Atherosclerosis and Heart Disease Prevention
• Omega-3 Fatty Acids, Lifestyle Changes
• Antioxidants, Astragalus, Bilberry Fruit and Leaf, Chocolate, Chromium, Coenzyme Q10, Copper, Flaxseed, Garlic, Genistein, Ginger, Ginkgo, Grass Pollen, Green Tea or Black Tea, Hawthorn, Lipoic Acid, Lutein, Magnesium, Mesoglycan, Oligomeric Proanthocyanidins (OPCs), Red Yeast Rice, Resveratrol, Sea Buckthorn, Selenium, Trimethylglycine (TMG), Turmeric, Vitamin C
Atherosclerosis, often known as hardening of the arteries, leads to cardiovascular disease, and is the leading cause of death in men over age 35 and all people over 45. Most heart attacks and strokes are due to atherosclerosis. Although the origin of this condition is not completely understood, we know that it is accelerated by factors such as hypertension (high blood pressure), high cholesterol, diabetes , and milder forms of impaired glucose tolerance, smoking , physical inactivity, and obesity . Chronic inflammation in the body (of various types) is also hypothesized to play a role.
Current theories suggest that atherosclerosis begins with injury to the lining of the arteries. High blood pressure physically stresses this lining, while circulating substances such as low-density lipoprotein (LDL) cholesterol, homocysteine, free radicals, and nicotine chemically damage it. White blood cells then attach to the damaged wall and take up residence. Then, for reasons that are not entirely clear, the artery lining begins to accumulate cholesterol and other fats. Platelets also latch on, releasing substances that cause the formation of fibrous tissue. The overall effect is a thickening of the artery wall called a fibrous plaque.
Over time, the thickening increases, narrowing the bore of the artery. When blockage of the coronary arteries (the arteries supplying the heart) reaches 75% to 90%, symptoms of angina develop. In the lower legs, blockage of the blood flow leads to leg pain with exercise, a condition called intermittent claudication .
Blood clots can develop on the irregular surfaces of arteries and may become detached and block downstream blood flow. Fragments of plaque can also detach. Heart attacks are generally caused by such blood clots, whereas strokes are more often caused by plaque fragments or gradual obstruction. Furthermore, atherosclerotic blood vessels are weak and can burst.
With a disease as serious and progressive as atherosclerosis, the best treatment is prevention. Conventional medical approaches focus on lifestyle changes, such as increasing aerobic exercise , reducing the consumption of saturated fats, and quitting smoking. The regular use of aspirin also appears to be quite helpful by preventing platelet attachment and blood clot formation. If necessary, drugs may be used to lower cholesterol levels or blood pressure.
Principal Proposed Natural Treatments
This section presents some promising and not-so-promising natural approaches for preventing cardiovascular disease by fighting atherosclerosis. Note that we have left out two classes of treatments: those that reduce elevated cholesterol or blood pressure . These are discussed in their own articles. It has also been suggested that reducing levels of homocysteine might reduce cardiovascular disease risk, a subject also discussed in a separate article. In addition, other sections of this database contain articles on several conditions caused by atherosclerosis, such as angina , heart attacks , intermittent claudication , and stroke .
Omega-3 Fatty Acids
Omega-3 fatty acids are healthy fats, found in certain foods such as cold-water fish. Some evidence suggests fish or fish oil might help fight atherosclerosis. However, study results on fish or fish oil for cardiovascular disease have yielded contradictory results. 97-115,156,168 A 2002 review (technically a meta-analysis) of many studies on the subject concluded that when all the evidence is put together, it appears that fish or fish oil can slightly reduce overall mortality, heart disease mortality, and sudden cardiac death (heart stoppage due to arrhythmia). 157 However, a subsequent comprehensive review published in 2004 included additional studies and came to a more pessimistic conclusion. 190 According to the authors, working for the prestigious Cochrane Collaboration, "It is not clear that dietary or supplemental omega-3 fats alter total mortality, combined cardiovascular events or cancers in people with, or at high risk of, cardiovascular disease or in the general population."
A gigantic study (over 18,000 participants) published in 2007 was widely described in the media as finally proving beyond a shadow of a doubt that fish oil helps prevent heart problems. 211 Unfortunately, this study lacked a placebo group, and therefore failed to provide reliable evidence.
If it does provide benefit for atherosclerosis, fish oil is thought to do so primarily by reducing serum triglycerides . Like cholesterol, triglycerides are a type of fat in the blood that tends to damage the arteries, leading to heart disease. According to most, but not all studies, fish oil can modestly reduce triglyceride levels. 81-84,86,169,200 However, the standard drug, gemfibrozil, appears to be more effective than fish oil for this purpose. 85 The most important omega-3 fatty acids found in fish oil are called eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA may have different effects on triglycerides, but as typical for studies involving marginally effective treatments, study results are not consistent; some found EPA more effective than DHA, while others did not find a difference. 170-175
Similarly, some but not all studies also suggest that fish, fish oil, or EPA or DHA separately can modestly raise levels of HDL ("good") cholesterol. 87,88,169,174,175
For more information, including dosage and safety issues, see the full Fish Oil article.
Flaxseed oil (another source of omega-3 fatty acids) has been suggested as an alternative to fish oil. While fish oil is much better studied, there is some evidence, including two double-blind studies, that flaxseed oil or whole flaxseed may reduce LDL ("bad") cholesterol, perhaps slightly reduce hypertension, and slow down atherosclerosis. 118-124
Finally, while it is commonly stated that people require a certain optimum ratio of omega-3 to omega-6 fatty acids in the diet, there is no real evidence that this is true, and some evidence that it is false. 210
There is no doubt that quitting smoking will significantly reduce heart disease risk. Increasing exercise and losing weight (if you are overweight) will most likely help as well. Although for years there has been an emphasis on reducing fat in the diet, the balance of current evidence indicates that it's more useful to substitute healthy fats (such as the monounsatured fats in olive oil) for saturated fats than to try to reduce total fat intake. 191-194,201,223 Evidence suggests that any low-calorie diet, whether low-carb, low-fat, or in-between, will result in weight loss and reduced cardiac risk—provided you stick to it. 195
However, while it may not be important to cut down on total fat, accumulating evidence hints that trans-fatty acids, a type of fatty acid found in margarine and other hydrogenated oils, increase risk of cardiovascular disease. In July 2002, the US Institute of Medicine concluded that there is no safe intake level of trans-fatty acids and recommended that overall consumption should be kept as low as possible.
The moderate use of alcohol is thought to help reduce cardiovascular risk, but the evidence regarding this subject is both inherently unreliable (because it is based on observational studies ) and self-contradictory. 72-75,186,222 According to the best current evidence available, it appears to be the alcohol in alcoholic drinks that provides benefits rather than, as previously thought, particular substances found in wine. 222 The optimal intake appears to be about one drink per day for women, and 1-2 drinks per day for men. However, all of these statements are subject to revision, because, as discussed above, they are based on problematic evidence.
Other Proposed Natural Treatments
Several natural products have shown some promise for helping to prevent atherosclerosis.
Garlic is generally said to produce several effects that together reduce atherosclerosis risk. 155 Although garlic is no longer believed to strongly reduce cholesterol levels, it may improve cholesterol profiles to a modest extent; in addition, it may mildly lower blood pressure levels, as well as protect against free radicals and reduce the tendency of the blood to coagulate. 2-29 However, the actual evidence for benefit is quite incomplete.
Garlic preparations have been shown to slow the development of atherosclerosis in rats, rabbits, and human blood vessels, reducing the size of plaque deposits by nearly 50%. 30-31 Furthermore, in a double-blind, placebo-controlled study that followed 152 individuals for 4 years, standardized garlic powder at a dosage of 900 mg per day significantly slowed the development of atherosclerosis as measured by ultrasound. 32 Unfortunately, this study suffered from some significant statistical problems.
An observational study of 200 people suggests that garlic protects the arteries in other ways as well. 33 The study measured the flexibility of the aorta, the main artery exiting the heart. Participants who took garlic showed less evidence of damage to their arteries. However, observational studies are notoriously unreliable.
Finally, in another study, 432 people who had suffered a heart attack were given either garlic oil extract or no treatment over a period of 3 years. 34 The results showed a significant reduction of second heart attacks and an approximately 50% reduction in death rate among those taking garlic. Unfortunately, the researcher's failure to use a placebo in this trial greatly decreases the meaningfulness of the results.
For more information, including dosage and safety issues, see the full Garlic article.
Other Potentially Beneficial Treatments
The substance red yeast rice has shown promise for reducing cholesterol levels. A double-blind study performed in China compared red yeast rice against placebo in almost 5,000 people with heart disease. 53 Over a four-year study period, use of the supplement reportedly reduced heart attack rate by about 45% as compared to placebo and total mortality by about 35%. However, these levels of reported benefit are so high that they raise questions about the study’s reliability.
Mesoglycan is a substance obtained from the intestines of pigs. In one study, 200 mg per day of mesoglycan significantly slowed the rate of thickening of arteries. 125 After 18 months of treatment, the additional layering of the inside vessel lining was 7.5 times less in the group receiving mesoglycan than in the group that did not receive any treatment. However, because this was not a double-blind, placebo-controlled trial, the results can't be taken as truly reliable. Preliminary evidence suggests that this supplement may work in several ways: supplying material for repair of arteries, "thinning" the blood, and improving cholesterol levels. 126,127
Magnesium also appears to be helpful. In a 6-month, double-blind, placebo-controlled study, 187 individuals with angina were given either 365 mg of magnesium daily or placebo. 130 The results showed that use of magnesium significantly improved exercise capacity, lessened exercise-induced chest pain, and improved general quality of life. Additionally, magnesium may reduce the atherosclerosis risk caused by hydrogenated oils, margarine-like fats found in many "junk" foods. 129
Mildly impaired responsiveness to insulin (short of outright diabetes) is a fairly common condition that appears to increase the risk of heart disease. 131-138Chromium supplementation might restore normal insulin responsiveness, as well as aid in weight loss and possibly improve cholesterol levels. The net result might be decreased risk of heart disease. In support of this theory, an observational trial found associations between higher chromium intake and reduced risk of heart attack. 139
Some but not all observational studies suggest that green tea might help prevent heart disease. 140-143Black tea has shown inconsistent promise as well. 202-204Chocolate contains some of the same active ingredients as tea, and on this basis, it is sometimes mentioned as a potentially heart-healthy food.224
Many herbs and supplements appear to decrease platelet stickiness, including bilberry , feverfew , ginger , ginkgo , policosanol , and hawthorn . Whether this translates into an actual benefit for preventing atherosclerosis remains unknown.
Frequent consumption of nuts may reduce the risk of heart disease, 150,151,187 probably because the monounsaturated fats in nuts reduce cholesterol levels.
Wholegrain oats may help prevent heart disease, but the supporting evidence is almost entirely limited to studies conducted by manufacturers of wholegrain oat products. 212 There is little to no evidence of benefit for other whole grains because studies have not been performed.
For other natural substances that may help prevent atherosclerosis by lowering its major risk factors, see the articles on Cholesterol and Hypertension . For natural substances that may be helpful for the consequences of atherosclerosis, see the articles on Angina , Congestive Heart Failure , Heart Attack , Intermittent Claudication , and Stroke .
Chelation therapy , a technique that involves intravenous administration of the substance EDTA, is widely promoted in some alternative medicine circles as a treatment for atherosclerosis. However, there is no meaningful evidence that it works, and growing evidence that it does not work. 128,177,178
Antioxidants: Probably Not Effective
The body is engaged in a constant battle against damaging chemicals called free radicals, or pro-oxidants. These highly reactive substances are believed to play a major role in atherosclerosis, cancer, and aging in general.
To counter the harmful effects of free radicals, the body manufactures antioxidants to chemically neutralize them. However, the natural antioxidant system may not always be equal to the task. Sources of free radicals, such as cigarette smoke and smoked meat, may overwhelm this defense mechanism.
Certain dietary nutrients augment the body's natural antioxidants and may be able to help out when the primary system is under stress. Vitamins E and C and beta-carotene are the best known, but many other substances found in fruits and vegetables are also strong antioxidants. For years we've been thinking that antioxidant supplements might offer considerable protection against heart disease, especially vitamin E. However, current evidence appears to dampen these high expectations.
Before presenting this disappointing information, it is necessary to explain the weaknesses of the observational studies that raised our hopes. Observational studies are relatively inexpensive and are often used to evaluate the potential health benefits of nutrients such as antioxidants. This type of study follows large groups of people for years and keeps track of a great deal of information about them, including diet. Researchers then examine the data closely and try to identify which dietary factors are associated with better health and longer life.
However, the results can be misleading. For example, if an observational study finds that people who take vitamin supplements live longer, it is not necessarily the vitamins that deserve the credit. Vitamin users also tend to exercise more and to eat more healthful foods, habits that may play a more important role than the vitamins. It is impossible to know for sure simply by evaluating the results of such a study.
Similarly, several observational studies have found that men who consume more foods that are rich in lycopene are less likely to develop prostate cancer. But does this mean that taking lycopene supplements will reduce prostate cancer risk? Not necessarily. Such foods contain many other nutrients as well, and they may be more important than lycopene.
A more reliable kind of study is the intervention trial . In these studies, some people are given a specific substance, such as a vitamin, and then compared to others who are given a placebo (or sometimes no treatment at all). The best intervention trials use a double-blind, placebo-controlled design. The results of intervention trials are far more conclusive than those of observational studies. In the field of antioxidant therapy for preventing atherosclerosis, observational studies raised hopes, but intervention trials dashed them. (For more information on why double-blind trials are essential, see Why Does This Database Rely on Double-Blind Studies?)
Most but not all observational studies have found associations between high intake of vitamin E and reduced risk of cardiovascular disease. 48-51,162,163 However, as noted above, observational studies alone cannot be relied upon to identify useful treatments. Intervention trials, which provide much more convincing evidence of effectiveness, have overall failed to find vitamin E supplements effective. 209
The Heart Outcomes Prevention Evaluation (HOPE) trial found that natural vitamin E (d-alpha-tocopherol) at a dose of 400 IU daily did not reduce the number of heart attacks, strokes, or deaths from heart disease any more than placebo. 39 The details of this well-designed, double-blind trial were published in the January 20, 2000, issue of The New England Journal of Medicine . The trial followed more than 9,000 men and women who had existing heart disease or were at high risk for it.
In addition, a large open trial compared the effectiveness of aspirin and vitamin E for the prevention of heart attacks, strokes, and other diseases related to atherosclerosis. 41 While aspirin treatment proved somewhat helpful, vitamin E produced little to no benefit.
When the results of these studies began to come in, some antioxidant proponents suggested that the individuals enrolled in these trials already had too advanced disease for vitamin E to help. However, a large trial found vitamin E ineffective for slowing the progression of heart disease in healthy people as well. 179
On balance, the evidence strongly suggests that vitamin E in the form used in these studies (alpha-tocopherol) is not helpful for preventing heart disease. 196,197 It has been suggested that another form of vitamin E, gamma-tocopherol might be more helpful than alpha-tocopherol. 159-161,167 Gamma-tocopherol is present in the diet much more abundantly than alpha-tocopherol, and it could be that the studies showing benefits with dietary vitamin E actually tracked the influence of gamma-tocopherol. However, an observational study specifically looking to see if gamma-tocopherol levels were associated with risk of heart attack found no relationship between the two. 161 Nonetheless, intervention trials of gamma-tocopherol are currently underway.
For more information, including dosage and safety issues, see the full Vitamin E article.
The study results involving beta-carotene are interesting. Beta-carotene is one member of a large category of substances in foods known as carotenoids , which are found in high levels in yellow, orange, and dark green vegetables.
Many studies suggest that eating foods high in carotenoids can prevent atherosclerosis. 60 However, isolated beta-carotene in supplement form may not help, and could actually increase your risk, especially if you consume too much alcohol. 61
A huge, double-blind intervention trial involving 29,133 Finnish male smokers found 11% more deaths from heart disease and 15% to 20% more strokes in those participants taking beta-carotene supplements. 62 This certainly does not encourage one to take it.
Similar poor results with beta-carotene were seen in another large, double-blind study in smokers. 63 Furthermore, beta-carotene supplementation was also found to increase the incidence of angina in smokers. 64
What is happening here? Clearly, smoking presents a challenge to antioxidants. However, the question remains: Why should beta-carotene not only fail to help but actually worsen the situation?
One possible explanation is that beta-carotene in the diet always comes along with other naturally occurring carotenes. It is quite likely that other carotenoids in the diet are equally or more important than beta-carotene alone. 65 Taking beta-carotene supplements may actually promote deficiencies of other natural carotenes, 66 and overall that may hurt more than it helps.
The moral of the story is that you should eat your vegetables but maybe not take beta-carotene supplements.
A single, double-blind study suggests that the antioxidant coenzyme Q10 may help prevent the progression of atherosclerosis after a heart attack. 198 Many other antioxidant vitamins, supplements, and herbs have been suggested as preventive treatments for atherosclerosis, including selenium , OPCs from grape seed or pine bark, lipoic acid , turmeric , and resveratrol from red wine and grape skins. However, although a number of interesting studies have suggested that these substances may be beneficial, the state of the evidence is still too preliminary to draw any conclusions.
Like other berries, sea buckthorn contains high levels of natural antioxidants. It has been widely advertised as effective for preventing heart disease, but the studies upon which this claim is based are far too preliminary to prove anything at all. 213-220
It has been suggested that the best approach is to use a combination of antioxidants. This makes sense theoretically because, for example, vitamin E fights free radicals that dissolve in fats while vitamin C fights those that dissolve in water. However, evidence for benefit with such combinations comes only from observational studies. 68 A 3-year, double-blind, placebo-controlled study of 160 individuals found no benefit with combined antioxidant treatment providing vitamin E (800 IU), vitamin C (1,000 mg), beta-carotene (25 mg), and selenium (100 mcg). 69 Similarly, a 3-year, double-blind, placebo-controlled study of 423 menopausal women with coronary artery disease found no benefit with combined vitamin E (800 IU daily) and vitamin C (1000 mg daily). 189 Furthermore, a 7-year, double-blind, placebo-controlled study of more than 13,000 French men and women failed to find any significant reduction of cardiovascular disease rates through use of a daily supplement containing 120 mg of vitamin C, 30 mg of vitamin E, 6 mg of beta-carotene, 100 mcg of selenium, and 20 mg of zinc. 199
Herbs and Supplements to Use Only With Caution
Various herbs and supplements may interact adversely with drugs used to treat atherosclerosis. For more information on this potential risk, see the individual drug article in the Drug Interactions section of this database.
10. 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 Am Coll Cardiol. 2000;35:321-326.
23. Mader FH. Treatment of hyperlipidaemia with garlic-powder tablets. Evidence from the German Association of General Practitioners' multicentric placebo-controlled double-blind study. Arzneimittelforschung. 1990;40:1111-1116.
24. Steiner M, Khan AH, Holbert D, et al. A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids. Am J Clin Nutr. 1996;64:866-870.
29. Bordia A. Garlic and coronary heart disease. The effects of garlic extract therapy over three years on the reinfarction and mortality rate [translated from German]. Dtsch Apoth Ztg. 1989;129(suppl 15):16-17.
34. Bordia A. Garlic and coronary heart disease. The effects of garlic extract therapy over three years on the reinfarction and mortality rate [translated from German]. Dtsch Apoth Ztg. 1989;129(suppl 15):16-17.
39. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154-160.
40. Lonn EM, Yusuf S, Dzavik V, et al. Effects of Ramipril and vitamin E on atherosclerosis. The study to evaluate carotid ultrasound changes in patients treated with Ramipril and vitamin E (SECURE). Circulation. 2001;103:919-925.
42. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997;349:1715-1720.
44. Albanes D, Heinonen OP, Huttunen JK, et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr. 1995;62(suppl):1427S-1430S.
45. Tornwall ME, Virtamo J, Haukka JK, et al. Alpha-tocopherol (vitamin E) and beta-carotene supplementation does not affect the risk for large abdominal aortic aneurysm in a controlled trial. Atherosclerosis. 2001;157:167-173.
51. Bazzano LA, He J, Ogden LG, et al. Dietary vitamin E intake and risk of coronary heart disease in a representative sample of US adults: NHANES I Epidemiologic Follow-up Study [abstract]. Circulation. 2001;103:1366.
52. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the established populations for epidemiologic studies of the elderly. Am J Clin Nutr. 1996;64:190-196.
53. Du BM, Lu ZL, Chen Z, et al. The beneficial effects of lipid-lowering therapy with Xuezhikang on cardiac events and total mortality in coronary heart disease patients with or without hypertension: a random, double-blinded, placebo controlled clinical trial. Zhonghua Xin Xue Guan Bing Za Zhi. 2006;34:890-894.
54. Rimm EB, Ascherio A, Giovannucci E, et al. A prospective study of vitamin E and coronary heart disease among men: is benefit restricted only to primary prevention [abstract]. Circulation. 2001;103:1347.
62. [No authors listed]. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330:1029-1035.
63. Rapola JM, Virtamo J, Ripatti S, et al. Randomized trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997;349:1715-1720.
66. White WS, Stacewicz-Sapuntzakis M, Erdman JW Jr, et al. Pharmacokinetics of beta-carotene and canthaxanthin after ingestion of individual and combined doses by human subjects. J Am Coll Nutr. 1994;13:665-671.
67. Khaw KT, Bingham S, Welch A, et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. Lancet. 2001;357:657-663.
68. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr. 1996;64:190-196.
69. Brown BG, Zhao XQ, Chait A, et al. Niacin plus simvastatin, but not antioxidant vitamins, protect against atherosclerosis and clinical events in CAD patients with low HDLC. Presented at: 73rd Scientific Sessions of the American Heart Association; November 12-15, 2000; New Orleans, LA.
70. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99:779-785.
74. Hammar N, Romelsjo A, Alfredsson L. Alcohol consumption, drinking pattern and acute myocardial infarction. A case referent study based on the Swedish twin register. J Intern Med. 1997;241:125-131.
82. Durrington PN, Bhatnagar D, Mackness MI, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart. 2001;85:544-548.
84. Nenseter MS, Osterud B, Larsen T, et al. Effect of Norwegian fish powder on risk factors for coronary heart disease among hypercholesterolemic individuals. Nutr Metab Cardiovasc Dis. 2000;10:323-330.
91. Radack K, Deck C, Huster G. The effects of low doses of n-3 fatty acid supplementation on blood pressure in hypertensive subjects. A randomized controlled trial. Arch Intern Med. 1991;151:1173-1180.
95. Whelton PK, Kumanyika SK, Cook NR, et al. Efficacy of nonpharmacologic interventions in adults with high-normal blood pressure: Results from phase 1 of the Trials of Hypertension Prevention. Am J Clin Nutr. 1997;65(suppl 2):S652-S660.
109. [No authors listed]. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354:447-455.
111. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995;274:1363-1367.
115. Nilsen DW, Albrektsen G, Landmark K, et al. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am J Clin Nutr. 2001;74:50-56.
121. Singer P, Jaeger W, Berger I, et al. Effects of dietary oleic, linoleic, and alpha-linolenic acids on blood pressure, serum lipids, lipoproteins and the formation of eicosanoid precursors in patients with mild essential hypertension. J Hum Hypertens. 1990;4:227-233.
123. Jenkins DJ, Kendall CW, Vidgen E, 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.
125. Laurora G, Cesarone MR, Belcaro G, et al. Control of the progress of arteriosclerosis in high risk subjects treated with mesoglycan. Measuring the intima media [translated from Italian]. Minerva Cardioangiol. 1998;46:41-47.
126. Laurora G, Cesarone MR, De Sanctis MT, et al. Delayed arteriosclerosis progression in high-risk subjects treated with mesoglycan. Evaluation of intima-media thickness. J Cardiovasc Surg. 1993;34:313-318.
127. Tanganelli P, Bianciardi G, Carducci A, et al. Updating on in-vivo and in-vitro effects of heparin and other glycosaminoglycans (mesoglycan) on arterial endothelium: a morphometrical study. Int J Tissue React. 1992;14:149-153.
130. Schecter M, Bairey Merz CN, Stuehlinger HG, et al. Effects of oral magnesium therapy on exercise tolerance, exercise-induced chest pain, and quality of life in patients with coronary artery disease. Am J Cardiol. 2003;91:517-521.
131. Laws A, King AC, Haskell WL, et al. Relation of fasting plasma insulin concentration to high density lipoprotein cholesterol and triglyceride concentrations in men. Arterioscler Thromb. 1991;11:1636-1642.
133. Fontbonne A, Tchobroutsky G, Eschwege E, et al. Coronary heart disease mortality risk: plasma insulin level is a more sensitive marker than hypertension or abnormal glucose tolerance in overweight males. The Paris Prospective Study. Int J Obes. 1988;12:557-565.
135. Pyorala K, Savolainen E, Kaukola S, et al. Plasma insulin as coronary heart disease risk factor: relationship to other risk factors and predictive value during 9-1/2 year follow-up of the Helsinki Policemen Study population. Acta Med Scand Suppl. 1985;701:38-52.
136. Lamarche B, Tchernof A, Mauriege P, et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA. 1998;279:1955-1961.
143. van het Hof KH, de Boer HSM, Wiseman SA, et al. Consumption of green or black tea does not increase resistance of low-density lipoprotein to oxidation in humans. Am J Clin Nutr. 1997;66:1125-1132.
152. Tham DT, Gardner CD, Haskell WL. Clinical review 97: Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab. 1998;83:2223-2235.
153. Crouse JR III, 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 Intern Med. 1999;159:2070-2076.
154. Nestel PJ, Yamashita T, Sasahara T, et al. Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler Thromb Vasc Biol. 1997;17:3392-3398.
156. Angerer P, Stork S, Kothny W, et al. Effect of marine omega-3 fatty acids on peripheral atherosclerosis in patients with coronary artery disease—a randomised 2 year intervention trial [abstract]. Eur Heart J. 2001;22(suppl):162.
159. Kristenson M, Zieden B, Kucinskiene Z, et al. Antioxidant state and mortality from coronary heart disease in Lithuanian and Swedish men: concomitant cross sectional study of men aged 50. BMJ. 1997;314:629-633.
164. Leppala JM, Virtamo J, Fogelholm R, et al. Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. 2000;20:230-235.
168. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105:1897-1903.
170. Mori TA, Burke V, Puddey IB, et al. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr. 2000;71:1085-1094.
174. Davidson MH, Maki KC, Kalkowski J, et al. Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr. 1997;16:236-243.
179. Hodis HN, Mack WJ, LaBree L, et al. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002;106:1453-1459.
182. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98:204-210.
184. Willems F, Aengevaeren W, Boers G, et al. Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease. J Am Coll Cardiol. 2002;40:766.
185. Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteine-lowering therapy with folic Acid, vitamin B 12 , and vitamin B 6 on clinical outcome after percutaneous coronary intervention: the swiss heart study: a randomized controlled trial. JAMA. 2002;288:973-979.
187. Jenkins DJ, Kendall CW, Marchie A, et al. Dose response of almonds on coronary heart disease risk factors: blood lipids, oxidized low-density lipoproteins, lipoprotein(a), homocysteine, and pulmonary nitric oxide: a randomized, controlled, crossover trial. Circulation. 2002;106:1327-1332.
188. Lonn E, Yusuf S, Hoogwerf B, et al. Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care. 2002;25:1919-27.
189. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002;288:2432-2440.
191. Pelkman CL, Fishell VK, Maddox DH, et al. Effects of moderate-fat (from monounsaturated fat) and low-fat weight-loss diets on the serum lipid profile in overweight and obese men and women. Am J Clin Nutr. 2004;79:204-212.
195. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Related articles, links abstract comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. 2005;293(1):43-53.
199. Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004;164:2335-2342.
201. Howard BV, Van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295:655-666.
207. Stone PH, Lloyd-Jones DM, Kinlay S, et al. Effect of Intensive Lipid Lowering, With or Without Antioxidant Vitamins, Compared With Moderate Lipid Lowering on Myocardial Ischemia in Patients With Stable Coronary Artery Disease. The Vascular Basis for the Treatment of Myocardial Ischemia Study. Circulation. 2005 Apr 4. [Epub ahead of print]
211. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.
213. Larmo P, Alin J, Salminen E, et al. Effects of sea buckthorn berries on infections and inflammation: a double-blind, randomized, placebo-controlled trial. Eur J Clin Nutr. 2007 Jun 27. [Epub ahead of print]
214. Suomela JP, Ahotupa M, Yang B, et al. Absorption of flavonols derived from sea buckthorn ( Hippophae rhamnoides L. ) and their effect on emerging risk factors for cardiovascular disease in humans. J Agric Food Chem. 2006;54:7364-7369.
215. Zhu F, Huang B, Hu CY, et al. Effects of total flavonoids of Hippophae rhamnoides L. on intracellular free calcium in cultured vascular smooth muscle cells of spontaneously hypertensive rats and Wistar-Kyoto rats. Chin J Integr Med. 2005;11:287-292.
216. Cheng J, Kondo K, Suzuki Y, et al. Inhibitory effects of total flavones of Hippophae Rhamnoides L. on thrombosis in mouse femoral artery and in vitro platelet aggregation. Life Sci. 2003;72:2263-2271.
218. Liu FM, Li ZX, Shi S. Effects of total flavones of Hippophae rhamnoides L. on cultured rat heart cells and on cAMP level and adenylate cyclase in myocardium]. Zhongguo Yao Li Xue Bao. 1988;9:539-542.
219. Wang Y, Lu Y, Liu X, et al. The protective effect of Hippophae rhamnoides L. on hyperlipidemic serum cultured smooth muscle cells in vitro]. Zhongguo Zhong Yao Za Zhi. 1992;17:601,624-626 [ inside back cover].
221. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med. 2007;167:1610-1618.
223. Berglund L, Lefevre M, Ginsberg HN, et al. Comparison of monounsaturated fat with carbohydrates as a replacement for saturated fat in subjects with a high metabolic risk profile: studies in the fasting and postprandial states. Am J Clin Nutr. 2007;86:1611-1620.
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