Person:

Newburger, Jane

Background: We sought to characterize growth between birth and age 3 years in infants with hypoplastic left heart syndrome who underwent the Norwood procedure. Methods and Results: We performed a secondary analysis using the Single Ventricle Reconstruction Trial database after excluding patients <37 weeks gestation (N=498). We determined length‐for‐age z score (LAZ) and weight‐for‐age z score (WAZ) at birth and age 3 years and change in WAZ over 4 clinically relevant time periods. We identified correlates of change in WAZ and LAZ using multivariable linear regression with bootstrapping. Mean WAZ and LAZ were below average relative to the general population at birth (P<0.001, P=0.05, respectively) and age 3 years (P<0.001 each). The largest decrease in WAZ occurred between birth and Norwood discharge; the greatest gain occurred between stage II and 14 months. At age 3 years, WAZ and LAZ were <−2 in 6% and 18%, respectively. Factors associated with change in WAZ differed among time periods. Shunt type was associated with change in WAZ only in the Norwood discharge to stage II period; subjects with a Blalock‐Taussig shunt had a greater decline in WAZ than those with a right ventricle‐pulmonary artery shunt (P=0.002). Conclusions: WAZ changed over time and the predictors of change in WAZ varied among time periods. By age 3 years, subjects remained small and three times as many children were short as were underweight (>2 SD below normal). Failure to find consistent risk factors supports the strategy of tailoring nutritional therapies to patient‐ and stage‐specific targets. Clinical Trial Registration URL: http://clinicaltrials.gov/. Unique identifier: NCT00115934.

Background: Somatic growth in childhood is accompanied by substantial remodeling of the aorta. Obesity is associated with increased aortic stiffness and flow and may interfere with aortic remodeling during growth. Wide pulse pressure (PP) indicates mismatch between aortic impedance and pulsatile flow and increases risk for future systolic hypertension and cardiovascular disease (CVD). We hypothesized that the rise of pediatric obesity would be associated with a temporal trend to higher PP. Methods and Results: We analyzed demographic, anthropometric, and blood pressure (BP) data for 8‐ to 17‐year‐old children (N=16 457) from the cross‐sectional National Health and Nutrition Examination Surveys (NHANES) for 1976 through 2008. Multivariable adjusted survey regression was used to examine temporal trends in PP and mean arterial pressure (MAP) and the relation to obesity. Across this period, unadjusted PP was higher (0.29 mm Hg/y, 95% CI 0.26 to 0.33 mm Hg/y; P<0.0001), while MAP was lower (−0.24 mm Hg/y, 95% CI −0.27 to −0.20 mm Hg/y; P<0.0001) across examinations. Adjusting for body mass index partially attenuated the temporal trend for PP by 32% (P<0.0001). Obesity amplified the relation between taller height and higher PP (from 0.23 [95% CI 0.19 to 0.28] to 0.27 [95% CI 0.21 to 0.34] mm Hg/cm height in boys and from 0.08 [95% CI 0.04 to 0.13] to 0.22 [95% CI 0.13 to 0.31] mm Hg/cm height in girls; P<0.01 for both). Conclusions: PP has increased during the rise of pediatric obesity. Higher PP may indicate mismatch between aortic diameter, wall stiffness, and flow in obese children during a period of rapid somatic growth when the aorta is already under considerable remodeling stress.

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Absence of definitive diagnostic markers limits the accuracy of clinical evaluations of suspected KD with significant increases in morbidity. In turn, incomplete understanding of its molecular pathogenesis hinders the identification of rational targets needed to improve therapy. We used high-accuracy mass spectrometry proteomics to analyse over 2000 unique proteins in clinical urine specimens of patients with KD. We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A. Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients. Meprin A and filamin C exhibited superior diagnostic performance as compared to currently used markers of disease in a blinded case-control study of 107 patients with suspected KD, with receiver operating characteristic areas under the curve of 0.98 (95% confidence intervals [CI] of 0.97–1 and 0.95–1, respectively). Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD. In all, urine proteome profiles revealed novel candidate molecular markers of KD, including filamin C and meprin A that exhibit excellent diagnostic performance. These disease markers may improve the diagnostic accuracy of clinical evaluations of children with suspected KD, lead to the identification of novel therapeutic targets, and allow the development of a biological classification of Kawasaki disease.

Background: Socioeconomic status (SES) is known to influence children’s health-related quality of life. Many SES indicators assess distinct dimensions of a family’s position rather than measuring the same underlying construct. Many researchers, however, see SES indicators as interchangeable. The primary aim of this study was to determine which measure of SES had the strongest impact on health-related quality of life. Methods: This is a secondary analysis of the Pediatric Cardiac Quality of Life Inventory Validation Study. The SES variables were family income, Hollingshead Index (occupational prestige), and highest parent educational attainment level. Health-related quality of life was measured using the Pediatric Cardiac Quality of Life Inventory. Correlations tested the relationship among the three SES indicators. Regression-based modeling was used to calculate the strength of the association between SES measures and the Pediatric Cardiac Quality of Life Inventory. Results: The correlations among the SES measures were moderately high, with the correlation between the Hollingshead Index and parental education being r = 0.62 (95% CI = 0.56-0.65). There were equally high correlations between family income and the Hollingshead (r = 0.61, 95% CI = 0.57-0.65) and a slightly lower correlation between family income and parental education (r = 0.55, 95% CI = 0.52-0.59). Family income had the highest explanatory value compared to the Hollingshead Index or parental educational attainment, while controlling for sex, race, current cardiac status, and original diagnosis, accounting for 4-5% of the variation in patient and parent Pediatric Cardiac Quality of Life Inventory Total score, respectively, compared to the other SES measures. Conclusion: Family income as an SES measure demonstrated the greatest fidelity with respect to health-related quality of life as measured by the Pediatric Cardiac Quality of Life Inventory across respondent groups and explained more of the variation compared to the Hollingshead Index or highest parental educational attainment.

Background: Few studies have described the neuropsychological outcomes and frequency of structural brain or genetic abnormalities in adolescents with single ventricle who underwent the Fontan procedure. Methods and Results: In a cross‐sectional, single‐center study, we enrolled 156 subjects with single ventricle, mean age 14.5±2.9 years, who had undergone the Fontan procedure. Scores in the entire cohort on a standard battery of neuropsychological tests were compared with those of normative populations or to those of a group of 111 locally recruited healthy adolescents. They also underwent brain magnetic resonance imaging and were evaluated by a clinical geneticist. Genetic abnormalities were definite in 16 subjects (10%) and possible in 49 subjects (31%). Mean Full‐Scale IQ was 91.6±16.8, mean Reading Composite score was 91.9±17.2, and mean Mathematics Composite score was 92.0±22.9, each significantly lower than the population means of 100±15. Mean scores on other neuropsychological tests were similarly lower than population norms. In multivariable models, risk factors for worse neuropsychological outcomes were longer total support and circulatory arrest duration at first operation, presence of a genetic abnormality, more operations and operative complications, more catheterization complications, and seizure history. The frequency of any abnormality on magnetic resonance imaging was 11 times higher among Fontan adolescents than referents (66% versus 6%); 19 (13%) patients had evidence of a stroke, previously undiagnosed in 7 patients (40%). Conclusions: The neuropsychological deficits and high frequencies of structural brain abnormalities in adolescents who underwent the Fontan procedure highlight the need for research on interventions to improve the long‐term outcomes in this high‐risk group.

The neonatal brain is extremely vulnerable to injury during periods of hypoxia and/or ischemia. Risk of brain injury is increased during neonatal cardiac surgery, where pre-existing hemodynamic instability and metabolic abnormalities are combined with long periods of low cerebral blood flow and/or circulatory arrest. Our understanding of events associated with cerebral hypoxia-ischemia during cardiopulmonary bypass (CPB) remains limited, largely due to inadequate tools to quantify cerebral oxygen delivery and consumption non-invasively and in real-time. This pilot study aims to evaluate cerebral blood flow (CBF) and oxygen metabolism (CMRO2) intraoperatively in neonates by combining two novel non-invasive optical techniques: frequency-domain near-infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS). CBF and CMRO2 were quantified before, during and after deep hypothermic cardiopulmonary bypass (CPB) in nine neonates. Our results show significantly decreased CBF and CMRO2 during hypothermic CPB. More interestingly, a change of coupling between both variables is observed during deep hypothermic CPB in all subjects. Our results are consistent with previous studies using invasive techniques, supporting the concept of FD-NIRS/DCS as a promising technology to monitor cerebral physiology in neonates providing the potential for individual optimization of surgical management.

Background: Surgical complexity and related morbidities may affect long‐term patient quality of life (QOL). Aristotle Basic Complexity (ABC) score and Risk Adjustment in Congenital Heart Surgery (RACHS‐1) category stratify the complexity of pediatric cardiac operations. The purpose of this study was to examine the relationship between surgical complexity and QOL and to investigate other demographic and clinical variables that might explain variation in QOL in pediatric cardiac surgical survivors. Methods and Results: Pediatric Cardiac Quality of Life (PCQLI) study participants who had undergone cardiac surgery were included. The PCQLI database provided sample characteristics and QOL scores. Surgical complexity was defined by the highest ABC raw score or RACHS‐1 category. Relationships among surgical complexity and demographic, clinical, and QOL variables were assessed using ordinary least squares regression. A total of 1416 patient–parent pairs were included. Although higher ABC scores and RACHS‐1 categories were associated with lower QOL scores (P<0.005), correlation with QOL scores was poor to fair (r=−0.10 to −0.29) for all groups. Ordinary least squares regression showed weak association with R 2=0.06 to R 2=0.28. After accounting for single‐ventricle anatomy, number of doctor visits, and time since last hospitalization, surgical complexity scores added no additional explanation to the variance in QOL scores. Conclusions: ABC scores and RACHS‐1 categories are useful tools for morbidity and mortality predictions prior to cardiac surgery and quality of care initiatives but are minimally helpful in predicting a child's or adolescent's long‐term QOL scores. Further studies are warranted to determine other predictors of QOL variation.

Background: Kawasaki disease (KD) is an acute self-limited vasculitis and the leading cause of acquired heart disease in children in developed countries. No etiologic agent(s) has been identified, and the processes that mediate formation of coronary artery aneurysms and abatement of fever following treatment with intravenous immunoglobulin (IVIG) remain poorly understood. Results: In an initial survey, we used DNA microarrays to examine patterns of gene expression in peripheral whole blood from 20 children with KD; each was sampled during the acute, subacute, and convalescent phases of the illness. Acute KD was characterized by increased relative abundance of gene transcripts associated with innate immune and proinflammatory responses and decreased abundance of transcripts associated with natural killer cells and (CD8^+) lymphocytes. There was significant temporal variation in transcript levels during the acute disease phase and stabilization thereafter. We confirmed these temporal patterns in a second cohort of 64 patients, and identified additional inter-individual differences in transcript abundance. Notably, higher levels of transcripts of the gene for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) were associated with an increased percentage of unsegmented neutrophils, fewer days of illness, higher levels of C-reactive protein, and subsequent non-response to IVIG; this last association was confirmed by quantitative reverse transcription PCR in a third cohort of 33 patients, and was independent of day of illness. Conclusion: Acute KD is characterized by dynamic and variable gene-expression programs that highlight the importance of neutrophil activation state and apoptosis in KD pathogenesis. Our findings also support the feasibility of extracting biomarkers associated with clinical prognosis from gene-expression profiles of individuals with systemic inflammatory illnesses.

Patients with congenital heart disease (CHD) are at risk for neurocognitive impairments. Little is known about the impact of CHD on the organization of large-scale brain networks. We applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 49 adolescents with dextro-transposition of the great arteries (d-TGA) repaired with the arterial switch operation in early infancy and 29 healthy referent adolescents. We examined whether differences in neurocognitive functioning were related to white matter network topology. We developed mediation models revealing the respective contributions of peri-operative variables and network topology on cognitive outcome. Adolescents with d-TGA had reduced global efficiency at a trend level (p = 0.061), increased modularity (p = 0.012), and increased small-worldness (p = 0.026) as compared to controls. Moreover, these network properties mediated neurocognitive differences between the d-TGA and referent adolescents across every domain assessed. Finally, structural network topology mediated the neuroprotective effect of longer duration of core cooling during reparative neonatal cardiac surgery, as well as the detrimental effects of prolonged hospitalization. Taken together, worse neurocognitive function in adolescents with d-TGA is mediated by global differences in white matter network topology, suggesting that disruption of this configuration of large-scale networks drives neurocognitive dysfunction. These data provide new insights into the interplay between perioperative factors, brain organization, and cognition in patients with complex CHD.

Background: Multicenter studies on idiopathic or viral pericarditis and pericardial effusion (PPE) have not been reported in children. Colchicine use for PPE in adults is supported. We explored epidemiology and management for inpatient hospitalizations for PPE in US children and risk factors for readmission. Methods and Results: We analyzed patients in the Pediatric Health Information System database for (1) a code for PPE; (2) absence of codes for underlying systemic disease (eg, neoplastic, cardiac, rheumatologic, renal); (3) age ≥30 days and <21 years; and (4) discharge between January 1, 2007, and December 31, 2012, from 38 hospitals contributing complete data for each year of the study period. Among 11 364 hospitalizations with PPE codes during the study period, 543 (4.8%) met entry criteria for idiopathic or viral PPE. Significantly more boys were noted, especially among adolescents. No temporal trends were noted. Median age was 14.5 years (interquartile range 7.3 to 16.6 years); 78 patients (14.4%) underwent pericardiocentesis, 13 (2.4%) underwent pericardiotomy, and 11 (2.0%) underwent pericardiectomy; 157 (28.9%) had an intensive care unit stay, including 2.0% with tamponade. Median hospitalization was 3 days (interquartile range 2 to 4 days). Medications used at initial admission were nonsteroidal anti‐inflammatory drugs (71.3%), corticosteroids (22.7%), aspirin (7.0%), and colchicine (3.9%). Readmissions within 1 year of initial admission occurred in 46 of 447 patients (10.3%), mostly in the first 3 months. No independent predictors of readmission were noted, but our statistical power was limited. Practice variation was noted in medical management and pericardiocentesis. Conclusions: Our report provides the first large multicenter description of idiopathic or viral PPE in children. Idiopathic or viral PPE is most common in male adolescents and is treated infrequently with colchicine.