Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study.

BACKGROUND: Higher carotid intimal-medial thickness (IMT) is associated with cardiovascular risk factors and is predictive of coronary artery disease and stroke in older adults. Carotid IMT was measured in young and middle-aged adults to determine its relationship with risk factors measured (1) in childhood, (2) currently, and (3) as a "load" from childhood to adulthood. METHODS AND RESULTS: Carotid ultrasound studies were performed in 346 men and 379 women aged 33 to 42 years who were representative of a cohort followed since childhood and who live in Muscatine, Iowa. The mean of the measurements of maximal carotid IMT at 12 locations was determined for each subject. A medical questionnaire was completed, and measurements of anthropometric characteristics and risk factors were obtained. The mean maximum carotid IMT was 0.79+/-0.12 mm for men and 0.72+/-0.10 mm for women. On the basis of multivariable analysis, the significant current predictors of IMT were age and LDL cholesterol in both sexes and diastolic blood pressure in women. Total cholesterol was a significant childhood predictor in both sexes, while childhood body mass index was significant only in women. For men, LDL cholesterol, HDL cholesterol, and diastolic blood pressure were predictive of carotid IMT in a risk factor load model, whereas in women, LDL cholesterol, body mass index, and triglycerides were predictive. CONCLUSIONS: Higher carotid IMT in young and middle-aged adults is associated with childhood and current cardiovascular risk factors, as well as risk factor load.

Usefulness of the Framingham risk score and body mass index to predict early coronary artery calcium in young adults (Muscatine Study).

The value of a coronary artery disease prediction algorithm, the Framingham risk score (score), for detecting coronary artery calcium (CAC) was examined in 385 men and 472 women, aged 29 to 43 years. Scores were compared in subjects with and without CAC and were also used to predict presence of CAC. Receiver-operating characteristic curves were computed to compare different prediction models. The score model was compared with age only, natural logarithm of body mass index (lnBMI) only, and score plus lnBMI models. CAC was detected in 30% of men and 16% of women. The mean score was significantly higher in men and women with CAC. For every 2-point increase in the score, the odds of CAC increased by 30% in women and 20% in men. Significant associations between CAC status and risk factors were observed for age in women, and high- density lipoprotein cholesterol and blood pressure in men and women. The area under the receiver-operating characteristic curve for the score was 0.67 and 0.57 for women and men, respectively. When lnBMI was added to the score model, the area increased to 0.76 in women (lnBMI p <0.0001, score p <0.005). For men, the area increased from 0.57 to 0.67, and the score was no longer significant (p >0.60) in the model with lnBMI (p <0.0001). Score predicts CAC in asymptomatic young adults. Inclusion of lnBMI in the score model adds significantly to the prediction of CAC in women and men. The lnBMI model has a greater predictive value than the score in this young population.

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.

Automated analysis of Doppler ultrasound velocity flow diagrams.

A highly automated method for the identification and quantization of maximum blood velocity curves from Doppler ultrasound flow diagrams is presented. The method uses an image processing scheme to analyze video-recorded image sequences of flow diagrams. The sequences are acquired, a sequence of images relating to chronological cardiac cycles is extracted, and a maximum blood velocity envelope is determined and quantified. The results are verified against hand-traced reference curves. Excellent correlation of r = 0.99 is achieved.

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,

Increased carotid intimal-medial thickness and coronary calcification are related in young and middle-aged adults. The Muscatine study.

BACKGROUND: Increased carotid intimal-medial thickness (IMT) and coronary artery calcification (CAC) are used as 2 markers of early atherosclerosis. Our objectives were to assess whether increased IMT and CAC are related and to determine the relationship between cardiovascular risk factors and carotid IMT in young adults. METHODS AND RESULTS: A sample of 182 men and 136 women aged 33 to 42 years living in Muscatine, Iowa, underwent B-mode carotid ultrasound to determine the mean of 12 measurements of maximal carotid IMT. CAC was defined as calcification in the proximal coronary arteries in >/=3 contiguous pixels with a density of >/=130 HU. The mean IMT was 0.788 mm (SD 0.127) for men and 0.720 mm (SD 0.105) for women. CAC was present in 27% of men and 14% of women and was significantly associated with IMT in men (P<0.025) and women (P<0.005). With multivariate analysis, after adjustment for age, significant risk factors for carotid IMT were LDL cholesterol (P<0.001) and pack-years of smoking (P<0.05) in men and LDL cholesterol (P<0.001) and systolic blood pressure (P<0.01) in women. These risk factors remained significant after CAC was included in the multivariate model. CONCLUSIONS: There is an association between increased carotid IMT and CAC and between cardiovascular risk factors and increased IMT in young adults. Carotid IMT may provide information in addition to CAC that can be used to identify young adults with premature atherosclerosis.

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.

Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis.

The identification of genetic loci involved in most forms of congenital heart disease has been hampered by the complex inheritance patterns of these disorders. Atrioventricular canal defects (AVCDs) are most commonly associated with Down syndrome, although non-syndromic cases also occur. Non-syndromic AVCDs have been attributed to multifactorial inheritance. However, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families. We have used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred. In so doing, we have identified a genetic locus on chromosome 1 shared by all affected individuals. Our data demonstrate the existence of a congenital heart defect susceptibility gene, inherited as an autosomal dominant with incomplete penetrance, involved in AVCD. Furthermore, our data demonstrate the power of using key isolated kindreds in combination with high density genomic screens to identify loci involved in complex disorders such as congenital heart defects.

Obesity in childhood: the Muscatine Study.

Beginning in 1971 children in grades kindergarten through the 12th grade were examined on alternate years until 1992 in Muscatine, Iowa, in these examinations the following variables were assessed: height, weight, skinfold thickness, lipids, lipoproteins, smoking behaviors, as well other variables. In order to lend relevance to risk factors in childhood a number strategies have been used. These include: 1) Examination of familial aggregation and mortality; 2) Segregation analysis of genetic mechanisms; 3) Relationship of obesity in childhood to other established risk factors; 4) Examination of the relationship of childhood obesity to the development of coronary artery calcification as assessed by electron beam computed tomography. In these studies we have shown that obese children's siblings, mothers, fathers, aunts and uncles have significant greater body mass indices than leaner children. Children who are obese have significantly higher systolic and diastolic blood pressure, higher plasma triglycerides and lower HDL-cholesterol levels. The first and second degree relatives of obese hypertensive children have a higher mortality rate from cardiovascular disease than leaner children's relatives. From complex segregation analyses about 35% of the population of Muscatine appear to carry a gene for obesity and 6% appear homozygous. Over the past decade we have observed that the children in Muscatine, Iowa have become more obese than previously. Our longitudinal observations indicate that obesity acquired in childhood is predictive of adult obesity and is also predictive of the development of coronary artery calcification. Thus obesity in childhood is not only an important risk factor in children but also a growing public health problem for children and adolescents.

Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study.

OBJECTIVES: This study was designed to estimate the prevalence of coronary artery calcification in young adult men and women and to examine the association between the presence of coronary artery calcification and coronary risk factors measured in childhood and young adult life. BACKGROUND: Electron beam computed tomography is a sensitive, noninvasive method for detecting coronary artery calcification, a marker of the atherosclerotic process. Coronary artery calcification is associated with coronary risk factors in older adults. METHODS: Subjects (197 men, 187 women) had coronary risk factors measured in childhood (mean age 15 years) and twice during young adult life (mean ages 27 and 33 years). Each underwent an electron beam computed tomographic study at their second young adult examination. RESULTS: The prevalence of coronary artery calcification was 31% in men and 10% in women. Increased body size, increased blood pressure and decreased high density lipoprotein (HDL) cholesterol levels were the coronary risk factors that showed the strongest association with coronary artery calcification. Significant odds ratios for coronary artery calcification, using standardized risk factor measurements at a mean age of 33 years in men and women, respectively, were 6.4 and 13.6 for the highest decile of body mass index, 6.4 and 6.4 for the highest decile of systolic blood pressure and 4.3 and 4.7 for the lowest decile of HDL cholesterol. CONCLUSIONS: Coronary artery calcification is more prevalent in men in this young adult population. Coronary risk factors measured in children and young adults are associated with the early development of coronary artery calcification. Increased body mass index measured during childhood and young adult life and increased blood pressure and decreased HDL cholesterol levels measured during young adult life are associated with the presence of coronary artery calcification in young adults.

Molecular analysis of nondisjunction in Down syndrome patients with and without atrioventricular septal defects.

BACKGROUND: Congenital heart disease is common in Down syndrome patients, with atrioventricular septal defects accounting for a majority of the abnormalities. The molecular mechanisms of meiotic nondisjunction resulting in Down syndrome were studied for associations with the presence of atrioventricular septal defects. METHODS AND RESULTS: Twenty highly polymorphic chromosome 21 microsatellite markers were used to genotype two groups of patients (group 1: Down syndrome with atrioventricular septal defects, n = 43; and group 2: Down syndrome without cardiac defects, n = 51) to determine (1) the parental origin of the extra chromosome, (2) the stage of meiotic nondisjunction resulting in the trisomy, (3) the presence or absence of disomic homozygosity or heterozygosity, and (4) the degree of recombination in the nondisjoined chromosomes. The parental origin of the nondisjoined chromosome was maternal in 86.2% of the families, with no significant differences between groups. The most centromeric marker was nonreduced, indicating a meiosis I nondisjunction in 76.5% of maternally derived trisomies, and reduced, indicating a meiosis II nondisjunction in 76.9% of paternally derived trisomies, with no significant differences between groups. There were no significant differences in the proportion of reduced markers at any locus between groups. The distribution of the number of crossovers was significantly different between groups (chi 2 = 14.12, P < .001), with less recombination observed in group 1. CONCLUSIONS: In Down syndrome patients, no association was found between the presence of an atrioventricular septal defect and the parent of origin, stage of meiotic nondisjunction, or disomic homozygosity or heterozygosity. A significant association was found between the presence of an atrioventricular septal defect and reduced frequency of recombination.

Coronary risk factors in adolescents related to their knowledge of familial coronary heart disease and hypercholesterolemia: the Muscatine Study.

OBJECTIVE: To determine the utility of a school-based questionnaire, to identify adolescents with adverse coronary risk factor levels. DESIGN: In Muscatine, IA, students (9th through 12th grade) completed a questionnaire providing medical history information about first- and second-degree relatives. Anthropometric measures were obtained and blood pressure, lipid, lipoprotein, and apolipoprotein levels were determined. RESULTS: A history of parental coronary heart disease (CHD) was rare and a history of parental high cholesterol frequently was unknown; however, when known, a history of high cholesterol or early (30 to 55 years of age) or later (> 55 years of age) CHD (myocardial infarction, coronary bypass, or death from a heart attack) in grandfathers enriched the identification of adolescents with adverse coronary risk factors. Parental history of CHD was associated with an increased risk for high body mass index and low apolipoprotein A1 levels in their children. Grandfather history of early or later CHD was associated with an increased risk for low apolipoprotein A1 and high density lipoprotein cholesterol levels and high body mass index in their grandchildren. Students with positive grandfather histories of high cholesterol had higher total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and low density lipoprotein cholesterol to high density lipoprotein cholesterol ratios. Grandmother histories, because most were negative, did not help identify adolescents in this population with adverse coronary risk factors. CONCLUSIONS: A parental history of CHD as well as a grandfather history of high cholesterol or CHD enriches the identification of children with adverse coronary risk factor levels. The positive predictive values associated with using a school-based history obtained from adolescents, many with the aid of their parents, are small and many adolescents do not know their family history. It is essential that pediatricians inquire about parental and especially grandparental medical histories in accordance with the National Cholesterol Education Program guidelines to help identify children at highest familial risk. The importance of determining parental and grandparental histories of CHD or hypercholesterolemia should be emphasized to families who are uncertain of their histories to identify children and adolescents who require a physician's care. It is also important for pediatricians to remind their colleagues who care for patients with premature ischemic heart disease to refer their progeny for pediatric care so that their lipids and lipoproteins may be screened and counseling provided.

Linkage analysis of autosomal dominant atrioventricular canal defects: exclusion of chromosome 21.

The association between trisomy 21 and a high incidence of atrioventricular canal defects (AVCDs) indicates that a locus on chromosome 21 is involved in this congenital heart defect. We have investigated whether a genetic locus on chromosome 21 is also involved in familial nonsyndromic AVCDs. Short tandem repeat polymorphisms (STRPs) from chromosome 21 were used for linkage analysis of a family having multiple members affected with AVCDs. In this family, the gene for AVCDs is transmitted as an autosomal dominant with incomplete penetrance. The affected family members are nonsyndromic and have normal karyotypes. Two-point and multipoint linkage analyses produced significantly negative LOD scores for all informative markers. A comparison of the overlapping exclusion distances obtained for each marker at LOD equal -2.0 with the 1000:1 consensus genetic map of the markers, excludes chromosome 21 as the genetic location for AVCDs in this family. The exclusion of chromosome 21 indicates that another gene, not located on chromosome 21, is involved in atrioventricular canal defect formation.