Association of Isolated Congenital Heart Disease with Fetal Brain Maturation.

BACKGROUND AND PURPOSE: Brain MRI of newborns with congenital heart disease show signs of immaturity relative to healthy controls. Our aim was to determine whether the semiquantitative fetal total maturation score can detect abnormalities in brain maturation in fetuses with congenital heart disease in the second and third trimesters. MATERIALS AND METHODS: We analyzed data from a prospective study of fetuses with and without congenital heart disease who underwent fetal MR imaging at 25-35 weeks' gestation. Two independent neuroradiologists blinded to the clinical data reviewed and scored all images using the fetal total maturation score. Interrater reliability was evaluated by the intraclass correlation coefficient using the individual reader scores, which were also used to calculate an average score for each subject. Comparisons of the average and individual reader scores between affected and control fetuses and relationships with clinical variables were evaluated using multivariable linear regression. RESULTS: Data from 69 subjects (48 cardiac, 21 controls) were included. High concordance was observed between readers with an intraclass correlation coefficient of 0.98 (95% CI, 0.97-0.99). The affected group had significantly lower fetal total maturation scores than the control group (ß-estimate, -0.9 [95% CI, -1.5 to -0.4], P = .002), adjusting for gestational age and sex. Averaged fetal total maturation, germinal matrix, myelination, and superior temporal sulcus scores were significantly delayed in fetuses with congenital heart disease versus controls (P < .05 for each). The fetal total maturation score was not significantly associated with any cardiac, anatomic, or physiologic variables. CONCLUSIONS: The fetal total maturation score is sensitive to differences in brain maturation between fetuses with isolated congenital heart disease and healthy controls.

Delayed cortical development in fetuses with complex congenital heart disease.

Neurologic impairment is a major complication of complex congenital heart disease (CHD). A growing body of evidence suggests that neurologic dysfunction may be present in a significant proportion of this high-risk population in the early newborn period prior to surgical interventions. We recently provided the first evidence that brain growth impairment in fetuses with complex CHD has its origins in utero. Here, we extend these observations by characterizing global and regional brain development in fetuses with hypoplastic left heart syndrome (HLHS), one of the most severe forms of CHD. Using advanced magnetic resonance imaging techniques, we compared in vivo brain growth in 18 fetuses with HLHS and 30 control fetuses from 25.4-37.0 weeks of gestation. Our findings demonstrate a progressive third trimester fall-off in cortical gray and white matter volumes (P < 0.001), and subcortical gray matter (P < 0.05) in fetuses with HLHS. Significant delays in cortical gyrification were also evident in HLHS fetuses (P < 0.001). In the HLHS fetus, local cortical folding delays were detected as early as 25 weeks in the frontal, parietal, calcarine, temporal, and collateral regions and appear to precede volumetric brain growth disturbances, which may be an early marker of elevated risk for third trimester brain growth failure.

The Pediatric Heart Network: a primer for the conduct of multicenter studies in children with congenital and acquired heart disease.

Most contemporary diagnostic and treatment strategies for pediatric patients with cardiovascular disease are not supported by evidence from clinical trials but instead are based on expert opinion, single-institution observational studies, or extrapolated from adult cardiovascular medicine. In response to this concern, the National Heart, Lung, and Blood Institute established the Pediatric Heart Disease Clinical Research Network (PHN) in 2001. The purposes of this article are to describe the initiation, structure, and function of the PHN; to review the ongoing studies; and to address current and future challenges. To date, four randomized clinical trials and two observational studies have been launched. Design and conduct of complex, multicenter studies in children with congenital and acquired heart disease must address numerous challenges, including identification of an appropriate clinically relevant primary endpoint, lack of preliminary data on which to base sample size calculations, and recruitment of an adequate number of subjects. The infrastructure is now well developed and capable of implementing complex, multicenter protocols efficiently and recruiting subjects effectively. The PHN is uniquely positioned to contribute to providing evidence-based medicine for and improving the outcomes of pediatric patients with cardiovascular disease.

Sustained activation of neutrophils in the course of Kawasaki disease: an association with matrix metalloproteinases.

Kawasaki disease (KD) is an acute febrile syndrome of childhood, characterized by vasculitis of the medium-sized arteries. White blood cell counts and the inflammatory parameter C-reactive protein (CRP) are known to be elevated in the acute phase of the disease. In this study we investigated the course of inflammatory cell type-specific parameters in KD over a longer period of time. Plasma levels of human neutrophil elastase (HNE), matrix metalloproteinases-2 and -9 (MMP2, MMP9), and neutrophil gelatinase-associated lipocalin (NGAL), macrophage neopterin and CRP were measured. Plasma samples were collected in the acute, subacute and early convalescent stage, and three months after the onset of disease. Median CRP and neopterin normalized within two weeks. In contrast, six weeks and three months after onset of disease, levels of HNE were still elevated, with median values of 163 ng/ml and 156 ng/ml, respectively (control children median < 50 ng/ml; for all time-points P < 0.0001). Values of NGAL correlated with the levels of HNE (r = 0.39, P = 0.013). These results demonstrate a longer state of neutrophil activation in KD than was previously assumed. The potential relationship between this prolonged neutrophil activation, coronary artery lesion formation and their persistence, as well as the risk of premature atherosclerosis warrants further evaluation.

Family-based association analysis implicates IL-4 in susceptibility to Kawasaki disease.

Several compelling lines of evidence suggest an important influence of genetic variation in susceptibility to Kawasaki disease (KD), an acute vasculitis that causes coronary artery aneurysms in children. We performed a family-based genotyping study to test for association between KD and 58 genes involved in cardiovascular disease and inflammation. By analysis of a cohort of 209 KD trios using the transmission disequilibrium test, we documented the asymmetric transmission of five alleles including the interleukin-4 (IL-4) C(-589)T allele (P=0.03). Asymmetric transmission of the IL-4 C(-589)T was replicated in a second, independent cohort of 60 trios (P=0.05, combined P=0.002). Haplotypes of alleles in IL-4, colony-stimulating factor 2 (CSF2), IL-13, and transcription factor 7 (TCF7), all located in the interleukin gene cluster on 5q31, were also asymmetrically transmitted. The reported associations of KD with atopic dermatitis and allergy, elevated serum IgE levels, eosinophilia, and increased circulating numbers of monocyte/macrophages expressing the low-affinity IgE receptor (FCepsilonR2) may be related to effects of IL-4. Thus, the largest family-based genotyping study of KD patients to date suggests that genetic variation in the IL-4 gene, or regions linked to IL-4, plays an important role in KD pathogenesis and disease susceptibility.

General health status of children with D-transposition of the great arteries after the arterial switch operation.

BACKGROUND: To study the long-term impact on general health status of D-transposition of the great arteries (D-TGA) after the arterial switch operation (ASO) during infancy, we asked parents to complete the Child Health Questionnaire, Parent Form-50 when their children were 8 years old. METHODS AND RESULTS: Of 160 eligible patients, questionnaires were completed for 155 subjects (96%). Median age at surgery was 6 days (range 1 to 67 days), and median age at completion of the Child Health Questionnaire was 8.1 years (7.6 to 10.0 years). Subsequent to questionnaire completion, children underwent psychometric testing. Mean Physical Health Summary and Psychosocial Summary scores were 54.0+/-6.1 and 49.7+/-9.9, respectively, which were similar to those of normal subjects. Compared with the normative sample, parents of D-TGA patients reported more problems with attention, learning, and speech, as well as greater frequency of developmental delay (P<0.001 for each). Worse Psychosocial Summary scores were significantly associated with lower full-scale IQ (P=0.001) and lower achievement in reading (P=0.005) and math (P=0.007). Worse Physical Health Summary scores were associated with longer hospital stay after the ASO (P=0.02). General health status scores were not significantly related to presence of ventricular septal defect, age at surgery, perfusion variables during the ASO, sex, or history of cardiac reoperation. CONCLUSIONS: At age 8 years, children with D-TGA after ASO have an overall physical and psychosocial health status similar to that of the general population. Lower IQ and academic achievement are associated with worse psychosocial health status, whereas longer hospital course after initial surgery is associated with worse physical health status.

Increased frequency of alleles associated with elevated tumor necrosis factor-alpha levels in children with Kawasaki disease.

Genetic polymorphisms influence the magnitude of the cytokine response after an inflammatory stimulus. To determine whether such polymorphisms might play a role in Kawasaki disease (KD), we analyzed white and Japanese children with KD and control populations for two polymorphic loci in which the A allele is associated with high tumor necrosis factor-alpha secretion. The lymphotoxin-alpha+250 A/A genotype was overrepresented among white children with KD compared with controls (0.59 versus 0.36; p = 0.013). The tumor necrosis factor-alpha-308 A/G genotype was overrepresented among whites with KD who had coronary artery abnormalities compared with those with normal echocardiograms (0.36 versus 0.09; p = 0.044). No significant difference was seen at either locus between Japanese children with KD and Japanese controls. The increased frequency of the high secretor alleles in white children with KD suggests that these loci may be related to susceptibility to KD and to outcome after disease.

Developmental and neurologic effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants.

OBJECTIVES: In a randomized single-center trial, we compared developmental and neurologic outcomes at 1 and 2 to 4 years of age in children who underwent reparative cardiac operations at less than 9 months of age after use of the alpha-stat versus pH-stat strategy during deep hypothermic cardiopulmonary bypass. METHODS: Among 168 children eligible for follow-up, 1-year developmental evaluations were carried out on 111, neurologic evaluations on 110, and electroencephalographic evaluations on 102. Parents of 122 children completed questionnaires on behavior and development when children were 2 to 4 years of age. RESULTS: The Psychomotor Development Index scores of the alpha-stat and pH-stat groups did not differ significantly (P =.97). For Mental Development Index scores, the treatment group effect differed according to diagnosis (P =.007). In the D -transposition of the great arteries (n = 59) and tetralogy of Fallot (n = 36) subgroups, the pH-stat group had slightly higher Mental Development Index scores than the alpha-stat group, although these differences were not statistically significant. In the ventricular septal defect subgroup (n = 16), the alpha-stat group had significantly higher scores. Psychomotor Development Index and Mental Development Index scores were significantly higher in the group with D -transposition of the great arteries than in the other 2 groups (P =.03 and P =.01, respectively). Across all diagnoses, Mental Development Index scores were significantly higher than Psychomotor Development Index scores (P <.001). Treatment group assignment was not significantly associated with abnormalities on neurologic examination (P =.70) or electroencephalographic examination (P =.77) at 1 year or with parents' ratings of children's development (P =.99) or behavior (P =.27) at age 2 to 4 years. CONCLUSIONS: Use of alpha-stat versus pH-stat acid-base management strategy during reparative infant cardiac operations with deep hypothermic cardiopulmonary bypass was not consistently related to either improved or impaired early neurodevelopmental outcomes.

Work-family issues and perceptions of stress among pediatric faculty and house staff.

OBJECTIVES: To examine work-family balance issues and predictors of stress related to work-family balance among pediatric house staff and faculty. METHODS: Data were obtained through an anonymous mail survey. Univariate analyses assessed associations between work-family issues (work-related factors that affect work-family balance, perceived support, work-family--related stress, and proposed solutions) and the following variables: gender, parental status, working status of spouse, and academic rank. Multiple linear regression examined independent predictors of perceived stress. RESULTS: Fifty percent of the 327 respondents cared for dependent children, and 20% expected to care for an elderly person in the next 5 years. Only 5% strongly agreed that their division or department was concerned about supporting members' work-family balance, and 4% strongly agreed that existing programs supported their needs. Eighty-three percent reported feeling stressed as a result of efforts to balance work and family. Independent predictors of stress included perceived need to choose between career and family, increasing age, dependent children, less support from colleagues and supervisors, and female gender. CONCLUSIONS: Work-family balance issues are responsible for substantial perceived stress. Academic departments should consider a commitment to supporting faculty who are struggling with these issues, including creation of work-family policies and programs, development of mentoring systems, and reexamination of existing expectations for work practices.

Long-term cardiac sequelae of Kawasaki disease.

Kawasaki disease is the leading cause of acquired heart disease in childhood. Despite treatment with intravenous gamma globulin, 2% to 4% of patients have coronary abnormalities. Those with giant aneurysms are at risk for stenosis and myocardial ischemia/infarction, and require aggressive anticoagulation with frequent follow-up, including stress testing and coronary angiography. In rare cases, patients will have coronary artery bypass grafting. Those with less severe coronary involvement need antiplatelet therapy and infrequent noninvasive testing. Patients with normal echos after the acute phase are not treated, but the future impact of the disease is not certain particularly in the setting of adult onset coronary artery disease.

Psoriatic eruption in Kawasaki disease.

We describe 10 patients who developed a psoriatic skin eruption during either the acute or convalescent phase of Kawasaki disease. The skin eruption was pustular in 3 patients, but more typical psoriasiform skin lesions were seen in the remaining 7 patients. No patient has yet developed chronic psoriasis.

Cognitive development after the Fontan operation.

BACKGROUND: Patients with a single ventricle have multiple risk factors for central nervous system injury, both before and after the Fontan procedure. METHODS AND RESULTS: A geographically selected cohort was invited to undergo standardized testing, including age-appropriate measures of intelligence quotient (IQ) and achievement tests. Historical information was obtained by chart review and patient questionnaires. Of the 222 eligible patients, 133 (59.9%) participated. Median age at testing was 11.1 years (range, 3. 7 to 41.0 years), 6.0 years (range, 1.6 to 19.6 years) after surgery. Mean full-scale IQ was 95.7+/-17.4 (P<0.006 versus normal); 10 patients (7.8%) had full-scale IQ scores <70 (P=0.001). After adjustment for socioeconomic status, lower IQ was associated with the use of circulatory arrest before the Fontan operation (P=0.002), the anatomic diagnoses of hypoplastic left heart syndrome (P<0.001) and "other complex" (P=0.05), and prior placement of a pulmonary artery band (P=0.04). Mean composite achievement score was 91.6+/-15. 4 (P<0.001 versus normal); 14 patients (10.8%) scored <70 (P<0.001). After adjustment for socioeconomic status, independent risk factors for low achievement scores included the diagnoses of hypoplastic left heart syndrome (P=0.004) and "other complex" (P=0.003) or prior use of circulatory arrest (P=0.03), as well as a reoperation with cardiopulmonary bypass within 30 days of the Fontan (P=0.01). CONCLUSIONS: Most individual patients palliated with the Fontan procedure in the 1970s and 1980s have cognitive outcome and academic function within the normal range, but the performance of the cohort is lower than that of the general population.

The impact of managed care insurance on use of lower-mortality hospitals by children undergoing cardiac surgery in California.

CONTEXT: Managed care plans aggressively seek to contain costs, but few data are available regarding their impact on access to high quality care for their members. OBJECTIVE: To assess the impact of managed care health insurance on use of lower-mortality hospitals for children undergoing heart surgery in California. DESIGN: Retrospective cohort study using state-mandated hospital discharge datasets. SETTING: Pediatric cardiovascular surgical centers in California. PATIENTS: Five thousand seventy-one children admitted for open cardiac surgical procedures during 1992-1994. RESULTS: Hospitals were divided into lower- and higher-mortality groups according to adjusted surgical mortality. Using multivariate logistic regression analysis to control for medical, socioeconomic, demographic, and distance factors, children with managed care insurance were less likely to be admitted to a lower-mortality hospital for surgery relative to children with indemnity insurance (odds ratio:.53; 95% confidence interval:.45,.63). Similar findings resulted when the analysis was stratified by race/ethnicity. In addition, length of stay, a correlate of health care costs, was no longer for children admitted to lower-mortality centers than for those at higher-mortality centers (adjusted difference:.54 days shorter at lower-mortality centers; 95% confidence interval: -1.50,. 41). CONCLUSIONS: During this study, children with managed care insurance had significantly reduced use of lower-mortality hospitals for pediatric heart surgery in California compared with children with indemnity insurance. Further study is necessary to determine the mechanisms of this apparent insurance-specific inequity.

The relationship between managed care insurance and use of lower-mortality hospitals for CABG surgery.

CONTEXT: Explicit information about the quality of coronary artery bypass graft (CABG) surgery has been available for nearly a decade in New York State; however, the extent to which managed care insurance plans direct enrollees to the lowest-mortality CABG surgery hospitals remains unknown. OBJECTIVE: To compare the proportion of patients with managed care insurance and fee-for-service (FFS) insurance who undergo CABG surgery at lower-mortality hospitals. DESIGN: A retrospective cohort study of CABG surgery discharges from 1993 to 1996, using New York Department of Health databases and multivariate analysis to estimate the use of lower-mortality hospitals by patients with different types of health insurance. SETTING: Cardiac surgical centers in New York, of which 14 were classified as lower-mortality hospitals (mean rate, 2.1%) and 17 were classified as higher-mortality hospitals (mean rate, 3.2%). PATIENTS: A total of 58,902 adults older than 17 years who were hospitalized for CABG surgery. Patients were excluded if their CABG surgery was combined with any valve procedure or left ventricular aneurysm resection or if they were younger than 65 years and enrolled in Medicare FFS or Medicare managed care. MAIN OUTCOME MEASURE: Probability of a patient receiving CABG surgery at a lower-mortality hospital. RESULTS: Compared with patients with private FFS insurance (n = 18,905), patients with private managed care insurance (n=7169) and Medicare managed care insurance (n=880) were less likely to receive CABG surgery at a lower-mortality hospital (relative risk [RR] of surgery at a lower-mortality hospital compared with patients with private FFS insurance, 0.77; 95% confidence interval [CI], 0.74-0.81; P<.001; and RR, 0.61; 95% CI, 0.54-0.70; P<.001, respectively, after controlling for multiple potential confounding factors). Patients with Medicare FFS insurance used lower-mortality hospitals at rates more similar to those with private FFS insurance (n = 31,948; RR, 0.95; 95% CI, 0.91-0.98; P=.004). CONCLUSIONS: Patients in New York State with private managed care and Medicare managed care insurance were significantly less likely to use lower-mortality hospitals for CABG surgery compared with patients with private FFS insurance.

Ticlopidine plus aspirin for coronary thrombosis in Kawasaki disease.

Selective inhibitors of the adenosine 5'-diphosphate pathway of platelet activation have been used rarely in children in the United States. We report the successful use of ticlopidine, together with aspirin, in a 7-month-old infant with Kawasaki disease complicated by a thrombus in a giant coronary aneurysm that failed to resolve with thrombolytic therapy. Kawasaki disease, coronary aneurysms, antithrombotic therapy, ticlopidine, children.

Abnormal myocardial mechanics in Kawasaki disease: rapid response to gamma-globulin.

BACKGROUND: The time course and rate of recovery of myocardial dysfunction in association with Kawasaki disease in response to intravenous gamma-globulin is unknown and may provide mechanistic clues. METHODS AND RESULTS: The acute changes in myocardial contractility in 25 patients with Kawasaki disease were evaluated by noninvasive stress-shortening and stress-velocity analysis. Echocardiograms were performed before and then daily for 4 days during which the patients received gamma-globulin 1.6 to 2 g/kg. Before treatment, contractility was abnormally low (<2 SD) in 14 patients (56%). Contractility increased significantly (2 SD increase) in 17 (68%), including 13 of 14 with depressed contractility and 4 whose initial contractility fell within normal limits. Of the 14 patients with depressed contractility, 8 (57%) normalized within 24 hours and a further 5 (35.7%) normalized within 6 months. A clinical response to treatment (fall in C-reactive protein by 50% and/or resolution of fever within 4 days) was seen in 22 patients (88%). Contractility increased in 17 of the 22 clinical responders and was normal before therapy in the other 5. The 3 patients who did not respond clinically also had no change in contractility with gamma-globulin therapy. Long-term (more than 12 months) follow-up was available in 19 patients. All patients had normal contractility at late follow-up. CONCLUSIONS: More than half the patients with Kawasaki disease have abnormal contractility at presentation. Myocardial response to gamma-globulin therapy is associated with rapid improvement in myocardial mechanics, with a high concordance between the clinical and myocardial response to therapy. The speed of recovery suggests that depressed contractility in patients with Kawasaki disease is caused by a rapidly reversible process such as circulating toxins or activated cytokines. Long-term outcome is good even in those patients with slow recovery of myocardial function.