Association between a leukotriene C4 synthase gene promoter polymorphism and coronary artery calcium in young women: the Muscatine Study.

OBJECTIVE: A majority of the recognized risk factors for atherosclerosis and the development of cardiovascular disease have been derived from the study of older populations who have already manifested clinical symptoms. If risk factors can be identified earlier in life, such as genetic variation, preventive measures may be taken before overt symptoms of pathology have manifested, and when treatments may be most effective. METHODS AND RESULTS: In an effort to identify individuals at increased risk for cardiovascular disease, we genotyped 732 members of the Muscatine Study Longitudinal Adult Cohort for candidate genetic markers associated with several pathogenetic processes. We identified age-adjusted increased risks for coronary artery calcium (OR 4.29; 95% CI 1.78, 10.31) and increased mean carotid artery intimal-medial thickness associated with the (-444)A>C promoter polymorphism of Leukotriene C4 Synthase (LTC4S) in women. There were no similar associations in men. CONCLUSIONS: LTC4S plays a key role in the process of inflammation as the rate limiting enzyme in the conversion of arachidonic acid to cysteinyl-leukotrienes, important mediators of inflammatory responses. The (-444)C variant upregulates LTC4S mRNA expression, increasing the synthesis of proinflammatory leukotrienes. Our results support genetic variation modifying inflammatory pathways as an important mechanism in the development of atherosclerosis.

Diet and sex hormones in boys: findings from the dietary intervention study in children.

CONTEXT: Diet reportedly alters serum sex hormone concentrations in adults, but little is known about the influence of diet during puberty on these hormones. OBJECTIVE: We aimed to determine whether an intervention to lower fat intake during adolescence alters serum sex hormone concentrations and progression through puberty. DESIGN: In 1990-1997, we conducted an ancillary study to the Dietary Intervention Study in Children, a multicenter, randomized, controlled clinical trial to test the safety and efficacy of a cholesterol-lowering dietary intervention in children. PARTICIPANTS: Healthy, prepubertal, 8 to 10 yr olds with elevated low-density lipoprotein cholesterol were randomized to usual care or a behavioral intervention. Of 362 randomized Dietary Intervention Study in Children boys, 354 participated in the ancillary study. Eighty-four percent of boys attended last visits when their median time on trial was 7.1 yr. INTERVENTION: The behavioral intervention continued throughout the duration of the trial and promoted a diet with 28% energy from total fat, less than 8% from saturated fat, 9% or less from polyunsaturated fat, and less than 75 mg cholesterol per 1000 kcal. OUTCOME MEASURES: The main outcome measure for boys formulated before study initiation was non-SHBG bound testosterone concentration. Secondary outcomes included serum total testosterone, dihydrotestosterone, androstenedione, estradiol, estrone, SHBG, and Tanner stage. RESULTS: There were no significant treatment group differences in boys' serum hormone levels, SHBG, or Tanner stages at any individual visit or over the course of the trial when evaluated by longitudinal models. CONCLUSION: Modest reductions in total fat, saturated fat, and possibly energy intake do not alter progression through puberty or serum sex hormone concentrations in adolescent boys.

Influence of body size and section level on calcium phantom measurements at coronary artery calcium CT scanning.

PURPOSE: To determine whether differences in body mass index (BMI) and image section levels representing the proximal through the distal sections of the heart are associated with attenuation differences in images of calcium phantoms scanned during computed tomographic (CT) imaging of study subjects. MATERIALS AND METHODS: Mean attenuation values for three calcium phantoms (each with a different calcium hydroxyapatite concentration), as measured at each of four different image section levels, were obtained for 691 participants in the Muscatine CT Vascular Calcium Study. The subjects were grouped according to sex-specific BMI quartiles, and the degree of attenuation in each phantom was investigated as a function of image section level and BMI quartile. Spearman rank order correlation coefficients and one-, two-, and three-factor repeated-measures analysis of variance were used to examine the association between section level and BMI and the mean phantom attenuations. RESULTS: Attenuation was, for the most part, significantly associated with both section level (P <.005) and BMI quartile (P <.0025-.05). The degree of attenuation tended to decrease in images obtained at the more distal cardiac levels and to increase with increasing BMI quartile. CONCLUSION: Differences in attenuation related to BMI and image section level appear to have a significant effect on current calcium scoring methods.

A summary of results of the Dietary Intervention Study in Children (DISC): lessons learned.

Prevention of cardiovascular disease must begin in childhood, preferably before risk factors develop. Elevated low-density lipoprotein cholesterol levels in children are likely to track over time and become high-risk levels in adults. The Dietary Intervention Study in Children (DISC) was a multicenter, collaborative randomized trial in pre-adolescent children designed to test the efficacy and safety of a dietary intervention to lower saturated fat and cholesterol intake among growing children with elevated low-density lipoprotein cholesterol. Numerous DISC results, which include findings on lipids-lipoproteins, genetics, and nutrient adequacy, as well as descriptions of the behavioral intervention strategies, have been reported. A summary of practical findings and their potential clinical applications have not previously been published. Highlights of key lessons learned from DISC and translational applications of potential interest to nurses and other health care providers are presented.

Diet and sex hormones in girls: findings from a randomized controlled clinical trial.

BACKGROUND: Results of several studies have suggested that diet during adolescence may influence the risk of breast cancer in adulthood. We evaluated whether an intervention to lower fat intake among adolescent girls altered their serum concentrations of sex hormones that, in adults, are related to breast cancer development. METHODS: We conducted an ancillary hormone study among 286 of the 301 girls who participated between 1988 and 1997 in the Dietary Intervention Study in Children, in which healthy, prepubertal, 8- to 10-year-olds with elevated low-density lipoprotein cholesterol were randomly assigned to usual care or to a behavioral intervention that promoted a low-fat diet. Median time on the intervention was 7 years. Blood samples collected before randomization and at the year 1, year 3, year 5, and last visits were assayed to determine the girls' serum levels of sex hormones. All P values are two-sided. RESULTS: At the year 5 visit, girls in the intervention group had 29.8% (95% confidence interval [CI] = 5.4% to 47.9%; P =.02) lower estradiol, 30.2% (95% CI = 7.0% to 47.7%; P =.02) lower non-sex hormone binding globulin-bound estradiol, 20.7% (95% CI = 4.7% to 34.0%; P =.02) lower estrone, and 28.7% (95% CI = 5.1% to 46.5%; P =.02) lower estrone sulfate levels during the follicular phase of the menstrual cycle and 27.2% (95% CI = 5.7% to 53.1%; P =.01) higher testosterone levels during the luteal phase of the menstrual cycle than did girls in the usual care group. At the last visit, the luteal phase progesterone level was 52.9% (95% CI = 20.0% to 72.3%) lower for girls in the intervention group than for girls in the usual care group (P =.007). CONCLUSION: Modest reductions in fat intake during puberty are associated with changes in sex hormone concentrations that are consistent with alterations in the function of the hypothalamic-pituitary-ovarian axis. Whether these changes influence breast cancer risk is currently unknown.

Preferential transmission of the MTHFR 677 T allele to infants with Down syndrome: implications for a survival advantage.

We have examined the transmission frequencies of the methylenetetrahydrofolate reductase (MTHFR) 677 T and C alleles from heterozygous parents to children with Down syndrome (trisomy 21) in 202 Caucasian families. Our results indicated that the MTHFR 677T allele was transmitted to children with Down syndrome at a significantly higher rate than would be expected based on Mendelian inheritance patterns, and the C allele was transmitted at a significantly lower rate (P < 0.009). Transmission frequencies were also examined independently for maternally and paternally transmitted alleles to assess potential parent-of-origin effects. Because the vast majority of conceptions with trisomy 21 end in pregnancy loss, we questioned whether the observed preferential transmission of the T allele to this population of liveborn infants with Down syndrome could reflect a survival advantage. A plausible biochemical interpretation of these results is presented based on a maternal-fetal MTHFR 677T allele interaction in the context of the constitutive overexpression of three copies of the cystathionine beta synthase gene in the trisomy 21 fetus. Published 2002 Wiley-Liss, Inc.

Beta 1 integrin activation mediates adhesive differences between trisomy 21 and non-trisomic fibroblasts on type VI collagen.

Trisomy 21 (Down syndrome) is a common genetic condition with a high incidence of congenital heart defects (CHD), particularly those involving abnormal development of the embryonic atrioventricular (AV) canal. Type VI collagen (Col VI) is expressed in the developing AV canal extracellular matrix, and has been associated with trisomy 21 AV canal defects in human genetic studies. Although the molecular mechanisms linking Col VI and trisomy 21 AV canal defects are not well understood, a computer model predicts increased cell adhesiveness is responsible for these CHD. We compared integrin-mediated cell adhesive properties for skin fibroblasts isolated from trisomy 21 and non-trisomic individuals on Col VI, fibronectin (FN) and type I collagen (Col I). Cell lines demonstrate similar adhesion profiles to FN and Col I, but all trisomy 21 cells display increased adhesive capacity for Col VI compared to non-trisomic fibroblasts. Cell adhesion to type VI collagen was shown to be GRGDS independent, but beta(1) integrin family dependent. Function-blocking antibodies identified alpha(3)beta(1) as the predominant integrin mediating trisomy 21 and non-trisomic skin fibroblast adhesion on Col VI. Trisomy 21 and non-trisomic fibroblasts display similar expression levels for each of the integrin receptors examined. A beta(1) integrin-activating antibody augments non-trisomic cell adhesion on Col VI, but has no effect upon trisomy 21 fibroblasts. These results demonstrate that beta(1) integrin family members mediate trisomy 21 and non-trisomic skin fibroblast adhesion for Col VI. Altered activation state of the beta(1) integrin is a mechanism responsible for increased trisomy 21 cell adhesion on Col VI.

Automated analysis of brachial ultrasound image sequences: early detection of cardiovascular disease via surrogates of endothelial function.

Early detection of cardiovascular disease would allow timely institution of preventive measures. Arterial endothelium play a primary role in processes leading to the development of atherosclerotic plaque and cardiovascular disease in general. Determination of flow-mediated dilatation (FMD) of brachial arteries from B-mode ultrasound image sequences offers a noninvasive surrogate index of endothelial function. A highly automated method for analysis of brachial ultrasound image sequences is reported and its performance assessed. The method overcomes the variability of brachial ultrasound images across subjects by incorporating machine learning and quality control steps. The automated method outperformed conventional manual analysis by providing a decreased analysis bias, increased reproducibility, and improved measurement accuracy. Consequently, it decreases inter- and intraobserver as well interinstitution variability. The method has been employed in a number of population studies with thousands of subjects analyzed.

Children and cholesterol: potential prevention for future good health

The prevention of cardiovascular disease beginning in chilhood may be affected with two strategies. The first is a population approach to lower the cholesterol levels in all American children. The second is an individualized strategy to identify and treat children at particularly high risk in the health cara system