Atherosclerosis and Heart Disease Prevention
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.97-115,156,168,225228,229 A 2002 review 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." And a 2012 review of 14 randomized, controlled trials involving over 20,000 people further questions the supplement's value in patients with cardiovascular disease.228 Researchers concluded that omega-3 fatty acids (ranging from 0.4-4.8 g/day) were no better than placebo at reducing rates of cardiovascular events or cardiovascular-related death. 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
A specially-processed, FDA-approved omega-3 product called Omacor (Lovaza) is widely advertised as being more effective than ordinary fish oil in reducing high triglyceride levels. A very large randomized trial, though, did not find evidence to support Omacor in people with diabetes and prediabetes.229 Over 12,000 people with type 2 diabetes or prediabetes were randomized to receive Omacor (1 g) or placebo. All of the study participants had cardiovascular disease or had risk factors for the disease. Six years later at the follow-up, researchers found that there were no differences between the two groups in regards to cardiovascular-related death, heart attacks, strokes, or heart-related hospitalizations and surgeries. The only bright spot was that Omacor did help to reduce high triglyceride levels.
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
Alpha-linolenic acid (ALA) is an omega-3 fatty acid derived from plants. There is some evidence that flaxseed oil, which contains ALA, or whole flaxseed may reduce LDL ("bad") cholesterol, perhaps slightly reduce hypertension, and slow down atherosclerosis.118-124 But, a 2010 review of ALA's potential effects on cardiovascular health did not report such promising results.227 For example, an analysis of short-term trials (lasting 6-12 weeks) involving healthy adults did not find that ALA improved cholesterol levels. There were also conflicting results pertaining to ALA’s effect on inflammation in the body and glucose metabolism (two possible risk factors for developing heart disease). ALA may, though, offer some protection against nonfatal heart attacks, but there’s no evidence that this type of omega-3 can protect against heart failure, atrial fibrillation, or sudden death.
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 monounsaturated 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 Nuts, a food known to be high in healthy fats, have been associated with improved heart health. A large cohort analyzed data of 118,962 patients from Nurse's Health Study and the Health Professionals Follow-up study. Participants that consumed two servings of any nut per week (56 grams) had lower overall mortality and mortality due to heart disease and cancer than those who consumed no nuts.232
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.
A randomized trial of 246 postal workers showed a decrease in 10-year risk assessment of heart disease when naturopathic care was added to usual care for 1 year compared to usual care alone. Naturopathic care included individualized health promotion, diet and lifestyle counseling, nutritional medicine, or dietary supplements. Keep in mind that this trial assessed the risk of heart disease it did not follow participants to see who actually developed heart disease. The trial also had some technical and statistical challenges that may have affected the outcome.231
An evaluation of 23 randomized trials with 1,461 people with coronary artery disease compared the addition of music therapy to standard care and standard care alone on stress and anxiety levels. Music listening was associated with a moderate reduction of both stress and anxiety in people who had a heart attack, were facing heart surgery, or were in cardiac rehabilitation. Music also appeared to have a beneficial effect on blood pressure, heart and breathing rates, and pain.233
Physical activity is a must for reducing risk of cardiovascular disease. There are countless ways to get exercise, but finding the right one can be tricky. Some people prefer a more nontraditional route to increasing their physical activity level. Yoga is believed by its practitioners to provide benefits above and beyond simple exercise. However, there is only minimal scientific evidence that the practice of yoga actually provides any well-defined medical benefits.
This was highlighted in a recent review of 11 randomized trials of 800 people with moderate to high risk of cardiovascular disease. At least three months of yoga showed some improvement in lowering diastolic blood pressure, triglycerides, and raising high density lipoproteins (the good cholesterol) when compared to little or no intervention. However, the trials were small and of low quality, making it difficult to draw absolute conclusions about yoga's effects on blood pressure and cholesterol.234
Qigong involves physical exercise, mind regulation, and breathing control. In a review of 11 randomized trials with 1,369 adults who were either healthy or at high risk of heart disease, Qigong was associated with significant reductions in mortality and stroke when it was combined with medications to treat hypertension. The follow-up periods were 20-30 years but the authors did not know if the patients performed Qigong exercises throughout the follow-up period. Most of the trials had small sample groups and were at high risk for bias, which affects the end results. More structured studies will need to be done to determine Qigong's affect.235
Other Proposed Natural Treatments TOP
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 A review of several observational studies of 20,951 healthy adults found those with a habitual, high intake of chocolate (16-99 g daily) had a reduced risk of cardiovascular disease when compared to those who did not eat chocolate. Cardiovascular disease was defined as a fatal or non-fatal cardiovascular event, stroke, or coronary artery disease. Similar results were found in multiple reviews that included 144,823 adults. Consumption of 3-4 servings a weeks of chocolate was associated with a lower risk of heart attack, stroke, and coronary artery disease. The type of chocolate and the amount consumed per week were not identified.236
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 TOP
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 Moreover, in an extremely large placebo-controlled trial involving over 14,000 US male physicians at low risk for heart disease, 400 IU of vitamin E every other day failed to lower the risk of major cardiovascular events or mortality over a period of 8 years.226 On the contrary, vitamin E was associated with a slightly increased risk of stroke.
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.
Other Antioxidants TOP
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
One large, double-blind study explored the potential benefit of vitamin C for preventing cardiovascular problems in women at high risk for them, but failed to find benefit.221 And, in an extremely large placebo-controlled trial involving over 14,000 US male physicians at low risk for heart disease, 500 mg of vitamin C daily did not lower the risk of major cardiovascular events or mortality over a period of 8 years.226
Combined Antioxidants TOP
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
A review of 50 randomized trials consisting of 294,478 patients evaluated prevention of cardiovascular disease with vitamins A, B6, B12, C, D, E; folic acid; beta-carotene; and selenium. There was no significant association between vitamin and antioxidant supplementation and risk of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or angina.230
References[ + ]
1. Wald DS, Bishop L, Wald NJ, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med. 2001;161:695-700.
2. Qureshi AA, Abuirmeileh N, Din ZZ, et al. Inhibition of cholesterol and fatty acid biosynthesis in liver enzymes and chicken hepatocytes by polar fractions of garlic. Lipids. 1983;18:343-348.
3. Gebhardt R. Multiple inhibitory effects of garlic extracts on cholesterol biosynthesis in hepatocytes. Lipids. 1993;28:613-619.
4. Gebhardt R, Beck H, Wagner KG. Inhibition of cholesterol biosynthesis by allicin and ajoene in rat hepatocytes and HepG2 cells. Biochim Biophys Acta. 1994;1213:57-62.
5. Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol. A meta-analysis. Ann Intern Med. 1993;119:599-605.
6. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia. A meta-analysis of randomized clinical trials. Ann Intern Med..2000;133:420-429.
7. Gardner CD, Chatterjee LM, Carlson JJ. The effect of a garlic preparation on plasma lipid levels in moderately hypercholesterolemic adults. Atherosclerosis. 2001;154:213-220.
8. Neil HA, Silagy CA, Lancaster T, et al. Garlic powder in the treatment of moderate hyperlipidaemia: a controlled trial and meta-analysis. J R Coll Physicians Lond. 1996;30:329-334.
9. Simons LA, Balasubramaniam S, von Konigsmark M, et al. On the effect of garlic on plasma lipids and lipoproteins in mild hypercholesterolaemia. Atherosclerosis. 1995;113:219-225.
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.
11. Isaacsohn JL, Moser M, Stein EA, et al. Garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial. Arch Intern Med. 1998;158:1189-1194.
12. Silagy CA, Neil HA. A meta-analysis of the effect of garlic on blood pressure. J Hypertens. 1994;12:463-468.
13. Schulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physicians' Guide to Herbal Medicine. 3rd ed. Berlin Germany: Springer-Verlag; 1998:119.
14. Auer W, Eiber A, Hertkorn E, et al. Hypertension and hyperlipidaemia: Garlic helps in mild cases. Br J Clin Pract Symp. 1990;69(suppl):3-6.
15. Agarwal KC. Therapeutic actions of garlic constituents. Med Res Rev. 1996;16:111-124.
16. Legnani C, Frascaro M, Guazzaloca G, et al. Effects of a dried garlic preparation on fibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung. 1993;43:119-122.
17. Chutani SK, Bordia A. The effect of fried versus raw garlic on fibrinolytic activity in man. Atherosclerosis. 1981;38:417-421.
18. Kiesewetter H, Jung F, Pindur G, et al. Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxicol. 1991;29:151-155.
19. Reuter HD, Sendl A. Allium sativum and Allium ursinum: Chemistry, pharmacology and medicinal applications. Econ Med Plant Res. 1994;6:56-113.
20. Popov I, Blumstein A, Lewin G. Antioxidant effects of aqueous garlic extract, 1st communication: Direct detection using the photochemiluminescence. Arzneimittelforschung. 1994;44:602-604.
21. Torok B, Belagyi J, Rietz B, et al. Effectiveness of garlic on the radical activity in radical generating systems. Arzneimittelforschung. 1994;44:608-611.
22. Efendy JL, Simmons DL, Campbell GR, et al. The effect of the aged garlic extract, "Kyolic," on the development of experimental atherosclerosis. Atherosclerosis. 1997;132:37-42.
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.
25. Holzgartner H, Schmidt U, Kuhn U. Comparison of the efficacy and tolerance of a garlic preparation vs. bezafibrate. Arzneimittelforschung. 1992;42:1473-1477.
26. Santos OS de A, Johns RA. Effects of garlic powder and garlic oil preparations on blood lipids, blood pressure and well-being. Br J Clin Res. 1995;6:91-100.
27. Koscielny J, Klussendorf D, Latza R, et al. The antiatherosclerotic effect of Allium sativum.Atherosclerosis. 1999;144:237-249.
28. Breithaupt-Grogler K, Ling M, Boudoulas H, et al. Protective effect of chronic garlic intake on elastic properties of aorta in the elderly. Circulation. 1997;96:2649-2655.
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.
30. Efendy JL, Simmons DL, Campbell GR, et al. The effect of the aged garlic extract, 'Kyolic', on the development of experimental atherosclerosis. Atherosclerosis. 1997;132:37-42.
31. Schulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physicians' Guide to Herbal Medicine. 3rd ed. Berlin, Germany: Springer-Verlag; 1998:112.
32. Koscielny J, Klussendorf D, Latza R, et al. The antiatherosclerotic effect of Allium sativum.Atherosclerosis. 1999;144:237-249.
33. Breithaupt-Grogler K, Ling M, Boudoulas H, et al. Protective effect of chronic garlic intake on elastic properties of aorta in the elderly. Circulation. 1997;96:2649-2655.
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.
41. Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet. 2001;357:89-95.
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.
43. Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta-carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial. JAMA. 1996;275:693-698.
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.
46. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781-786.
48. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328:1450-1456.
49. Manson JE, Stampfer MJ, Willitt WC, et al. A prospective study of antioxidant vitamins and incidence of coronary heart disease in women [abstract]. J Am Coll Nutr. 1992;11:609.
50. Stampfer M, Hennekens C, Manson JE, et al. Vitamin E consumption and the risk of coronary heart disease in women. N Engl J Med. 1993;328:1444-1449.
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.
60. Kohlmeier L, Hastings SB. Epidemiologic evidence of a role of carotenoids in cardiovascular disease prevention. Am J Clin Nutr. 1995;62(suppl):1370S-1376S.
61. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999;69:1071-1085.
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.
64. Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial. JAMA. 1996;275:693-698.
65. Kohlmeier L, Hastings SB. Epidemiologic evidence of a role of carotenoids in cardiovascular disease prevention. Am J Clin Nutr. 1995;62(6 suppl):1370S-1376S.
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.
71. Kubow S. Lipid oxidation products in food and atherogenesis. Nutr Rev. 1993;51:33-40.
72. Pearson TA. Alcohol and heart disease. Circulation. 1996;94:3023-3025.
73. Rimm EB, Ellison RC. Alcohol in the Mediterranean diet. Am J Clin Nutr. 1995;61(6 suppl):1378S-1382S.
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.
75. Camargo CA Jr, Stampfer MJ, Glynn RJ, et al. Moderate alcohol consumption and risk for angina pectoris or myocardial infarction in U.S. male physicians. Ann Intern Med. 1997;126:372-375.
76. Kawachi I, Colditz GA, Stone CB. Does coffee drinking increase the risk of coronary heart disease? Results from a meta-analysis. Br Heart J. 1994;72:269-275.
77. Willett WC, Stampfer MJ, Manson JE, et al. Coffee consumption and coronary heart disease in women: a ten-year follow-up. JAMA. 1996;275:458-462.
78. Sesso HD, Gaziano JM, Buring JE, et al. Coffee and tea intake and the risk of myocardial infarction. Am J Epidemiol. 1999;149:162-167.
79. Kleemola P, Jousilahti P, Pietinen P, et al. Coffee consumption and the risk of coronary heart disease and death. Arch Intern Med. 2000;160:3393-3400.
80. Jee SH, He J, Appel LJ, et al. Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol. 2001;153:353-362.
81. Harris WS. N-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(5 suppl):S1645-S1654.
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.
83. Harris WS. N-3 fatty acids and lipoproteins: comparison of results from human and animal studies. Lipids. 1996;31:243-252.
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.
85. van Dam M, Stalenhoef AF, Wittekoek J, et al. Efficacy of concentrated n-3 fatty acids in hypertriglyceridaemia: a comparison with gemfibrozil. Clin Drug Invest. 2001;21:175-181.
86. Montori VM, Farmer A, Wollan PC, et al. Fish oil supplementation in type 2 diabetes: a quantitative systematic review. Diabetes Care. 2000;23:1407-1415.
87. Cobiac L, Clifton PM, Abbey M, et al. Lipid, lipoprotein, and hemostatic effects of fish vs fish-oil n-3 fatty acids in mildly hyperlipidemic males. Am J Clin Nutr. 1991;53:1210-1216.
88. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(suppl 5):S1645-S1654.
89. Dyerberg J. N-3 fatty acids and coronary artery disease. Potentials and problems. Omega-3, Lipoproteins, and Atherosclerosis. 1996;27:251-258.
90. Lungershausen YK, Abbey M, Nestel PJ, et al. Reduction of blood pressure and plasma triglycerides by omega-3 fatty acids in treated hypertensives. J Hypertens. 1994;12:1041-1045.
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.
92. Singer P, Jaeger W, Wirth M, et al. Lipid and blood-pressure-lowering effect of mackerel diet in man. Atherosclerosis. 1983;49:99-108.
93. Singer P, Melzer S, Goschel M, et al. Fish oil amplifies the effect of propranolol in mild essential hypertension. Hypertension. 1990;16:682-691.
94. Appel LJ, Miller ER III, Seidler AJ, et al. Does supplementation of diet with 'fish oil' reduce blood pressure? A meta-analysis of controlled clinical trials. Arch Intern Med. 1993;153:1429-1438.
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.
96. Mori TA, Bao DQ, Burke V, et al. Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans. Hypertension. 1999;34:253-260.
97. Guallar E, Hennekens CH, Sacks FM, et al. A prospective study of plasma fish oil levels and incidence of myocardial infarction in U.S. male physicians. J Am Coll Cardiol. 1995;25:387-394.
98. Iso H, Rexrode KM, Stampfer MJ, et al. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA. 2001;285:304-312.
99. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312:1205-1209.
100. Shekelle RB, Missell LV, Paul O, et al. Fish consumption and mortality from coronary heart disease [letter]. N Engl J Med. 1985;313:820-821.
101. Dolecek TA, Granditis G. Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial (MRFIT). World Rev Nutr Diet. 1991;66:205-216.
102. Kromhout D, Feskens EJM, Bowles CH. The protective effect of a small amount of fish on coronary heart disease mortality in an elderly population. Int J Epidemiol. 1995;24:340-345.
103. Vollset SE, Heuch I, Bjelke E. Fish consumption and mortality from coronary heart disease [letter]. N Engl J Med. 1985;313:820-821.
104. Curb JD, Reed DM. Fish consumption and mortality from coronary heart disease [letter]. N Engl J Med. 1985;313:821-822.
105. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757-761.
106. Ascherio A, Rimm EB, Stampfer MJ, et al. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men. N Engl J Med. 1995;332:977-982.
107. Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation. 1994;90:2248-2257.
108. Sacks FM, Stone PH, Gibson CM, et al. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. J Am Coll Cardiol. 1995;25:1492-1498.
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.
110. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343:1454-1459.
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.
112. Billman GE, Hallaq H, Leaf A. Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids. Proc Natl Acad Sci USA. 1994;91:4427-4430.
113. Sellmayer A, Witzgall H, Lorenz RL, et al. Effects of dietary fish oil on ventricular premature complexes. Am J Cardiol. 1995;76:974-977.
114. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757-761.
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.
118. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(suppl):1645S-1654S.
119. Prasad K. Dietary flax seed in prevention of hypercholesterolemic atherosclerosis. Atherosclerosis. 1997;132:69-76.
120. Arjmandi BH, Khan DA, Juma S, et al. Whole flaxseed consumption lowers serum LDL-cholesterol and lipoprotein(a) concentrations in postmenopausal women. Nutr Res. 1998;18:1203-1214.
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.
122. Prasad K. Reduction of serum cholesterol and hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglucoside isolated from flaxseed. Circulation. 1999;99:1355-1362.
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.
124. Tarpila S, Kivinen A. Ground flaxseed is an effective hypolipidemic bulk laxative [abstract]. Gastroenterology. 1997;112:A836.
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.
128. Anderson TJ, Hubacek J, Wyse DG, et al. Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH substudy. J Am Coll Cardiol. 2003;41:420-425.
129. Kummerow FA, Zhou Q, Mahfouz MM. Effect of trans fatty acids on calcium influx into human arterial endothelial cells. Am J Clin Nutr. 1999;70:832-838.
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.
132. Job FP, Wolfertz J, Meyer R, et al. Hyperinsulinism in patients with coronary artery disease. Coron Artery Dis. 1994;5:487-492.
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.
134. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996;334:952-957.
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.
137. Saydah SH, Loria CM, Eberhardt MS, et al. Subclinical states of glucose intolerance and risk of death in the U.S. Diabetes Care. 2001;24:447-453.
138. Haffner SM. The importance of hyperglycemia in the nonfasting state to the development of cardiovascular disease. Endocr Rev. 1998;19:583-592.
139. Guallar E, Jimenez J, van t' Veer P, et al. The association of chromium with the risk of a first myocardial infaction in men. The EURAMIC Study [abstract]. Circulation. 2001;103:1366.
140. Imai K, Nakachi K. Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases. BMJ. 1995;310:693-696.
141. Kono S, Shinchi K, Ikeda N, et al. Green tea consumption and serum lipid profiles: a cross-sectional study in northern Kyushu, Japan. Prev Med. 1992;21:526-531.
142. Tsubono Y, Tsugane S. Green tea intake in relation to serum lipid levels in middle-aged Japanese men and women. Ann Epidemiol. 1997;7:280-284.
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.
144. Barrett-Connor E, Goodman-Gruen D. Dehydroepiandrosterone sulfate does not predict cardiovascular death in postmenopausal women. The Rancho Bernardo Study. Circulation. 1995;91:1757-1760.
145. Herrington DM, Nanjee N, Achuff SC, et al. Dehydroepiandrosterone and cardiac allograft vasculopathy. J Heart Lung Transplant. 1996;15:88-93.
146. Jesse RL, Loesser K, Eich DM, et al. Dehydroepiandrosterone inhibits human platelet aggregation in vitro and in vivo.Ann N Y Acad Sci. 1995;774:281-290.
147. Barrett-Connor E, Khaw K-T, Yen SSC. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med. 1986;315:1519-1524.
148. Nafziger AN, Herrington DM, Bush TL. Dehydroepiandrosterone and dehydroepiandrosterone sulfate: their relation to cardiovascular disease. Epidemiol Rev. 1991;13:267-293.
149. Barrett-Connor E, Khaw K-T. Absence of an inverse relation of dehydroepiandrosterone sulfate with cardiovascular mortality in postmenopausal women [letter]. N Engl J Med. 1987;317:711.
150. Fraser GE, Sabate J, Beeson WL, et al. A possible protective effect of nut consumption on risk of coronary heart disease. The Adventist Health Study. Arch Intern Med. 1992;152:1416-1424.
151. Hu FB, Stampfer MJ, Manson JE, et al. Frequent nut consumption and risk of coronary heart disease in women: prospective cohort study. BMJ. 1998;317:1341-1345.
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.
155. Ackermann RT, Mulrow CD, Ramirez G, et al. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med. 2001;161:813-824.
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.
157. Bucher HC, Hengstler P, Schindler C, et al. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2002;112:298-304.
158. Ohrvall M, Sundlof G, Vessby B. Gamma, but not alpha, tocopherol levels in serum are reduced in coronary heart disease patients. J Intern Med. 1996;239:111-117.
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.
160. Kontush A, Spranger T, Reich A, et al. Lipophilic antioxidants in blood plasma as markers of atherosclerosis: the role of alpha-carotene and gamma-tocopherol. Atherosclerosis. 1999;144:117-122.
161. El-Sohemy A, Baylin A, Spiegelman D, et al. Dietary and adipose tissue gamma-tocopherol and risk of myocardial infarction. Epidemiology. 2002;13:216-223.
162. Muntwyler J, Hennekens CH, Manson JE, et al. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch Intern Med. 2002;162:1472-1476.
163. Marchioli R, Schweiger C, Levantesi G, et al. Antioxidant vitamins and prevention of cardiovascular disease: epidemiological and clinical trial data. Lipids. 2001;36:S53-63.
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.
165. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23-33.
166. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.
167. Jiang Q, Christen S, Shigenaga MK, Ames BN. Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74:714-722.
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.
169. Yam D, et. al. The effect of omega-3 fatty acids on risk factors for cardiovascular diseases. Harefuah. 2001;140:1156-1158.
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.
171. Rambjor GS, Walen AI, Windsor SL. Eicosapentaenoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans. Lipids. 1996;31(suppl):S45-49.
172. Agren JJ, Hanninen O, Julkunen A, et al. Fish diet, fish oil and docosahexaenoic acid rich oil lower fasting and postprandial plasma lipid levels. Eur J Clin Nutr. 1996;50:765-771.
173. Childs MT, King IB, Knopp RH. Divergent lipoprotein responses to fish oils with various ratios of eicosapentaenoic acid and docosahexaenoic acid. Am J Clin Nutr. 1990;52:632-639.
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.
175. Leigh-Firbank EC, Minihane AM, Minihane AM, et al. Eicosapentaenoic acid and docosahexaenoic acid from fish oils: differential associations with lipid responses. Br J Nutr. 2002;87:435-445.
176. Schmitz PG, McCloud LK, Reikes ST, et al. Prophylaxis of hemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial. J Am Soc Nephrol. 2002;13:184-190.
177. Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA. 2002;287:481-486.
178. Ernst E. Chelation therapy for coronary heart disease: An overview of all clinical investigations. Am Heart J. 2000;140:4-5.
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.
180. Aronow WS. Association between plasma homocysteine and vascular atherosclerotic disease in older persons. Prev Cardiol. 2000;3:89-91.
181. Desouza C, Keebler M, McNamara DB, et al. Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs. 2002;62:605-616.
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.
183. Sen S, Oppenheimer SM, Lima J, et al. Risk factors for progression of aortic atheroma in stroke and transient ischemic attack patients. Stroke. 2002;33:930-935.
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.
186. Gronbaek M Alcohol, type of alcohol, and all-cause and coronary heart disease mortality. Ann N Y Acad Sci. 2002;957:16-20.
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.
190. Hooper L, Thompson R, Harrison R, et al. Omega 3 fatty acids for prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev. 2004;CD003177.
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.
192. Lichtenstein AH. Dietary fat and cardiovascular disease risk: quantity or quality? J Womens Health (Larchmt). 2003;12:109-114.
193. Hu FB, Willett WC. Optimal diets for prevention of coronary heart disease. JAMA. 2002;288:2569-2578.
194. Sacks FM, Katan M. Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease. Am J Med. 2002;113:13S-24S.
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.
196. Eidelman RS, Hollar D, Hebert PR, et al. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med. 2004;164:1552-1556.
197. Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003;361:2017-2023.
198. Singh RB, Neki NS, Kartikey K, et al. Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction. Mol Cell Biochem. 2003;246:75-82.
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.
200. Balk EM, Lichtenstein AH, Chung M et al. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: A systematic review. Atherosclerosis. 2006 Mar 9. [Epub ahead of print].
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.
202. Hakim IA, Alsaif MA, Alduwaihy M, et al. Tea consumption and the prevalence of coronary heart disease in Saudi adults: results from a Saudi national study. Prev Med. 2002;36:64-70.
203. Vinson JA. Black and green tea and heart disease: a review. Biofactors. 2001;13:127-132.
204. Sesso HD, Paffenbarger RS Jr, Oguma Y, et al. Lack of association between tea and cardiovascular disease in college alumni. Int J Epidemiol. 2003;32:527-533.
205. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338-1347.
206. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005;294:56-65.
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]
208. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2004 Dec 10. [Epub ahead of print]
209. Buring JE. Aspirin prevents stroke but not MI in women; vitamin E has no effect on CV disease or cancer. Cleve Clin J Med. 2006;73:863-870.
210. Harris WS. The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep. 2006;8:453-459.
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.
212. Kelly S, Summerbell C, Brynes A, et al. Wholegrain cereals for coronary heart disease. Cochrane Database Syst Rev. 2007 Apr 18;CD005051.
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.
217. Wang ZR, Wang L, Yin HH, et al. Effect of total flavonoids of hippophae rhamnoides on contractile mechanics and calcium transfer in stretched myocyte. Space Med Med Eng (Beijing). 2000;13:6-9.
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].
220. Eccleston C, Baoru Y, Tahvonen R, et al. Effects of an antioxidant-rich juice (sea buckthorn) on risk factors for coronary heart disease in humans. J Nutr Biochem. 2002;13:346-354.
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.
222. O'Keefe JH, Bybee KA, Lavie CJ. Alcohol and cardiovascular health: the razor-sharp double-edged sword. J Am Coll Cardiol. 2007;50:1009-1014.
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.
224. Hooper L, Kroon PA, Rimm EB, et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2008;88:38-50.
225. Ong HT, Cheah JS. Statin alternatives or just placebo: an objective review of omega-3, red yeast rice and garlic in cardiovascular therapeutics. Chin Med J (Engl). 2008;121:1588-1594.
226. Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2008;300:2123-2133.
227. Geleijnse JM, de Goede J, Brouwer IA. Alpha-linolenic acid: is it essential to cardiovascular health? Curr Atheroscler Rep. 2010;12(6):359-367.
228. Kwak SM, Myung SK, Lee YJ, Seo HG. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012 Apr 9.
229. ORIGIN Trial Investigators, Bosch J, Gerstein HC, et al. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309-318.
230. Myung SK, Ju W, Cho B, et al. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2013;346:f10.
231. Seely D, Szczurko O, et al. Naturopathic medicine for the prevention of cardiovascular disease: a randomized clinical trial. CMAJ. 2013;185(9):E409-E416.
232. Bao Y, Han J, et al. Association of nut consumption with total and cause-specfiic mortality. N Engl J Med. 2013;369(21):2001-2011.
233. Bradt J, Dileo C. Music for stress and anxiety reduction in coronary heart disease patients. Cochrane Database Syst Rev. 2009;(2):CD006577.
234. Hartley L, Dyakova M, et al. Yoga for the primary prevention of cardiovascular diseases. Cochrane Database Syst Rev. 2014;5:CD010072.
235. Hartley L, Lee MS, Kwong JS, et al. Qigong for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2015;6:CD010390.
236. Larsson SC, Åkesson A, Gigante B, Wolk A. Chocolate consumption and risk of myocardial infarction: a prospective study and meta-analysis. Heart. 2016 ;102(13):1017-1722.
Last reviewed December 2015 by EBSCO CAM Review Board
Last Updated: 10/14/2016
EBSCO Information Services is fully accredited by URAC. URAC is an independent, nonprofit health care accrediting organization dedicated to promoting health care quality through accreditation, certification and commendation.
This content is reviewed regularly and is updated when new and relevant evidence is made available. This information is neither intended nor implied to be a substitute for professional medical advice. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with questions regarding a medical condition.
To send comments or feedback to our Editorial Team regarding the content please email us at firstname.lastname@example.org. Our Health Library Support team will respond to your email request within 2 business days.