 9 to 14 per cent and there was no effect on HDL-C.28,29 A reduction of 25 per cent risk of heart disease can be expected with these LDL-cholesterol changes. Intakes greater than 3g/day do not seem to further decrease any additional total-C and LDL-C.
Soy Protein And Isoflavones
Soy protein and isoflavones are used in the form of isolated soy protein or textured soy protein and isoflavones as genistein and daidzein. In 38 clinical trials totalling 743 patients, an average consumption of 47g/day soy protein (range 18 to 124g/day), in place of animal protein, lowered total cholesterol, LDL cholesterol and triacylglycerol concentrations by about nine per cent (0.60mmol/L), 13 per cent (0.56 mmol/L), and 11 per cent (0.15mmol/L), respectively.30 No changes were found in serum HDL cholesterol concentrations. The changes in serum total and LDL cholesterol concentrations, however, depended on the initial serum total cholesterol concentration. That is, the higher the starting point, the greater the decline.
Based on studies with cell cultures, animals or humans, proposed mechanisms include increases in LDL receptor activity, increases in the synthesis and faecal excretion of bile acids, and a suppression of cholesterol absorption.
The effects of isoflavones on CHD risk factors are controversial. Overall, the total cholesterol is decreased by 5 to 9 per cent, LDL-C by 6 to 8 per cent at active doses of >20g/day of soy protein and >27mg/day isoflavones.30,31 Hypocholesterolemic effect of isoflavones was not reported in all studies. The significance of inconsistent findings on the effects of isoflavones on lipids and lipoproteins remains uncertain. It is not clear whether isoflavones in the soy are responsible for the proposed hypocholesterolemic effects. However, in October 1999, the FDA approved a heart-health claim for 25g/day soy protein for foods containing at least 6.25g soy protein per serving, allowing producers to state it may reduce the risk of heart disease.
Soybean protein peptide is a biologically active peptide substance composed of two or more units of amino acids. The human body can easily absorb soybean protein peptide to meet the body's demands for energy to accelerate metabolism and improve immune function.
Recently conducted research suggests soy protein-derived peptides represent a potential source of bioactive components that can be incorporated into foods and thereby contribute to the hypothesised health benefits of soy foods. Studies have shown that soybean peptides can lower blood pressure and blood fat levels, enhance immunity, lower cholesterol, prevent cardiac and brain blood-vessel diseases, and inhibit the growth of tumours. Researchers have hypothesised that specific peptides from soy proteins can beneficially modulate cholesterol homeostasis in an in vitro system, which may not be possible in vivo because large undigested peptides are unlikely to cross the intestinal barrier and appear in the circulation.32 Others have suggested that one or more peptides escaping detection in vivo might reach the liver after intestinal digestion, thus eliciting a cholesterol-lowering effect.33
Moreover, these data indicate that the protein moiety, devoid of isoflavone components, is responsible for the biochemical effect. One study reported that a commercial isoflavone-free, heat-hydrolyzed soy concentrate (Croksoy) was effective in type II hypercholesterolemic patients via LDL-receptor activation.34
Researchers at the University of Milan in Italy conducted in vitro and in vivo studies to investigate the hypothesis that soybean globulins might be involved in the direct up-regulation of liver or peripheral lipoprotein receptors.32,35,36 The results of these studies suggest that soybean globulins, especially the 7S globulin, may stimulate high-affinity LDL-cholesterol receptors in human liver cell cultures. Furthermore, animals on a hypercholesterolemic diet that were fed isolated 7S globulin experienced a significant lowering of blood cholesterol.32 Further studies are required to explore the mechanism of action of these peptides to reduce CHD events. Table 3 summarises the cholesterol-lowering effects of soy protein and isoflavones, plant stanols and sterols, niacin and policosanol.
Vitamins And Minerals
Antioxidant vitamin supplementation may help to prevent coronary heart disease (CHD). Epidemiologic and clinical studies have shown that antioxidants in foods or supplements lower CHD morbidity and mortality.37 Although basic research suggests that vitamins may have an important role in the prevention of cardiovascular diseases, the data from cohort studies and clinical trials have been inconclusive. Current evidence suggests that patients with CHD would probably benefit from taking vitamin E in a dosage of 400IU per day and vitamin C in a dosage of 500 - 1,000mg/day. The results of beta-carotene studies were not supportive for smokers with CHD.
Niacin is available in a number of different formulations according to the speed of drug release. Studies have found immediate-release and the intermediate, or extended-release, to be equivalent with respect to their efficacy in decreasing triglycerides and increasing HDL-C. A 2000 study published in the Journal of the American Medical Association reported that niacin was the most effective in raising HDL but can significantly increase blood glucose, particularly at a high dose.38
Niacin at modest doses (750 to 2,000mg/day) can reduce LDL-C, triglycerides and increase HDL-C. Niacin produces beneficial effects on lipoprotein subclasses, specifically decreasing the more atherogenic small, dense LDL particles and enhancing the cardioprotective large HDL particles. Niacin appears to raise HDL cholesterol by reducing hepatic apolipoprotein A-l clearance and enhancing reverse cholesterol transport.
Improved serum lipid levels during niacin therapy have been associated with clinical and angiographic evidence of reduced coronary artery disease, especially when combined with statins. However its effects in diabetes are controversial. One recent report indicated that an induction of insulin resistance by nicotinic acid increases the availability of circulating fatty acids to muscle rather than with increased muscle lipid content.40
Chromium as chromium picolinate reduces coronary risk lipids and lipoproteins in hypercholesterolemia, dyslipidemia.41 Chromium levels that are low are associated with an insulin resistance and an increased risk of CHD.42 Each micrograms-per-litre decrease in serum chromium concentration had a 6.4 per cent increase in probability. Researchers in a recent study reported that the effect of chromium supplementation (200 to 1000mcg/day) on blood lipid profiles has been tested in five placebo-controlled, double-blind clinical trials (total of 318 subjects and duration of 6 to 16 weeks). Four studies showed decreases in total cholesterol and/or LDL-C.42
Other chromium forms, such as chromium chloride, chromium polynicotinate and high-chromium yeast are used but have less research to back them. The polynicotinate form is bound with niacin. In one randomised, double-blind, placebo-controlled study, 40 hypercholesterolemic subjects with total cholesterol levels between 210 and 300mg/dL received either placebo, 200mcg/day chromium polynicotinate, 100mg/day grape seed extract, or a combination of chromium and the grape seed extract. After two months, the combination significantly lowered LDL-C by 20 per cent compared to a 3 per cent lowering with placebo. Neither HDL-C nor triglyceride concentrations were significantly different.43 Chromium supplementation as Cr picolinate and Cr yeast in humans demonstrated a significant decrease of total - C, LDL-C, triglycererides, Apo-B and an increase of HDL-C. Studies have shown that chromium improves insulin sensitivity reduces elevated blood sugar and glycated hemoglobin levels.44,45The reduced blood-sugar levels and insulin improvement may reduce the risk of macro and micro vascular complications. Thus, chromium supplementation may help reduce the risk of an early onset of coronary heart disease by reducing the associated coronary risk complications. Further studies are required to explore the mechanism of action on CHD events reduction.
Other compounds, such as ubiquinone (Co-Q10), bioflavonoids, selenium, garlic and other supplements have not been adequately tested for CHD event reduction, appropriate dosing, reliability or long-term safety.
Functional bioactive compounds such as conjugated linoleic acid, CLA isomers (t10, c12), omega-3 fatty acids, monounsaturated fatty acids, lycopene, resveratrol, beta-glucan, phytochemical compounds from oil seeds, nuts, Gugulipid (resin of the Commiphora mukul tree) arginine and silica are showing significant improvement in the endothelial function and reductions in the coronary-risk lipids and lipoproteins. Long-term consumption of these compounds and clinical manifestation of CHD need to be studied with an effective combination of with and without drugs.
An overall balanced and nutritious dietary regimen will reduce the risk of CHD. Some of the nutritional bioactive compounds are showing therapeutic use of lowering risk of coronary heart disease. Hence, it is important to document its mechanism, under various conditions, such as in combination with cholesterol-lowering diets or drugs, and in different population groups. Long-term studies are required for the additional health benefits of these compounds and for any adverse health effects.
Vijaya Juturu, PhD, is a nutritional scientist in Research and Development, Technical Services and Scientific Affairs at Nutrition 21 Inc in Purchase, New York.
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