Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC).

OBJECTIVE: Diets reduced in fat and cholesterol are recommended for children over 2 years of age, yet long-term safety and efficacy are unknown. This study tests the long-term efficacy and safety of a cholesterol-lowering dietary intervention in children. METHODS: Six hundred sixty-three children 8 to 10 years of age with elevated low-density lipoprotein cholesterol (LDL-C) were randomized to a dietary intervention or usual care group, with a mean of 7.4 years' follow-up. The dietary behavioral intervention promoted adherence to a diet with 28% of energy from total fat, <8% from saturated fat, up to 9% from polyunsaturated fat, and <75 mg/1000 kcal cholesterol per day. Serum LDL-C, height, and serum ferritin were primary efficacy and safety outcomes. RESULTS: Reductions in dietary total fat, saturated fat, and cholesterol were greater in the intervention than in the usual care group throughout the intervention period. At 1 year, 3 years, and at the last visit, the intervention compared with the usual care group had 4.8 mg/dL (.13 mmol/L), 3.3 mg/dL (.09 mmol/L), and 2.0 mg/dL (.05 mmol/L) lower LDL-C, respectively. There were no differences at any data collection point in height or serum ferritin or any differences in an adverse direction in red blood cell folate, serum retinol and zinc, sexual maturation, or body mass index. CONCLUSION: Dietary fat modification can be achieved and safely sustained in actively growing children with elevated LDL-C, and elevated LDL-C levels can be improved significantly up to 3 years. Changes in the usual care group's diet suggest that pediatric practices and societal and environmental forces are having positive public health effects on dietary behavior during adolescence.

Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: the Dietary Intervention Study in Children.

BACKGROUND: Few studies have shown the efficacy and safety of lower-fat diets in children. OBJECTIVE: Our objective was to assess the efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol to decrease LDL-cholesterol concentrations in children. DESIGN: A 6-center, randomized controlled clinical trial was carried out in 663 children aged 8-10 y with LDL-cholesterol concentrations greater than the 80th and less than the 98th percentiles for age and sex. The children were randomly assigned to either an intervention group or a usual care group. Behavioral intervention promoted adherence to a diet providing 28% of energy from total fat, <8% from saturated fat,

Stress management intervention for primary prevention of hypertension: detailed results from Phase I of Trials of Hypertension Prevention (TOHP-I).

PURPOSE: Stress Management Intervention (SMI) was one of seven nonpharmacologic approaches evaluated in Phase I Trials of Hypertension Prevention (TOHP-I) for efficacy in lowering diastolic blood pressure (BP) in healthy men and women aged 30 to 54 years with diastolic BP 80-89 mm Hg. METHODS: A total of 242 and 320 participants were randomized to SMI or an "assessment only" SMI Control, respectively, at four clinical centers. The SMI consisted of 37 contact hours in 21 group and two individual meetings over 18 months and included: training in four relaxation methods, techniques to reduce stress reactions, cognitive approaches, communication skills, time management, and anger management within a general problem-solving format. Standardized protocols detailed methods and timing for collecting BP, psychosocial measures, and urinary samples from both SMI and SMI Control participants. RESULTS: In intention-to-treat analyses, although significant baseline to termination BP reductions were observed in both groups, net differences between the SMI and SMI Control groups' BP changes (mean (95% CI)) were not significant: -0.82 (-1.86, 0.22) for diastolic BP, and -0.47 (-1.96, 1.01) for systolic BP. Extensive adherence sub-group analyses found one effect: a significant 1.36 mm Hg (p = 0.01) reduction in diastolic BP relative to SMI Controls at the end of the trial for SMI participants who completed 61% or more of intervention sessions. CONCLUSIONS: While the TOHP-I SMI was acceptable to participants as evident from high levels of session completion, the absence of demonstrated BP lowering efficacy in intention-to-treat analyses suggests that the TOHP-I SMI is an unlikely candidate for primary prevention of hypertension in a general population sample similar to study participants. The isolated finding of significant diastolic BP lowering in SMI participants with higher adherence provides very weak evidence of SMI BP lowering efficacy and may be a chance finding. Whether similar or other stress management interventions can produce significant BP lowering in populations selected for higher levels of BP, stress, or intervention adherence remains to be demonstrated.

The associations between health and domestic violence in older women: results of a pilot study.

This study examined the association of domestic violence (DV) with the general physical and mental health of older women. This pilot cross-sectional survey studied 257 women, aged 50-79, who came for screening visits to the Observational Study arm of the Women's Health Initiative's (WHI) Newark, NJ, site between June 1995 and August 1996. A 27-item, interviewer-administered questionnaire was used to detect DV. To measure overall health status, we used questions from the Medical Outcomes Study Short Form 36. Of the 257 women interviewed, 82 (31.9%) had experienced DV at some point in their life; 51 (22.6%) had been threatened, and 31 (15%) had experienced physical assault. Women who were either physically assaulted or threatened had lower mental component summary (MCS) scores (50.0 versus 53.7). Women who had only been threatened had a mean MCS score of 49.7 compared with 53.8 for nonthreatened women. Both of these MCS scores indicate poorer mental health. DV, which about 1 in 4 women experience over their lifetime, has a negative relationship to health status. Women who have experienced DV have lower MCS scores than those who have not. They also tend to have lower physical component summary scores. These findings suggest the importance that detection and prevention of DV have for women's health.

Safety of a fat-reduced diet: the Dietary Intervention Study in Children (DISC).

OBJECTIVE: To assess the relationship between energy intake from fat and anthropometric, biochemical, and dietary measures of nutritional adequacy and safety. DESIGN: Three-year longitudinal study of children participating in a randomized controlled trial; intervention and usual care group data pooled to assess effects of self-reported fat intake; longitudinal regression analyses of measurements at baseline, year 1, and year 3. PARTICIPANTS: Six hundred sixty-three children (362 boys and 301 girls), 8 to 10 years of age at baseline, with elevated low-density lipoprotein cholesterol, who are participants of the Dietary Intervention Study in Children. MEASURES: Energy intake from fat assessed from three 24-hour recalls at each time point was the independent variable. Outcomes were anthropometric measures (height, weight, body mass index, and sum of skinfolds), nutritional biochemical determinations (serum ferritin, zinc, retinol, albumin, beta-carotene, and vitamin E, red blood cell folate, and hemoglobin), and dietary micronutrients (vitamins A, C, E, thiamin, riboflavin, niacin, vitamins B-6, B-12, folate, calcium, iron, zinc, magnesium, and phosphorus). RESULTS: Lower fat intake was not related to anthropometric measures or serum zinc, retinol, albumin, beta-carotene, or vitamin E. Lower fat intake was related to: 1) higher levels of red blood cell folate and hemoglobin, with a trend toward higher serum ferritin; 2) higher intakes of folate, vitamin C, and vitamin A, with a trend toward higher iron intake; 3) lower intakes of calcium, zinc, magnesium, phosphorus, vitamin B-12, thiamin, niacin, and riboflavin; 4) increased risk of consuming less than two-thirds of the Recommended Dietary Allowances for calcium in girls at baseline, and zinc and vitamin E in boys and girls at all visits. CONCLUSIONS: Lower fat intakes during puberty are nutritionally adequate for growth and for maintenance of normal levels of nutritional biochemical measures, and are associated with beneficial effects on blood folate and hemoglobin. Although lower fat diets were related to lower self-reported intakes of several nutrients, no adverse effects were observed on blood biochemical measures of nutritional status. Current public health recommendations for moderately lower fat intakes in children during puberty may be followed safely.

Nutrient intake and blood pressure in the Dietary Intervention Study in Children.

Delineating the role that diet plays in blood pressure levels in children is important for guiding dietary recommendations for the prevention of hypertension. The purpose of this study was to investigate relationships between dietary nutrients and blood pressure in children. Data were analyzed from 662 participants in the Dietary Intervention Study in Children who had elevated low-density lipoprotein cholesterol and were aged 8 to 11 years at baseline. Three 24-hour dietary recalls, systolic pressure, diastolic pressure, height, and weight were obtained at baseline, 1 year, and 3 years. Nutrients analyzed were the micronutrients calcium, magnesium, and potassium; the macronutrients protein, carbohydrates, total fat, saturated fat, polyunsaturated fat, and monounsaturated fat; dietary cholesterol; and total dietary fiber. Baseline and 3-year longitudinal relationships were examined through multivariate models on diastolic and systolic pressures separately, controlling for height, weight, sex, and total caloric intake. The following associations were found in longitudinal analyses: analyzing each nutrient separately, for systolic pressure, inverse associations with calcium (P < .05); magnesium, potassium, and protein (all P < .01); and fiber (P < .05), and direct associations with total fat and monounsaturated fat (both P < .05); for diastolic pressure, inverse associations with calcium (P < .01); magnesium and potassium (both P < .05), protein (P < .01); and carbohydrates and fiber (both P < .05), and direct associations with polyunsaturated fat (P < .01) and monounsaturated fat (P < .05). Analyzing all nutrients simultaneously, for systolic pressure, direct association with total fat (P < .01); for diastolic pressure, inverse associations with calcium (P < .01) and fiber (P < .05), and direct association with total and monounsaturated fats (both P < .05). Results from this sample of children with elevated low-density lipoprotein cholesterol indicate that dietary calcium, fiber, and fat may be important determinants of blood pressure level in children.

Efficacy of nonpharmacologic interventions in adults with high-normal blood pressure: results from phase 1 of the Trials of Hypertension Prevention. Trials of Hypertension Prevention Collaborative Research Group.

Phase 1 of the Trials of Hypertension Prevention was conducted in 2182 adults, aged 35-54 y, with diastolic blood pressure of 80-89 mm Hg to test the feasibility and blood pressure-lowering effects of seven nonpharmacologic interventions (weight loss, sodium reduction, stress management, and supplementation with calcium, magnesium, potassium, and fish oil). At 6 and 18 mo, weight loss and sodium reduction were well-tolerated and produced significant declines in systolic and diastolic blood pressures (-2.9/-2.4 and -2.1/-1.2 mm Hg for weight loss and sodium reduction, respectively, at 18 mo). None of the other interventions lowered blood pressure significantly at either the 6- or 18-mo follow-up visits. These results suggest that both weight loss and sodium reduction provide an effective means to prevent hypertension. The long-term effects of both of these interventions are being tested in phase 2 of the trial.

Design of a multicenter trial to evaluate long-term life-style intervention in adults with high-normal blood pressure levels. Trials of Hypertension Prevention (phase II). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.

Phase II of the Trials of Hypertension Prevention (TOHP) is a multicenter, randomized trial sponsored by the National Heart, Lung, and Blood Institute designed to test whether weight loss alone, sodium reduction alone, or the combination of weight loss and sodium reduction will decrease diastolic (DBP) and systolic blood pressure (SBP) as well as the incidence of hypertension (DBP > or = 90 mm Hg, SBP > or = 140 mm Hg, and/or use of antihypertensive medications) in subjects with high-normal DBP (83 to 89 mm Hg) and SBP less than 140 mm Hg at entry. These interventions were chosen for longer-term testing with end points including hypertension prevention as well as blood pressure (BP) change based on their demonstrated short-term efficacy in reducing BP in phase I of TOHP. The phase II study population is comprised of 2382 participants (1566 men and 816 women) who are 110 to 165% of desirable body weight, allocated at random to the four treatment arms using a 2 x 2 factorial design. The trial has 80% power to detect an overall treatment effect on DBP of 1.2 mm Hg for weight loss or sodium reduction and a difference of 1.6 mm Hg between the combined intervention and placebo groups. BP observers are blinded to participant treatment assignments. Participants will be followed for 3 to 4 years. This trial may have important public policy implications concerning the ability of life-style modifications to reduce BP and prevent the development of hypertension over the long term, thereby avoiding the need for drug therapy which while effective is costly and may have side effects.

Trials of hypertension prevention. Phase I design.

Phase I of the Trials of Hypertension Prevention (TOHP) was a National Heart, Lung, and Blood Institute-sponsored, 3-year, national, multicenter, randomized, controlled trial designed to test the feasibility and efficacy of three life-style (weight loss, sodium restriction, and stress management) and four nutrition supplement (calcium, magnesium, fish oil, and potassium) interventions aimed at lowering diastolic blood pressure in those whose blood pressure was initially in the high normal range (80 to 89 mm Hg). A total of 2182 volunteers were recruited and allocated to the various treatment arms, such that each hypothesis was tested with a power of 85% or higher to detect a diastolic blood pressure treatment effect of 2 mm Hg. The four nutrition supplement interventions were delivered in a double-blinded fashion and the three life-style interventions, single (observed) -blinded. Phase I was designed to provide a rigorous test of short-term lowering of blood pressure for each of the seven treatments chosen and provides the basis for planning of a subsequent long-term trial of hypertension prevention.

Prazosin versus hydrochlorothiazide as initial antihypertensive therapy in black versus white patients.

A randomized, drug-controlled trial was conducted to evaluate the comparative efficacy of hydrochlorothiazide versus prazosin in controlling mild diastolic hypertension in black and white patients. Serum lipid and lipoprotein levels were also studied. Overall, 22 men and 14 women, of whom 50 percent were black, aged 21 to 69 years, were randomly assigned to treatment with either of these two agents. If diastolic blood pressure was not reduced below 90 mm Hg, the other agent was added. Results showed that hydrochlorothiazide and prazosin lowered blood pressure effectively in both black and white patients, but there was a trend for more patients receiving hydrochlorothiazide to need combination therapy than for those receiving prazosin, regardless of ethnic status. Prazosin therapy reduced total cholesterol levels by 20.5 mg/dl and low-density lipoprotein cholesterol levels by 19.0 mg/dl, and hydrochlorothiazide increased total cholesterol levels by 11.4 mg/dl and increased low-density lipoprotein levels by 9.3 mg/dl; but no differences in triglyceride, high-density lipoprotein, plasma high-density lipoprotein2, or high-density lipoprotein3 levels were noted. Both agents were well tolerated in black and white patients. The combination of effective blood pressure control with no adverse effects on the serum lipid profile may make prazosin preferable to hydrochlorothiazide for treating mild diastolic hypertension in black as well as white patients.

Effects of antihypertensive therapy on blood pressure control, cognition, and reactivity. A placebo-controlled comparison of prazosin, propranolol, and hydrochlorothiazide.

A randomized, placebo-controlled trial was conducted to compare the effects of treatment with prazosin, propranolol, or hydrochlorothiazide on the following variables: blood pressure, cognitive and psychomotor skills, cardiovascular reactivity to natural and laboratory challenges, and serum lipid and lipoprotein levels. Side effects were recorded and patients evaluated how they felt during their treatment. Sixty-nine men, 35 percent black, aged 25 to 55 (mean 51.3) years, with diastolic blood pressures between 90 and 104 mm Hg (mean, 93.3 mm Hg), completed the study. There were no differences between active treatment groups in the proportion of patients with controlled blood pressure during the maintenance phase of the study. In the cognitive and psychomotor tests, the hydrochlorothiazide group showed significantly less improvement from baseline than the other treatment groups on the block design subscale of the Wechsler Adult Intelligence Scale-Revised, and there was a trend for the propranolol group to have less improvement from baseline than the other groups on the digit span subscale. There were no other significant pretreatment to post-treatment changes in the other cognitive or psychomotor tests, the Russell Revision of the Wechsler Memory Scale, or a number of computerized reaction-time and signal-detection tasks. In the reactivity testing, there was a significantly lower increase in heart rate in the prazosin group compared with placebo during the second laboratory challenge of the Stroop Color Interference Test. Post-treatment declines in ambulatory blood pressure were seen in all of the drug treatment groups in average and maximal diastolic and systolic blood pressures. Both propranolol and hydrochlorothiazide treatment resulted in low-density lipoprotein cholesterol levels that were higher than baseline and the hydrochlorothiazide treatment had significantly increased total cholesterol levels. In contrast, the prazosin-treated group experienced no adverse changes in these parameters. Overall, the propranolol group had significantly more moderate and severe side effects than did the other three groups. Considering the pattern of blood pressure control, cognitive and psychomotor effects, changes in lipid levels, and magnitude of side effects, prazosin seems to have the most advantageous profile in this study of the three anti-hypertensive agents evaluated.

Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia.

To investigate the lipoprotein effect of fenofibrate in hypercholesterolemia or combined hyperlipidemia (types II A and II B hyperlipidemias, respectively), 240 patients were recruited and 227 randomized to a double-blind randomized trial lasting 24 weeks and 192 patients continued to participate in an open-label phase for another 24 weeks. A 100-mg dose of fenofibrate or a matching placebo was given three times daily. Fenofibrate side effects in excess of placebo affected 6 percent of fenofibrate users and were confined almost entirely to skin rashes. In 180 hypercholesterolemic patients randomly assigned to receive fenofibrate versus placebo, triglyceride and very low-density lipoprotein cholesterol levels decreased 38 percent, total cholesterol levels decreased 17.5 percent, and low-density lipoprotein cholesterol levels decreased 20.3 percent with fenofibrate treatment. High-density lipoprotein cholesterol levels increased 11.1 percent with a decrease in the low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio of 27 percent. All differences were statistically significant (p less than 0.01). In combined hyperlipidemic (type II B) patients, triglyceride levels decreased by 45 percent, very low-density lipoprotein cholesterol levels decreased 52.7 percent, total cholesterol levels decreased 16 percent, low-density lipoprotein cholesterol levels decreased 6 percent, and high-density lipoprotein levels increased 15.3 percent for a low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio decrease of 13 percent. All differences were again statistically significant (p less than 0.01). In both groups of patients, the onset of the drug effect was generally rapid, with maximal total and low-density lipoprotein cholesterol level lowering achieved within four weeks in hypercholesterolemic patients and maximal triglyceride and cholesterol level lowering in hypertriglyceridemic patients achieved in two weeks. Maximum high-density lipoprotein increases occurred after four weeks in type II A patients and 12 to 16 weeks in type II B patients. Fenofibrate is a well-tolerated drug in the fibric acid series and has putatively beneficial effects on triglyceride, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations in both type II A and type II B hyperlipidemic patients. If the lipid hypothesis of atherosclerosis applies to the lipoprotein changes induced by fenofibrate, reductions in cardiovascular disease risk in both type II A and II B hyperlipidemic patients should result from fenofibrate treatment.

Effects of fenofibrate on plasma lipids. Double-blind, multicenter study in patients with type IIA or IIB hyperlipidemia.

Of 240 patients with Type IIa and IIb hypercholesterolemia recruited in 11 centers, 227 were randomized to double-blind treatment with either fenofibrate (100 mg three times daily) or matching placebo for 24 weeks. A group of 192 of these patients were studied for a further 24 weeks during which all received fenofibrate in open label fashion. For the 92 Type IIa patients receiving fenofibrate in the double-blind phase, there were significant reductions (p less than 0.01 compared to baseline) in total plasma cholesterol (-18%), LDL-cholesterol (-20%), VLDL-cholesterol (-38%) and total triglycerides (-38%). Mean plasma HDL-cholesterol in these patients increased by 11% (p less than 0.01). With the exception of LDL, which was not high before treatment, similar changes were seen in the 24 fenofibrate-treated Type IIb subjects. Lipid parameters of placebo-treated patients did not change significantly. This pattern of change was repeated in the open period for the 94 patients previously on placebo, while the 98 who had been on fenofibrate remained stable with small further reductions in total and LDL cholesterol (-38% and -5.5% respectively). Adverse effects were some allergic-type skin reactions early in treatment and an occasional increase in transaminases, BUN, or creatinine. The results were similar to those obtained in European open trials of fenofibrate and were better than the lipid changes seen at comparable times in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) cholestyramine study.

The MRFIT behavior pattern study. II. Type A behavior and incidence of coronary heart disease.

Behavior pattern was assessed by interview for 3,110 men at eight centers in the Multiple Risk Factor Intervention Trial (1973-1976). The Type A pattern was not significantly associated with risk of first major coronary events (coronary death and definite nonfatal myocardial infarction) after a mean follow-up of 7.1 years. Crude relative risks for Types A1-A2 versus X-B were 1.08 in usual care, 0.82 in special intervention, and 0.92 overall. Adjustment for age, blood pressure, cigarette smoking, serum cholesterol, consumption of alcohol, and educational attainment yielded relative risks of 0.99 in usual care, 0.81 in special intervention, and 0.87 overall (95% confidence interval = 0.59-1.28). The Jenkins Activity Survey Type A score, obtained for 12,772 men at all 22 centers, was also not significantly associated with risk of first major coronary events. Overall, crude risks in the lowest (Type B) through highest (Type A) quintiles of the score's distribution were 5.0%, 4.4%, 4.0%, 4.3%, and 4.1%, respectively. The proportional hazards regression coefficient, adjusted for the variables listed above, was -0.006 (95% confidence interval = -0.015-0.003). These results raise questions regarding the robustness of the Type A hypothesis in its present form. Further studies are needed to investigate these questions and to evaluate the validity of procedures used to assess behavior patterns.

Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial.

The Multiple Risk Factor Intervention Trial was a randomized clinical trial that studied the efficacy of multiple risk factor reduction in lowering coronary heart disease mortality in high-risk men. Nutrition counseling based on a fat-modified eating pattern resulted in a significant reduction of total cholesterol and low-density lipoprotein cholesterol. However, based on further analysis not involving comparisons of randomized groups, the reduction in total cholesterol appeared to be blunted by the effects of the antihypertensive medication utilized in the stepped-care therapy in this study. The use of diuretics was associated with an increase in triglycerides and a lesser decrease in total plasma cholesterol when compared with non-diuretic users. The use of diuretic therapy was also associated with a slight decrease in high-density lipoprotein cholesterol, when compared with changes in those not receiving diuretic therapy. The combination of diuretics plus propranolol was related to a substantial decrease in high-density lipoprotein cholesterol in both the Special Intervention and Usual Care participants. The changes in lipoproteins for men receiving diuretic therapy are probably influenced substantially by nutritional factors, especially weight change. Concomitant nutritional changes must be considered when analyzing the short- and long-term effects of therapy with diuretics or other antihypertensive drugs on lipoprotein metabolism.

Serum lipoproteins of normal and cholesterol-fed rats.

The density distribution of lipoproteins in rats fed chow or chow containing 1% cholesterol and 10% olive oil was studied. Lipoprotein fractions were prepared in the ultra-centrifuge between narrow density bands within the density range of 1.006-1.21 and were analyzed by chemical, electrophoretic, and immunological methods. In serum from normal rats there were three major lipoprotein fractions, with densities less than 1.006, 1.030-1.063, and 1.063-1.21. Almost no lipoprotein was found between d 1.006 and 1.030. Most of the low density lipoprotein appeared between a density of 1.04 and 1.05. In the density range 1.05-1.07, small amounts of both low density and high density lipoprotein were found. Feeding a diet high in cholesterol resulted in a marked increase in the concentration of lipoproteins of density less than 1.006, and a new lipoprotein fraction appeared between d 1.006 and 1.030; this fraction contained immunologically demonstrable low density and high density lipoproteins. In addition, there was a decrease in the high density lipoprotein fraction between d 1.070 and 1.21.