![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Medical College of Georgia, Augusta, Georgia
INTRODUCTION BACKGROUND DIET MODIFICATIONS AND HEART DISEASE RISK AND OUTCOMES INTERVENTION STUDIES WITH WALNUTS OBSERVATIONAL STUDIES ON CONSUMPTION OF WALNUTS AND OTHER NUTS AND CORONARY HEART DISEASE OTHER RELEVANT OBSERVATIONAL STUDIES MECHANISMS WALNUTS AS A FOOD COMPOSITION OF WALNUTS CONTROLLED INTERVENTION STUDIES WITH NUTS OTHER THAN WALNUTS PROTEINS IN NUTS AND AS A FACTOR IN HEART DISEASE RISK OVERVIEW AND SUMMARY OF CLINICAL TRIALS WEIGHT OF EVIDENCE CONCLUSIONS
 |
ABSTRACT |
|---|
 TOP Next |
|---|
KEY WORDS: • walnuts • coronary heart disease • nuts • legumes • polyunsaturated fatty acids
|
INTRODUCTION |
|---|
|
TOPPreviousNext |
|---|
Investigating the relation of diet to disease prevention can encompass evaluating foods for specific nutrients or nonnutrient chemicals, alone or in combination; however, whole foods, or their constituents, may have disparate effects. An example is the relation of fruits and vegetables and their content of antioxidants to the prevention of heart disease or cancer. Because the detailed composition of individual meals consumed by humans is not well documented, attention to individual foods is necessary. Dietary studies rarely enroll sufficient subjects to evaluate the effect of a single change of diet on cardiovascular morbidity or mortality. More often investigators use surrogate endpoints or biomarkers, eg, blood lipids and lipoproteins or blood pressure (BP) that are risk factors for vascular disease. Other risk factors such as cigarette smoking, obesity, family history, glucose intolerance, level of physical activity, age, and gender may be confounders. Atherosclerosis is a progressive disease of the arteries; its pathogenesis continues to undergo active investigation.
|
BACKGROUND |
|---|
|
TOPPreviousNext |
|---|
Research for more than 45 y has defined the relationship of CHD to total cholesterol (TC) and the major lipoprotein fractions. There is almost complete agreement that hypercholesterolemia [elevated TC and low-density lipoprotein-cholesterol (LDL-C)] is a risk factor for CHD. The ranges of concentrations that define the risk are agreed upon, and changes in risk of CHD in relation to changes in cholesterol concentrations have been demonstrated in prospective trials. Changes in the cholesterol concentrations of populations have been related to the incidence of CHD in numerous observational studies. The positive relationship of high-density lipoprotein-cholesterol (HDL-C) to the reduction of heart disease risk also has been defined. The contribution of genetic makeup to the lipid and lipoprotein risk factors is recognized conceptually. Any modulation of lifestyle may be limited by the inherent genetic makeup of the subject (see section on Fats and fatty acids in relation to blood lipids and lipoproteins and artherosclerosis).
CHD is the leading cause of death in the United States: 32% of females and 50% of males will develop CHD, and it is the cause of death in 24% of females and 31% of males. Increasing the serum TC level raises the risk of CHD and decreasing it will reduce risk. The risk of developing CHD is continuous over the range of serum TC levels, with moderate risk associated with levels exceeding 5.2 mmol/L (200 mg/dL), and high risk with >6.2 mmol/L (240 mg/dL). LDL-C levels can be classified similarly into low, moderate, and high risk. Coronary events are reduced by 2-3% for every 1% decrease in LDL-C, as reported in the Helsinki Heart Study (1
). Small, dense LDL particles are associated with a tripling of the risk of myocardial infarction (MI) compared to the larger, more buoyant LDL particles. An elevated level of lipoprotein (a) [Lp (a)] also increases the risk of atherosclerosis. The smaller Lp (a) particles are more atherogenic, and may act by promoting LDL oxidation and decreasing endothelial-dependent vasodilatation and by enhancing retention of LDL in the arterial wall. Lp (a) may also have antifibrinolytic activity, an independent risk factor for atherothrombosis (2
).
In contrast, HDL-C levels are inversely related to the risk of CVD. Risk is appreciably higher in subjects with HDL levels < 0.9 mmol/L (35 mg/dL), and risk decreases as HDL levels increase to > 1.6 mmol/L (60 mg/dL). The highest levels of HDL-C are considered a negative risk factor, ie, they reduce the risk of CVD. Coronary events are reduced by 3% for every 1% increase in HDL-C. The ratios of TC:HDL-C and LDL:HDL-C indicate varying degrees of the risk of CVD.
The results of a more recent multicenter randomized clinical study—the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial, as reported by Rubins and Robins (3
) and Rubins et al. (4
)—showed the benefit of raising HDL and lowering triacylglycerol levels, independent of effects on the LDL-C level. As a result of dietary intervention in this study, subjects showed no change in LDL-C, a 31% reduction in triacylglycerol, a 6% increase in HDL, a 22% reduction in CHD death and nonfatal MI, and a 29% decrease in stroke. The triacylglycerol level in blood is elevated by increases in energy, fat, carbohydrates, and alcohol. Recent data support the concept that higher triacylglycerol levels increase the risk of CHD, independent of HDL levels or other confounding factors of the dyslipidemic syndrome (ie, glucose intolerance, hyperinsulinism, obesity, and hypertension). This relationship applies especially to diabetic persons and females. Triacylglycerol levels > 2.6 mmol/L (100 mg/dL) increase the risk of CVD, independent of the usual accompanying low HDL. Fasting hypertriglyceridemia may be a stronger predictive risk factor than TC (5
), as reported in a meta-analysis of 17 population-based studies on triacylglycerol levels and CVD. The Physicians’ Health Study (6
) also supports triacylglycerol as an independent risk factor of MI.
Other predictive risk factors for CVD may include levels of fasting plasma insulin and apolipoprotein B (apo B), LDL particle size, and levels of circulating apoproteins. Absolute levels of apoproteins, or changes in lipoprotein particle size, or single amino acid mutations (as in apo-E isoforms) may be better predictors of CHD than lipid levels. It is not known whether these putative risk factors are responsive to dietary change or relevant beyond the specific subpopulations in which they have been evaluated, thus their value for planning dietary interventions is not clear. The relationship of apoprotein polymorphism to diet responsiveness is intriguing and under scrutiny. Elevated triacylglycerol levels may help identify individuals at high risk because of the associated predominance of small, dense LDL particles in these individuals. Elevated levels of insulin as a result of fasting are associated with impaired fibrinolysis and hypercoagulability in individuals with normal or abnormal glucose tolerance, thus enhancing the potential for acute thrombosis.
Although the relationship of the concentration and composition of blood lipids and lipoproteins to cardiovascular risk and atherosclerosis has been suspected for a century, the usefulness of various parameters in predicting disease or CHD events, or their responses to manipulations of lifestyle remain to be elucidated.
Fats and fatty acids in relation to blood lipids and lipoproteins and atherosclerosis
Current scientific consensus supports the value of using lifestyle modifications as a primary prevention mechanism to lower blood cholesterol in order to decrease heart disease risk. Not all of the population is responsive to such interventions, and CHD occurs in the presence of cholesterol levels within the "normal" range.
Feldman (7
) has surveyed the association of diet and CVD. Dietary fats, especially saturated fat (SF) and cholesterol, raise the levels of serum/plasma TC, LDL-C, and triacylglycerol that increase CHD risk. Components of the diet may affect HDL-C, the lipoprotein that lessens CHD risk. Antioxidants (eg, vitamins E and C) may lessen the risk of CVD by decreasing oxidized LDL, which is more atherogenic. High blood levels of the amino acid homocysteine (Hcy) are associated with increased atherosclerosis and are decreased by the intake of folate and vitamins B6 and B12 (see section on Factors and mechanisms other than fats or blood lipids that affect CVD risk).
From the decline in cardiovascular mortality that was observed due to dietary restrictions during the Great Depression and World War II, we can infer the relation of the fat content and the fatty acid composition of the diet to the pathogenesis of atherosclerosis. The dietary fat-heart hypothesis was proposed by Keys (8
) and Keys et al. (9
) and related CHD rates to the intake of dietary fat, especially SF. A recent 25-year follow-up report (10
) of the earlier study by Keys confirmed that the relative increase in CHD mortality due to a given cholesterol increase was similar in all cultures except Japan. A 0.52 mmol (20 mg) increase in serum TC corresponded to an increase in CHD mortality of 12%, increasing to 17% when adjusted for regression dilution bias.
Similarly, diets that are high in total fat (TF), SF, and cholesterol are atherogenic for many animal species. Cholesterol is found in the diet only in animal products and is not present in any plant sources. Long-chain saturated fatty acids (SFAs) in animal or vegetable fats raise plasma cholesterol levels and decrease LDL receptor activity. Paradoxically, these fats also raise HDL-C levels. Liquid vegetable oils with high concentrations of monounsaturated fatty acids (MUFAs) may have a cholesterol-lowering effect and decrease LDL-C, but not HDL-C; some monounsaturated oils may lower triacylglycerol. Polyunsaturated fats (PUFAs) of the n-6 series in liquid vegetable oils decrease LDL-C; increased amounts of PUFA may lower HDL-C. The n-3 series of very long-chain, more unsaturated PUFAs found in fish and fish oils have variable effects on TC, LDL, and HDL-C, and lower the triacylglycerol levels. Trans-fatty acids are produced with some processes of partial hydrogenation of unsaturated liquid vegetable oils (in the United States, predominantly soybean oil). These fatty acids raise LDL-C somewhat less than the long- or medium-chain SFAs of butter, but, in contrast, lower HDL-C.
Theories of atherogenesis propose that LDL-C is the offending agent, delivering cholesterol to the arterial wall and initiating the pathogenic sequelae including endothelial injury. Endothelial injury initiates proliferation of vascular smooth muscle cells (SMCs) and conversion of monocytes to macrophages (cholesterol ester-laden foam cells) with proliferation of fibroblasts under the influence of growth factors and cytokines. Endothelial erosion is associated with atherosclerosis. Oxidized LDL accelerates the formation of foam cells, atheroma, and fibrous plaque. Plaque rupture initiates the events of MI. CHD progression is related directly to levels of TC and LDL-C, and inversely to HDL-C, especially HDL2-C (a fraction of HDL-C) or the ratio of HDL2-C:LDL-C. Levels of triacylglycerol > 6.5 mmol/L (250 mg/dL) increase the risk for MI and warrant intervention; more recent data on risk prevention suggest lowering this risk level, perhaps to 2.6 mmol/L (100 mg/dL). When LDL-C levels are reduced, cholesterol is removed from plaque thereby leading to regression of atherosclerosis. The National Cholesterol Education Program (11
) has set a goal of LDL 
2.6 mmol/L (100 mg/dL) in secondary prevention of CHD (ie, in those who have already suffered an MI). This level of LDL usually parallels a TC value < 4.7 mmol/L (180 mg/dL).
Current theories of atherogenesis implicate plaque rupture with the release of a necrotic lipid core as the precipitating factor for thrombosis at the site and MI. Lipid-lowering, especially of LDL-C, stabilizes the plaque and reduces the risk of MI. Lower lipid levels may also decrease local concentrations of modified lipoproteins that have proinflammatory effects. With intervention, CVD mortality may be decreased by 25%, and incidence of MI by 50%. A significant drop in LDL-C has been shown to halt the progression of coronary atherosclerosis (12
). The percent drop in LDL correlates 1:1 with the decrease in coronary events. Maximal dietary therapy typically reduced LDL-C levels by 0.39-0.65 mmol/L (15-25 mg/dL), or about 5–10%.
The 2001 National Cholesterol Education Program (13
) proposed a multifaceted approach, designated "therapeutic lifestyle changes", to reduce the risk for CHD.
) recommends a total dietary fiber intake of 25–30 g/day from food, about double the current intake in the United States.
) is based on a soluble fiber intake of 3 g/day (3 servings of oatmeal, 28 g each, each with 1 g of ß-glucan soluble fiber). This soluble fiber can decrease TC and LDL-C by approximately 0.13 mmol/L (16
).
,18
).
The American Heart Association recently issued a revised set of dietary guidelines (19
) that are more individualized than before and that are food-based. There are four population-wide goals:
Major guidelines are set for each goal. In the detailed American Heart Association scientific statement, nuts are specified in several guidelines. Nuts are referred to under Goal 1 in a paragraph about soluble fibers, viz., "Grains, vegetables, fruits, legumes, and nuts are good sources of fiber."
For Goal 3, nuts are listed under a guideline that limits foods with a high content of SF and cholesterol. The dietary recommendation is to "substitute grains and unsaturated fatty acids from fish, vegetables, legumes, and nuts." In a more detailed discussion, the report states that meta-analysis showed that 1 g of soluble fiber in the substituted foods (including nuts) would be expected to decrease LDL-C by an average of 0.057 mmol/L (2.2 mg/dL) (16
). This section of the revised American Heart Association guidelines also discusses the evidence that foods rich in long-chain n-3 PUFAs confer cardioprotective effects beyond their effect on the improvement of the lipoprotein profile. These include reduction in sudden death (20
,21
), decreased risk of arrhythmia (22
), lower plasma triacylglycerol levels (23
), and a reduced blood-clotting tendency with eicosapentaenoic acid (20:5n-3, EPA) (24
) and docosahexaenoic acid (22:6n-3, DHA) (25
). In females, 
-linolenic acid (18:3n-3) reduces risk of MI and fatal ischemic heart disease (IHD) (26
,27
). The report also cited the randomized controlled Lyon heart diet trial (28
) that demonstrated the beneficial effects of -linolenic acid on both coronary morbidity and mortality in patients with CHD. Nuts are specified as foods high in n-3 fatty acids, as are other plant sources (eg, flaxseed and flaxseed oil, canola oil, and soybean oil) and fatty fish. Under the heading "issues that merit further research," the section on n-3 fatty acid supplements states that intakes of EPA and DHA of approximately 900 mg/day could beneficially affect CHD mortality rates in patients with coronary disease.
Goal 4 recommends consuming a dietary pattern that emphasizes fruits, vegetables, LF dairy products, and is reduced in fat and cholesterol. The revised American Heart Association guidelines also discuss the study known as the Dietary Approaches to the Study of Hypertension (DASH) (29
). The DASH clinical trial includes nuts in the dietary pattern and results in reduced systolic and diastolic BP, especially in African American hypertensive patients. Recent study results on DASH have been published by Conlin et al. (30
), Sacks et al. (31
), and Svetkey et al. (32
).
Factors and mechanisms other than fats or blood lipids that affect CVD risk
Other proposals have emphasized increasing the intake of n-3 fatty acids in fish and n-3 oils like flaxseed for prevention of CHD, in part because of their favorable action on prostaglandins. Cholesterol-lowering plant sterols, or their derivatives (ie, esters of sitosterol and sitostanol) have been added to fats and salad dressings. The FDA has authorized a health benefit claim for plant sterol/stanol esters and CHD (33
). Other dietary components that lower cholesterol or reduce oxidized cholesterol include 25 g/day of soy protein (34
), and perhaps 37 mg/day of the soy isoflavones (35
), and the antioxidant vitamins E and C (explained below). The amount and type of dietary protein can affect levels of TC and LDL-C. Animal proteins are hypercholesterolemic, and plant proteins are hypocholesterolemic. This may be attributed to the content of the amino acids lysine and methionine in animal proteins and arginine in plant proteins (see section on Proteins in nuts as a factor in heart disease risk).
Moderate intake of alcoholic beverages (1–2/day, 10/week) raises HDL-C levels, and intake of rice bran or olive and canola oils may as well. The tocotrienols, plant sterols, or flavonoids in these oils may be partially responsible for an antiatherogenic effect. As vascular biologists derive more scientific data, they may find that foods influence atherogenesis by mechanisms that are less dependent on lipid:lipoprotein levels and more dependent on vascular reactivity and thrombus formation, in part mediated by nitric oxide (NO). Thus, the diet-heart hypothesis has evolved from the direct relationship of fat-to-heart-disease via blood lipids to more complex associations of foods, nutrients, and phytochemicals, along with genetic and molecular mechanisms of CVD, its pathology and clinical expression.
An elevated blood Hcy level is a risk factor for CVD. Hcy increases in relation to deficient intake or metabolism of folate, and vitamins B6 and B12. The following conclusions have been drawn from several recent studies on Hcy. First, Hcy is an independent risk factor for CHD equivalent in importance to hyperlipidemia and smoking, is a strong predictor of CVD mortality, and accounts for 10% of the attributed risk of CHD (36
). Second, Hcy promotes prothrombotic changes in the vascular environment, arterial narrowing and endothelial cell toxicity, affects platelets and clotting control mechanisms, and stimulates smooth muscle cell proliferation. Third, investigators (37
) have linked hyperhomocysteinemia with premature vascular occlusive diseases, viz., carotid occlusive disease, cerebrovascular disease, CHD, peripheral arterial occlusive disease, and veno-occlusive disease. The issue of Hcy and cardiovascular risk is addressed in a recent editorial (38
) in the American Journal of Clinical Nutrition and in two articles written from opposite standpoints (39
,40
).
The relative risk (RR) of CVD is increased significantly when Hcy levels exceed 
15.8 µmol/L (41
). Apparently, there is a graded effect of the Hcy level on the risk of CVD (42
). Elevated blood levels of Hcy can be normalized with vitamin supplements (0.2–1 mg folic acid, with or without 0.4 mg cyanocobalamin, 10 mg pyridoxal), potentially decreasing cardiovascular risk (1
). Emphasis should be placed on meeting daily requirements for folate and vitamins B6 and B12 in the diet.
The possible role of antioxidant vitamins (ie, vitamins E and C) and dietary supplements in reducing CVD risk is under investigation. The dose of vitamin E that may be effective and safe, and the minimum duration of treatment for protection, are unknown (43
–45
). The GISSI-Prevenzione trial in Italy (46
), a multicenter, open-label design, with random allocation of 11,324 male and female patients to daily n-3 PUFA and/or vitamin E (300 mg) doses, reported that vitamin E administered alone had no statistically significant benefit on survival after MI. This conclusion was based on the combined endpoints and their individual components when analyzed according to the factorial design. However, a statistically significant beneficial effect of vitamin E was determined from the secondary analyses of cardiovascular deaths and the three component subsets, and was comparable to the beneficial effect of n-3 PUFA. The report noted that the vitamin E dose was in excess of any dose achievable through dietary intake, corresponding to 200 tablespoons (3.0 L) of olive oil daily, and is much higher than the recommended dietary allowances for optimum health in adults. Several prospective intervention studies have found no reduction in coronary disease with vitamin C supplementation (43
,47
–50
).
Diets for primary and secondary prevention of coronary heart disease
Diets for primary or secondary prevention of CHD should:
These nutrients can affect not only recognized risk factors such as lipids and lipoproteins, but also vascular mechanisms, clinical symptoms, and heart disease outcomes (such as morbidity and mortality).
|
DIET MODIFICATIONS AND HEART DISEASE RISK AND OUTCOMES |
|---|
|
TOPPreviousNext |
|---|
It is well-established (51
) that SFA increases the risk of heart disease by increasing the levels of TC, LDL-C, apoprotein B (apo B), and increasing the ratios of TC:HDL-C and LDL-C:HDL-C. The main sources of SFA in the diet are animal fats, particularly in dairy and meat products. Decreasing SFA to 10% of energy will reduce TC and LDL-C.
MUFA sources shown to be effective in lowering risk of CVD include tree and ground (legume) nuts as well as popular liquid vegetable oils such as olive oil ("Mediterranean" diet) or peanut oil ("Asian" diet). Neither of these diets specifies a particular diet per se, but references the dietary habits of the inhabitants in the geographic regions where olive or peanut oils predominate and are preferentially used. MUFA-rich foods like avocado also should be acceptable. These additions provide more variety to the standard or "prudent" diet. These MUFA-enriched diets, however, are higher in fat and may be high in energy, thus presenting a potential problem to the overweight. In contrast, substituting high-carbohydrate foods for fat also may add energy (and weight), especially if sugars are increased rather than whole grain complex carbohydrates.
Beneficial effects on the lipid profile of the intake of n-6 PUFAs have been reported in many studies published since the late 1950s (52
–64
). This report is limited to recent reviews and meta-analyses of data from controlled studies. Seminal articles by Keys et al. (65
) and Hegsted et al. (66
) established predictive equations that related levels of fat intake to serum cholesterol levels. This established the initial prediction that PUFAs lowered cholesterol whereas SFAs increased cholesterol.
Salonen et al. (67
), from Finland, studied the relationship of dietary intake of -linolenic acid to BP. Intake obtained from 4-day food records (-linolenic acid ranged from 0.6 to 4.1 g/day, mean 1.7 g/day) inversely related to mean resting BP. The authors did not provide data on the food sources of the fatty acid. The intake of -linolenic acid ranged from 0.6 to 4.1 g/day, mean 1.7 g/day.
Another study, by Berry et al. (68
), investigated the relationship of the fatty acid concentration in adipose tissue and BP in 399 free-living males in New York City. The investigators concluded that -linolenic acid had a disproportionate association with BP, ie, a 1% increase in -linolenic acid reduced BP 5 mm Hg. The authors cited the principal food sources of linolenic acid in the diet as flaxseed (linseed) oil, legumes, and tree nuts (including walnuts and chestnuts).
Kang and Leaf (69
) have reviewed the possible antiarrhythmic effect of n-3 and n-6 PUFAs, with a significant decrease in sudden death associated with their intake. The authors postulated that the fatty acids are incorporated into the sarcolemmal phospholipids of myocytes, perhaps binding to the protein of the sodium channel.
Mutanen and Freese (70
) and Mutanen (71
) reviewed the effects of PUFA on platelet aggregation, citing contradictory results. The evidence concerning linoleic acid (18:2 n-6) is not consistent, but intervention studies show increased platelet aggregation to agonists after high linoleate diets. Intake of -linolenic acid either has no effect or leads to decreased platelet aggregation.
Reviews of the studies relating to the consumption of n-3 fatty acids from fish oils have examined their possible role in preventing restenosis in patients after stent angioplasty. Results were variable, but none of these studies utilized -linolenic acid. Instead, they used long-chain, more polyunsaturated marine oils, compared at times with olive oil. Effects on BP, and production of cytokines and growth factors, were investigated in addition to stenosis. Future studies with plant sources of -linolenic acid would be interesting.
Effects of fats on lipid profile – meta-analyses
Results of a quantitative meta-analysis of 395 metabolic ward controlled studies of fat intake and blood cholesterol indicated that in the British diet, for example, replacing 60% of SFA by other fats and avoiding 60% of dietary cholesterol would reduce blood TC by 10–15% (about 0.8 mmol/L), with 80% of the reduction occurring in LDL-C (72
). Median duration of studies was 1 mo. This dietary change could be accomplished by the isocaloric replacement of 10% of SFA with complex carbohydrates, or the isocaloric replacement of 5% of complex carbohydrates by PUFA, and decreasing total daily dietary cholesterol by 200 mg. A 5% increase in MUFA had no significant effect on TC or LDL-C. A decrease in SFA provided the greatest cholesterol- and LDL-C-lowering effect; an increase in PUFA and decrease in cholesterol had about equal effect, about one quarter that of SFA reduction.
Mensink et al. (73
), in a meta-analysis of 27 controlled diet trials, found that the most favorable lipoprotein risk profile for CHD was achieved if SFA were replaced by unsaturated fatty acid with no decrease in TF intake, assuming no increase in BW. Replacing 10% of total energy (TE) as SFA by carbohydrates would lower LDL-C by 0.34 mmol/L (13 mg/dL) and HDL-C by 0.12 mmol/L (4.67 mg/dL). Replacement by MUFA would reduce LDL-C by 0.39 mmol/L (15 mg/dL) and HDL-C by 0.31 mmol/L (1.2 mg/dL); replacement with PUFA would reduce LDL-C by 0.47 mmol/L (18 mg/dL) and HDL-C by 0.57 mmol/L (2.2 mg/dL).
Gardner and Kraemer (74
) reported a meta-analysis to examine whether oils high in MUFA or PUFA had differential effects on serum lipid levels. The authors analyzed data from 14 small-to-medium diet trials and found no difference in the effect of increasing MUFA or PUFA on lowering TC or LDL-C, or in the effect on HDL-C. There may have been a slight TC-lowering effect of PUFA. They noted that other components in the oils and foods besides fatty acids may influence the outcome. MUFA studies included olive, canola, peanut, sunflower, and high-oleic safflower oils; PUFA studies included grapeseed, high-linoleic safflower oil, and corn oil. The authors considered the effects of decreasing or increasing each type of fatty acid by 10%. The SFA diet was 19% SFA, 13% MUFA, and 6% PUFA; the MUFA diet was 9% SFA, 19% MUFA, and 6% PUFA; and the PUFA diet was 9% SFA, 10% MUFA, and 16% PUFA. The authors compared n-6 with n-3 PUFA and n-3 from plant sources with n-3 from fish, suggesting that triacylglycerol-lowering may be attributed to a higher n-3 content of diets. They indicated that associated micronutrients and factors other than fat in these oils or in foods could modify their effects on blood lipids. The authors reviewed the mixed findings that unsaturated fats may or may not have a differential influence on apoproteins, lipoprotein subclasses, blood glucose, and indexes of thrombosis and cancer. They suggested that outcomes other than serum cholesterol levels should be investigated as the basis for future dietary recommendations for the use of foods high in one unsaturated fat in preference to another.
|
INTERVENTION STUDIES WITH WALNUTS |
|---|
|
TOPPreviousNext |
|---|
Each study is summarized and reviewed from the perspective of the effects on biomarkers and indicators of heart disease (viz., lipids, lipoproteins, BP, pathology, and clinical events). The study is then examined for strengths and/or weaknesses in design, subject demography, dietary intervention, exposure dose, clinical and laboratory measurements, and data analysis. Next the study is evaluated in terms of quality, consistency (ie, agreement) and magnitude of the effect, and the strength and relevance of the association of walnuts with the outcome. Finally, all of the studies are presented in chronological order of publication.
Study 1.
Sabaté et al. (75
) reported the effects of walnuts on serum lipid levels and BP. The investigators studied 18 healthy, normal weight, young (mean 30 y) adult males with "normal" lipid levels (20th–80th percentile) and BP, who did not eat nuts frequently. The subjects were placed on a National Cholesterol Education Program/American Heart Association Step 1 diet (30% fat), either with or without 20% of energy from walnuts, in a single-blind, randomized, crossover design with two 4-week feeding periods. Walnuts reduced the TC, LDL-C, and HDL-C values by 12% (22 mg), 16% (18 mg), and 5% (2 mg), respectively; all changes were statistically significant. There was no effect on BP. Triacylglycerol levels tended to decrease, but not significantly; the ratios of TC:HDL-C and LDL-C:HDL-C decreased significantly. The Walnut diet caused a slight increase in the intake of TF. SFA intake decreased by one-third, PUFA increased 80%, and cholesterol declined 50% in comparison to the Step 1 reference diet (RD), which included no walnuts. Comparing the Walnut and RD periods, the investigators noticed that the fatty acid composition of serum cholesterol esters reflected significant decreases in oleic (18:1 n-9) and arachidonic (20:4 n-6) acids and increases in linoleic and -linolenic acids in the Walnut diet.
Although there was a 5-day run-in period, there was no washout between the 4-week duration of each diet (with or without walnuts). The study personnel were blinded to the patients’ study sequence, ie, one group was consuming the Walnut diet first and then crossed over; the other group was eating the diet without walnuts first and then crossed over. The nutrition research kitchen provided all meals; common, normal food items comprised the menus. The Walnut diet substituted three servings (28 g each) of walnuts daily (for a total of 84 g daily per 2,500 kcal) in place of other foods. Walnuts were used for snacks, mixed in salads and breakfast cereals, or cooked with dinner entrees. The composition of duplicate samples of the two study diets was determined by analyses of samples collected randomly. There were no side effects from the Walnut diet.
Lipid and BP measurements were standardized and validated. The two-tailed t test was used for statistical analyses.
The major difference between the two diets was the increase in PUFA in the Walnut diet, with the percent of -linolenic acid tripling and total PUFA increasing 2.5-times. The response of the subjects was consistent regardless of the sequence of the diets, baseline lipid values, or body size. During the Walnut diet, walnuts contributed 55%, 14%, and 10% of TF, protein, and fiber, respectively.
The investigators concluded that replacing a portion of the fat in a cholesterol-lowering diet with walnuts further lowers serum cholesterol levels and produces a more favorable lipoprotein profile. They suggested that an increase in walnut consumption from a current average of 4 g/week to 28 g/day would lower cholesterol and LDL-C by 4 and 6%, respectively. They also suggested that incorporating walnuts into the diet as snacks, or components of desserts, breads, or entrees would be acceptable to most people as part of a cholesterol-lowering diet.
The investigators noted that their study did not include females or subjects with hypercholesterolemia, and included only younger subjects, and that 4 weeks was a short interval. The results, therefore, could not be extrapolated directly to the population at higher risk of CHD. The issue of free-living subjects was not addressed.
This study was well-designed and controlled, insofar as a diet study with a whole food cannot be blinded to the subject. The small number of subjects, consisted only of young adult males; nevertheless, the dietary intervention was practical for the "real world" and a healthy population. A 4-week study is enough time in which to detect changes in blood lipids, but not long enough to address maintenance. The energy intake was controlled, but the proportion of fat energy from walnuts was too high to be practical. The extrapolation to one-third of that intake (ie, 28 g) and prediction of appreciable lipid-lowering need to be validated by direct study at that level. The magnitude of the lipid effect (cholesterol and LDL-C reduction) is significant and could provide risk reduction for heart disease for the population that is comparable to oatmeal and oat bran (15
,76
) or soy protein (77
,78
). The 5% fall in HDL is noteworthy, but is counterbalanced by the significant decrease in the ratios of cholesterol and LDL:HDL. The trend to decrease TGs by 10% might achieve statistical significance with a small increase in the number of subjects (perhaps to 25 individuals).
Study 2.
Abbey et al. (79
) studied 16 normolipidemic males, mean age of 41 y, with a 36% fat diet for periods of 3 weeks. The investigators compared a diet enriched with peanuts and coconut that was similar to the usual Australian diet in fat composition (SFA:MUFA:PUFA ratios) with an almond-enriched diet and one enriched in walnuts (68 g/day, 46 g fat). The nuts provided about half of the fat energy. All subjects were fed the diets in the same order. The Walnut diet was continued for an additional 3 weeks. Both almonds and walnuts similarly lowered TC and LDL-C significantly, 6 and 10%, respectively, after 3 weeks compared with the RD. The HDL-C and triacylglycerol values did not differ among the three diets. The plasma fatty acid composition with the Walnut diet showed significant decreases in oleic and arachidonic acids and significant increases in linoleic and -linolenic acids. Plasma and dietary fatty acid composition were measured as were plasma lipids and lipoproteins using validated methods. Data were analyzed by paired t tests.
The dietary intake was monitored by food records, with special emphasis on fat intake, and reviewed by the dietitian. The diets were well matched. The investigators were concerned about possible adverse effects of the high PUFA content of the Walnut diet on lipid peroxidation and the formation of oxidized LDL, although this was not studied. The relatively high content of tocopherols in walnuts might be protective (Table 1
). They also discussed the possible influence on the results of elevated myristic acid (14:0) in the RD. They suggest that PUFA- and MUFA-rich nuts should be included in the diet as a replacement for some of the SFA.
|
) prediction of appreciable lipid-lowering, and needs to be validated by a clinical study at that dose. The magnitude of the lipid effect (cholesterol and LDL-C reduction) is significant and could provide risk reduction for heart disease for the population that is comparable to oatmeal and oat bran (15
) or soy protein (78
). The lack of effect on HDL is encouraging and may reflect either the lower level of intake of walnuts or the longer duration of feeding. It is interesting that the results with almonds did not differ from those achieved with walnuts, despite the difference in fatty acid composition, ie, almonds are high in MUFAs and walnuts in PUFAs (Table 1
).
Study 3.
Chisholm et al. (80
) reported a study of 21 males (16 with full dietary records), mean age 45 y, with moderate hypercholesterolemia (polygenic hyperlipidemia), without CHD. The randomized, crossover design compared the effects on lipid metabolism for 4 weeks of two "LF" diets (ie, 30 and 38% TE). A diet with 38% energy from fat is not LF, as described by the investigators. Walnuts (78 g/day) were included only in the 38% LF diet. With the Walnut diet, the significant decreases in TC (4%) and LDL-C (8%) compared to the baseline diet, were about twice that observed with the 30% LF diet. HDL-C increased significantly (42%) with the Walnut diet compared to baseline, and apo B levels decreased significantly (10%) with the Walnut diet compared to baseline, with no significant change from baseline with the 30% LF diet. Neither triacylglycerol nor apo-A levels differed from baseline with either the Walnut or 30% LF diet. Comparing the Walnut diet and RD, the investigators found that the fatty acid composition of plasma triacylglycerol, cholesterol esters, and phospholipids showed significant decreases in 18:1 and 20:4 and increases in 18:2 in the three lipid classes, with an increase in 18:3 in triacylglycerol. Investigators ascribed the absence of more extensive differences between the two diets as possibly being caused by the relatively low levels of myristic acid in both. They noted that the Walnut diet had significantly less SFA, more PUFA, and less cholesterol than the 30% LF diet and recommended that an increase in TF be avoided when nuts are included in the diet.
The experimental design included a run-in period on a LF diet for 1 week before randomization into two groups, with one group continuing on the 30% LF diet, and the other switched to the Walnut diet. There was no washout between crossover periods. Dietary intake was recorded on 2 days of each week of the study. Meals were eaten at home, with individualized menus and recipes; walnuts were provided. Walnuts contributed 20% of the TE of the diet. The lipid measurements were validated for precision and accuracy, and the variances were provided. Data were analyzed using ANOVA with repeated measurements.
Despite the unintended 8% increase in TE from fat on the Walnut diet, the two diets were isocaloric. The subjects did not differ in BW or weight gain with either one of the diets. The investigators concluded that walnuts influence the plasma fatty acid profile in a way expected to reduce the risk of CHD, and is thereby cardioprotective. They were unable to demonstrate convincingly that the Walnut diet was superior to the 30% LF diet in improving the lipoprotein profile. They cautioned that an increase in TF should be avoided in order to improve study design in future interventions with nuts or in advising an increase in nut consumption.
This study did not achieve the desired fat content for the Walnut diet that would provide a better comparison with a LF diet. There was a modest lowering of cholesterol and LDL-C with both diets, especially considering the high intake of walnuts. Again, the number of subjects was small and consisted only of males. These subjects, however, were hyperlipidemic, rather than representative of the healthy population. This 4-week study was adequate to detect changes in blood lipids, but inadequate in terms of addressing sustainability over time. The energy intake was controlled, but the proportion of fat energy from walnuts was too high to be practical. The extrapolation to one-third of that intake (ie, 26 g) would not produce significant enough reduction of cholesterol and LDL-C risk factors for heart disease (ie, 1–2%) to indicate significant protection. The notable increase in HDL-C levels could provide a reduction in risk for heart disease for this population.
Study 4.
Zambón et al. (81
) reported on the Barcelona Walnut trial. The randomized, crossover design feeding study was carried out on 23 females and 26 males with polygenic hypercholesterolemia, mean age 56 y. Patients were recruited from a lipid clinic where they had been placed on a cholesterol-lowering "Mediterranean" diet. They were free of disease other than CHD (7 subjects), took no lipid-lowering medications or dietary supplements, and did not consume nuts frequently. A high-MUFA diet ("Mediterranean" diet consisting of olive oil and natural food stuffs) was compared to a high-PUFA diet (walnuts, 56 g/day) during 6-week feeding periods with random assignment to one of two sequences. There was a 1-week pretrial period for indoctrination and counseling, and no washout period between diets. The MUFA diet was 30% fat, 5% SFA, 21% MUFA, and 4% PUFA, and the PUFA diet was 33% fat, 5% SFA, 16% MUFA, and 12% PUFA. Raw, shelled walnuts were provided daily in packages varying between 41-56 g (8–11 walnuts), affording 18% of TE. Walnuts were consumed in desserts or salads, or as snacks. Diets were monitored by unannounced weekly telephone 24-h recalls. Serum lipids, Lp (a), apoproteins A-1 and B, and LDL resistance in vitro to oxidative stress were measured, as well as the fatty acid composition of LDL lipids in blood samples obtained at 5 and 6 weeks of each dietary period.
TC decreased by 9% on the Walnut diet (by 5% on the control diet); LDL-C declined by 11% (by 6% on the control diet), with parallel changes in apo B levels. Lp (a) levels were decreased (9 vs. 3%) with the control diet. The change in Lp (a) levels was statistically significant only in males and in subjects with levels of 
0.78 mmol/L (30 mg/dL). There were no significant differences in the effects of the two diets on levels of HDL-C, triacylglycerol, or apo A-1 (both diets decreased these variables). The LDL:HDL ratio declined 8% with the Walnut diet and was unchanged with the control diet. Resistance of LDL to oxidative stress was preserved during the Walnut diet. There was no difference between the Walnut and control diets in the -tocopherol content or in the lag time of conjugated dienes (CDs) formation during copper-induced oxidation. Oleic acid was decreased, whereas linoleic and -linolenic acids were increased in LDL-cholesterol ester fatty acids, LDL phospholipid, and triacylglycerol with the Walnut. There was no evidence of a carryover effect.
BW was stable and most subjects tolerated the Walnut diet well, although a few reported mild symptoms of postprandial bloating or heaviness. The energy value and nutrient composition of the two diets (other than the fat) had minor differences besides lower cholesterol content in the Walnut diet, and were insufficient to explain the differences in blood lipids and lipoproteins that were observed with the diets.
Investigators concluded that substituting walnuts for part of the MUFA in a cholesterol-lowering "Mediterranean" diet further reduces TC and LDL-C in males and females with hypercholesterolemia. The Walnut diet effect was observed without changing dietary SFA. They suggested that nonfat components of the walnut matrix may influence blood lipids, and that the lipid effects of whole walnuts should be compared with that of walnut oil. They also noted that the content of -linolenic acid in walnuts may reduce the risk for CHD deaths through its antiarrhythmic properties or other antiatherogenic effects (see below). They proposed that even greater benefits than they encountered studying the "Mediterranean" diet would be obtained by replacing the traditional "Western" dietary fat with walnuts.
Although the results show no change in triacylglycerol levels with either diet, an asterisk in Figure 2 in Zambon (81
) indicates a significant lowering of triacylglycerol with the Walnut diet. This would sustain evidence that walnuts have another favorable lipid effect in addition to those on cholesterol and lipoproteins. This study was well designed and controlled. The number of subjects was greater, included females and males, with a broader age range, and with elevated lipid levels. The 6-week study is not considered long-term. The caloric intake was controlled, but the TE from fat was higher with the Walnut diet, achieving a moderate fat rather than a LF intake. The proportion of fat calories from walnuts was double that considered practical. The extrapolation to half of that intake (ie, 25 g) and prediction of 4-5% cholesterol or LDL cholesterol-lowering needs to be validated by direct clinical study at that intake level. The magnitude of the lipid effect could provide risk reduction for heart disease for the population. The 3% fall in the HDL level is counterbalanced by the significant (8%) decrease in the ratio of LDL:HDL. A significant decrease in triacylglycerol would be an added benefit. The absence of an increase in oxidative stress with the Walnut diet also is favorable. The strength of this intervention diet is that the SFA content was the same for the two diets, so that the increase in PUFA was the significant change and was not accompanied by a decrease in an "unfavorable" nutrient.
Study 5.
Almario et al. (82
) reported the effects of a Walnut diet on plasma lipids and lipoproteins in patients with combined hyperlipidemia. Four diets were studied: the habitual diet (HD) (31% fat) and a LF (20% fat) diet; and the same diets supplemented with walnuts (48 g/8460 kJ). Thirteen postmenopausal females and 5 males, age 60 ± 8 y, completed the four periods. Comparing the Walnut diet with the HD and LF diets, patients lost weight on the LF diet, but did not gain weight with either Walnut diet, despite an increased TE intake of 20 and 23%, respectively.
During the LF + walnuts period, decreases in TC (8%) and LDL-C (12%) were significant, compared with the LF diet alone. Triacylglycerol did not differ among the four diets, and cholesterol was decreased significantly in intermediate density lipoprotein (IDL) and redistributed from the more atherogenic small, dense LDL to larger LDL particles. Plasma apo B was not effected by walnut supplementation but decreased with the LF compared to the HD. The HDL-C decreased (10%) significantly when comparing either the walnut supplemented HD or LF to HD. Apo A-1 increased with the addition of walnuts to the HD. Apo A-1 decreased during the LF diet and remained low after the addition of walnuts. Adding walnuts to the HD or the LF diet alone caused significant shifts in cholesterol that redistributed it from larger into smaller HDL particles. Lipid particle changes occurred in the absence of lipid lowering, suggesting a favorable antiatherogenic effect of walnuts that is independent of any changes in circulating lipid levels.
The patients’ health was stable and their lifestyle was monitored. All patients followed the diet according to the following sequence: 4 weeks on the HD diet then 6 weeks each on the HD + walnuts, LF diet, LF + walnuts, respectively. There were no washout periods. Patients were counseled individually before the LF diet intervention and with group sessions during those periods.
The quantity of walnuts was selected to provide an amount of -linolenic acid similar to the amount that lowered triacylglycerol in fish oil studies. Walnuts were consumed mainly from prepacked rations that were provided. Although the patients were seen and blood samples were drawn at mid- and endpoints of each period, only the terminal samples were used for data analysis. Lipoprotein particle sizes were determined by nuclear magnetic resonance techniques. Diets were monitored from 7-day food records for each period. Data analysis used general linear modeling procedures and correlations.
The walnuts added to the HD increased the fat content from 31 to 37%. Linoleic acid intake increased from 11 to 30 g and -linolenic acid from 1.3 to 5.4 g. The SFA in HD and HD + Walnuts were 11 and 10%, respectively. MUFA were 12 and 13% and PUFA were 6 and 16% in HD and HD + walnuts, respectively. During the LF diet, the TE decreased by about 12% compared to the HD; this was reversed during the LF + walnuts diet. The LF diet contained 20% fat, 8% SFA, 8% MUFA, and 5% PUFA. LF + walnuts contained 34% TF, 8% SFA, 12% MUFA, and 16% PUFA. Addition of walnuts to either the HD or LF diet increased plasma concentrations of linoleic and -linolenic acids and decreased palmitic (16:0), oleic, and arachidonic acids without changing concentrations of EPA and DHA.
The investigators suggest that the absence of effect of the LF diet is because these hyperlipidemic subjects were already following a diet restricted in fat and SF. They noted that the cholesterol-lowering caused by adding walnuts to the LF diet could not be explained in terms of decreasing SFA, but rather was a specific effect of the PUFA and MUFA content. They suggest further examination of possible effects of PUFA on lipoprotein metabolism via effects on lipoprotein lipase, hepatic lipase, lecithin-cholesterol acyltransferase, or cholesterol ester transfer protein, which are all involved in lipoprotein metabolism. Walnuts have a unique elevation of both n-6 (linoleic) and n-3 (-linolenic) acids compared to other nuts. Their metabolic effects should be specifically elucidated and not extrapolated from other unsaturated fats and oils, even of similar fatty acid composition (eg, soybean and wheat germ oils).
This study was well designed and controlled. A small number of hyperlipidemic females and males were studied and fed diets for 6 weeks. Adding walnuts to either diet caused variation in the caloric intake and increased TE by 20%. This might be expected when adding walnuts to a LF diet but not, perhaps, to the HD. Also, the LF diet provided only 82% of the TE of the HD. The walnut intake is about twice that which is practical to include in the diet. The extrapolation to half that intake (24g) and prediction of appreciable lipid-lowering needs to be validated by direct study at that level. The magnitude of the lipid effect (cholesterol and LDL-C reduction) is significant and could reduce the population’s risk for heart disease to an extent that is comparable to oatmeal and oat bran (15
) or soy protein (78
). The fall in HDL is noteworthy, although the LF diet produced a similar decrease. The ratios of cholesterol and LDL:HDL were not calculated. The intriguing findings of changes in lipoprotein particle sizes and composition need confirmation. The results obtained by the investigators from the emerging nuclear magnetic resonance methodology need to be related to the traditional procedures.
Study 6.
In the Jerusalem Nutrition Study (83
), walnuts were one component of a high-PUFA diet study, although there were no data on the amount of walnuts subjects consumed. The intervention study compared 32% fat, high-MUFA and -PUFA diets in 26 healthy, normolipidemic, young males who were randomized to either diet in a 12-week crossover design. The MUFA diet was 8% SFA, 16% MUFA, and 7% PUFA with fat sources from olive oil, avocado, and almonds. The PUFA diet was 7% SFA, 6% MUFA, and 16% PUFA with fat from safflower and soy oils and walnuts. There was a 4-week washout before cross over to the other diet for an additional 12 weeks.
The PUFA diet reduced TC and LDL-C by 16%, whereas the MUFA diet reduction was 10%. There was no change in HDL-C or triacylglycerol. There was an increase in response to oxidative stress as determined by measurements of thiobarbituric acid reactive substances (TBARS) with the PUFA vs. MUFA diets. LDL receptor activity and lipoprotein profiles and composition (studied in about half the subjects chosen at random) were not significantly different between the two diets.
All food, consisting of natural and common food items, was served in a central kitchen. There was a 4-week run-in period on their usual diet (41% fat, 10% SFA, 12% MUFA, and 16% PUFA). Menus were prepared in 12-day rotations. Samples of the diet were analyzed for fatty acid composition by gas-liquid chromatography. Standard procedures were used to measure the lipids and lipoproteins. Statistical analysis was by means of the t test, comparing the means of two determinations at 10 and 12 weeks of the diets and two baseline samples. Dietary compliance by the subjects was monitored by determining the fatty acid composition of the lipids in the RBC membrane. The investigators demonstrated a seasonal effect on fatty acid levels, especially of triacylglycerol, but also of LDL-C, that might be related to dietary changes in Israel vis-à-vis religious observances.
This study focused on the demonstration that MUFAs were equivalent to PUFAs in cholesterol-lowering. In fact, they showed a better effect by PUFAs, which included walnuts as a source. The amount of walnuts was not specified, however, which makes this study interesting but probably not suitable for inclusion in this report as a walnut intervention study. Rather, it supports the direct intervention data. The study resembles, in part, the comparison in Abbey’s study (79
) of an Almond diet with a Walnut one. The study shows that PUFAs do not adversely affect HDL, but also supports an adverse effect of PUFAs on oxidative stress (see section on Possible adverse effects of walnut components).
Summary of clinical human intervention trials with walnuts
Summaries of the six clinical human intervention studies published or in press are presented in
Table 2
. They are consistent in showing decreases in TC and LDL-C that should lower risk of CHD. These results are achieved with intakes of walnuts that would amount to two or three servings daily. There appears to be a null effect on triacylglycerol. Effects on HDL-C are inconsistent, with some studies showing a decrease, others no change, and one an increase. Not all the studies have included the ratios of TC:HDL-C or LDL-C:HDL-C. Where evaluated, these ratios decreased, indicating lessening of risk, even when HDL-C is decreased. In one trial, although HDL-C decreased, apo A-1 increased, providing another favorable outcome. A few studies have included apo B and have shown decreases as well, again favoring risk reduction. These results have been achieved whether the walnuts were included in a usual diet higher in fat, a Step 1 diet, a LF diet, or in a diet already increased in PUFAs.
|
). Among the deficiencies in these trials is that no study included a large number of subjects, encompassing males and females, of a broad age range, and studied over a long period of time. Each involved a level of walnut consumption that is not considered practical in the "real world." No significant adverse effects have been reported in any of the studies. Although the walnut consumption may add calories, net BW gains did not occur. The concern about increased oxidative stress in these studies mirrors the concern with diets that increase PUFAs. The data are inconsistent; the one Walnut trial that examined this possibility showed no adverse effect. The effect of walnut ingestion at a practical level, ie, one serving daily, has not been evaluated. The walnut effect at higher intakes (two to three servings daily) resembles that of oat fiber and soy protein, where the amounts tested in trials exceed usual intakes.
The mechanism of the walnut effect is unclear. The diets used generally reflect a ratio of SFA:PUFA of 1:2, which was a dietary recommendation made early in efforts to reduce the risk of heart disease. Investigators have claimed that the risk reduction with walnuts may exceed that predicted from their fatty acid concentrations and composition, suggesting other factors (see below). Walnuts are unique among nuts in that both -linolenic acid and linoleic acid levels are increased. The dietary intake of walnuts significantly increased levels of both PUFAs in the body, thus demonstrating bioavailability. Risk factors of interest that were addressed only in a single trial include Lp (a), which has not been shown to respond readily to dietary intervention, and LDL and HDL particle sizes, which are emerging as more specific risk factors than the levels of LDL or HDL-C. These particle sizes may have different effects on risk (ie, not all LDLs are "bad" and not all HDLs are " good").
A possible effect on Hcy also needs to be examined in a strong study. Similarly, the significance of the lysine:arginine ratio remains to be defined.
|
OBSERVATIONAL STUDIES ON CONSUMPTION OF WALNUTS AND OTHER NUTS AND CORONARY HEART DISEASE |
|---|
|
TOPPreviousNext |
|---|
.
|
The AHS is a large, prospective study of Seventh-day Adventists (SDAs) in California (84
–87
), in which 31,208 non-Hispanic white subjects were followed for 6 y (1977–1982). Excluding people with heart disease or diabetes, at baseline 26,473 males and females over age 25 were evaluated for first events of MI or CHD. Nut consumption ranged from never to daily. Nut consumption was related inversely to nonfatal MI or death from IHD, or to all-cause mortality. RR of MI and IHD in persons who ate nuts more than 4 times/week were half the RR of subjects who consumed nuts less than once weekly (RR 1). People who ate nuts 1–4 times/week had a 22% reduced risk of acute MI, compared with those eating nuts less than once a week.
The population was predominantly nonsmoking, did not use alcohol, and generally followed a lacto-ovo-vegetarian diet. Diet was assessed by a semiquantitative food frequency questionnaire (FFQ). Participants’ health status was queried annually, and medical records were reviewed for the diagnosis of CVD, nonfatal or fatal, according to the International Classification of Diseases codes. The association of nuts and CVD was undiminished when analyzed in the elderly subgroup, and did not differ by sex, BP, relative weight, nor was there any significant confounding by other foods. Although the investigators did not distinguish between different kinds of nuts, a substudy showed that 32% of nuts consumed were peanuts (legumes or ground nuts), 29% were almonds, 16% were walnuts, and 23% were other kinds of nuts. The authors concluded that frequent consumption of nuts might be protective for both fatal and nonfatal CHD events.
Fraser (85
) has proposed that high nut consumption postpones the development of IHD for several years and confers an 18% lifetime risk reduction of CHD compared with 30% in consumers of low quantities of nuts.
There are several publications by investigators involved in the AHS prospective observational studies on SDA cohort populations. Fraser and colleagues (88
) estimated the effects of particular practices or risk factors, such as consumption of nuts, on the lifetime risk of CHD and the time of first expression in 26,321 non-Hispanic, white SDAs. Their analyses:
A population of African American SDAs in California was analyzed for health habits, risk factors, and all-cause mortality (89
). The same factors were found to operate also in this population. Frequent consumption of nuts appears protective in that population (1,668 subjects), reducing all-cause mortality in both sexes to 0.6, adjusted for age, smoking, and exercise. In the "old-old" cohort (603 female and male subjects, age 84 y (90
), all-cause mortality was decreased to 0.75 (adjusted multivariate RR 0.82) comparing high to low nut consumption. Mortality from CHD was reduced to 0.55 for high vs. low nut consumption (multivariate adjusted RR 0.61).
A report in 1999 (91
) showed that there was a significant protective association between nut consumption and fatal and nonfatal CHD in SDA males and females, RR 0.5 comparing high to low nut consumption, and reduced lifetime risk of CHD by 31% in frequent nut consumers. Results were adjusted for age, sex, smoking, exercise, BMI, hypertension, and consumption of bread, beef, fish, cheese, coffee, legumes, and fruit. Subjects with diabetes were excluded.
The Iowa Women’s Health Study (92
,93
) is a prospective cohort study of postmenopausal females. Prineas reported the effects of nut consumption on CHD mortality in the 41,837 females enrolled. Predominantly white females, 55–69 y of age, completed a FFQ that asked about the frequency of nut consumption as 1-oz (28 g) portions. Over 5-y, 154 of the 34,484 females free of CHD at baseline died of CHD. Coronary mortality was inversely associated with nut intake, with an adjusted RR of 0.6 for eating nuts 1–3-times a mo, 0.75 for eating nuts once a week, and 0.43 for eating nuts 2–4-times a week, p = 0.06.
Kushi et al. (92
) reported the results of follow up for 7 y, with 242 females dying of CHD. The primary finding was a strong inverse association of vitamin E consumption from food with the risk of CHD death. Multivariate adjusted RR in the highest quintile, ingesting 9.64 International Units (IUs) of vitamin E daily, was 0.38. In a subgroup, multivariate analysis of food sources of vitamin E showed the strongest inverse association was with nuts and seeds, exceeding margarine and mayonnaise and creamy salad dressings. RR for the highest quartile of nuts and seeds, >4 x/mo, was 0.60, but adjustment for vitamin E reduced this to 0.72, p = 0.11. The varieties of nuts consumed were not reported.
Combining the AHS and Iowa Women’s Health Study studies (84
,85
), there seems to be a threshold effect of nut consumption at a frequency of once weekly. An inverse, graded relation was observed between nut consumption and CHD events.
In the NHS (27
), of 86,016 female registered nurses (RNs), those consuming at least 5 oz (140 g) of nuts/week had a 35% lowering in nonfatal MI compared with those eating less than 1 oz (28 g) of nuts/mo (rare), RR = 0.65. The RNs ranged in age from 34 to 59 y at baseline. Coronary disease measures included nonfatal MI and fatal CHD. During 14 y of follow-up, 861 cases of MI and 394 deaths occurred. Dietary information was obtained 4 times during the study, and frequency of nut consumption was evaluated for total nuts [later separating peanuts (ground nuts) from tree nuts]. The investigators commented that nut consumption declined over the length of the follow-up period. When peanuts were separated from total nuts, there were few cases of females consuming either peanuts or tree nuts at the highest two quartiles. Multivariate RR for either group was statistically significant (0.79 for other nuts, p = 0.62; 0.66 for peanuts, p = 0.06). Medical records were reviewed for cases, and the World Health Organization criteria were used for diagnosis.
Hu et al. (94
) reported data relating dietary intake of -linolenic acid and risk of IHD among the females enrolled in the NHS cohort study. A higher intake of -linolenic acid was associated with an RR of 0.55 in the lowest quintile, p for trend 0.01. The multivariate risk calculation was adjusted for age, standard coronary risk factors (ie, smoking, BMI, hypertension, diabetes, menopausal status, and parental history of premature MI) and dietary intake of -linoleic acid, alcohol, SF, vitamin C, vitamin E, total energy, and the use of vitamin supplements. The -linolenic acid intake ranged from 0.71 g/day in the lowest quintile to 1.36 g/day in the highest quintile.
In the Physician’s Health Study (95
), of 22,000 males followed prospectively for 12 y, as nut consumption increased the risk for cardiac and sudden cardiac deaths decreased significantly. There were 133 sudden cardiac deaths and 449 cardiac deaths. The investigators suggest that after adjustments their data indicate that nut consumption reduces risk of total cardiac deaths and perhaps of sudden cardiac death.
Lavedrine et al. (96
) reported a cross-sectional study of a population of farmers in the walnut-producing Grenoble region of France consuming its habitual diet that examined a possible association between walnut consumption (walnut oil and kernels) and blood lipids. In 793 healthy subjects (426 males and 367 females), 18 to 65 y of age (average age 50 y), the subjects had completed a FFQ covering the previous year. Blood TC, lipoprotein-cholesterol, and apoprotein levels were measured. Increased HDL-C and apo A-1 were associated with walnut consumption, but not TC, LDL-C, or apo B.
The participants attended a health-screening visit with blood sample analysis, filled out a medical questionnaire, and answered the FFQ. The lipid analyses were performed by using standard methods in a laboratory that conformed to national quality assurance plans. The data were analyzed by using multiple linear regression models including possible confounding nutritional and demographic variables. The association was stronger with walnut oil alone than with the oil and kernels. The investigators concluded that there might be a protective effect against CVD of usual walnut and walnut oil consumption by increasing serum levels of HDL-C and apo A-1.
The investigators did not evaluate either fiber or fish consumption or TE intake; however, they did include biomarkers for heart disease risk.
|
OTHER RELEVANT OBSERVATIONAL STUDIES |
|---|
|
TOPPreviousNext |
|---|
Leng et al. (97
) reported the results of the Edinburgh Artery study that addressed a possible association of plasma triacylglycerol, cholesterol ester, phospholipid, and RBC fatty acid levels with CVD, primarily evaluating peripheral vascular disease. More than 1,100 males and females, 60–80 y of age, were sampled at random. Their health status was assayed by questionnaire and medical records. Diagnosing CVD by using the International Classification of Diseases codes, researchers characterized those subjects having MI (143), stroke (38), or diseases of the lower limb (200). BP in the extremities was measured with a sphygmomanometer and by ultrasonography. Lipids were separated by thin-layer chromatography, and fatty acids were assayed by gas-liquid chromatography. Data were expressed as geometric means. Disease and no-disease categories were compared. Logistic regression was used to develop odds ratios from log-transformation of fatty acid levels.
The results were confusing and difficult to interpret. The triacylglycerol fatty acids showed a significant increase in linoleic acid in patients with MI. RBC phospholipid fatty acids showed that -linolenic acid was significantly lower in those with stroke and lower-limb disease. The investigators interpreted their data to suggest that -linolenic acid, but not linoleic acid, was decreased in subjects with stroke, and that 18:3 in the diet might be protective against it. One limitation of this study design is that patients with disease may have modified their diets during the study and that plasma triacylglycerol fatty acids primarily reflect recent dietary intake.
Guallar et al. (26
) reported the results of the European Multicenter Case-control Study on Antioxidants, Myocardial Infarction and Breast Cancer (EURAMIC) in eight European countries (Finland, Germany, The Netherlands, Norway, Russia, Spain, Switzerland, and the United Kingdom) and Israel. The study related adipose tissue n-3 fatty acids with the risk of MI in males. There were 638 cases of first MI recruited within the first week after the event, and 700 matched controls. The -linolenic acid concentration was significantly lower in the cases than in controls. The adjusted RR of MI for the highest quintile of -linolenic acid compared to the lowest (0.68) was not statistically significant.
Fatty acids were determined by capillary gas chromatography. The composition should have reflected long-term intake of essential fatty acids, ie, in the previous 2–3 y. However, the investigators did not assess nutrient intake, so that calorie adjustments could not be made. They note the possibility of measurement error in the analysis of components that represent <1% of total fatty acids. They did not measure plasma lipid fatty acids, and referred to other prospective studies [Health Professionals, NHS, and Multiple Risk Factor Intervention Trial (MRFIT) follow-up] (see below), where intake of -linolenic acid was related inversely to the risk of cardiovascular mortality. The EURAMIC study design did not allow evaluation of sudden cardiac death cases.
Secondary prevention studies of -linolenic acid
This report of PUFA studies does not include or cite studies with fish or fish oils except in passing and as considered relevant, and focuses only on walnuts, other nuts, or plant sources of PUFA. Simon et al. (98
) related the plasma levels of -linolenic acid to the risk of stroke in a nested case-control study of 96 middle-aged (mean age of 50 y) males in the United States enrolled in the MRFIT study who developed stroke during a 6.9 y follow-up. They were analyzed in relation to 96 matched controls enrolled in MRFIT, a primary prevention trial in males at high risk of developing CHD. The fatty acid composition of cholesterol esters and phospholipids was measured in stored frozen serum samples that were collected at the outset of the study. Data were analyzed by a stepwise conditional logistic regression that controlled for BP and smoking. An increase of one standard deviation (SD) in the serum level of -linolenic acid in cholesterol esters was related to a 37% reduction of stroke risk. Levels of -linolenic acid in cholesterol esters were lowered more significantly in stroke case subjects than in controls. The result was not related to differences in BP or blood lipids, and was independent of the risk-enhancing effects of systolic BP and cigarette smoking. The authors commented that sources of -linolenic acid in the diet are linseed, canola, soy, and walnut oils (intakes not evaluated), and that the protective effect may be related to a reduction in platelet aggregability and blood viscosity.
Another study from the MRFIT (99
) found the habitual intake of -linolenic acid to be 1.688 g (SD 0.736) whereas the habitual intake of linoleic acid was 14.6 g (SD 6.957). The ratio of -linolenic acid:linoleic acid was associated with a decrease in CVD mortality and all-cause mortality. Dietary intake was analyzed in the usual care (nonintervention) group by 24-h recalls at yearly intervals.
The Lyon Diet Heart Study (28
,100
) is an intervention trial comparing the "Mediterranean" diet which incorporates -linolenic acid (219 patients), with a "prudent" diet (192 patients) in secondary prevention of CHD. The diet did not specifically evaluate nuts, but rather added -linolenic acid in amounts similar to the walnut studies in the form of a canola oil-based margarine and salad dressings. Olive oil was also advised. The reinfarction rate in these MI patients was halved within 27 mo, with similar reductions in cardiac death and nonfatal MI. The investigators also reported an extended follow-up of 46 mo, with 275 events including evaluation of secondary events and minor events requiring hospitalization. Compared with the control diet, the experimental diet was significantly lower in calories, TF, SFA (8.3% of calories experimental, 11.7% control), linoleic acid (3.6 and 5.3%, respectively), and cholesterol (217 and 318 mg, respectively), and significantly higher in oleic acid and -linolenic acid (0.81% of calories experimental, 0.27% of calories control).
Adjusted RRs were 0.35 for sudden cardiac death, 0.28 for total primary endpoints, 0.44 for all-cause deaths, 0.33 for total primary and secondary endpoints, and 0.53 for total major and minor endpoints. Results were independent of traditional risk factors, eg, high blood cholesterol, indicating that the experimental diet did not alter the usual relationships between major risk factors and recurrence. The authors suggest a combined approach of a cardioprotective diet with other means (pharmacological) that reduce modifiable risk factors.
The patient’s physician prescribed a "prudent" diet. Diet instruction for the experimental group was customized, and the diet was monitored. Plasma fatty acids were analyzed in both groups 2 mo after randomization. Data were analyzed on the intention-to-treat principle. RRs and associations were calculated. Disease outcomes were evaluated in hospitalized patients. Neither the patients nor their physicians were informed that this was a dietary trial. Only plasma -linolenic acid was associated significantly with an improved prognosis. The profile of plasma fatty acids of the experimental group differed significantly from the control group, with more oleic, less linoleic, more -linolenic acids and less arachidonic acid, and more EPA. The data for the experimental group derive from 1–4 y follow-up.
|
MECHANISMS |
|---|
|
TOPPreviousNext |
|---|
This abbreviated discussion of mechanisms is merely illustrative, and is not intended to be comprehensive. Various mechanisms have been postulated in explaining the favorable effect of nuts in reducing CVD risk. Earlier investigations emphasized differences in the fat composition, eg, unsaturation. The results reviewed, however, may go beyond favorably affecting serum lipid and lipoprotein levels and may be manifested rapidly. Changes may occur in lipoprotein composition, independent of concentration. Other mechanisms may involve dietary fiber, NO formation from the increase in arginine in protein, which could influence endothelial function and inhibit platelet aggregation, monocyte adherence, chemotaxis, and vascular smooth muscle cell proliferation. Also, the antioxidant action of vitamin E could reduce LDL oxidation. The content of folic acid could lower the amount of Hcy and perhaps the effect of other phytochemicals such as plant sterols, etc., with possible health benefits that are worth examining.
|
WALNUTS AS A FOOD |
|---|
|
TOPPreviousNext |
|---|
). Ravai (102
) has provided data from the Walnut Marketing Board on consumer usage of walnuts in the United States, which include baking (49%), snacks (25%), cooking (11%), salad dressings (11%), and ice cream topping (4%). Walnuts are stable, especially in the shells. When kept in a cool, dry environment they have a shelf life of 12 mo. Payne (103
) used ground walnuts instead of egg protein as whipping agents. Walnuts add and intensify flavor, and lighten foods by fluffing or foaming; they also have rising or puffing properties. Walnuts can be used in making dry cereals, multigrained breads, cookies, "veggie" burgers, stuffing mixes; walnut paste can be used in salad dressings and can replace croutons in salads. |
COMPOSITION OF WALNUTS |
|---|
|
TOPPreviousNext |
|---|
Nuts are very high in fat (73–90% of TE, 48–63 g/100g edible portion) (see Table I
). Most nuts are rich in the MUFA, oleic acid, whereas walnuts are high in the PUFAs, linoleic and -linolenic acids. The dietary fiber content in nuts is high, ranging from 5–9% by weight. Nuts are good sources of arginine-rich protein, potassium, copper, and magnesium. Nuts also are good sources of the antioxidant vitamin E and other compounds with biological activity such as flavonoids, other polyphenols, and sterols.
The composition of English walnuts (Juglans regia L.) (Table I)
is adapted from the database at the U. S. Department of Agriculture, Agricultural Research Service, Nutrient Database for Standard Reference, Release 13, 1999 (104
). This high-fat, high-energy food is relatively high in protein, potassium, phosphorus, and folate, with a good content of fiber and vitamin E, and low sugar. Selected values/100 g edible portion include: energy (654 kcal); fat (65.2 g); protein (15.2 g); fiber (6.7 g); phosphorus (346 mg); potassium (441 mg); folate (98 µg); and vitamin E (2.9 mg). The lipid content consists of SFAs (6.1 g), predominantly palmitic (4.4 g) and stearic (1.7 g) acids; MUFAs (8.9 g) almost entirely oleate; and PUFAs (47.2 g), predominantly linoleic (38.1 g) and -linolenic (9.1 g) acids. There are 72 mg of phytosterols. The amino acid composition is highest in glutamic acid (2.8 g), arginine (2.3 g), aspartic acid (1.8 g), leucine (1.2 g), serine (0.93 g), glycine (0.82 g), valine (0.75 g), phenylalanine (0.71 g), alanine (0.7 g), proline (0.7 g), isoleucine (0.62 g), and threonine (0.6 g). The concentrations of methionine and cystine are both low. A study by Pennington (96
) contains comprehensive data on the nutrient content of individual nuts including English and black walnuts (J. nigra L.).
Zwarts et al. (105
) provided data on the fatty acid composition of walnuts (oil extracted from walnut kernels of J. regia L.) from ten different New Zealand, European, and United States commercial cultivars collected over two growing seasons and found a distinctive fatty acid profile. The total oil content ranged from 62.4 to 68.7%. Oleic acid (18:1 n-9) content ranged from 14.3 to 26.1% of the total fatty acids, whereas the linoleic acid (18:2 n-6) content ranged from 49.3 to 62.3% and the linolenic acid (18:3 n-3) from 8.0 to 13.8%. Flavor stability was affected by shelf life. The PUFA content of walnut oil as a percent of total fatty acids also can vary from 47% in France to 81% in the Ashley cultivar from California (106
). Some walnut oils have been reported to contain up to 90% PUFA. Glycolipids have been examined in walnuts (107
). The sugar was exclusively galactose. The lipid distribution was similar to that in rice bran oil and in soybeans. The sterol was predominantly ß-sitosterol. The essential volatile oils in walnuts that are rich in aliphatic hydrocarbons have been quantified (108
).
The tocopherols in walnuts, in contrast to other nuts, are uniquely enriched in 
-tocopherol (109
). The authors analyzed the tocopherols in French and United States walnuts and found that -tocopherol ranged from 1.08 to 4.05, -tocopherol from 21.8 to 26.5, and 
-tocopherol from 2.51 to 4.53 mg/100 g. Levels declined about 30% after 3 mo of refrigeration.
Cardozo and Li (110
) analyzed eight varieties of nuts for total dietary fiber content. Macadamia nuts, with 14.87 g/100 g were highest in fiber followed by walnuts (9.79 g/100 g) that, in turn, exceeded almonds (9.11 g/100 g) and pecans (9.00 g/100 g). Cashews, peanuts, and pistachios were lower in fiber (3.91, 6.23, and 6.98 g/100 g, respectively). Nuts, including walnuts, are high in phytate (111
). Walnuts contain 982 mg/100 g, a value similar to almonds (1,138 mg) and roasted peanuts (952 mg), but higher than hazelnuts (648 mg) and lower than Brazil nuts (1,719 mg).
Other phytochemicals that may be biologically active in walnuts that have been quantitated in small amounts and studied include n-alkanes (which are low in walnut oil) (112
), tannins (111
,113
), and juglone, a naphthoquinone with antimicrobial activity (114
). Macfarlane’s analysis of walnuts showed them to contain >1,500 mg polyphenols/100 g, a value more than double that of the other nuts tested.
Possible adverse effects of walnut components
Lipid peroxidation.
Intake of MUFA relative to diets rich in PUFA may increase the resistance of LDL to in vitro peroxidation (74
), although data on the effect of PUFA on LDL oxidation are conflicting. Relevant studies include the Barcelona Walnut trial (81
,115
), which showed no increase in oxidative stress with walnuts as a source of increased PUFA, and Berry’s Jerusalem Nutrition Study (83
), which included walnuts in the high-PUFA diet and showed an increase in oxidative stress. Reaven et al. (116
) reported at the same time that liquid formula diets enriched in MUFA (85% of fatty acids as oleate) had decreased rate of formation of CDs as compared to diets enriched with PUFA (60% as linoleate), with no difference in TBARS, and an increase in macrophage degradation. This 39% fat diet was fed to five (MUFA) and four (PUFA) subjects. The liquid formulas were equal in vitamin E concentration (which might have a protective effect against oxidative stress if increased in relation to PUFA, as in walnuts). This study appeared to provide about 2.5-times the amount of linoleate as the Walnut clinical intervention trials.
Binding of iron.
Macfarlane et al. (111
) noted that 50 g nut meal paste in a sandwich markedly reduced iron absorption; this was reversible by 50 mg ascorbic acid. This reduction was similar to effects of soy protein and wheat bran, whereas ascorbic acid had only minor effects to improve iron absorption with these foods. Effects were ascribed primarily to the content of phytate and polyphenols. Nuts included walnuts, almonds, peanuts, hazelnuts, and Brazil nuts, all of which inhibit iron absorption, and coconuts, which had no effect.
|
CONTROLLED INTERVENTION STUDIES WITH NUTS OTHER THAN WALNUTS |
|---|
|
TOPPreviousNext |
|---|
Spiller et al. (117
) reported the effects of ingesting 100 g almonds (600 kcal) on serum lipids in hypercholesterolemic subjects. Groups of 15 subjects each, mostly females, were randomized to either the almond-based diet, an olive oil-based diet, or, as a control, a dairy-based primary source of fat. The study lasted 4 weeks, with a 1-week run-in period; there was no cross over. Significant decreases in TC, LDL-C, and the LDL:HDL ratio were observed on the almond-based diet with no change in HDL-C. No changes were observed with the olive oil diet, whereas TC and HDL-C increased significantly with the cheese and butter diet. All subjects were prescribed a similar background diet (BD) and provided many foods. The almond diet was lower in cholesterol than the other diets. BW did not change. Duplicate samples for lipid analyses were obtained along with 3-day food records. Dietary compliance was monitored with random 24-h telephone recalls. Lipid analytic procedures were standardized with quality controls. Data analyses were by ANOVA.
Subjects ingesting the almond diet consumed more energy as fat (39 vs. 35%), while the olive oil group ingested the most calories. The almond diet was high in MUFA, lowest in SFA, and highest in PUFA. The authors suggested that further studies on nut fibers be carried out.
Sabaté et al. (118
) reported a metabolic feeding study in 25 normocholesterolemic males and females with an almond diet replacing 20% of TE in a Step 1 diet, each fed for 4 weeks in a crossover design. Both diets lowered TC and LDL-C in comparison to baseline, with the almond diet further decreasing these parameters and triacylglycerol 4–6% in comparison with the Step 1 diet. The authors did not indicate if these results were statistically significant and did not provide the data for these measurements. HDL-C was unchanged and the LDL:HDL ratio decreased on the almond diet. Fasting glucose significantly decreased on the almond diet.
The study by Curb et al. (119) was a well-controlled, randomized, crossover trial carried out in healthy, young-to-middle-aged males and females with normal lipids or with hypercholesterolemia. The investigators compared a "typical American" diet with 37% of energy from fat (16% SFA, 14% MUFA, and 7% PUFA) with an American Heart Association Step 1 diet (30% fat, 9% SFA, 14% MUFA, and 7% PUFA), and a macadamia nut, MUFA-enriched diet (37% fat, 9% SFA, 21% MUFA, and 7% PUFA). Both modified diets improved the lipid profile significantly compared with the "typical American" diet.
Finely ground macadamia nuts were used as ingredients in other foods. Although both modified diets had similar lowering effects on TC and LDL-C, the macadamia diet lowered triacylglycerol, whereas triacylglycerol increased with the Step1 diet. Both diets lowered HDL-C by about 4%. The results suggest the lipid-lowering benefits of an alternative to the "step 1 diet" reduction in TF and SF. Instead, the investigators suggested substituting sources of MUFA, such as nuts, for some SFA.
Macadamia nuts, like other nuts, are high in fat (75% by weight) with oleic acid predominating, which is similar to the contents in almonds and peanuts. Macadamias, however, have a large amount of a less common MUFA, palmitoleic acid (16:1). This fatty acid has not been compared with the more common long-chain fatty acids, so that possible benefits (or adverse effects) of enrichment with this fatty acid are unknown. This study did not include measurements of other lipid and lipoprotein risk factors such as the apoproteins, or the subclasses of HDL or LDL, or Lp (a) that are emerging as important predictors of CHD. The authors did not provide information about the exact amount of nuts eaten daily, nor the foods in which they were incorporated, nor meal plans, menus, or recipes. In a pilot study, investigators reported that subjects ingested 45-90 g of nuts daily. The subjects probably consumed from 45-50 g of nuts as whole nuts, nut meal, and other products, which was about one-third of their daily fat intake.
A related study from Australia (120
) reported a crossover, randomized trial in males (n = 7) and females (n = 7) comparing a high-MUFA (42% fat) diet incorporating macadamia nuts with a 20% LF diet high in complex carbohydrates. The data showed significant lowering of TC and LDL-C with both diets. Triacylglycerol decreased and there was no change in HDL-C with the macadamia diet in contrast to lowering of HDL-C with the LF diet. In this study, 25-50 nuts were consumed daily, added to salads and desserts, or as snacks. The investigators analyzed the fatty acid composition of the nuts: 0.8% myristic (14:0); 8% palmitic (16:0); 19% palmitoleic (16:1); 4% stearic (18:0); 56% oleic (18:1); 2% linoleic (18:2); 3% arachidic (20:0); and 3% gadoleic (20:1). Some studies with palmitoleic acid from macadamia oil suggested favorable properties beyond those of oleic acid in preventing CVD. They suggest incorporating macadamia nuts in cereal mixes, spreads, flavorings, and ice cream.
Tung et al. (121
) reported the results of a randomized, crossover study of a macadamia nut-based diet and a "typical American" diet. Both diets contained 38% fat, with the macadamia diet lower in SFA (9%) and higher in MUFA (22%); the control diet had 20% SFA and 11% MUFA. Twenty-two healthy male and female volunteers, 20–52 y of age, were fed each diet for 8 weeks, with a 2-mo washout period. TC and LDL-C were significantly lower with the macadamia diet, and large particle LDL3 (a fraction of LDL-C) also decreased along with mean LDL particle concentration and particle size. The latter changes would adversely affect the risk of CVD.
Edwards et al. (122
) used a random, crossover design and reported the effects in 10 healthy, moderately hypercholesterolemic males and females of adding pistachio nuts as snacks, 100 g providing 20% of calories, during a 3-week intervention. Comparing the pistachio diet with the regular diet, researchers found that TC, TC:HDL-C, and LDL-C:HDL-C decreased significantly, with no significant changes in LDL-C, HDL-C, or triacylglycerol. BW and BP were unchanged. With the pistachio diet, SFA decreased and MUFA, PUFA, and fiber increased significantly.
Rajaram et al. (123
) reported the effects of a pecan-rich diet on serum lipids and lipoproteins in 23 normocholesterolemic males and females. After a run-in period of 2 weeks on a "typical American" diet, subjects were fed for 4 weeks either the pecan diet or a Step 1 diet in a randomized, controlled, crossover design. The pecan diet was higher in TF (42 vs. 30%); both diets had 8% SFA whereas the pecan diet was higher in MUFA (24 vs. 15%) and PUFA (10 vs. 7%). The pecan diet significantly decreased serum cholesterol, LDL-C, triacylglycerol, apo B, and Lp (a) levels and increased HDL-C and apo A-1 levels compared with the Step 1 diet.
Other data from this study, reported by Haddad et al. (124
), showed that the pecan diet increased stool fat excretion. Stools were collected for 48 h in six subjects during each of the diet periods. Stool fat (25 g pecan, 6 g Step 1) and the percentage of fat in the stool (8% pecan, 3% Step 1) increased significantly with the pecan diet. The authors suggest that these changes may explain, in part, why the added fat or calories in a nut-based diet do not lead to weight gain. The pecan fat may not have been as well-absorbed because of the structure of lipid-storing granules in nuts or the fiber components of the nuts.
Peanuts are ground nuts or legumes, rather than tree nuts, which is the category that includes the varieties of nuts already described. Nonetheless, consumers perceive them as nuts and eat them as snacks and use them as condiments. Their consumption in the United States exceeds that of tree nuts. The fatty acid composition of peanuts resembles most tree nuts, ie, they contain primarily MUFAs. Peanuts, however, are uniquely enriched in very long-chain SFAs and contain plant proteins rich in arginine and phytochemicals.
Peanut oil has been studied extensively in relation to experimental atherosclerosis. Results are controversial in terms of the atherogenicity of peanut oil, in part depending on the species tested.
Since peanuts are widely consumed, and peanut oil is a major fat source in many populations, this report summarizes the data from recent controlled studies relating the consumption of peanuts to the risk of heart disease.
Kris-Etherton and collaborators (125
) compared the lipid profile of a high-MUFA diet of peanuts and peanut butter providing one-half the fat, with two other high-MUFA diets—olive oil and peanut oil—a Step 2 American Heart Association diet, and an "average American" diet (AAD) with 34% TF. The study was randomized, double-blind, and had five crossover periods. Twenty-two healthy, normocholesterolemic males and females were fed each diet for 24 day, with 4-to-11-day breaks between periods. All meals were provided. The three high-MUFA diets, equal in TF to the AAD (34%), were lower in SFA (7 vs. 16%) and cholesterol (200 vs. 400 mg); the Step 2 diet was 25% fat. The MUFA and Step 2 diets were similar in their lowering of TC and LDL-C compared with the AAD. Triacylglycerol concentrations were lower with the MUFA diets and increased with the Step 2 diet; HDL-C was unchanged with the MUFA diet and lower with the Step 2 diet. Apo A-1 and apo B and the ratios of TC:HDL-C and LDL-C:HDL-C were lower with the MUFA diets. Standard lipid methods were used to assay plasma lipids and lipoproteins and diet fatty acid composition, with quality control. Data, which were analyzed by ANOVA, showed no appreciable differences among the MUFA diets. The authors concluded that a high-MUFA, cholesterol-lowering diet that includes peanuts and nuts is an acceptable dietary approach toward favorably affecting CVD risk status.
O’Byrne et al. (126
,127
) described studies with high-oleic peanuts fed for 6 mo that evaluated effects on serum lipids, lipoproteins, apoproteins, and lipoprotein oxidation. In one study, subjects were older, healthy hypercholesterolemic females. The high-oleic peanut cultivar contains 76-80% of fat as MUFA. Prepackaged daily rations of dry roasted peanuts were provided, and subjects consumed 35–68 g daily. LDL fatty acid composition and oxidation were measured in five subjects eating the peanut diet (26% fat, 14% MUFA) and in six subjects following a LF diet. The LDL oxidation parameters (viz., CD and lipid peroxidation) were improved with the peanut diet.
In groups of 12 and 13 females, in which each ate the peanut and LF diets, TC and LDL-C decreased and the proportion of larger, lipid-rich, less atherogenic LDL increased with the peanuts. Serum triacylglycerol, HDL-C, and apo A-1 levels were unchanged.
Jenkins et al. (128
) reported effects on serum lipids of a diet high in nuts (60–100 g almonds, cashews, and peanuts) in a 2-week random, crossover-designed study of 10 healthy, young, normolipidemic Canadian males and females. The nuts were included in a plant-based diet high in green, leafy vegetables and fruits and low in fat (25% of TE). The control diet was their HD (fat intake 29% of TE). Significant differences observed with the plant-based diet were decreases in LDL-C and the ratios of TC:HDL-C, apo B:A-1, and Lp (a).
When the control period preceded the plant-based diet, there was no washout. When the vegetable diet was given first, the investigators waited 5 mo to study the HD in order to avoid carry-over habits from that period. Nuts were provided to the subjects. Samples for lipid analysis were drawn once per treatment period and analyzed by validated methods. Data of percent change in variables were analyzed by t test, multiple regressions, and correlation coefficients. The vegetable diet was significantly lower in SFA and cholesterol and higher in fiber compared to the control diet.
The study was limited by small sample size and short duration. The diet not only was enriched in nuts, but eliminated animal products, and so may not easily be extrapolated to less extreme dietary modifications. The investigators noted, however, that the observed changes in LDL-C were double that predicted from the change in fatty acid content.
A related study from India reported effects of a vegetarian diet on the outcome of acute MI during a 6-week follow-up (129
). Immediately after a MI, patients were randomized to a vegetarian diet which included fruits, vegetables, almonds, and walnuts (204 patients) or their physician’s prescribed "prudent" diet (202 patients). The lipid profile improved on the vegetarian diet with decreases in TC, LDL-C, and triacylglycerol, and there was a 34% decrease in total cardiac endpoints. The diet was significantly lower than the diet prescription in energy, SFA, cholesterol, caffeine, and salt, and increased in fiber, vegetable protein, vitamins C and E, magnesium, potassium, copper, selenium, and chromium.
This study might indicate the value of a plant-based diet that includes walnuts in the early management of acute MI and could be compared with studies reviewed on nutritional factors in relation to cardiac arrhythmias or thrombosis.
These clinical human dietary intervention studies are summarized in
Table 2
.
|
PROTEINS IN NUTS AND AS A FACTOR IN HEART DISEASE RISK |
|---|
|
TOPPreviousNext |
|---|
).
Plant proteins differ in their amino acid composition from animal proteins; they are enriched in arginine and low in lysine. A diet rich in plant proteins (eg, plant-based, vegetarian), in contrast to animal proteins (eg, casein, beef), reduces the risk of atherosclerosis, in part by favorably influencing the lipid profile. The ratio of lysine:arginine was implicated in hypercholesterolemia and atherosclerosis in earlier animal studies (130
,131
). More recently, with the evolution of our understanding of the significance of NO in vascular biology, arginine emerges with new importance as the precursor of NO.
Many studies support the hypothesis that plant proteins, and specifically arginine or the low lysine:arginine ratio, reduce experimental atherosclerosis. The investigators implicated mechanisms related to lipids, lipoproteins, lipid oxidation, stimulation of the vascular endothelium, and the effects on coagulation (platelet aggregation) mediated by prostaglandins and cytokines, as well as on arrhythmias. Studies with arginine investigating reduction of CVD mortality and morbidity report beneficial effects on heart failure, BP, and stroke. Studies have administered L-arginine, arginine-enriched proteins, nut-enriched diets and, specifically, walnut-enriched diets. The lysine:arginine ratio of walnuts is low (0.16). Soy protein, for example, has a ratio of 0.58–1, with animal proteins like casein or whole milk having ratios of 1.89 and 2.44, respectively (131
).
Kritchevsky (131
) observed that increasing arginine in the diet of hyperlipidemic rabbits or, more importantly, the low lysine:arginine ratio, had an antiatherogenic effect. Although the source of increased lysine:arginine ratio was fish protein (ratio of 1.44) and the investigators were unable to provide a mechanism for their results, the antiatherogenic effect has been extrapolated to later studies that used diets enriched in plant proteins with low ratios of lysine:arginine, or a plant source of arginine.
Ravel et al. (132
) studied the effect of walnut meal compared to soybean meal on hypercholesterolemia and growth rate in female rabbits. The hypercholesterolemia, which is correlated with hypertriglyceridemia, was reduced after 6 weeks on the walnut diet but the mechanism was not elucidated. The surviving animals had a net gain in BW of 10%.
Ravel et al. (133
) studied walnut meal as a source of arginine in feeding rabbits a semisynthetic diet compared with casein or soy protein diets. The walnut diet showed the greatest decrease in platelet aggregation and a decrease in TC. Platelet aggregability correlated best with the lysine:arginine (0.16 walnuts, 0.70 soybeans, and 1.54 casein) and the HDL:LDL ratios. The investigators proposed that an increase in the ratio 20:5 n-3:20:4 n-6 in platelets may have a favorable influence on their aggregation. This laboratory had published data that showed the hypocholesterolemic effect of vegetable proteins with significant lowering of LDL-C and the beneficial effect on platelet aggregability (134
). LDL-C has been shown to increase platelet aggregation and HDL-C to lower platelet reactivity.
Confirming the antiatherogenic effect in rabbits, Aji et al. (135
) reported that arginine prevents xanthomas and inhibits atherosclerosis in an LDL-receptor knockout mouse model of familial hypercholesterolemia. Mice were fed a high-cholesterol diet with or without arginine or with arginine and an inhibitor of nitric oxide synthase (NOS). A control group was fed a standard mouse laboratory stock diet. Arginine (2.25%) was added to the drinking water for 6 mo. All mice fed the high-cholesterol diet developed xanthomas, but none of the arginine-supplemented mice did. The size of aortic atherosclerotic lesions was reduced significantly in the arginine group compared with the mice fed the unsupplemented, high-cholesterol diet. The investigators concluded that the antiatherogenic effect of arginine was mediated by stimulating NOS and suggested that L-arginine might be helpful in treating familial hypercholesterolemia. In all groups fed the high-cholesterol diet, ie, with or without arginine or arginine and the NOS inhibitor, there were no differences in plasma cholesterol levels or in the distribution of cholesterol among atherogenic lipoprotein.
Adams et al. (136
) showed that increasing the intake of L-arginine improved platelet function markedly, but did not affect vascular reactivity. They administered 7 g arginine powder taken with meals 3 times/day for 3 day in a randomized, placebo-controlled, crossover study, with a washout period of 7–14 day. In the study subjects (12 healthy, young males), plasma arginine levels were about 2.5 times higher and platelet arginine increased seven-fold. The arginine intake was estimated to be about 4 times greater than the normal arginine daily intake that had been estimated in Australia at about 4 g per day in 1984. The inhibition of platelet aggregation correlated significantly with the plasma level of arginine. They interpreted their experimental data as showing a relatively platelet-specific effect of arginine in this brief period of oral administration to increase NO production locally but not systemically, and with no changes in vascular hemodynamics or plasma lipids. Although the authors indicated that they calculated LDL-C by using the Friedewald equation, they present numbers that indicate that they simply subtracted HDL-C from TC, even though they had data of triacylglycerol measurements to use in the calculation.
A randomized, double-blind, placebo-controlled study by Wolf et al. (137
) reported effects of feeding 8.6 g L-arginine for 2 weeks to 23 hypercholesterolemic subjects (17 males and 6 females). The study used a parallel design. These subjects were also compared with 14 normocholesterolemic control subjects (13 males and 1 female). Arginine was administered as capsules containing 700 mg; three capsules were taken 4 times daily. This regimen increased arginine intake about 50% compared to the 5.6 g reported as the usual daily intake in the United States in 1986. Plasma arginine increased 55%. Platelet aggregability increased moderately in hypercholesterolemic subjects compared with the normal control and improved modestly with arginine. The authors noted that endothelial vasodilator function is depressed in hypercholesterolemia due to increased degradation and/or reduced synthesis of NO. The abnormality can be corrected by administering L-arginine, which is then converted to NO. Future studies should address whether L-arginine, via its antiplatelet effects, will reduce vascular thrombosis and the progression of CVD.
Rector et al. (138
) reported a trial of arginine supplementation in heart failure. They compared the effects of arginine, 5.6–12.6 g daily for 6 weeks with a placebo (double-blind). The subjects were heart-failure patients (14 males and 1 female, mean age 56 y). With arginine, blood flow in the forearm and distance walked increased, an adverse functional score declined, arterial compliance increased, and circulating endothelin decreased. Plasma arginine increased about 15%.
These studies of arginine feeding in human subjects reported neither the diet of their subjects nor its arginine content. It would be of interest to know the current intake of arginine in the United States in order to optimize arginine intake. It remains to be elucidated whether arginine supplementation is a benefit if it is added to a vegetarian diet and to determine if there is a way to enrich the arginine content in the walnut crop.
Arginine studies are exciting in terms of possible effects on clinical manifestations of heart disease and mortality. Note that walnuts are especially rich in arginine (Table I)
.
Nitric oxide and vascular function and disease
This topic was reviewed in an editorial in the New England Journal of Medicine (139
). L-arginine is converted to L-citrulline and NO in a reaction catalyzed by NOS. Several isoforms of the enzyme are located in endothelium, macrophages, and neurons that respond variably to agonists and calcium induction. Exogenous arginine enhances NO synthesis. NO determines resting vascular tone and stimulates thrombin, adenosine diphosphate, and bradykinin; it is involved in shear stress and cyclic strain. NO induces smooth muscle cell relaxation by activating guanylate cyclase to produce cyclic guanosine monophosphate, the putative second messenger of NO. Endogenous NO determines the pressor response to sodium. NO also inhibits platelet adhesion, activation, and aggregation, and is antithrombotic. Other actions of NO include inhibition of growth of vascular SMCs. L-arginine administration in experimental animals may inhibit neointimal vascular proliferation of the aorta after balloon injury.
Other discussions on NO (135
,137
) and an editorial by de Lorgeril (140
) consider the effects of NO on BP. Additional actions of NO include the inhibition of monocyte adhesion to endothelial cells and expression of adhesion molecules, decreased expression of monocyte chemotactic proteins, and scavenging by superoxide radicals. These may reduce LDL oxidation and expression of redox-sensitive adhesion molecule genes. In hypercholesterolemic animals and humans, endothelial vasodilatation is depressed, either from increased degradation and/or reduced synthesis of NO. This abnormality can be prevented by administering L-arginine. Generating NO in vivo from blood vessels has been demonstrated. The relation of NO and arginine to eicosanoid production remains to be discovered.
De Lorgeril (140
) also discussed some paradoxes. Beef, pork, and lamb are high sources of arginine, albeit also high in SFAs, as are chicken and fish, foods that are recommended in diets to prevent heart disease. The n-3 fatty acids in fish have been related to increases in NO excretion, presumably by stimulating NO synthesis. This implies that the combination of n-3 fatty acids and arginine, with low SFAs and zero cholesterol, as in nuts, should be effective in cardioprevention diets. Emphasizing nut intake also may favorably affect Hcy levels that are lowered by folate (folate content is high in walnuts) and increased by methionine, which is low in nuts and high in meats. Since the vascular toxicity of Hcy may be related in part to inhibition of NO, increasing arginine consumption (by eating nuts) also improves the folic acid:methionine ratio and may have interrelated effects in preventing CVD independent of effects on lipids. Manipulation of the diet with foods in order to lower the risk for heart disease may be safer, less costly, and more acceptable to those at risk, perhaps delaying pharmacologic interventions, or at least decreasing the doses of drugs.
|
OVERVIEW AND SUMMARY OF CLINICAL TRIALS |
|---|
|
TOPPreviousNext |
|---|
200 healthy, young- to -middle-aged subjects, mostly Caucasian, about two-thirds of whom were males, tested usually for 4 to 6 weeks. TC and LDL-C have ranged from normal to moderately hypercholesterolemic. Some subjects have been overweight. The subjects are representative of the 51% of the adult population in the United States who are at higher risk of CHD. Daily intake of walnuts in these trials ranged from 48 to 84 g. Outcome variables have included serum plasma lipids, lipoproteins, lipid and lipoprotein classes and subclasses, apoproteins, and oxidative stress. The diet has been monitored variously by recall, food records, FFQ, or all foods were provided. Subjects have been studied under metabolic ward conditions or free-living. Analyses have been made of the fatty acid composition of the diet, plasma, lipid classes, or adipose tissue. Data analyses have used t tests, ANOVA measurements, linear modeling, and stepwise conditional logistic regression methods. The number of subjects enrolled in these trials has ranged from 16 to 49. Data have uniformly shown significant lowering of TC, LDL-C, and the ratio LDL-C:HDL-C. Apoprotein response has been variable. Changes in lipid particle size were assayed. Cholesterol was decreased significantly in IDL and redistributed from the more atherogenic small, dense LDL to larger LDL particles. Adding walnuts to diet was associated with significant shifts in cholesterol that redistributed it from larger into smaller HDL particles. Lipid particle changes occurred in the absence of lipid lowering, suggesting a favorable antiatherogenic effect of walnuts that is independent of any changes in circulating lipid levels. The fatty acid composition of plasma or RBC membranes, with increased PUFA, indicates that the subjects complied with the various diets.
Studies have rarely included patients with CHD. Evaluating cardiovascular outcomes would require more time and involve more subjects of both sexes. Some investigators had difficulty controlling fat and energy intake with the walnut diet. They observed that net BW did not increase; however this finding requires explanation. Data concerning oxidative stress were inconclusive, as one study showed an adverse effect and another reported no change.
|
WEIGHT OF EVIDENCE |
|---|
|
TOPPreviousNext |
|---|
). Specifically, the FDA document notes that: "... the assessment of significant scientific agreement then derives from the conclusion that there is a sufficient body of sound, relevant scientific evidence that shows consistency across different studies and among different researchers and permits the key determination of whether a change in the dietary intake of the substance will result in a change in a disease endpoint...."
Further, "... significant scientific agreement does not require a consensus or agreement based on unanimous and incontrovertible scientific opinion. However, on the continuum of scientific discovery that extends from emerging evidence to consensus, it represents an area on the continuum that lies closer to the latter than to the former."
In the context of the foregoing, interventional studies on human subjects were accorded the greatest scientific weight in reaching the conclusions presented here. The studies were well designed, executed, and controlled. The human subjects were representative of the 51% of the adult population of the United States at higher risk of CHD. The observational studies were supportive because walnuts were not always identified as an independent variable, and the data collection was semiquantitative.
Studies on tree and ground nuts other than walnuts were included in the scientific evaluation for completeness and to complement the findings reported in the observational studies. Similarly, abstracts were included to round out the literature, with the caveat that the evidence presented had not been peer-reviewed and could not be weighed. Moreover, none of the conclusions in this report is based on the abstracts cited.
|
CONCLUSIONS |
|---|
|
TOPPreviousNext |
|---|
|
FOOTNOTES |
|---|
2 Prepared for California Walnut Commission, 1540 River Park Drive, Suite 203, Sacramento, CA.
3 For correspondence, contact Michael Falk, Life Sciences Research Office, 9650 Rockville Pike, Bethesda, Maryland 20814-3998. Tel: (301) 530-7030, fax (301) 571-1876; email: falkm{at}lsro.faseb.org
|
REFERENCE LIST |
|---|
|
TOP |
|---|
1.
Manninen, V., Elo, M. O., Frick, M. H., Haapa, K., Heinonen, O. P., Heinsalmi, P., Helo, P., Huttunen, J. K., Kaitaniemi, P., Koskinen, P., Mäenpää, H., Mälkönen, M., Mänttäri, M., Norola, S., Pasternack, A., Pikkarainen, J., Romo, M., Sjöblom, T. & Nikkilä, E. A. (1988) Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 260:641-651.
2. Angles-Cano, E., de la Pena, D. A. & Loyau, S. (2001) Inhibition of fibrinolysis by lipoprotein(a). Ann. N.Y. Acad. Sci. 936:261-275.[Medline]
3. Rubins, H. B. & Robins, S. J. (2000) Conclusions from the VA-HIT Study. Am. J. Cardiol. 86:543-544.[Medline]
4.
Rubins, H. B., Robins, S. J., Collins, D., Fye, C. L., Anderson, J. W., Elam, M. B., Faas, F. H., Linares, E., Schaefer, E. J., Schectman, G., Wilt, T. J. & Wittes, J. (1999) Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N. Engl. J. Med. 341:410-418.
5. Austin, M. A. (1999) Epidemiology of hypertriglyceridemia and cardiovascular disease. Am. J. Cardiol. 83:13F-16F.[Medline]
6.
Stampfer, M. J., Krauss, R. M., Ma, J., Blanche, P. J., Holl, L. G., Sacks, F. M. & Hennekens, C. H. (1996) A prospective study of triglyceride level, low-density lipoprotein particles diameter, and risk of myocardial infarction. JAMA 276:882-888.
7. Feldman, E. B. (2001) Cardiovascular disease—prevention by diet. Berdanier, C.D. eds. CRC Handbook of Nutrition and Foods 2001 CRC Press Boca Raton, FL. (in press).
8. Keys, A. eds. Coronary Heart Disease in Seven Countries. American Heart Association Monograph. No. 29 1970:1-211 American Heart Association, Inc. New York, NY. .
9. Keys, A., Aravanis, C., Blackburn, H., Buzina, R., Djordjevíc, B. S., Dontas, A. S., Fidanza, F., Karvonen, M. J., Kimura, N., Menotti, A., Mohacek, I., Nedeljkovic, S., Puddu, V., Punsar, S., Taylor, H. L. & van Buchem, F. S. P. (1980) Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease 1980 Harvard University Press Cambridge, MA. .
10.
Verschuren, W. M. M., Jacobs, D. R., Bloemberg, B. P. M., Kromhout, D., Menotti, A., Aravanis, C., Blackburn, H., Buzina, R., Dontas, A. S., Fidanza, F., Karvonen, M. J., Nedeljkovic, S., Nissinen, A. & Toshima, H. (1995) Serum total cholesterol and long-term coronary heart disease mortality in different cultures. Twenty-five-year follow-up of the Seven Countries Study. JAMA 274:131-136.
11. Grundy, S. M., Bilheimer, D., Chait, A., Clark, L. T., Denke, M. A., Havel, R. J., Hazzard, W. R., Hulley, S. B., Hunninghake, D. B., Kreisberg, R. A., Kris-Etherton, P. M., McLKenney, J. M., Newman, M. A., Schaefer, E. J., Sobel, B. E., Somelofski, C. A. & Weinstein, M. C. (1994) National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. (Adult Treatment Panel II). Circulation 89:1333-1445.[Medline]
12. Ferraro-Borgida, M. & Waters, D. (2000) Biochemical correlates of plaque progression and coronary events. Grundy, S. M. eds. Cholesterol-lowering Therapy-Evaluation of Clinical Trial Evidence 2000:221-247 Marcel Dekker Inc. New York, NY. .
13. National Institutes of Health National Heart, Lung, and Blood Institute (2001) Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) 2001Accessed 11/20/2001. NIH Publication No. 01-3670. Web/URL: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm..
14.
Van Horn, L. (1997) Fiber, lipids, and coronary heart disease. A statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 95:2701-2704.
15. Food and Drug Administration (1997) Food labeling: health claims; oats and coronary heart disease; Final rule. Fed.Reg. 62(15):3584-3601.
16.
Brown, L., Rosner, B., Willett, W. W. & Sacks, F. M. (1999) Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am. J. Clin. Nutr. 69:30-42.
17. Lichtenstein, A. H., Kennedy, E., Barrier, P., Danford, D., Ernst, N. D., Grundy, S. M., Leveille, G. A., Van Horn, L., Williams, C. L. & Booth, S. L. (1998) Dietary fat consumption and health. Nutr. Rev. 56(5 Part II):S3-28.
18. Ludwig, D. S. & Ludwig, D. S. (2000) Dietary glycemic index and obesity. J. Nutr. 130:280S-283S.
19.
Krauss, R. M., Eckel, R. H., Howard, B., Appel, L. J., Daniels, S. R., Deckelbaum, R. J., Erdman, J. W., Jr, Kris-Etherton, P., Goldberg, I. J., Kotchen, T. A., Lichtenstein, A. H., Mitch, W. E., Mullis, R., Robinson, K., Wylie-Rosett, J., St.Jeor, S., Suttie, J., Tribble, D. L. & Bazzarre, T. L. (2000) AHA Dietary Guidelines. Revision 2000: A statement for healthcare professionals from the nutrition committee of the American Heart Association. Stroke 31:2751-2766.
20.
Albert, C. M., Hennekens, C. H., O’Donnell, C. J., Ajani, U. A., Carey, V. J., Willett, W. C., Ruskin, J. N. & Manson, J. E. (1998) Fish consumption and risk of sudden cardiac death. JAMA 279:23-28.
21.
Siscovick, D. S., Raghunathan, T. E., King, I., Weinmann, S., Bovbjerg, V. E., Kushi, L., Cobb, L. A., Copass, M. K., Psaty, B. M., Lemaitre, R., Retzlaff, B. & Knopp, R. H. (2000) Dietary intake of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. Am. J. Clin. Nutr. 71:208S-212S.
22.
Kang, J. X. & Leaf, A. (1994) Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes. Proc. Natl. Acad. Sci. U.S.A. 91:9886-9890.
23.
Harris, W. S. (1997) n-3 Fatty acids and serum lipoproteins: human studies. Am. J. Clin. Nutr. 65:1645S-1654S.
24.
Mori, T. A., Beilin, L. J., Burke, V., Morris, J. & Ritchie, J. (1997) Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 17:279-286.
25. Aring;gren, J. J., Väisänen, S., Hänninen, O., Muller, A. D. & Hornstra, G. (1997) Hemostatic factors and platelet aggregation after a fish-enriched diet or fish oil or docosahexaenoic acid supplementation. Prostaglandins Leukot. Essent. Fatty Acids 57:419-421.[Medline]
26.
Guallar, E., Aro, A., Jiménez, F. J., Martín-Moreno, J. M., Salminen, I., van’t Veer, P., Kardinaal, A. F. M., Gómez-Aracena, J., Martin, B. C., Kohlmeier, L., Kark, J. D., Mazaev, V. P., Ringstad, J., Guillén, J., Riemersma, R. A., Huttunen, J. K., Thamm, M. & Kok, F. J. (1999) Omega-3 fatty acids in adipose tissue and risk of myocardial infarction: The EURAMIC Study. Arterioscler. Thromb. Vasc. Biol. 19:1111-1118.
27.
Hu, F. B., Stampfer, M. J., Manson, J. E., Rimm, E. B., Colditz, G. A., Rosner, B. A., Speizer, F. E., Hennekens, C. H. & Willett, W. C. (1998) Frequent nut consumption and risk of coronary heart disease in women: prospective cohort study. BMJ 317:1341-1345.
28. de Lorgeril, M., Renaud, S., Mamelle, N., Salen, P., Martin, J.-L., Monjaud, I., Guidollet, J., Touboul, P. & Delaye, J. (1994) Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343:1454-1459.[Medline]
29.
Appel, L. J., Moore, T. J., Obarzanek, E., Vollmer, W. M., Svetkey, L. P., Sacks, F. M., Bray, G. A., Vogt, T. M., Cutler, J. A., Windhauser, M. M., Lin, P.-H. & Karanja, N. (1997) A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N. Engl. J. Med. 336:1117-1124.
30. Conlin, P. R., Chow, D., Miller, E. R., III, Svetkey, L. P., Lin, P.-H., Harsha, D. W., Moore, T. J., Sacks, F. M. & Appel, L. J. (2000) The effect of dietary patterns on blood pressure control in hypertensive patients: results from the Dietary Approaches to Stop Hypertension (DASH) trial. Am. J. Hypertens. 13:949-955.[Medline]
31. Sacks, F. M., Appel, L. J., Moore, T. J., Obarzanek, E., Vollmer, W. M., Svetkey, L. P., Bray, G. A., Vogt, T. M., Cutler, J. A., Windhauser, M. M., Lin, P.-H. & Karanja, N. (1999) A dietary approach to prevent hypertension: a review of the Dietary Approaches to Stop Hypertension (DASH) Study. Clin. Cardiol. 22(Suppl. III):III-6-10.
32.
Svetkey, L. P., Simons-Morton, D., Vollmer, W. M., Appel, L. J., Conlin, P. R., Ryan, D. H., Ard, J. & Kennedy, B. M. (1999) Effects of dietary patterns on blood pressure. Arch. Intern. Med. 159:285-293.
33. Food and Drug Administration (2000) Food labeling: health claims; plant sterol/stanol esters and coronary heart disease; Interim final rule. Fed. Reg. 65(175):54686-54739.
34. Baum, J. A., Teng, H., Erdman, J. W., Jr, Weigel, R. M., Klein, B. P., Persky, V. W., Freels, S., Surya, P., Bakhit, R. M., Ramos, E., Shay, N. F. & Potter, S. M. (1998) Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women. Am. J. Clin. Nutr. 68:545-551.[Abstract]
35.
Crouse, J. R., III, Morgan, T., Terry, J. G., Ellis, J., Vitolins, M. & Burke, G. L. (1999) 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. 159:2070-2076.
36.
Boushey, C. J., Beresford, S. A. A., Omenn, G. S. & Motulsky, A. G. (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA 274:1049-1057.
37.
Malinow, M. R., Bostom, A. G. & Krauss, R. M. (1999) Homocyst(e)ine, diet, and cardiovascular diseases. A statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 99:178-182.
38.
Scott, J. M. (2000) Homocysteine and cardiovascular risk. Am. J. Clin. Nutr. 72:333-334.
39.
Brattström, L. & Wilcken, D. E. L. (2000) Homocysteine and cardiovascular disease: cause or effect?. Am. J. Clin. Nutr. 72:315-323.
40.
Ueland, P. M., Refsum, H., Beresford, S. A. A. & Vollset, S. E. (2000) The controversy over homocysteine and cardiovascular risk. Am. J. Clin. Nutr. 72:324-332.
41.
Robinson, K., Arheart, K., Refsum, H., Brattström, L., Boers, G., Ueland, P., Rubba, P., Palma-Reis, R., Meleady, R., Daly, L., Witteman, J. & Graham, I. (1998) Low circulating folate and vitamin B6 concentrations. Risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation 97:437-443.
42. Pancharuniti, N., Lewis, C. A., Sauberlich, H. E., Perkins, L. L., Go, R. C. P., Alvarez, J. O., Macaluso, M., Acton, R. T., Copeland, R. B., Cousins, A. L., Gore, T. B., Cornwell, P. E. & Roseman, J. M. (1994) Plasma homocst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease. Clin. Nutr. 59:940-948.
43. Christen, W. G., Gaziano, J. M. & Hennekens, C. H. (2000) Design of Physicians’ Health Study II—a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann. Epidemiol. 10:125-134.[Medline]
44. Rimm, E. B. & Stampfer, M. J. (2000) Antioxidants for vascular disease. Med. Clin. North Am. 84:239-249.[Medline]
45. Lonn, E. M. & & Yusuf, S. (1997) Is there a role for antioxidant vitamins in the prevention of cardiovascular diseases? An update on epidemiological and clinical trials data. Can. J. Cardiol. 13:957-965.[Medline]
46. Marchioli, R. (2000) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 354:447-455.
47.
Loria, C. M., Klag, M. J., Caulfield, L. E. & Whelton, P. K. (2000) Vitamin C status and mortality in US adults. Am. J. Clin. Nutr. 72:139-145.
48. Hercberg, S., Preziosi, P., Galan, P., Faure, H., Arnaud, J., Duport, N., Malvy, D., Roussel, A. M., Briancon, S. & Favier, A. (1999) "The SU.VI.MAX Study": a primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers. Food Chem.Toxicol. 37:925-930.[Medline]
49.
Ascherio, A., Rimm, E. B., Hernán, M. A., Giovannucci, E., Kawachi, I., Stampfer, M. J. & Willett, W. C. (1999) Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann. Intern. Med. 130:963-970.
50.
Klipstein-Grobusch, K., Geleijnse, J. M., den Breeijen, J. H., Boeing, H., Hofman, A., Grobbee, D. E. & Witteman, J. C. (1999) Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam Study. Am. J. Clin. Nutr. 69:261--266.
51. National Research Council.Committee on Diet and Health (1989) Fat and Other Lipids. Diet and Health: Implications for Reducing Chronic Disease Risk 1989:159-258 National Academy Press Washington, DC. .
52. Shepherd, J., Packard, C. J. & Patsch, J. R. (1978) Effects of dietary polyunsaturated and saturated fat on the properties of high density lipoproteins and the metabolism of apolipoprotein A-1. J.Clin.Invest. 61:1582-1592.
53.
Schaefer, E. J., Levy, R. I., Ernst, N. D., van Sant, F. D. & Brewer, H. B., Jr (1981) The effects of low cholesterol, high polyunsaturated fat, and low fat diets on plasma lipid and lipoprotein cholesterol levels in normal and hypercholesterolemic subjects. Am. J. Clin. Nutr. 34:1758-1763.
54.
Jackson, R. L., Kashyap, M. L., Barnhart, R. L., Allen, C., Hogg, E. & Glueck, C. J. (1984) Influence of polyunsaturated and saturated fats on plasma lipids and lipoproteins in man. Am. J. Clin. Nutr. 39:589-597.
55.
Iacono, J. M. & Dougherty, R. M. (1991) Lack of effect of linoleic acid on the high-density-lipoprotein-cholesterol fraction of plasma lipoproteins. Am. J. Clin. Nutr. 53:660-664.
56. Leren, P. (1966) The effect of plasma cholesterol lowering diet in male survivors of myocardial infarction. A controlled clinical trial. Acta. Med. Scand. Suppl. 466:1-92.[Medline]
57. Dayton, S., Pearce, M. L., Hashimoto, S., Dixon, W. J. & Tomiyasu, U. (1969) A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 39 & 40(suppl. 2):II1-63.
58. Miettinen, M., Turpeinen, O., Karvonen, M. J., Elosuo, R. & Paavilainen, E. (1972) Effect of cholesterol-lowering diet on mortality from coronary heart-disease and other causes. A twelve year clinical trial in men and women. Lancet 2:835-838.[Medline]
59.
Friday, K. E., Failor, R. A., Childs, M. T. & Bierman, E. L. (1991) Effects on n-3 and n-6 fatty acid-enriched diets on plasma lipoproteins and apolipoproteins in heterozygous familial hypercholesterolemia. Arterioscler.Thromb. 11:47-54.
60. Reaven, P., Parthasarathy, S., Grasse, B. J., Miller, E., Steinberg, D. & Witztum, J. L. (1993) Effects of oleate-rich and linoleate-rich diets on the susceptibility of low density lipoprotein to oxidative modification in mildly hypercholesterolemic subjects. J. Clin. Invest. 91:668-676.
61. Hansen, H. S. (1994) New biological and clinical roles for the n-6 and n-3 fatty acids. Nutr. Rev. 52:162-167.[Medline]
62. Siguel, E. (1996) A new relationship between total/high density lipoprotein cholesterol and polyunsaturated fatty acids. Lipids 31:S51-S56.
63. Galli, C. & Marangoni, F. (1997) Recent advances in the biology of n-6 fatty acids. Nutrition 13:978-985.[Medline]
64.
Eritsland, J. (2000) Safety considerations of polyunsaturated fatty acids. Am. J. Clin. Nutr. 71:197S-201S.
65. Keys, A., Anderson, J. T. & Grande, F. (1965) Serum cholesterol response to changes in the diet. IV. Particular saturated fatty acids in the diet. Metabolism 14:776-787.
66. Hegsted, D. M., McGandy, R. B., Myers, M. L. & Stare, F. J. (1965) Quantitative effects of dietary fat on serum cholesterol in man. Am. J. Clin. Nutr. 17:281-295.[Medline]
67.
Salonen, J. T., Salonen, R., Ihanainen, M., Parviainen, M., Seppänen, R., Kantola, M., Seppänen, K. & Rauramaa, R. (1988) Blood pressure, dietary fats, and antioxidants. Am. J. Clin. Nutr. 48:1226-1232.
68.
Berry, E. M. & Hirsch, J. (1986) Does dietary linolenic acid influence blood pressure?. Am. J. Clin. Nutr. 44:336-340.
69.
Kang, J. X. & Leaf, A. (1996) Antiarrhythmic effects of polyunsaturated fatty acids. Recent studies. Circulation 94:1774-1780.
70. Mutanen, M. & Freese, R. (1996) Polyunsaturated fatty acids and platelet aggregation. Curr. Opin. Lipidol. 7:14-19.[Medline]
71. Mutanen, M. (1997) Comparison between dietary monounsaturated and polyunsaturated fatty acids as regards diet-related diseases. Biomed. Pharmacother. 51:314-317.[Medline]
72.
Clarke, R., Frost, C., Collins, R., Appleby, P. & Peto, R. (1997) Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies. BMJ 314:112-117.
73.
Mensink, R. P. & Katan, M. B. (1992) Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials. Arterioscler. Thromb. 12:911-919.
74.
Gardner, C. D. & Kraemer, H. C. (1995) Monounsaturated versus polyunsaturated dietary fat and serum lipids: a meta-analysis. Arterioscler. Thromb. Vasc. Biol. 15:1917-1927.
75.
Sabaté, J., Fraser, G. E., Burke, K., Knutsen, S. F., Bennett, H. & Lindsted, K. D. (1993) Effects of walnuts on serum lipid levels and blood pressure in normal men. N. Engl. J. Med. 328:603-607.
76. Food and Drug Administration (1996) Food labeling: health claims; oats and coronary heart disease; Proposed rule. Fed.Reg. 61(3):296-334.
77. Food and Drug Administration (1998) Food labeling: health claims; soy protein and coronary heart disease; Proposed rule. Fed. Reg. 63(217):62977-63015.
78. Food and Drug Administration (1999) Food labeling: health claims; soy protein and coronary heart disease; Final rule. Fed. Reg. 64(206):57700-57733.
79.
Abbey, M., Noakes, M., Belling, G. B. & Nestel, P. J. (1994) Partial replacement of saturated fatty acids with almonds or walnuts lowers total plasma cholesterol and low-density-lipoprotein cholesterol. Am. J. Clin. Nutr. 59:995-999.
80. Chisholm, A., Mann, J., Skeaff, M., Frampton, C., Sutherland, W., Duncan, A. & Tiszavari, S. (1998) A diet rich in walnuts favourably influences plasma fatty acid profile in moderately hyperlipidaemic subjects. Eur. J. Clin. Nutr. 52:12-16.[Medline]
81.
Zambón, D., Sabaté, J., Muñoz, S., Campero, B., Casals, E., Merlos, M., Laguna, J. C. & Ros, E. (2000) Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men and women: a randomized crossover trial. Ann. Intern. Med. 132:538-546.
82.
Almario, R. U., Vonghavaravat, V., Wong, R. & Kasim-Karakas, S. E. (2001) Effects of walnut consumption on plasma fatty acids and lipoproteins in combined hyperlipidemia. Am. J. Clin. Nutr. 74:72-79.
83.
Berry, E. M., Eisenberg, S., Haratz, D., Friedlander, Y., Norman, Y., Kaufmann, N. A. & Stein, Y. (1991) Effects of diets rich in monounsaturated fatty acids on plasma lipoproteins—the Jerusalem Nutrition Study: high MUFAs vs high PUFAs. Am. J. Clin. Nutr. 53:899-907.
84.
Sabaté, J. (1999) Nut consumption, vegetarian diets, ischemic heart disease risk, and all-cause mortality: evidence from epidemiologic studies. Am. J. Clin. Nutr. 70:500S-503S.
85. Fraser, G. E. (1999) Nut consumption, lipids, and risk of a coronary event. Clin. Cardiol. 22(Suppl. 3):III11-15.[Medline]
86. Sabaté, J. (1993) Does nut consumption protect against ischaemic heart disease?. Eur. J. Clin. Nutr. 47(Suppl 1):S71-S75.
87.
Fraser, G. E., Sabaté, J., Beeson, W. L. & Strahan, T. M. (1992) A possible protective effect of nut consumption on risk of coronary heart disease. The Adventist Health Study. Arch. Intern. Med. 152:1416-1424.
88.
Fraser, G. E., Lindsted, K. D. & Beeson, W. L. (1995) Effect of risk factor values on lifetime risk of and age at first coronary event: The Adventist Health Study. Am. J. Epidemiol. 142:746-758.
89. Fraser, G. E., Sumbureru, D., Pribis, P., Neil, R. L. & Frankson, M. A. C. (1997) Association among health habits, risk factors, and all-cause mortality in a black California population. Epidemiology 8:168-174.[Medline]
90.
Fraser, G. E. & Shavlik, D. J. (1997) Risk factors for all-cause and coronary heart disease mortality in the oldest-old. The Adventist Health Study. Arch. Intern. Med. 157:2249-2258.
91.
Fraser, G. E. (1999) Associations between diet and cancer, ischemic heart disease, and all-cause mortality in non-Hispanic white California Seventh-day Adventists. Am. J. Clin. Nutr. 70:532S-538S.
92.
Kushi, L. H., Folsom, A. R., Prineas, R. J., Mink, P. J., Wu, Y. & Bostick, R. M. (1996) Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N. Engl. J. Med. 334:1156-1162.
93. Prineas, R. J., Kushi, L. H., Folsom, A. R., Bostick, R. M., Wu, Y. & Kushi, L. H. () Walnuts and serum lipids. [letter re: Sabaté et al. "Effects of walnuts on serum lipid levels and blood pressure in normal men." N. Engl. J. Med. 1993. 328: 603–607]N. Engl. J. Med. 329:359(lett.).
94.
Hu, F. B., Stampfer, M. J., Manson, J. E., Rimm, E. B., Wolk, A., Colditz, G. A., Hennekens, C. H. & Willett, W. C. (1999) Dietary intake of a-linolenic acid and risk of fatal ischemic heart disease among women. Am. J. Clin. Nutr. 69:890-897.
95. Albert, C. M., Willett, W. C., Manson, J. E. & Hennekens, C. H. (1998) Nut consumption and the risk of sudden and total cardiac death in the physicians health study. Circulation 98(suppl. 1):582(abs.).
96. Lavedrine, F., Zmirou, D., Ravel, A., Balducci, F. & Alary, J. (1999) Blood cholesterol and walnut consumption: a cross-sectional survey in France. Prev. Med. 28:333-339.[Medline]
97.
Leng, G. C., Taylor, G. S., Lee, A. J., Fowkes, F. G. R. & Horrobin, D. (1999) Essential fatty acids and cardiovascular disease: the Edinburgh Artery Study. Vasc. Med. 4:219-226.
98.
Simon, J. A., Fong, J., Bernert, J. T. J. & Browner, W. S. (1995) Serum fatty acids and the risk of stroke. Stroke 26:778-782.
99. Dolecek, T. A. & Grandits, G. (1991) Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial (MRFIT). World Rev. Nutr. Diet. 66:205-216.[Medline]
100.
de Lorgeril, M., Salen, P., Martin, J.-L., Monjaud, I., Delaye, J. & Mamelle, N. (1999) Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 99:779-785.
101. Dreher, M. L., Maher, C. V. & Kearney, P. (1996) The traditional and emerging role of nuts in healthful diets. Nutr. Rev. 54:241-245.[Medline]
102. Ravai, M. (1995) California walnuts: the natural way to a healthier heart. Nutr. Today 30:173-176.
103. Payne, T. (1985) California walnuts and light foods. Cereal Foods World 30:215-218.
104. U.S. Department of Agriculture Agricultural Research Service (1999) Nuts, walnuts, English. USDA Nutrient Database for Standard Reference, Release 13 1999Accessed 3/29/2000. Web/URL: http://www.nal.usda.gov/fnic/cgi-bin/list_nut.pl. U.S. Department of Agriculture, Agricultural Services, Washington, DC..
105. Zwarts, L., Savage, G. P. & McNeil, D. L. (1999) Fatty acid content of New Zealand-grown walnuts (Juglans regia L.). Int. J. Food Sci. Nutr. 50:189-194.[Medline]
106.
Greve, L. C., McGranahan, G., Hasey, J., Snyder, R., Kelly, K., Goldhamer, D. & Labavitch, J. M. (1992) Variation in polyunsaturated fatty acids composition of Persian walnut. J. Am. Soc. Hort. Sci. 117:518-522.
107. Kulkarni, A. S., Khotpal, R. R. & Bhakare, H. A. (1991) Studies on glycolipids of Kenaf, English Walnut, Myrobalan and Manila Tamarind seeds of the Vidarbha region (India). J. Am. Oil Chem. Soc. 68:891-893.
108. Buchbauer, G. & Jirovetz, L. (1992) Volatile constituents of the essential oil of the peels of Juglans nigra L. J. Essent. Oil Res. 4:539-541.
109. Lavedrine, F., Ravel, A., Poupard, A. & Alary, J. (1996) Effect of geographic origin, variety and storage on tocopherol concentrations in walnuts by HPLC. Food Chem. 58:135-140.
110. Cardozo, M. S. & Li, B. W. (1994) Total dietary fiber content of selected nuts by two enzymatic-gravimetric methods. J. Food. Compos. Anal. 7:37-43.
111.
Macfarlane, B. J., Bezwoda, W. R., Bothwell, T. H., Baynes, R. D., Bothwell, J. E., MacPhail, A. P., Lamparelli, R. D. & Mayet, F. (1988) Inhibitory effect of nuts on iron absorption. Am. J. Clin. Nutr. 47:270-274.
112. McGill, A. S., Moffat, C. F., Mackie, P. R. & Cruickshank, P. (1993) The composition and concentration of n-alkanes in retail samples of edible oils. J. Sci. Food Agric. 61:357-362.
113. Peng, S. & Jay-Allemand, C. (1991) Use of antioxidants in extraction of tannins from walnut plants. J. Chem. Ecol. 17:887-896.
114. Daugherty, W., Smith, S., Wigal, C., Verhoek, S. & Williams, S. (1995) Distribution of 5-hydroxy-1, 4-naphthoqinone and other napthoquinone derivatives in the Juglandaceae (walnut family) and related families. Gustine, D. L. Flores, H. E. eds. Phytochemicals and Health 15:335-337 American Society of Plant Physiologists Rockville, MD. .
115. Zambón, D., Campero, B., Pérez-Heras, A., Rodríguez-Villar, C., Ros, E., Casals, E., Muñoz, S., Laguna, J. C. & Sabaté, J. (1998) Effects of walnuts on the serum lipid profile of hypercholesterolemic subjects: The Barcelona Walnut Trial. FASEB J. 12:A506(abs.).
116.
Reaven, P., Parthasarathy, S., Grasse, B. J., Miller, E., Almazan, F., Mattson, F. H., Khoo, J. C., Steinberg, D. & Witztum, J. L. (1991) Feasibility of using an oleate-rich diet to reduce the susceptibility of low-density lipoprotein to oxidative modification in humans. Am. J. Clin. Nutr. 54:701-706.
117.
Spiller, G. A., Jenkins, D. A. J., Bosello, O., Gates, J. E., Cragen, L. N. & Bruce, B. (1998) Nuts and plasma lipids: an almond-based diet lowers LDL-C while preserving HDL-C. J. Am. Coll. Nutr. 17:285-290.
118. Sabaté, J., Rajaram, S., Jambazian, P., Myint, T. & Haddad, E. (2000) Effects of almonds on serum lipids and fasting glucose levels in normocholesterolemic subjects. FASEB J. 14:A293(abs.).
119.
Curb, J. D., Wergowske, G., Dobbs, J. C., Abbott, R. D. & Huang, B. (2000) Serum lipid effects of a high-monounsaturated fat diet based on macadamia nuts. Arch. Intern. Med. 160:1154-1158.
120. Colquhoun, D. M., Humphries, J. A., Moores, D. & Somerset, S. M. (1996) Effects of a macadamia nut enriched diet on serum lipids and lipoproteins compared to a low fat diet. Food Aust. 48:216-222.
121. Tung, K. H., Waslien, C., Elmer, P. J., Otvos, J. D., Wergowske, G. & Curb, J. D. (2000) Effects of diets high in monounsaturated fatty acids on plasma LDL subclasses in healthy men and women: Macadamia Nut Study—Phase II. FASEB J. 14:A293(abs.).
122.
Edwards, K., Kwaw, I., Matud, J. & Kurtz, I. (1999) Effect of pistachio nuts on serum lipid levels in patients with moderate hypercholesterolemia. J. Am. Coll. Nutr. 18:229-232.
123. Rajaram, S., Myint, T., Connell, B., Burke, K. & Sabaté, J. (2000) Effect of pecan rich diet on serum lipids and lipoproteins in healthy men and women. FASEB J. 14:A293(abs.).
124. Haddad, E. & Sabaté, J. (2000) Effect of pecan consumption on stool fat. FASEB J. 14:A294(abs.).
125.
Kris-Etherton, P. M., Yu-Poth, S., Sabaté, J., Ratcliffe, H. E., Zhao, G. & Etherton, T. D. (1999) Nuts and their bioactive constituents: effects on serum lipids and other factors that affect disease risk. Am. J. Clin. Nutr. 70:504S-511S.
126. O’Byrne, D. J., Knauft, D. A. & Shireman, R. B. (1997) Low fat-monounsaturated rich diets containing high-oleic peanuts improve serum lipoprotein profiles. Lipids 32:687-695.[Medline]
127. O’Byrne, D. J., O’Keefe, S. F. & Shireman, R. B. (1998) Low-fat, monounsaturate-rich diets reduce susceptibility of low density lipoproteins to peroxidation ex vivo. Lipids 33:149-157.[Medline]
128. Jenkins, D. J. A., Popovich, D. G., Kendall, C. W. C., Vidgen, E., Tariq, N., Ransom, T. P. P., Wolever, T. M. S., Vuksan, V., Mehling, C. C., Boctor, D. L., Bolognesi, C., Huang, J. & Patten, R. (1997) Effect of a diet high in vegetables, fruit, and nuts on serum lipids. Metabolism 46:530-537.[Medline]
129. Singh, R. B., Rastogi, S. S., Verma, R., Bolaki, L. & Singh, R. (1992) An Indian experiment with nutritional modulation in acute myocardial infarction. Am. J. Cardiol. 69:879-885.[Medline]
130. Carroll, K. K. & Hamilton, R. M. G. (1975) Effects of dietary protein and carbohydrate on plasma cholesterol levels in relation to atherosclerosis. J. Food Sci. 40:18-23.
131. Kritchevsky, D., Tepper, S. A., Czarnecki, S. K. & Klurfeld, D. M. (1982) Atherogenicity of animal and vegetable protein. Influence of the lysine to arginine ratio. [letter re: Weigensberg et al. "Effect of lysine deficiency on cholesterol atherosclerosis in rabbits." Exp. Mol. Path. (1964) 3:444.]Atherosclerosis 41:429-431(lett.).[Medline]
132. Ravel, A., Roussel, A. M., Decoux, G., Groslambert, P., Beriel, H., Boitard, M. & Cartier, G. (1982) Comparaison chez le lapin des proprietes nutritionnelles et hypocholesterolemiantes du tourteau de noix a celles du tourteau de soja et de la caseine. [Nutritional value and hypocholesterolemic effect of walnut meal, among rabbit, in comparison to soja bean meal and casein]. Med. Nutr. 18:304-315.
133. Ravel, A., Roussel, A. M., Alary, J. & Laturaze, J. (1988) Effects of varying dietary proteins on plasma lipids and rabbit platelet function. Thromb. Res. 49:405-414.[Medline]
134. Roussel, A. M., Ravel, A. & Groslambert, P. (1984) Action d’huiles polyinsaturees (noix et maïs) sur quelques parametres lipidques du serum et l’agregation plaquettaire du lapin. [Effect of polyunsatured oils (walnut and corn) on lipid metabolism and blood platelet aggregation on rabbits]. Med. Nutr. 20:17-22.
135.
Aji, W., Ravalli, S., Szabolcs, M., Jiang, X.-C., Sciacca, R. R., Michler, R. E. & Cannon, P. J. (1997) L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice. Circulation 95:430-437.
136. Adams, M. R., Forsyth, C. J., Jessup, W., Robinson, J. & Celermajer, D. S. (1995) Oral L-arginine inhibits platelet aggregation but does not enhance endothelium-dependent dilation in healthy young men. J. Am. Coll. Cardiol. 26:1054-1061.[Abstract]
137. Wolf, A., Zalpour, C., Theilmeier, G., Wang, B.-Y., Ma, A., Anderson, B., Tsao, P. S. & Cooke, J. P. (1997) Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J. Am. Coll. Cardiol. 29:479-485.[Abstract]
138.
Rector, T. S., Bank, A. J., Mullen, K. A., Tschumperlin, L. K., Sih, R., Pillai, K. & Kubo, S. H. (1996) Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation 93:2135-2141.
139. Loscalzo, J. () Nitric oxide and vascular disease. N. Engl. J. Med. 333:251-253(lett.).
140.
de Lorgeril, M. (1998) Dietary arginine and the prevention of cardiovascular diseases. Cardiovasc.Res. 37:560-563.
141. Food and Drug Administration Center for Food Safety and Applied Nutrition (2000) 2000Accessed: 1/7/2000. Guidance for Industry Significant Scientific Agreement in the Review of Health Claims for Conventional Foods and Dietary Supplements. Web/URL: http://vm.cfsan.fda.gov/~dms/. U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Rockville, MD..
142.
Berry, E. M., Eisenberg, S., Friedlander, Y., Harats, D., Kaufmann, N. A., Norman, Y. & Stein, Y. (1992) Effects of diets rich in monounsaturated fatty acids on plasma lipoproteins—the Jerusalem Nutrition Study. II. Monounsaturated fatty acids vs carbohydrates. Am. J. Clin. Nutr. 56:394-403.
143. Spiller, G. A., Jenkins, D. J. A., Cragen, L. N., Gates, J. E., Bosello, O., Berra, K., Rudd, C., Stevenson, M. & Superko, R. (1992) Effect of a diet high in monounsaturated fat from almonds on plasma cholesterol and lipoproteins. J. Am. Coll. Nutr. 11:126-130.[Abstract]
144. Fraser, G. E. (1999) Diet as primordial prevention in Seventh-Day Adventists. Prev. Med. 29:S18-S23.[Medline]
This article has been cited by other articles:
|
|
 |
|
  D. K Banel and F. B Hu Effects of walnut consumption on blood lipids and other cardiovascular risk factors: a meta-analysis and systematic review Am. J. Clinical Nutrition, July 1, 2009; 90(1): 56 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Olmedilla-Alonso, F. Granado-Lorencio, C. Herrero-Barbudo, I. Blanco-Navarro, S. Blazquez-Garcia, and B. Perez-Sacristan Consumption of Restructured Meat Products with Added Walnuts Has a Cholesterol-Lowering Effect in Subjects at High Cardiovascular Risk: A Randomised, Crossover, Placebo-Controlled Study J. Am. Coll. Nutr., April 1, 2008; 27(2): 342 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L Halvorsen, M. H Carlsen, K. M Phillips, S. K Bohn, K. Holte, D. R Jacobs Jr, and R. Blomhoff Content of redox-active compounds (ie, antioxidants) in foods consumed in the United States Am. J. Clinical Nutrition, July 1, 2006; 84(1): 95 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Mukuddem-Petersen, W. Oosthuizen, and J. C. Jerling A Systematic Review of the Effects of Nuts on Blood Lipid Profiles in Humans J. Nutr., September 1, 2005; 135(9): 2082 - 2089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Eastman and B. J. Clayshulte Pecan Effects on Serum Lipoproteins and Dietary Intakes of Hyperlipidemic Individuals Consuming Self-Selected Diets Family and Consumer Sciences Research Journal, March 1, 2005; 33(3): 197 - 207. [Abstract] [PDF]
|
|
|
|
 |
|
 L. C. Tapsell, L. J. Gillen, C. S. Patch, M. Batterham, A. Owen, M. Bare, and M. Kennedy Including Walnuts in a Low-Fat/Modified-Fat Diet Improves HDL Cholesterol-to-Total Cholesterol Ratios in Patients With Type 2 Diabetes Diabetes Care, December 1, 2004; 27(12): 2777 - 2783. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Seddon, J. Cote, and B. Rosner Progression of Age-Related Macular Degeneration: Association With Dietary Fat, Transunsaturated Fat, Nuts, and Fish Intake Arch Ophthalmol, December 1, 2003; 121(12): 1728 - 1737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Hasler Functional Foods: Benefits, Concerns and Challenges--A Position Paper from the American Council on Science and Health J. Nutr., December 1, 2002; 132(12): 3772 - 3781. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
