Small lesions in the heart identified at electron beam CT: calcification or noise?

PURPOSE: To identify a minimum definition of coronary artery calcification (CAC) at electron beam computed tomography (CT) that would give repeatable results and be accurate as a marker for coronary artery disease. MATERIALS AND METHODS: Hyperattenuating (> 130 HU) foci 0.69-3.09 mm2 in area were evaluated for 256 subjects who underwent two sequential electron beam CT examinations to determine the percentage of hyperattenuating foci seen on a first examination that were seen again on a second examination. Accuracies of varying minimum definitions of CAC were determined in 160 subjects who underwent electron beam CT and coronary arteriography. RESULTS: Hyperattenuating foci more than 2 mm2 in area were seen again at a second examination in more than 50% of cases (P < .0001). At this minimum definition of CAC, the sensitivity and specificity for identifying any angiographically defined coronary artery disease were 82% and 85%, respectively. CONCLUSION: The 2-mm2-area definition of CAC was reliable and provided an accurate indication of coronary artery disease.

Detection of heart calcification with electron beam CT: interobserver and intraobserver reliability for scoring quantification.

PURPOSE: To assess interobserver and intraobserver reliability of three quantitative measures of coronary artery calcium burden: calcium "score," number of calcified lesions, and calcified area. MATERIALS AND METHODS: Electron beam computed tomographic (CT) scanning was used in a series of 25 patients to detect coronary artery calcification. Scan results were reviewed for quality by a radiologist, then scored by two radiologic technologists and by another radiologist. RESULTS: Many interobserver and intraobserver disagreements were noted on a lesion-by-lesion basis. Since most disagreements involved very small lesions, however, their impact was negligible for all three measures of calcium burden. CONCLUSION: It is not useful for more than one observer to independently score a single CT examination obtained to detect cardiac calcification, even when the arteries are heavily calcified.

Circulating heart autoantibodies in familial as compared with nonfamilial idiopathic dilated cardiomyopathy.

BACKGROUND: Idiopathic dilated cardiomyopathy (DCM) is a serious heart disease characterized by enlargement of one or both ventricles and ventricular dysfunction. Although most patients have sporadic disease, 20% have been found to have familial DCM when relatives are investigated by echocardiography. No other factors have been identified to date that consistently distinguish familial from nonfamilial DCM. Although some patients have a family history of DCM, a "negative" family history does not exclude familial DCM because affected family members may be presymptomatic or undiagnosed. Because some patients have life-threatening complications at the time of initial assessment of DCM, identifying a serum marker predictive of familial disease would help determine which families would most likely benefit from echocardiographic investigation. OBJECTIVE: In this study, our objective was to determine whether antiheart autoantibodies could be used to distinguish familial from nonfamilial idiopathic DCM. METHODS: We analyzed serum specimens for antiheart antibodies from 19 patients categorized as having familial DCM and 15 classified as having nonfamilial DCM on the basis of echocardiographic investigation of first-degree relatives. The mean duration of disease in these 34 patients was 50 months at the time the serum specimens were obtained. RESULTS: Titers of antibodies against the adenine nucleotide translocator, branched-chain keto acid dehydrogenase, and cardiac myosin did not distinguish between familial and nonfamilial cases of DCM.

Dystrophin analysis in idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy (DCM) is characterised by ventricular dilatation and impaired systolic function resulting in congestive heart failure and frequently death. A dilated cardiomyopathy is common in patients with symptomatic Duchenne/Becker muscular dystrophy, a disease caused by dystrophin gene defects. However, cardiomyopathy is rarely the predominant clinical feature of this form of muscular dystrophy. To determine whether dystrophin gene defects might account for a significant number of patients with apparently isolated idiopathic DCM, we performed dystrophin gene analysis in 27 DCM patients, who were ascertained as part of a prospective study on idiopathic DCM. No dystrophin gene defects were found in our patients, whose average age was 50 years. These data suggest that dystrophin defects are not a common cause of idiopathic DCM in this age group in the absence of skeletal muscle cramps or weakness.

Insulinemia in children at low and high risk of NIDDM.

OBJECTIVE: Fasting hyperinsulinemia in the presence of normoglycemia usually indicates insulin resistance and is characteristic of populations at high risk for developing NIDDM. Hyperinsulinemia predicts the development of impaired glucose tolerance and NIDDM in Pima Indians, a population with a high incidence of NIDDM. Insulin concentrations in population-based samples of children who have different risks of developing NIDDM later in life have not been reported previously. RESEARCH DESIGN AND METHODS: We compared fasting insulin concentrations in two populations of nondiabetic children, 6-19 yr of age: Pima Indians from southern Arizona and Caucasians from Minnesota. RESULTS: Insulin concentration varied with age, sex, glucose concentration, and relative weight. Mean fasting insulin concentration was 140.3 pM in Pima Indian males, 94.4 pM in Caucasian males, 171.5 pM in Pima Indian females, and 107.1 pM in Caucasian females. For each sex, the mean fasting insulin concentration, controlled for age, glucose, and relative weight, was significantly higher in the Pima Indians than in the Caucasians (P < 0.001). CONCLUSIONS: From a young age, Pima Indian children have higher fasting insulin concentrations than Caucasian children. As hyperinsulinemia predicts subsequent NIDDM, these data suggest that the susceptibility to NIDDM is manifest at a young age as fasting hyperinsulinemia.

Genetic models of human obesity--family studies.

Childhood obesity is predictive of obesity as an adult, and individual differences in body weight relative to height (body mass index) in adults are important predictors of morbidity as well as mortality from atherosclerotic cardiovascular disease. The observation of strong familial correlations does not ensure that genes are involved in the determination of body mass index, because individuals in families share environments as well as genes. However, several recent studies have found evidence for both additive (polygene) and nonadditive (major gene) components. A question that results from these analyses is--what gene(s) has been inherited that carries an associated risk, most likely mediated by environmental exposures, for obesity? Studies to identify genetic loci linked to familial obesity should add to our understanding of the genetic factors involved in the determination of obesity and may lead to early identification of individuals and families at high risk for the chronic disorders that are associated with obesity.

Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease.

To assess the relationship of coronary artery calcification to angiographically detectable disease, the authors evaluated 100 patients less than 60 years of age who underwent clinically indicated coronary angiography and ultrafast computed tomography (CT). The ultrafast CT technique consisted of 3-mm-thick contiguous sections and a 100-msec acquisition time. All patients with clinically significant disease at angiography (defined as at least one stenosis with a diameter narrowing of at least 50%) had some coronary artery calcification present at ultrafast CT (100% sensitivity in this population). The absence of calcification at ultrafast CT had a 100% negative predictive value for clinically significant coronary artery disease. Specificity and positive predictive value were 47% and 62%, respectively. Sensitivity and specificity of ultrafast CT in the detection of patients with angiographically detectable disease were 94% and 72%, respectively. Ultrafast CT of the heart is an anatomically based, noninvasive test with high sensitivity for the detection of coronary artery calcification. Ultrafast CT may be beneficial in the screening of selected populations for the presence of atherosclerotic coronary disease.

Nonclinical factors associated with surgery received for treatment of early-stage breast cancer.

BACKGROUND: Women diagnosed with early breast cancer have had the opportunity to receive breast-conserving surgical treatment, which reduces the physical and psychological morbidity heretofore associated with breast removal. METHODS: Nonclinical factors associated with women receiving partial mastectomies with radiation (P + R) compared with modified radical mastectomies without radiation (MOR) were examined in 2238 Black and White women diagnosed, in 1985 through 1987, with early-stage breast cancer in the metropolitan Detroit area. RESULTS: Age at diagnosis and size of hospital were the strongest predictors of type of surgery received, with younger women (less than 55 years of age) and women treated in larger hospitals (more than 500 beds) more than twice as likely to receive P + R. Stratifying on race, age at diagnosis remained the strongest predictor for White women, followed by hospital size. Among Black women, hospital size was more strongly associated with surgery received than was age. CONCLUSIONS: Younger women and women undergoing treatment at large hospitals are more likely to receive the breast-conserving P + R. Black women treated in small hospitals appear to be particularly unlikely to receive P + R.

Increased familial cardiovascular mortality in obese schoolchildren: the Muscatine Ponderosity Family Study.

Total and cause-specific mortality was investigated in 387 first- and second-degree deceased adult relatives of three groups of children selected from those who participated in three biennial school surveys in Muscatine, Iowa: the lean group (students in the first quintile of relative weight on all three surveys); the random group (a random sample of all eligible students); and the heavy group (students in the fifth quintile of relative weight on all three surveys). A greater proportion of death certificates for heavy group relatives listed a cardiovascular cause of death (60%) compared with lean (48%) and random (43%) group relatives. The relative risk of dying of cardiovascular disease for heavy group vs random group relatives was 1.41 (95% confidence interval 1.01, 1.98). In a subset of heavy group families identified by children with elevated systolic blood pressure, the proportion of death certificates listing a cardiovascular cause was even higher (76%) and the estimate of relative risk vs random group relatives was 2.20 (95% confidence interval 1.43, 3.37). These results indicate that persistent obesity in children, particularly when accompanied by persistent blood pressure elevation, identifies families whose members are at increased risk of dying of cardiovascular disease.

The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy is characterized by an increase in ventricular size and impairment of ventricular function. Most cases are believed to be sporadic, and familial dilated cardiomyopathy is usually considered to be a rare and distinct disorder. We studied the proportion of cases of idiopathic dilated cardiomyopathy that were familial in a large sequential series of patients whose first-degree relatives were investigated regardless of whether these relatives had cardiac symptoms. METHODS: We studied relatives of 59 index patients with idiopathic dilated cardiomyopathy of obtaining a family history and performing a physical examination, electrocardiography, and two-dimensional, M-mode, and Doppler echocardiography. A total of 315 relatives were examined. RESULTS: Eighteen relatives from 12 families were shown to have dilated cardiomyopathy. Thus, 12 of the 59 index patients (20.3 percent) had familial disease. There was no difference in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features between the index patients with familial disease and those with nonfamilial disease. A noteworthy finding was that 22 of 240 healthy relatives (9.2 percent) with normal ejection fractions had increased left ventricular diameters during systole or diastole (or both), as compared with 2 of 112 healthy control subjects (1.8 percent) who were studied separately. CONCLUSIONS: Dilated cardiomyopathy was found to be familial in at least one in five of the patients in this study, a considerably higher percentage than in previous reports. This finding has important implications for family screening and provides direction for further investigation into the causes and natural history of dilated cardiomyopathy.

The genetic and environmental sources of body mass index variability: the Muscatine Ponderosity Family Study.

The role of genetic and environmental factors in determining the variability in body mass index (BMI; kg/m2) was investigated in 1,302 relatives identified through 284 schoolchildren from Muscatine, IA. BMI levels were first adjusted for variability in age, by gender and by relative type. There was significant familial aggregation of adjusted BMI in the pedigrees, as indicated by inter- and intraclass correlation coefficients significantly different from zero. A mixture of two normal distributions fit the adjusted BMI data better than did a single normal distribution. Genetic and environmental models that could explain both the familial aggregation and the mixture of normal distributions were investigated using complex segregation analysis. There was strong support for a single recessive locus with a major effect that accounted for almost 35% of the adjusted variation in BMI. Polygenic loci accounted for an additional 42% of the variation. Approximately 23% of the adjusted variation was not explained by genetic factors. For spouses living in the same household, their shared environment accounted for 12% of their variation. For siblings living in the same household, their shared environment accounted for 10% of their variation. While shared environments contributed to variation in adjusted BMI, more than 75% of the variation was explained by genetic factors that include a single recessive locus. Approximately 6% of the individuals in the population from which these pedigrees were sampled are predicted to have two copies of the recessive gene, while 37% of the individuals are predicted to have one copy of the gene.

Heterogeneity of breast cancer risk in families of young breast cancer patients and controls.

Familial heterogeneity of breast cancer risk was assessed among 4,159 first-degree female relatives of 1,074 population-based, young breast cancer cases (aged 20-54 years) diagnosed from December 1, 1980 to December 31, 1982 and 4,120 first-degree female relatives of 998 age- and race-matched, population-based controls from the metropolitan Detroit, Michigan, area. The family risk index method used for analysis considers family size, age, and race differences among families in the assessment of family risk. Families of cases showed a higher risk of breast cancer than did families of controls, with case families 1.80 to 4.24 times more likely to be defined as high risk than control families; the magnitude of the risk differential was dependent on the definition of high risk. Within the case families only, familial heterogeneity of risk was suggested, with a small proportion of families (less than 5%) at lower risk of breast cancer than most case families. A number of reproductive risk factors, age, race, and histologic type of cancer for the proband, and several family characteristics were investigated to help characterize the case families at higher and lower risk.

Levels of lipids, lipoproteins, and apolipoproteins in a defined population.

As part of a large cross-sectional investigation--the Rochester Family Heart Study--plasma levels of lipids, lipoproteins, and apolipoproteins were measured in a sample from the general population of male and female subjects who ranged in age from 5 to 90 years. Polyclonal radioimmunoassays developed at the Mayo Clinic were used for measurement of apolipoproteins A-I, A-II, C-II, C-III, and E, whereas a monoclonal enzyme-linked immunosorbent assay was used for apolipoprotein B. On the basis of 984 subjects who reported that they were fasting, were not pregnant, had never smoked, and were taking no medications thought to influence lipid levels, we determined age- and gender-specific percentiles for plasma levels of cholesterol, triglycerides, high-density lipoprotein cholesterol, and six apolipoproteins. These percentiles will facilitate identification of persons who are in the highest and lowest percentiles for their age and gender. The levels of the apolipoproteins varied for both age and gender. This is the first study to provide a reference sample for plasma levels of these apolipoproteins for male and female subjects 5 to 90 years of age selected from the general population.

Evidence that a single gene with gender- and age-dependent effects influences systolic blood pressure determination in a population-based sample.

A biometrical study was carried out to evaluate the role of genetic variation in determining interindividual differences in systolic blood pressure (SBP) in the population at large. SBP was measured in 1,266 Caucasian individuals in 278 pedigrees ascertained through children enrolled in the Rochester, MN, school system. The sample included 646 males and 620 females 550 years of age and not taking antihypertensive medication or oral contraceptives. Complex segregation analysis was first applied to these data by using a regression model for age, in which the intercept was gender and ousiotype specific but in which the slope was only gender specific. When the slope was independent of ousiotype, neither variation at a single gene combined with polygenic effects (mixed genetic model) nor variation in a single environmental factor combined with polygenetic effects (mixed environmental model) explained the distribution of SBP in this sample. However, when the regression model for age allowed both the intercept and slope to be gender and ousiotype specific, the mixed environmental model was rejected whereas the mixed genetic model was not. These results suggest that variability in SBP may be influenced by major effects of allelic variation at a single gene that are both gender and age dependent. This study (1) suggests that particular genotypes determined by a single gene are associated with a steeper increase of SBP with age among males and females 550 years of age in the general population and (2) illustrates the need to consider models that more realistically represent the relationship between genotypic variability and phenotypic variability, to understand the genetics of human quantitative traits.

Genetic and environmental explanations for the distribution of sodium-lithium countertransport in pedigrees from Rochester, MN.

An elevated level of erythrocyte sodium-lithium (Na-Li) countertransport has been suggested as a predictor of predisposition to essential hypertension. In order to evaluate whether a single genetic or environmental factor with large effects explains the mixture of distributions in Na-Li countertransport in the general population, complex segregation analyses were conducted by using 1,273 individuals more than age 20 years from 276 pedigrees selected without respect to disease risk factors or health status. Either a single genetic locus or a single environmental factor with large gender-specific effects explained the mixture of distributions for Na-Li countertransport in this sample equally well. In the subsample of pedigrees supporting a single-locus etiology, the single genetic locus explained 29.0% of the variability in adjusted Na-Li countertransport in males and 16.6% of that in females. In a subsample of pedigrees supporting an environmental factor etiology, the environmental factor explained 35.2% of the adjusted Na-Li countertransport in males and 20.5% of that in females. These results suggest that there are at least two different explanations for the mixture of distributions in Na-Li countertransport in the general population. Attempts to relate genetic variation in Na-Li countertransport to risk of essential hypertension must consider that the factor with large phenotypic effects on this trait is gender specific and may not be a single major locus in all pedigrees.

Commingling and segregation analyses: comparison of results from a simulation study of a quantitative trait.

Commingling analysis is commonly used to provide preliminary evidence for a single genetic locus with a major effect on the quantitative trait of interest. In this paper, the effectiveness of commingling analysis as a screening technique to identify samples for segregation analysis is assessed by applying both commingling and segregation analyses to samples of simulated pedigree data in which a major locus is segregating in the presence of polygenes and an individual-specific environmental effect. Under the circumstances simulated here, there is evidence for a single locus from segregation analysis but not from commingling analysis in at least 20% of the samples. No more than 2% of the samples provided evidence for commingling but not for segregation of a single locus. Comparisons of the samples that give evidence for both commingling and segregation, evidence for one but not the other, and no evidence for either show that evidence for commingling depends on the distributional characteristics of the trait in the sample, while support for the single locus from segregation analysis depends on both the distributional characteristics as well as the transmission of the rarer allele from parents to offspring. Since lack of commingling does not rule out the existence of a single locus in the realistic situations considered here, commingling analysis has limited usefulness as a screening technique for the presence for a single locus. In contrast, evidence for commingling does suggest the possibility that a single locus has a major effect on the trait and commingling analysis can provide guidance in the choice of initial parameter estimates for segregation analysis.

Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes.

The incidence of end-stage renal disease in patients with diabetes mellitus is reportedly higher among blacks than among whites. This finding may be explained by the greater prevalence of diabetes among blacks. The relation of the type of diabetes to the risk of diabetic end-stage renal disease is largely unstudied. We addressed these issues in a study of all the black and white diabetic patients with end-stage renal disease (470 blacks and 861 whites) reported to the Michigan Kidney Registry who began treatment during 1974 through 1983. We also reviewed the medical records of a subpopulation of such patients (284 blacks and 310 whites) who were less than 65 years of age at the start of treatment for end-stage renal disease to determine what type of diabetes they had. In this study, we made use of national data on the prevalence of diabetes. We found that the incidence of diabetic end-stage renal disease was 2.6-fold higher (P less than or equal to 0.0001) among blacks after we adjusted for the higher prevalence of diabetes among blacks, with the excess risk occurring predominantly among blacks with non-insulin-dependent diabetes mellitus (NIDDM). Most black patients with diabetic end-stage renal disease had NIDDM (77 percent), whereas most white patients with diabetic end-stage renal disease had insulin-dependent diabetes mellitus (IDDM) (58 percent) (P less than or equal to 0.0005 for the difference between the races). For both races combined, the risk of diabetic end-stage renal disease during the 10-year period we studied was markedly greater for patients with IDDM (5.8 percent) than for those with NIDDM (0.5 percent). Our results indicate an increased risk of diabetic end-stage renal disease among blacks as compared with whites, particularly blacks with NIDDM. Although the risk of diabetic end-stage renal disease is higher in patients with IDDM, the majority of patients with diabetic end-stage renal disease in the population we studied had NIDDM.

The relation between ponderosity and coronary risk factors in children and their relatives. The Muscatine Ponderosity Family Study.

A family study was conducted in Muscatine, Iowa in 1984-1985 to evaluate the relation between ponderosity in children and coronary risk factor levels in these children and in their family members, and the genetic contribution to familial clustering of levels of ponderosity (body weight relative to height). Four groups of probands were selected from the 1,783 students who participated in three consecutive biennial school surveys. A random group (n = 70), a random sample of students from the entire pool; a lean group (n = 72), students in the lowest quintile of relative weight on all three surveys; a gain group (n = 70), students who gained at least two quintiles of relative weight over the four-year period; and a heavy group (n = 72), students in the highest quintile of relative weight on all three surveys. The parents, siblings, a related aunt or uncle, and a first cousin of these probands were also examined. The data show that levels of high density lipoprotein (HDL) cholesterol, apolipoproteins A-1 and B, and systolic blood pressure in heavy group probands are consistent with increased coronary risk. This same association exists among the relatives with excess ponderosity. Levels of body mass index in the mothers, fathers, and siblings cluster with the levels in the probands, and genetic differences among persons explain 36-52 per cent of the variability in body mass index across the range of ponderosity represented by the probands and their relatives. While the contribution from genes is strong, these data suggest that the contribution from environmental factors is equally as important.