Identification of high risk relatives for coronary heart disease.

The family at increased risk for future coronary heart disease is the family with a member who has 1) had one or more myocardial infarctions before age 55 years; 2) has levels of LDL cholesterol greater than 75th percentile for age; 3) has excessively low levels of HDL2 cholesterol; 4) has hypertension or has had a stroke, or both; 5) has excessive weight at any age and excessive weight gain during adulthood, or 6) smokes in the household.

Aortic stiffness: a new Doppler echocardiographic measure predictive of systolic blood pressure in children.

Aortic stiffness, the maximal frequency shift in the descending aorta divided by the Doppler acceleration time, was studied in 384 eleven year old twin children. The extent to which this measurement provided a prediction of systolic blood pressure that was independent of body size, heart rate, cardiac contractility and left ventricular mass was investigated. Aortic stiffness, after adjustment for height and weight, correlated significantly with systolic blood pressure (r = 0.22, p less than 0.01), but not with diastolic blood pressure. The short- (r = 0.82) and longer- (r = 0.68) term reproducibility of aortic stiffness was high. This measure appears to be a more powerful predictor of systolic blood pressure than is left ventricular mass. Aortic stiffness is a highly reproducible Doppler variable that may explain in part the contribution of the aortic wall elastic properties to the level of systolic blood pressure in preadolescent children at rest.

Measurement of left ventricular wall mass in pediatric populations.

This paper reviews the techniques for obtaining technically adequate echocardiograms for epidemiologic studies. When these techniques were applied to studies of pediatric populations the following objectives were achieved: reproducible echocardiograms, observations about the relationship of echocardiographic variables to cardiovascular variables, and information about the relationship of echocardiographic and electrocardiographic variables to each other and to blood pressure. We documented the precision of M-mode left ventricular chambers and dimensions, interobserver and intraobserver variability, and the day-to-day variability of these measures. Left ventricular wall mass was significantly larger than expected for age and body size in children with persistently elevated blood pressure. The relationship between the echocardiographic and electrocardiographic variables was poor. Moreover, the electrocardiographic measures of ventricular hypertrophy did not correlate with blood pressure.

Left ventricular hypertrophy in children with blood pressures in the upper quintile of the distribution. The Muscatine Study.

From echocardiography measurements of left heart dimensions, cardiac output was estimated in 264 school children whose systolic blood pressure persisted in the lowest, middle, or highest quintile of the distribution for their age and sex. Children with blood pressure in the upper quintile were taller, heavier, and more obese. Echocardiographically determined left ventricular wall mass, corrected for body size, was significantly greater in these children than those in the lower quintiles of blood pressure. These children displayed a continuum of cardiac output. Those with the highest cardiac output in the upper blood pressure quintile had the greatest left ventricular wall mass.

The cardiovascular responses to exercise in children across the blood pressure distribution. The Muscatine study.

Children with elevated systolic blood pressure have a wide range of cardiac output. To better understand the mechanisms regulating resting and exercise blood pressure, we investigated the cardiovascular responses to both dynamic and isometric exercise in 264 children who were selected from the low, middle, and upper quintile of the distribution of blood pressure of an entire school population. We sought to identify patterns of response to exercise that correlated with both resting cardiac output and resting blood pressure. During isometric exercise, systolic pressure adjusted for age and body size increased in all groups. The low group's mean pressure remained significantly lower than the high group's pressure throughout the entire exercise period. Body size adjusted group systolic and diastolic blood pressure level differences exist during dynamic exercise. The product of the systolic blood pressure times the heart rate, in the high blood pressure group, was significantly higher throughout dynamic exercise than in the other two groups. Elevated resting resistance is correlated with elevated resistance during isometric exercise and elevated diastolic blood pressure during dynamic exercise. Cardiac index had a significant negative correlation to age (r = -0.58) at all levels of blood pressure. This observation, in children, lends some support to the concept of the evolution from a hyperkinetic circulation in early childhood to a circulation with lower cardiac output and more elevated systemic vascular resistance at an older age.

Left ventricular mass and exercise responses predict future blood pressure. The Muscatine Study.

Increased blood pressure and left ventricular mass are associated with increased morbidity and mortality in adults with coronary heart disease. To define the predictors of subsequent childhood blood pressure and left ventricular mass, serial echocardiograms and blood pressure responses during exercise were studied in 274 children aged 6 to 15 years, whose systolic blood pressures were in the high, middle, or low range. Persistence of rank order for left ventricular mass and blood pressure, at rest and during exercise, was maintained over a mean follow-up period of 3.4 years, with correlations ranging from 0.33 to 0.44. Subsequent systolic blood pressure was best predicted from initial resting and maximal exercise systolic blood pressures and left ventricular mass. Subsequent left ventricular mass was best predicted from initial left ventricular mass and maximal exercise diastolic blood pressure, but resting systolic blood pressure did not add to this latter prediction. Since left ventricular mass relates best to exercise blood pressure and not to resting blood pressure, left ventricular mass may provide an integrated view of the effects of blood pressure both at rest and during stress. We speculate that increased left ventricular mass in childhood may be an important predictor of subsequent hypertension and its consequences.

Altered blood pressure reactivity in adolescent diabetics.

OBJECTIVE: We examined hemodynamic responses to a variety of physiologic stimuli in 14 normotensive adolescents with type I diabetes and 45 healthy controls to determine whether structural vascular changes contribute to a reduced vasodilator capacity in adolescent diabetics. We asked, in adolescents with type I diabetes: (1) Are structural vascular changes present? (2) Are changes in the systemic vascular bed reflected in abnormal blood pressure regulation? and (3) Is abnormal vascular reactivity associated with either diabetes duration or control? METHODOLOGY: Diabetic subjects were outpatients treated at the Medical College of Virginia, ages 13 to 18 years. Diabetes duration averaged 7.5 years. Each subject underwent an echocardiogram, dynamic and isometric exercise testing, and forearm plethysmography. RESULTS: Compared to controls, diabetic subjects had (1) higher systolic and diastolic blood pressure during dynamic and handgrip exercise, (2) decreased forearm vasodilator capacity in response to ischemia, and (3) an increased aortic peak velocity. Group diastolic filling abnormalities were found, but these did not persist after adjustment for heart rate. The following variables were related to both diabetes duration and control (average glycosylated hemoglobin): (1) diastolic blood pressure during dynamic exercise, (2) resting forearm vascular resistance, and (3) forearm vascular reactivity. In addition, diabetes duration correlated with isometric exercise diastolic blood pressure, and diabetes control correlated with resting diastolic blood pressure. CONCLUSION: In young diabetics we found that (1) abnormalities of the resistance vessels of the forearm may be present, (2) the degree of vascular change is related to diabetes duration and control, and (3) aortic distensibility may be impaired.

Echocardiographic abnormalities in acute rheumatic fever.

The echocardiographic velocity of circumferential fiber shortening and left atrial dimension were measured serially in two groups of children with acute rheumatic fever: Group I, six patients with valve regurgitation without congestive heart failure, and Group II, seven patients with regurgitation and congestive heart failure. In Group I, the initial velocity of circumferential fiber shortening was increased to 1.90 +/- 0.31 circumferences per second (circ/sec) (mean +/- standard deviation). In group II, it was decreased (1.18+/-0.25). In group I velocity of circumferential fiber shortening subsequently decreased but remained above the normal level; in Group II it increased to exceed the expected normal value. Concurrent changes in left atrial dimension were observed in both groups. The initial left atrial dimension of Group I (2.2 +/- 0.75 cm/m2) was slightly increased and returned to normal (1.70 +/- 0.32) on follow-up study. The left atrial dimension of Group II was greatly increased initially (2.70 +/- 0.81 cm/m2) and remained large (2.50 +/- 0.67). Three patients in Group II experienced rebound during corticosteroid withdrawal. In each the velocity of circumferential fiber shortening decreased, suggesting impaired cardiac contractility. The echocardiogram thus facilitates serial assessment of the severity of carditis in acute rheumatic fever.

Bivariate genetic analysis of left ventricular mass and weight in pubertal twins (the Medical College of Virginia twin study).

Left ventricular (LV) hypertrophy in adults is a recognized risk factor for the subsequent development of cardiovascular morbidity. To make informed preventive health decisions it is important to understand the interaction of genes and environment on LV mass. In both children and adults, weight is a strong correlate of LV mass. We hypothesized that genetic influences common to both of these variables could in part explain the strong relation between weight and LV mass in children. In a population of 341 twins (11 years old), these questions were asked: (1) How much of the total variance of LV mass is under genetic control? (2) After accounting for weight and weight adjusted for sexual maturity, how much of the remaining variance is genetic? (3) Of the total genetic variance, what proportion is specific for LV mass and what proportion is common to both weight and LV mass? (4) How much of the correlation between these 2 variables is explained by genes common to both LV mass and weight? Univariate genetic analyses documented that genes operating at different magnitudes in boys (63%) and girls (71%) explain a significant proportion of the variance of LV mass. After removing the effect of weight and sexual maturity by regression methods, genes remain an important influence. Bivariate genetic analyses confirmed that genes common to LV mass and weight significantly influence the covariation of these variables and that greater than 90% of the correlation of LV mass and weight is due to common genes.

Univariate genetic analysis of blood pressure in children (the Medical College of Virginia Twin Study).

The relative contributions of genetic, individual environmental and shared environmental effects on resting blood pressure (BP) and heart rate (HR) were studied in prepubescent twins. The study population consisted of 251 caucasian 11-year-old twin pairs. Correlations were higher for all variables in monozygotic twins compared to dizygotic twins; this is consistent with a significant genetic effect. Path analysis revealed that the model of additive genetic and individual environmental effects fit systolic BP, diastolic BP and HR. In boys and girls, sex-specific genetic effects controlled systolic BP. The magnitudes of the sex-specific genetic effects on systolic BP were similar in both boys and girls and accounted for 66% of the variance. In boys, for diastolic BP, genetic effects accounted for 64% of the variance while in girls they accounted for 51%. These results provide no evidence for different genetic effects on HR in boys or girls. No shared environmental effects were detected. The large sample size and design, using different-sex dizygotic twins of the same age, establish that genes play an important role in the influence of resting BP and HR and that there are sex-specific genetic contributions in early pubertal children.

Common fragile site expression in lymphocytes from an individual mosaic for trisomy 8.

During the course of a survey of fragile site expression in lymphocytes from twins one member of a dizygotic pair was found to be mosaic for trisomy 8. One hundred fifty metaphases from this individual were analyzed (100 treated with aphidicolin and 50 untreated); 43% were 46,XY and 57% 46,XY,+8. No differences were observed between the treated and control cultures in either the proportions of normal and trisomic metaphases or the overall or specific fragile site expression in the normal and trisomic cells.

Septation of the univentricular heart. Transatrial approach.

The technique of septation of the univentricular heart via a transatrial approach is described in detail. Clinical details of four patients having Type A-III univentricular heart document the feasibility of working through the right-sided atrioventricular valve to place a cloth prosthesis into the ventricle to divide it into approximately equal chambers. Improved hemodynamics were observed in the postoperative period, which probably were related to retaining the integrity of the ventricular wall. This approach seems best suited to the ventricular chamber estimated to be large by echocardiography without severe pulmonary outflow tract obstruction. Techniques for enlargement of the pulmonary outflow tract are also described.

Hypoplastic left heart syndrome: successful palliation with a new operation.

A new operative procedure is described for the palliation of hypoplastic left heart syndrome. The operation consists of anastomosis of a tubular prosthesis between the proximal pulmonary artery and the aortic arch. A calibrated opening in the graft is brought into continuity with the distal pulmonary artery to provide balanced pulmonary and systemic blood flow. The atrial septum is excised and the ductus arteriosus ligated. A successful case report documents that this operation satisfies criteria required to reverse heart failure in infants with hypoplastic left heart syndrome.

Blood pressure response to exercise. A marker for future hypertension?

Whether or not an exaggerated blood pressure response to exercise in childhood predicts adult-onset essential hypertension is not known. While peak systolic blood pressure during exercise can indicate future hypertension, left ventricular mass (measured echocardiographically) and resting systolic blood pressure seem to be much better predictors. However, the blood pressure response to exercise in groups of normotensive individuals, such as those with a family history of hypertension, may identify physiologic changes associated with the early hypertensive state.

Genetic influences on ambulatory blood pressure patterns. The Medical College of Virginia Twin Study.

The genetic influence of ambulatory blood pressure and heart rate was examined in 38 pairs of monozygotic twins, 17 pairs of same-sex dizygotic twins, and 11 pairs of opposite-sex dizygotic twins, all aged 15 or 17 years. The data were analyzed taking into consideration that the response was multivariate (24-h values) instead of the usual univariate response. The results demonstrated the heritability of ambulatory blood pressure and heart rate. This was true regardless of whether the estimate of heritability involved monozygotic twin pairs compared to same-sex dizygotic twin pairs only, or all dizygotic twin pairs. The time-related intraclass correlation coefficient within each twin classification indicated that the patterns of response within twin pairs correlated more for monozygotic twin pairs than within twin pairs for either set of dizygotic twin pairs. In addition, although the opposite-sex dizygotic twin pairs may have different mean levels of response, they exhibit a similarity of patterns of response akin to that seen within same-sex dizygotic twin pairs.

Childhood passive smoking, race, and coronary artery disease risk: the MCV Twin Study. Medical College of Virginia.

BACKGROUND: Children with long-term exposure to passive cigarette smoke may be at elevated risk for the development of premature coronary artery disease (CAD). OBJECTIVE: To examine how CAD risk factors, exposure to passive smoking, sex, and race are related in pubertal children and to determine if there is an identifiable childhood risk profile (i.e., does passive smoking interact with other coronary risk factors to increase the risk of developing premature CAD). DESIGN: Cohort analytic study. SETTING: The Medical College of Virginia (MCV) Twin Study, Richmond, Va. SUBJECTS: Randomly selected twins from 408 11-year-old twin pairs recruited from nearby schools. METHODS: Data collection occurred at 18-month intervals on family and health histories, smoking and alcohol consumption, blood pressure, anthropometrics, and biochemical assays. Data from cohorts of 11-year-olds studied through age 15 years were analyzed by repeated-measures analyses of variance using a mixed modeling approach. Models for high-density lipoprotein cholesterol (HDL-C) included race, sex, passive smoking status, weight, systolic and diastolic blood pressures, and all interactions. RESULTS: Passive smoke exposure was greater in white families than in black families. Levels of HDL-C and HDL2-C (HDL subfraction 2 cholesterol) were lower in white children than in black children (visit 1: HDL-C, mean +/- SD, 1.21+/-0.26 vs. 1.31+/-0.26 mmol/L [47.0+/-10.1 vs. 50.6+/-10.1 mg/dL], P< or =.01; HDL2, mean +/- SD, 0.31+/-0.18 vs. 0.41+/-0.19 mmol/L [12.3+/-7.0 vs. 15.9+/-7.4 mg/dL], P< or =.001). Children with a family history of cardiovascular disease had differences in HDL-C levels related to race that were worsened by exposure to cigarette smoke. In these children, HDL-C level was lower in those exposed to passive smoking (visit 1: 1.18+/-0.23 vs. 1.25+/-0.23 mmol/L [45.6+/-9 vs. 48.2+/-9 mg/dL] and visit 4: 0.98+/-0.10 vs. 1.19+/-0.18 mmol/L [37.8+/-4 vs. 46.0+/-7 mg/dL]; P<.001), with white children having lower HDL-C levels than black children (visit 1: 1.12+/-0.21 vs. 1.36+/-0.23 mmol/L [43.2+/-8 vs. 52.7+/-9 mg/ dL] and visit 4: 0.97+/-0.31 vs. 1.01+/-0.31 mmol/L [37.6+/-12 vs. 39.0+/-12 mg/dL]; P = .004). In white families, as weight increased, boys exposed to passive smoking showed the greatest decrease in HDL-C level (P<.01 for weight by sex and passive smoking interaction). Risk factors for CAD, such as blood pressure, interacted with HDL-C and these relationships varied by race and sex. CONCLUSIONS: Pubertal children with long-term passive cigarette smoke exposure have lower HDL-C levels. Racial differences in HDL-C levels are related to passive smoke exposure. In children with a family history of cardiovascular disease, interactions exist between passive smoking, HDL-C level, and blood pressure that differ by sex and race. White males exposed to passive smoking who have a family history of cardiovascular disease and higher weights and diastolic blood pressures may be at special risk for premature CAD.

Cardiovascular reactivity in isometric exercise and mental arithmetic in children.

In children, we studied noninvasively the cardiovascular stress responses, including changes over time of systolic blood pressure (SBP), heart rate (HR), and stroke volume (SV) in isometric handgrip (IHG) and mental arithmetic. Specifically, we asked whether 1) these cardiovascular stress responses were different for the two stress conditions in children, 2) these responses differed in boys and girls, and 3) the anthropometric variables related to these stress responses. SV differed significantly between IHG and mental arithmetic over the entire stress period. This may reflect higher systemic vascular resistance during IHG. HR in boys was lower than in girls over the entire period of stress in both stress tests. This observation cannot be attributed to differences in conditioning, because this should not influence responses to isometric or mental stress. A larger left ventricular mass was related to higher SVs. A marked relationship was found between HR and SBP and between HR and SV. No relationship was found between SBP and SV.

The management of the family at high risk for coronary heart disease.

The family at risk has at least one member who has (1) hyperlipidemia; (2) low HDL2-cholesterol; (3) essential hypertension; (4) a family history of premature CHD; or (5) actively smokes. The predictive value of CHD risk factors in adults is well documented and quantified. Familial aggregation, genetic studies, and tracking of blood pressure provide evidence that children born to families with a high prevalence of hypertension or who as adolescents track in the upper part of the blood pressure distribution are themselves at risk for hypertension. Similarly, familial aggregation, tracking, and autopsy studies provide evidence for the relationship of serum lipids to the subsequent development of coronary atherosclerosis. Smoking by parents adversely affects the hearts and lungs of children. In addition, the child with a parent who smokes is more likely to become an active smoker. Preventive strategies are now available to the pediatrician to reduce the risk of premature CHD.

Genetic factors that predispose the child to develop hypertension.

Familial aggregation, population, and twin studies all point to important genetic influences on the level of blood pressure in childhood and adolescence. Whether a major gene effect operates during childhood has not been determined. The investigation of polygenic paths leads to the study of variables such as ion transport and reactivity paths that appear to be under strong genetic influences. The evidence suggests that abnormalities in these paths might be linked to a prehypertensive state. Univariate genetic analyses of systolic and diastolic blood pressure show that a significant portion of the variability of these variables is under genetic control. Moreover, during early adolescence, boys differ from girls in the regulation of their resting blood pressure. Multivariate genetic analyses show that in these young adolescents, genetic paths shared with body mass index appear to influence systolic but not diastolic blood pressure. The genetic relationship between systolic and diastolic blood pressure appears largely to be independent of body mass index. Genetic studies can partition the genetic and environmental influences on blood pressure and identify shared paths with variables previously believed to be linked epidemiologically. This information may have the capacity to be the framework for public health guidelines developed to lower the incidence of adult hypertension.

Balloon dilation of discrete subaortic stenosis associated with other cardiac defects in children.

Balloon dilation (BD) is reported as an effective treatment for isolated discrete thin membranous subaortic stenosis (SAS). We asked if BD of SAS with associated cardiac defects: 1) is effective; 2) creates or worsens mitral insufficiency in the presence of valvar membrane attachment; and 3) creates or worsens aortic insufficiency. BD was performed on 13 patients (9 females, 4 males with a mean age of 5.8 years and an age range of 1-14 years old) for SAS with the following associated defects: VSD (6 patients), coarctation (4 patients), complete atrioventricular canal (1 patient), tetralogy of Fallot (1 patient), and abnormal mitral valve (4 patient). Prior intracardiac surgical procedures (3 for SAS resection) had been performed in 46% of the study group. Peak gradient was reduced from 53 +/- 40 mmHg to 31 +/- 25 mmHg (p < 0.01). The resulting gradient was related to the predilation gradient (r = 0.71; p =.006). Thin membranes (< 3 mm) were associated with lower initial gradient (p < 0.02), lower resulting gradient (p < 0.001) and a greater percent gradient reduction (76% versus 36%; p < 0.01). Aortic insufficiency, which was present predilation in 77%, did not change and was not created in any patient. Mitral valve membrane attachment was present in 69% and associated with a lower resulting gradient (p < 0.006). Mitral insufficiency was not created in 10 patients, was unchanged in 2 and was improved in 1 patient. Surgical procedures were ultimately required in 8 patients during follow-up. BD of SAS associated with other cardiac defects achieves the following: 1) reduces SAS gradient in selected patients without creating or worsening aortic insufficiency; 2) does not create or worsen mitral insufficiency when mitral valve membrane attachment is present; 3) improves preoperative hemodynamics; and 4) is unlikely to be effective in post-surgical recurrence.