Nancy Burnham

Apolipoprotein E Genotype Modifies the Risk of Behavior Problems After Infant Cardiac Surgery

OBJECTIVE: The goal was to evaluate polymorphisms of the APOE gene as modifiers of neurobehavioral outcomes for preschool-aged children with congenital heart defects, after cardiac surgery. METHODS: A prospective observational study with neurodevelopmental evaluation between the fourth and fifth birthdays was performed. Attention and behavioral skills were assessed through parental report. RESULTS: Parents of 380 children completed the neurobehavioral measures. Child Behavior Checklist scores for the pervasive developmental problem scale were in the at-risk or clinically significant range for 15% of the cohort, compared with 9% for the normative data (P < .00001). Attention problem scores were in the at-risk or clinically significant range for 12% of the cohort, compared with 7% for the normative data (P = .0002). The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Preschool Version, was completed for 378 children; 30% scored in the clinically significant range for inattention and 22% for impulsivity. After adjustment for covariates, the APOE ε2 allele was significantly associated with higher scores (worse problems) for multiple Child Behavior Checklist indices, including somatic complaints (P = .009), pervasive developmental problems (P = .032), and internalizing problems (P = .009). In each case, the ε4 allele was associated with a better outcome. APOE ε2 carriers had impaired social skills, compared with ε4 carriers (P = .009). CONCLUSIONS: For preschool-aged children with congenital heart defects requiring surgery, parental rating scales showed an increased prevalence of restricted behavior patterns, inattention, and impaired social interactions. The APOE ε2 allele was associated with increased behavior problems, impaired social interactions, and restricted behavior patterns.

Population pharmacokinetics of milrinone in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction

We performed a blinded, randomized pharmacokinetic study of milrinone in 16 neonates with hypoplastic left heart undergoing stage I reconstruction to determine the impact of cardiopulmonary bypass and modified ultrafiltration on drug disposition and to define the drug exposure during a continuous IV infusion of drug postoperatively. Neonates received an initial dose of either a 100 or 250 &mgr;g/kg of milrinone into the cardiopulmonary bypass circuit at the start of rewarming. Postoperatively, milrinone was infused to clinical needs. A mixed-effect modeling approach was used to characterize milrinone pharmacokinetics during cardiopulmonary bypass, modified ultrafiltration, and postoperatively using the NONMEM algorithm. All patients in this study demonstrated a modified ultrafiltration concentrating effect that occurred despite a modified ultrafiltration drug clearance of 3.3 mL · kg−1 · min−1. The infants in this study demonstrated an impaired renal clearance during the immediate postoperative period. A constant infusion of 0.5 &mgr;g · kg−1 · min−1 resulted in drug accumulation during the initial 12 h of drug administration. Postoperatively, milrinone clearance was significantly impaired (0.4 mL · kg−1 · min−1), improved by the 12th postoperative hour, and approached steady-state clearance (2.6 mL · kg−1 · min−1) by postoperative day 4. In the postoperative setting of markedly impaired renal function, an infusion rate of 0.2 &mgr;g · kg−1 · min−1 should be considered.

Genetic factors are important determinants of impaired growth after infant cardiac surgery.

OBJECTIVESnWe sought to estimate the prevalence and identify the predictors of impaired growth after infant cardiac surgery.nnnMETHODSnWe performed a secondary analysis of a prospective study of the role of apolipoprotein E gene polymorphisms on neurodevelopment in young children after infant cardiac surgery. Prevalence estimates for growth velocity were derived by using anthropometric measures (weight and head circumference) obtained at birth and at 4 years of age. Genetic evaluation was also performed. Growth measure z scores were calculated by using World Health Organization Child Growth Standards. Growth velocity was evaluated by using 2 different techniques: first by clustering the children into one of 3 growth velocity subgroups based on z scores (impaired growth, difference < -0.5 standard deviation; stable growth, difference of -0.5 to 0.5 standard deviation; and improving growth, difference > 0.5 SD) and second by using continuous difference scores. Statistical analyses were conducted with a combination of proportional odds models for the ordered categories and simple linear regression for the continuous outcomes.nnnRESULTSnThree hundred nineteen full-term subjects had complete anthropometric measures for weight and head circumference at birth and 4 years. The cohort was 56% male. Genetic examinations were available for 97% (309/319) of the cohort (normal, 74%; definite or suspected genetic abnormality, 26%). Frequency counts for weight categories were as follows: impaired growth, 37%; stable growth, 31%; and improving growth, 32%. Frequency counts for head circumference categories were as follows: impaired growth, 39%; stable growth, 28%; and improving growth, 33%. The presence of a definite or suspected genetic syndrome (P = .04) was found to be a predictor of impaired growth for weight but not for head circumference. When growth z scores were used as continuous outcomes, the apolipoprotein E epsilon2 allele was found to be predictive of lower z scores for both weight (P = .02) and head circumference (P = .03).nnnCONCLUSIONSnImpaired growth for both weight and head circumference is common (both >30%) in this cohort of children after infant cardiac surgery. Both the apolipoprotein E epsilon2 allele and the presence of a definite or suspected genetic syndrome were associated with impaired weight growth velocity. The apolipoprotein E epsilon2 allele was also associated with impaired growth velocity for head circumference. Persistent poor growth might have long-term implications for the health and development of children with congenital heart defects.

Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival

OBJECTIVESnCopy number variants (CNVs) are duplications or deletions of genomic regions. Large CNVs are potentially pathogenic and are overrepresented in children with congenital heart disease (CHD). We sought to determine the frequency of large CNVs in children with isolated CHD, and to evaluate the relationship of these potentially pathogenic CNVs with transplant-free survival.nnnMETHODSnThese cases are derived from a prospective cohort of patients with nonsyndromic CHD (n = 422) identified before first surgery. Healthy pediatric controls (n = 500) were obtained from the electronic Medical Records and Genetic Epidemiology Network, and CNV frequency was contrasted for CHD cases and controls. CNVs were determined algorithmically; subsequently screened for >95% overlap between 2 methods, size (>300 kb), quality score, overlap with a gene, and novelty (absent from databases of known, benign CNVs); and separately validated by quantitative polymerase chain reaction. Survival likelihoods for cases were calculated using Cox proportional hazards modeling to evaluate the joint effect of CNV burden and known confounders on transplant-free survival.nnnRESULTSnChildren with nonsyndromic CHD had a higher burden of potentially pathogenic CNVs compared with pediatric controls (12.1% vs 5.0%; P = .00016). Presence of a CNV was associated with significantly decreased transplant-free survival after surgery (hazard ratio, 3.42; 95% confidence interval, 1.66-7.09; P = .00090) with confounder adjustment.nnnCONCLUSIONSnWe confirm that children with isolated CHD have a greater burden of rare/large CNVs. We report a novel finding that these CNVs are associated with an adjusted 2.55-fold increased risk of death or transplant. These data suggest that CNV burden is an important modifier of survival after surgery for CHD.

Patient Genotypes Impact Survival After Surgery For Isolated Congenital Heart Disease

BACKGROUNDnSurvival after cardiac surgery in infancy requires adaptive responses from oxidative stress management and vascular regulation pathways. We tested the hypothesis that genetic variation in these pathways influences postoperative survival in nonsyndromic congenital heart disease children.nnnMETHODSnThis is an analysis of a cohort of nonsyndromic congenital heart disease patients who underwent cardiac surgery with cardiopulmonary bypass before 6 months of age (n=422). Six single nucleotide polymorphisms (SNPs) in six genes involved in oxidative stress and vascular response pathways, identified through a priori literature search, were tested for effects on transplant-free survival. Survival curves, adjusting for confounding covariates, were calculated using the Cox proportional hazard models.nnnRESULTSnLong-term survival was strongly associated with vascular endothelial growth factor A gene SNP rs833069 (p=7.03×10(-4)) and superoxide dismutase 2 gene SNP rs2758331 (p=0.019). To test for joint effects of the two SNPs on transplant-free survival, the genotypes were grouped to form a risk score reflecting the cumulative number of risk alleles (0 to 4 alleles per patient). A higher risk score based on the VEGFA and SOD2 SNP genotypes was associated with worse transplant-free survival (p=3.02×10(-4)) after confounder adjustment. The total burden of risk alleles was additive; subjects with the highest risk score of 4 (n=59 subjects, 14.2% of the cohort) had a total covariate-adjusted hazard ratio of 15.64 for worse transplant-free survival.nnnCONCLUSIONSnAfter cardiac surgery, infants who are homozygous for the high-risk alleles for both the VEGFA and SOD2 SNPs have an approximately 16-fold increased risk of death or heart transplant, suggesting that genetic variants are important modifiers of survival after surgery for congenital heart disease.

Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome

OBJECTIVESnDespite improved survival in children with hypoplastic left heart syndrome (HLHS), significant concern persists regarding their neurodevelopmental (ND) outcomes. Previous studies have identified patient factors, such as prematurity and genetic syndromes, to be associated with worse ND outcomes. However, no consistent relationships have been identified among modifiable management factors, including cardiopulmonary bypass strategies, and ND outcomes after cardiac surgery in infancy. Studies in immature animals, including primates, have demonstrated neurodegeneration and apoptosis in the brain after certain levels and extended durations of anesthetic exposure. Retrospective human studies have also suggested relationships between adverse ND effects and anesthetic exposure.nnnMETHODSnCumulative minimum alveolar concentration hours (MAC-hrs) of exposure to volatile anesthetic agents (VAA) (desflurane, halothane, isoflurane, and sevoflurane) were collected from an anesthetic database and medical record review for 96 patients with HLHS or variants. ND testing was performed between ages 4 and 5xa0years, including full-scale IQ, verbal IQ, performance IQ, and processing speed. Four generalized linear modes were hypothesized a priori and tested using a Gaussian (normal) distribution with an identity link.nnnRESULTSnCumulative VAA exposure ranged from 0 to 35.3 MAC-hrs (median 7.5xa0hours). Using specified covariates identified previously as significant predictors of ND outcomes, statistically significant relationships were identified between total MAC-hrs exposure and worse full-scale IQ and verbal IQ scores (Psxa0<xa0.05) alone and after adjusting for relevant covariates.nnnCONCLUSIONSnIncreased cumulative MAC-hrs exposure to VAA is associated withxa0worse ND outcomes in certain domains in children with HLHS and variants.

Results of Genome-Wide Analyses on Neurodevelopmental Phenotypes at Four-Year Follow-Up following Cardiac Surgery in Infancy

Background Adverse neurodevelopmental sequelae are reported among children who undergo early cardiac surgery to repair congenital heart defects (CHD). APOE genotype has previously been determined to contribute to the prediction of these outcomes. Understanding further genetic causes for the development of poor neurobehavioral outcomes should enhance patient risk stratification and improve both prevention and treatment strategies. Methods We performed a prospective observational study of children who underwent cardiac surgery before six months of age; this included a neurodevelopmental evaluation between their fourth and fifth birthdays. Attention and behavioral skills were assessed through parental report utilizing the Attention Deficit-Hyperactivity Disorder-IV scale preschool edition (ADHD-IV), and Child Behavior Checklist (CBCL/1.5-5), respectively. Of the seven investigated, three neurodevelopmental phenotypes met genomic quality control criteria. Linear regression was performed to determine the effect of genome-wide genetic variation on these three neurodevelopmental measures in 316 subjects. Results This genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with three neurobehavioral phenotypes in the postoperative children ADHD-IV Impulsivity/Hyperactivity, CBCL/1.5-5 PDPs, and CBCL/1.5-5 Total Problems. The most predictive SNPs for each phenotype were: a LGALS8 intronic SNP, rs4659682, associated with ADHD-IV Impulsivity (Pu200a=u200a1.03×10−6); a PCSK5 intronic SNP, rs2261722, associated with CBCL/1.5-5 PDPs (Pu200a=u200a1.11×10−6); and an intergenic SNP, rs11617488, 50 kb from FGF9, associated with CBCL/1.5-5 Total Problems (Pu200a=u200a3.47×10−7). 10 SNPs (3 for ADHD-IV Impulsivity, 5 for CBCL/1.5-5 PDPs, and 2 for CBCL/1.5-5 Total Problems) had p<10−5. Conclusions No SNPs met genome-wide significance for our three neurobehavioral phenotypes; however, 10 SNPs reached a threshold for suggestive significance (p<10−5). Given the unique nature of this cohort, larger studies and/or replication are not possible. Studies to further investigate the mechanisms through which these newly identified genes may influence neurodevelopment dysfunction are warranted.

Seminal Postoperative Complications and Mode of Death After Pediatric Cardiac Surgical Procedures

BACKGROUNDnUnderstanding the seminal complications leading to death after pediatric cardiac surgical procedures may provide opportunities to reduce mortality. This study analyzed all deaths at two pediatric cardiac surgical programs and developed a method to identify the seminal complications and modes of death.nnnMETHODSnTrained nurses abstracted all cases of in-hospital mortality meeting inclusion criteria from each site over 5 years (2008 to 2012). Complication definitions were consistent with those of a multicenter clinical registry. An adjudication committee assigned a seminal complication in each case (the complication initiating the cascade of events leading to death). Seminal complications were grouped into categories to designate mode ofxa0death. The epidemiology of seminal complications and of mode of death was described.nnnRESULTSnIn 191 subjects, low cardiac output syndrome (71% of all subjects), cardiac arrest (52%), and arrhythmiaxa0(48%) were the most common complications. The committee assigned low cardiac output syndrome (30%), failure to separate from bypass (16%), and cardiac arrest (12%) most frequently as seminal complications. Seminal complications occurred a median 2 hours (interquartile range [IQR], 0 to 35 hours) postoperatively. Patients experienced a median of seven (IQR, 3 to 12) additional complications before death at a median of 15xa0days (IQR, 4xa0to 46). Systemic circulatory failure was thexa0most common mode of death (51%), followed by inadequate pulmonary blood flow (13%) and cardiac arrest (12%).nnnCONCLUSIONSnSeminal complications occurred early postoperatively, and systemic circulatory failure was the most common mode of death. Our classification system isxa0likely scalable for subsequent multicenter analysis toxa0understand cause-specific mortality variation across hospitals and to drive quality improvement.

Rates of autism and potential risk factors in children with congenital heart defects

OBJECTIVEnAtypical development, behavioral difficulties, and academic underachievement are common morbidities in children with a history of congenital heart defects and impact quality of life. Language and social-cognitive deficits have been described, which are associated with autism spectrum disorders. The current study aimed to assess the rates of autism spectrum disorders in a large sample of children with a history of congenital heart defects and to assess medical, behavioral, and individual factors that may be associated with the risk of autism spectrum disorders.nnnDESIGNnParticipants included 195 children with a history of congenital heart defects, who are followed in a large-scale longitudinal study. Measures included behavioral data from 4-year-old neurodevelopmental evaluations and parent-report data from a later annual follow-up.nnnRESULTSnUsing established cutoffs on an autism spectrum disorder screener, children with congenital heart defects showed higher rates of possible autism spectrum disorders than national rates, (Chi-square Test of Equal Proportions), all Psu2009<u2009.05. A stepwise variable selection method was used to create a best prediction model and multivariable logistic regression was used to identify variables predicting diagnostic status. Factors associated with diagnostic risk included medical (delayed sternal closure, prematurity, positive genetic findings), behavioral (cognitive, language, attention issues), and individual (socioeconomic, cultural/racial) variables. ROC analyses identified a cutoff of 7 to maximize sensitivity/specificity based on parent-reported diagnosis.nnnCONCLUSIONSnRisk of autism spectrum disorder screening status in children with congenital heart defects was higher than expected from population rates. Findings highlight the need for referral to a specialist to assess the presence and severity of social-communication issues and congenital heart defects population-specific screening thresholds for children with concern for autism spectrum disorders.

Autosomal Dominant Mannose-Binding Lectin (MBL) Deficiency is Associated with Worse Neurodevelopmental Outcomes After Cardiac Surgery in Infants

Objectives: The MBL2 gene is the major genetic determinant of mannose‐binding lectin (MBL)—an acute phase reactant. Low MBL levels have been associated with adverse outcomes in preterm infants. The MBL2Gly54Asp missense variant causes autosomal dominant MBL deficiency. We tested the hypothesis that MBL2Gly54Asp is associated with worse neurodevelopmental outcomes after cardiac surgery in neonates. Methods: This is an analysis of a previously described cohort of patients with nonsyndromic congenital heart disease who underwent cardiac surgery with cardiopulmonary bypass before age 6 months (n = 295). Four‐year neurodevelopment was assessed in 3 domains: Full‐Scale Intellectual Quotient, the Visual Motor Integration development test, and the Child Behavior Checklist to assess behavior problems. The Child Behavior Checklist measured total behavior problems, pervasive developmental problems, and internalizing/externalizing problems. A multivariable linear regression model, adjusting for confounders, was fit. Results: MBL2Gly54Asp was associated with a significantly increased covariate‐adjusted pervasive developmental problem score (&bgr; = 3.98; P = .0025). Sensitivity analyses of the interaction between age at first surgery and MBL genotype suggested effect modification for the patients with MBL2Gly54Asp (Pinteraction = .039), with the poorest neurodevelopment outcomes occurring in children who had surgery earlier in life. Conclusions: We report the novel finding that carriers of MBL2Gly54Asp causing autosomal dominant MBL deficiency have increased childhood pervasive developmental problems after cardiac surgery, independent of other covariates. Sensitivity analyses suggest that this effect may be larger in children who underwent surgery at earlier ages. These data support the role of nonsyndromic genetic variation in determining postsurgical neurodevelopment‐related outcomes in children with congenital heart disease.