ENC - Egg Nutrition Center

COMMON ABBREVIATIONS
BMI: body mass index (kg/m²)
CHD: coronary heart disease
CHO: carbohydrate
CI: confidence interval
CVD: cardiovascular disease
ene: energy
HDL: high density lipoprotein
LDL: low density lipoprotein
Lp(a): lipoprotein (a)
MI: myocardial infarction
MUFA: monounsaturated fatty acids
NCEP: National Cholesterol Education Program
P:S: dietary polyunsaturated:saturated fat ratio
PUFA: polyunsaturated fatty acids
RR: relative risk
SFA: saturated fatty acids
TAG: triacylglycerol
VLDL: very low density lipoprotein

Direct Correlation Between Saturated Fat Intake and Large LDL Particles

Many controversial theories have been introduced in the past several decades in the diet-heart disease field, but until now the negative effects of dietary saturated fat on plasma cholesterol levels and the benefits of lowering saturated fat in the diet have been unchallenged. However, a new study by Dreon et al. is questioning the universality of this hypothesis. In this cross-over diet study, 103 healthy, non-smoking men followed a low-fat (24% fat) versus high-fat (46% fat) diet for 6 weeks each. Dietary cholesterol, P:S ratio, protein, and fiber intakes were similar between the two diets. The percentage of energy from CHO was approximately 20% lower in the high-fat diet, while saturated fat and polyunsaturated fat intake were 12.5% and 7.2% higher.

Baseline plasma lipid and lipoprotein levels were TAG (121 mg/dl), total cholesterol (207 mg/dl), LDL (135 mg/dl), and HDL (47 mg/dl). After following the 2 test diets, lipid and lipoprotein values changed as follows: during the high-fat diet, LDL and HDL cholesterol concentrations increased to 142 mg/dl and 62 mg/dl, respectively, and TAG decreased to 99 mg/dl. Also, large LDL subfractions were higher following the high-fat diet compared to the low-fat diet (131 vs 92 mg/dl), but small LDL particles were higher with the low-fat diet (18 vs 11 mg/dl). Monounsaturated and polyunsaturated fatty acids in the diet did not correlate with lipoprotein changes. However, saturated fatty acids, especially myristic and palmitic acids did exhibit significant correlations with changes in plasma LDL levels and size in both high-fat and low-fat diet groups. Myristic acid was positively associated with large LDL particles and floatation rate, but negatively associated with small LDL particles. While palmitic acid in the diet was also positively associated with large LDL particles and LDL diameter, no such relationship was seen with dietary stearic acid.

Data from a subgroup of volunteers, 43 men, indicated correlations between fat intake and hepatic and lipoprotein lipase activities. While on a high fat diet, hepatic lipase activity was inversely related to dietary saturated fats, myristic and palmitic acid. However, no significant association was observed between saturated fat and lipoprotein lipase activity on either the low-fat or the high-fat diet. The changes in hepatic lipase activity were related to the changes in LDL particle size seen in this study

In conclusion, results from this study raise questions regarding the effects of saturated fat in the diet and its role in generating large LDL particles and decreasing levels of the more atherogenic small LDL particles in healthy men. Myristic acid was especially effective in generating large LDL particles. Also, dietary saturated fatty acids were directly associated with LDL particle diameter and peak flotation rate and inversely associated with hepatic lipase.

The counter intuitive nature of this study finding is that it contradicts the hyperlipidemic effects of saturated fat. However, the study by Dreon and colleagues suggest that saturated fat intake might have some beneficial effect by increasing LDL particle size, peak LDL diameter, and LDL flotation rate while decreasing small, dense LDL particles which are associated with increased risk of myocardial infarction. Therefore, results from this study indicate that at least in healthy men with normal lipoprotein concentrations, saturated fat intake might not be as detrimental to the lipoprotein profile as once thought.

KEY Messages

Dreon, D.M., Fernstrom, H.A., Campo, H., et al. Change in dietary saturated fat intake is correlated with change in mass of large low-density-lipoprotein particles in men. Am J Clin Nutr 1998;67:823-836.

Exercise Combined with a Low-fat Diet Lowers LDL Cholesterol

Stefanick et al. investigated the effects of the NCEP Step 2 diet plus exercise on plasma lipids of overweight middle-aged men and postmenopausal women with atherogenic lipoprotein profiles. The average baseline plasma LDL and HDL cholesterol concentrations in 180 women were 161±18 and 47±7 mg/dl, respectively, and in 197 males 156±14 and 36±4 mg/dl. Initially, the baseline dietary patterns of all subjects were within the NCEP Step 1 diet guideline. In order to test the individual effects which exercise and diet have on plasma lipoprotein levels, as well as their combined effects, subjects were divided into control (n=91), exercise only (n=90), diet only (n=95), and diet plus exercise (n=91) groups. Activity levels required in the exercise group were equivalent to 10 miles of brisk walking or jogging per week.

The change in plasma lipoprotein levels following a 1 year follow-up period showed that the diet plus exercise group achieved the greatest plasma LDL cholesterol reduction followed by the diet only, exercise only, and control groups. The table below presents the changes in plasma lipoprotein values for each group. Results from this study indicate that there is a wide heterogeneity associated with the plasma cholesterol response to diet therapy. However, exercise combined with the NCEP Step 2 diet can result in significantly greater plasma LDL cholesterol reductions. Dr. Ronald Krauss with the American Heart Association's Nutrition Committee was quoted in an AHA press release stating "Individuals should not be discouraged from trying to reduce levels of LDL cholesterol with diet, since many people can achieve a beneficial response. This study suggests the diet may be more effective when combined with increased physical activity," in response to the findings that reiterate the importance of physical activity in treating elevated LDL cholesterol.

Stefanick, M.L., Mackey, S., Sheehan, M., et al. Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol. N Engl J Med 1998;339:12-20.

High Simple Carbohydrate Intake Associated with Low HDL Cholesterol in Hyperlipidemic Children

The standard lipid lowering diet, low in dietary fat and high in CHO, has been used as the first line of treatment in hyperlipidemic populations. But results from recent studies show that this might not be the optimal choice due to its negative effects on plasma HDL levels. Starc and colleagues observed an inverse relationship between simple CHO intake and HDL cholesterol concentrations in 67 hypercholesterolemic children. The children were between 2-10 years old (mean 5.8±2.5 years) and not taking lipid lowering medications. The baseline blood samples indicated that the average total plasma cholesterol was 232±54 mg/dl, LDL cholesterol 168±57 mg/dl, HDL 44±8 mg/dl, and TAG 102±45 mg/dl. The plasma lipoprotein levels were similar between boys and girls. The BMI for the majority of children fell between the 50th and 75th percentile for 6 year olds. Using a 3 day diet record measure, Starc et al. determined that the children were consuming 59.9±6.5% of calories from CHO; 30.7±7.4% as simple CHO and 22.6±6.2% as complex CHO; 24.9±5.1% of calories from fat; 8.5±2.5% saturated fat, 8.9±2.1% monounsaturated fat, and 5.4±1.6% polyunsaturated fat.

Total dietary fat, saturated fat, and monounsaturated fat intakes were positively correlated with HDL cholesterol and TAG levels, but not with total and LDL cholesterol. However, an inverse relationship was significant between CHO and HDL cholesterol, r=-0.55 for total CHO and r=-0.40 for simple CHO. High CHO intake was associated with an elevated plasma TAG concentration. Fructose and glucose intake exhibited an inverse relationship with HDL levels but no correlation was noted for sucrose and lactose intake. However, "the sum of the simple sugars rather than individual simple sugars was the important predictor for HDL cholesterol." The average HDL cholesterol concentration in the highest quintile of simple CHO intake was 20% lower than values for the lowest quintile. Even with multivariate analysis, a significant inverse relationship was noted between simple CHO in the diet and HDL cholesterol levels.

From these findings, the researchers concluded that for hypercholesterolemic children on a reduced-fat diet, high simple CHO intake is inversely associated with plasma HDL cholesterol levels. However, due to the limitations associated with this study, it is not possible to determine if this relationship was the result of reduced fat intake instead of high CHO intake since parents of children in the study were highly motivated and had reduced fat intake prior to beginning the study.

The study does however raise questions regarding how low-fat diets are to be achieved in children and whether the value of lowering plasma LDL levels is greater than the potential adverse effects of lowering HDL levels.

Starc, T.J., Shea, A., Cohn, L.C., et al. Greater dietary intake of simple carbohydrate is associated with lower concentrations of high-density-lipoprotein cholesterol in hypercholesterol-emic children. Am J Clin Nutr 1998;67:1147-1154.

Dietary Intervention and Reduction in Plasma Cholesterol: A Meta-analysis

In this meta-analysis, Tang and associates investigated the effectiveness of NCEP Step 1 and Step 2 dietary interventions on blood cholesterol levels in free-living subjects. Nineteen trials met the defined meta-analysis criteria. The authors divided the studies into 4 subgroups based on dietary outcome: NCEP Step 1 or equivalent, NCEP Step 2 or equivalent, diets that increased the ratio of polyunsaturated to saturated fat, and low-fat diets. Results of the meta-analysis indicated that the average reduction in blood total cholesterol on the NCEP Step 1 diet was 3.0% (1.8% to 4.1%), 5.6% (4.7% to 6.5%) on the NCEP Step 2 diet, 7.6% (6.2% to 9.0%) with the high P:S ratio diet, and 5.8% (3.8% to 7.8%) for the low-fat diet. The overall reduction in blood total cholesterol for all dietary interventions was 5.7%. Long-term effectiveness of dietary intervention was poor as seen with decreasing reductions in blood cholesterol levels over time. For example, the reduction in total cholesterol was 6.6% at about week 6, 8.5% at about 3 months, 6.8% at 6 months, 5.5% at 12 months, and 4.4% at 24 months. Lastly, the authors noted that the majority of the studies reviewed did not achieve the dietary target set in their respective study protocols. However, 3 studies that did achieve their set dietary goals and the reductions in blood cholesterol were much larger than in the studies that did not meet the dietary targets.

The overall reductions in blood cholesterol levels from dietary interventions in free-living subjects (5.7%) were quite low compared to results obtained in metabolic ward studies (15%). Therefore, the researchers strongly recommended that nutrition educators set realist goals and develop effective tools to communicate messages regarding CHD risk factors and the efficacy of dietary interventions to lower plasma cholesterol levels.

Tang, J. L., Armitage, J.M., Lancaster, T., et al. Systematic review of dietary intervention trials to lower total cholesterol in free-living subjects. BMJ 1998;316:1213-1220.

Direct Relationship Between Multiple CVD Risk Factors and Atherosclerosis Lesions and Obesity

Previous studies have shown synergistic effects of different CVD risk factors on CVD in adults, however, data for children are limited. The studies by Berenson et al. and Chu et al. have addressed this question in children and young adults.

Using ante-mortem data from 93 subjects in the Bogalusa Heart Study, Berenson et al. examined the influence of multiple CVD risk factors on the extent of atherosclerosis in the aorta and coronary arteries. The following CVD risk factors were associated with increased fatty-streaks and fibrous-plaque lesions: systolic blood pressure (r=0.55), serum TAG (r=0.50), BMI (r=0.48), serum LDL cholesterol (r=0.43), and diastolic blood pressure (r=0.22). Researchers observed a direct correlation between the number of risk factors with an increased percentage of atherosclerosis involved intimal surface. For example, 19.1%, 30.3%, 37.9%, and 35% of the intimal surface of the aorta were covered with fatty-streaks in subjects with 0, 1, 2, and 3 or 4 risk factors. And 1.3%, 2.5%, 7.8%, and 11% of intimal surface of coronary arteries were covered with fatty-streak respectively with increase CVD risk factors. The percent of fibrous plaques in the aorta and coronary artery also increased with an increase in the number of CVD risk factors. The coronary artery fatty-streaks and fibrous plaque lesions in subjects with the highest number of risk factors were 8.5 times and 12 times greater than in those with no risk factors. Smoking was also associated with aortic and coronary lesions. Eight and three-tenth percent of coronary vessels in smokers had fatty streaks compared to 2.9% in nonsmokers.

Berenson and colleagues also observed that the prevalence of fatty-streaks and fibrous plaques on aortic and coronary vessels increased directly with age. Lastly, "the association between fatty streaks and fibrous plaques was much stronger in the coronary arteries (r=0.60) than in the aorta artery (r=0.23)."

Chu et al. reported that Taiwanese children have similar CVD risk factors as children in Western countries. In this cross-sectional survey with 1,366 children (681 boys and 685 girls) of an average age of 13.3 years old (range 12-16 years old), researchers observed that obese children were more likely to have risk factors for CVD than non-obese children. For example, 62% and 22% of obese subjects had one and 2 risk factors for CVD compared to 34% and 6% of non-obese children. The four most common risk factors associated with obesity were elevated blood pressure, total/HDL cholesterol ratio, and LDL cholesterol and reduced HDL cholesterol concentration. Also, high blood glucose concentrations were seen in obese boys. Even though this study showed a direct relationship between obesity and high blood pressure, blood glucose, and plasma lipid concentrations, the percentage of obese children in the study was small (12%).

These studies suggest that an increased number of CVD risk factors is associated with early stages of CVD in children as seen with higher percentage of atherosclerotic lesions. Elevated blood pressure, BMI, and LDL cholesterol are 3 CVD risk factors strongly associated with atherosclerosis and obesity in children and adolescents. In conclusion, both groups of researchers recommended effective means to identify, intervene, and prevent CVD in high risk children be initiated early in life since multiple CVD risk factors are present in early adolescence.

Berenson, G.S., Srinivasan, S.R., Bao, W., et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 1998;338:1650-1656.

Chu, N.F., Rimm, E.B., Wang, D.J., et al. Clustering of cardiovasular disease risk factors among obese children: the Taipei children heart study. Am J Clin Nutr 1998:67: 1141-1146.

A Possible Mechanism Behind the Beneficial Effects of Exercise on CVD Risk

In spite of the pro-oxidative effects of exercise, it has been widely recommended as a protective activity against CVD. This paradox is interesting since exercise, which promotes an oxidatively stressful environment which could lead to LDL oxidation and ultimately atherosclerosis, has been shown to deter CVD. Shern-Brewer et al. investigated the explanation for this phenomenon. In their first study, they compared fasting plasma lipoprotein levels and composition, and lag time of LDL oxidation in 8 exercises and 9 sedentary volunteers. The majority of the exercisers were males and the sedentary group was mainly females. As expected, subjects in the exercise group were more aerobically fit and had better lipid profiles than the sedentary group. However, the lag time for in vitro oxidation of LDL was significantly higher in the sedentary group than in exercisers (64±23.4 vs 38±18 minutes). The plasma and LDL alpha tocopherol and plasma lipid peroxide levels were similar between the two groups. Due to the gender difference between the study groups and possible confounding effects on the study finding, a second study was conducted. In the second study, 30 exercisers were equally divided between males and females and the sedentary group was made up of 21 females and 12 males. Like the first study, sedentary subjects had a more atherogenic lipid profile and a lower V0₂ max. However, unlike the results from the first study, the lag time of LDL oxidation was longer in exercisers (100.7±19.8 vs 93.4±22.6 minutes). The mean lag time for sedentary men and exercising men was 82.1±19 minutes and 104.8±20 minutes, respectively, but the difference between the 2 female groups was not significant (95.6±20 minutes for exercisers and 99.9±22 minutes for sedentary). The plasma LDL alpha tocopherol and fatty acid levels were similar for the two activity levels in females and males. However, male exercisers had significantly higher plasma myeloperoxidase levels than men that did not exercise.

Researchers speculated that this major difference between the two study findings is due to the difference in the definition of an exerciser. For example, exercisers in the first study were undergraduates in a physical education class while the exercisers in the second study were members of an organized track team, thus in better physical condition, as evidence by the more desirable lipid parameters. Lastly, Shern-Brewer et al. hypothesized "that short-term, aerobic activity may cause oxidative modification of LDL in the plasma and clearance via the liver, thus lowering blood cholesterol. Long-term aerobic exercise may enhance the resistance of LDL to oxidation, thus stabilizing already lower blood lipid levels."

The outcomes from this study indicate that sporadic exercise might promote plasma LDL oxidation, as evidenced by shorter lag time for in vitro oxidation of LDL in the first study. However, in males, chronic exercise resulted in significantly longer mean lag times thus decreasing LDL oxidation. Finally, even though the increased sensitivity to oxidation was not due to reduced plasma antioxidant levels, Shern-Brewer et al. recommended "... it may be judicious to ensure an adequate intake of dietary antioxidants for sporadic exerciser as well as the truly chronic exerciser" since mechanisms that control this process might be compromised due to poor diet, genetic factors, or chronic inflammation.

Shern-Brewer, R., Santanam, N., Wetzstein, C., et al. Exercise and cardiovascular disease. A new prospective. Arterioscler Thromb Vasc Biol 1998; 18;1181-1187

Plasma apo B Levels Are Associated with CAD Risk

Two recent studies by Westerveld et al. and Lamarche et at. indicated that elevated plasma apo B levels, which represents the number of atherogenic lipoproteins, can be an independent risk factor for CAD in both men an women. Both studies showed that plasma apo B levels were superior to total cholesterol, LDL, and HDL in predicting CAD. Westerveld and colleagues determined this association in 289 older Dutch women undergoing their first coronary angiography. The study subjects were divided into CAD+ (n=160) and CAD- (n=129) depending on stenosis of their coronary arteries. Visual observation of stenosis of greater than 60% in one or more coronary artery was classified as CAD+. Based on the baseline questionnaires completed, CAD+ women were significantly older and more likely to smoke and have diabetes and hypertension than CAD- counter parts. BMI was similar between the 2 groups and according to the fasting plasma samples, age adjusted plasma total cholesterol, LDL, TAG, and apo B levels were higher in the CAD+ population, while HDL cholesterol levels were higher in CAD- women. For example, total cholesterol, LDL, TAG, apo B and HDL levels between CAD+ and CAD- subjects were 269 vs 245 mg/dl, 182 vs 159 mg/dl, 175 vs 151 mg/dl, 1.48 vs 1.25 g/L, and 49.2 vs 52.7 mg/dl, respectively. Also, plasma apo B levels were higher in CAD+ women in the lowest quartiles of cholesterol, LDL, and TAG, however, total cholesterol, LDL, TAG, and HDL levels were not different in the four quartiles of apo B. The odds ratio for CAD were 11.1 for apo B (g/L), 1.5 for cholesterol (mmol/L), 1.66 for LDL cholesterol (mmol/L), 0.68 for HDL cholesterol (mmol/L), and 5.1 for log TAG (log scale) after correcting for clinical and life-style related confounders. Lastly, apo B was the most significant age adjusted factor associated with the highest number of stenotic arteries.

In the study by Lamarche et al., researches found a similar association between an elevated plasma apo B concentration and ischemic heart disease (IHD) in middle aged men. The 2,443 surviving members of the Quebec Cardiovascular Study who returned for the 1985 evaluation were enrolled in the current study. During the 5 year follow-up period, 114 men suffered IHD events and the data from 85 of these men were used in the present study. In this case-control study, researches observed a significant difference in levels of total cholesterol (8.9%), LDL (10.5%), TAG (18.2%), fasting insulin (18.9%), and apo B (15.9%) between the two groups. Based on the data, an elevated fasting plasma insulin concentration resulted in the highest risk of IHD with an odds ratio of 5.5, followed by elevated TAG (odds ratio of 3.5), elevated apo B (odds ratio=2.7), and small dense LDL (odds ratio=2.5). Also, the IHD case group was more likely to have all three nontraditional risk factors for IHD (fasting plasma insulin levels, apo B levels, and small, dense LDL particles) compared to the controlled group (45.8% vs 17.7%). However, surprisingly more controls had a higher incidence of having one nontraditional risk factors than cases (36.5% vs 21.2%). Similar trends were observed with the traditional risk factors: LDL cholesterol, TAG, and HDL cholesterol. Lamarche et al. concluded that the odds ratio for IHD was 18.2-fold and 5.2-fold in men having all 3 nontraditional and traditional risk factors, respectively, compared to men without any risk factors.

Results from both studies suggest that in addition to measuring LDL cholesterol, HDL cholesterol, and TAG, measuring nontraditional risk factors such as plasma apo B levels, can be major importance in identifying those individuals with increased risk for CAD.

Lamarche, B., Tchernof, A., Mauriege, P., et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 1998;279;1955-1961.

Westerveld, H.T., Roeters van lennep, J.E., Roeters van Lennep, H.W., et al. Apolipoprotein B and coronary artery disease in women. A cross-sectional study in women undergoing their first coronary angiography. Arterioscler Thromb Vasc Biol 1998; 18: 1101-1107.

Editorial:
Dietary Fat - The Lowest is Not Necessarily the Best

A new statement from the Nutrition Committee of the American Heart Association (AHA, Circulation 1998;98:935-939) addresses the issue of very low-fat diets as an intervention to reduce CHD risk. Very low-fat diets contain no more than 15 percent of total calories from dietary fat and have been recommended by some dietary programs as an effective dietary intervention to lower plasma total and LDL cholesterol levels as well as excess body weight. However, many investigators have raised concerns regarding the use of very low-fat diets, since they tend to lower plasma HDL cholesterol levels and raise plasma TAG. These adverse effects occur without comparable lowering of the atherogenic LDL cholesterol levels beyond that achieved with an NCEP Step 2 diet. The AHA states says that there is insufficient data to recommend very low-fat diets for the population to achieve either weight loss or reduced plasma LDL cholesterol levels. The report recognizes that very low-fat diets could pose health problems for young children, the elderly, pregnant women, and those with existing hypertriglyceridemia or IDDM. Another concern raised in the report dealt with problems related to vitamin and mineral intakes with a very low-fat diet.

Two reports reviewed in this issue of Nutrition Close-Up provide additional information on this issue. The study by Dreon et al. indicates that intake of a low-fat diet (24% vs 46% of calories as fat) is associated with changes in LDL particle diameter and flotation rate toward particles related to increased atherosclerosis. Since LDL subclasses are affected by both genetic and nongenetic factors, it is unclear whether diet-induced changes in LDL size have the same risk potential observed for genetic effects on subclass distributions. The report by Stefanick et al. illustrates the need for not only initiation of dietary interventions to lower LDL cholesterol levels but also the importance of physical activity to gain maximal benefit from implementation of the NCEP Step II diet.

The AHA recommends that a healthy eating plan contains a variety of foods, rich in fruits, vegetables, whole grains, low-fat dairy products and lean meats. They also recommend that the diet be coupled with regular exercise for about 30 minutes a day. Such recommendations go a long way to counteract the public's collective fat-phobia. An emphasis on what a healthy diet should contain, rather than solely what should be voided, serves the public more completely. The newest AHA statement may help the public to understand that they need not live their lives believing that the only "good foods" are fat-free foods, and that dietary extremes are not the route to risk reduction and nutritional well-being.

Executive Editor: Donald J. McNamara, Ph.D.
Writer/Editor: Linda Min, M.S., R.D.

Nutrition Close-Up is published quarterly by the Egg Nutrition Center. Nutrition Close-Up presents up-to-date reviews, summaries and commentaries on the latest research investigating the role of nutrition in health promotion and disease prevention, and the contributions of eggs to a nutritious and healthful diet. Nutrition and health care professionals can receive a FREE subscription for the newsletter by contacting the ENC.

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