Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. By analysis of exome sequencing of parent-offspring trios, we compared the incidence of de novo mutations in 362 severe CHD cases and 264 controls. CHD cases showed a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging mutations. Similar odds ratios were seen across major classes of severe CHD. We found a marked excess of de novo mutations in genes involved in production, removal or reading of H3K4 methylation (H3K4me), or ubiquitination of H2BK120, which is required for H3K4 methylation2–4. There were also two de novo mutations in SMAD2; SMAD2 signaling in the embryonic left-right organizer induces demethylation of H3K27me5. H3K4me and H3K27me mark `poised' promoters and enhancers that regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundred genes that collectively contribute to ~10% of severe CHD.

BACKGROUND The Norwood procedure with a modified Blalock–Taussig (MBT) shunt, the first palliative stage for single-ventricle lesions with systemic outflow obstruction, is associated with high mortality. The right ventricle–pulmonary artery (RVPA) shunt may improve coronary flow but requires a ventriculotomy. We compared the two shunts in infants with hypoplastic heart syndrome or related anomalies. METHODS Infants undergoing the Norwood procedure were randomly assigned to the MBT shunt (275 infants) or the RVPA shunt (274 infants) at 15 North American centers. The primary outcome was death or cardiac transplantation 12 months after randomization. Secondary outcomes included unintended cardiovascular interventions and right ventricular size and function at 14 months and transplantation-free survival until the last subject reached 14 months of age. RESULTS Transplantation-free survival 12 months after randomization was higher with the RVPA shunt than with the MBT shunt (74% vs. 64%, P = 0.01). However, the RVPA shunt group had more unintended interventions (P = 0.003) and complications (P = 0.002). Right ventricular size and function at the age of 14 months and the rate of nonfatal serious adverse events at the age of 12 months were similar in the two groups. Data collected over a mean (±SD) follow-up period of 32±11 months showed a nonsignificant difference in transplantation-free survival between the two groups (P = 0.06). On nonproportional-hazards analysis, the size of the treatment effect differed before and after 12 months (P = 0.02). CONCLUSIONS In children undergoing the Norwood procedure, transplantation-free survival at 12 months was better with the RVPA shunt than with the MBT shunt. After 12 months, available data showed no significant difference in transplantation-free survival between the two groups. (ClinicalTrials.gov number, NCT00115934.)

, for the International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators abstract BACKGROUND: Neurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD). METHODS:We analyzed individual participant data from studies of children evaluated with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI).RESULTS: Among 1770 subjects from 22 institutions, assessed at age 14.5 6 3.7 months, PDIs and MDIs (77.6 6 18.8 and 88.2 6 16.7, respectively) were lower than normative means (each P , .001). Later calendar year of birth was associated with an increased proportion of high-risk infants (complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for center and type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factors for lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly (all P # .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P , .001). After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval 0.05 to 0.71; P = .02).CONCLUSIONS: Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources.

Background Survivors of the Norwood procedure may suffer neurodevelopmental impairment. Clinical trials to improve outcomes have focused primarily on methods of vital organ support during cardiopulmonary bypass. Methods In the Single Ventricle Reconstruction trial of the Norwood procedure with modified Blalock-Taussig shunt vs. right-ventricle-to-pulmonary-artery shunt, 14-month neurodevelopmental outcome was assessed using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development®-II. We used multivariable regression to identify risk factors for adverse outcome. Results Among 373 transplant-free survivors, 321 (86%) returned at age 14.3±1.1 (mean±SD) months. Mean PDI (74±19) and MDI (89±18) scores were lower than normative means (each P<.001). Neither PDI or MDI score was associated with type of Norwood shunt. Independent predictors of lower PDI score (R2= 26%) were clinical center (P=.003), birth weight<2.5 kg (P=.023), longer Norwood hospitalization (P<.001), and more complications between Norwood procedure discharge and age 12 months (P<.001). Independent risk factors for lower MDI score (R2= 34%) included center (P<.001), birth weight<2.5 kg (P=.04), genetic syndrome/anomalies (P=.04), lower maternal education (P=.04), longer mechanical ventilation after the Norwood procedure (P<.001), and more complications after Norwood discharge to age 12 months (P<.001). We found no significant relationship of PDI or MDI score to, perfusion type, other aspects of vital organ support (e.g. hematocrit, pH strategy), or cardiac anatomy. Conclusion Neurodevelopmental impairment in Norwood survivors is more highly associated with innate patient factors and overall morbidity in the first year than with intraoperative management strategies. Improved outcomes are likely to require interventions that occur outside the operating room.

No abstract

Background In the Single Ventricle Reconstruction (SVR) trial, one-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt (MBTS). At 3 years, we compared transplant-free survival, echocardiographic right ventricular ejection fraction (RVEF), and unplanned interventions in the treatment groups. Methods and Results Vital status and medical history were ascertained from annual medical record, death index and phone interviews. The cohort included 549 patients randomized and treated in the SVR trial. Transplant-free survival for the RVPAS vs. MBTS groups did not differ at 3 years (67% vs. 61%, P=.15) or with all available follow-up of 4.8±1.1 years (logrank P=.14). Pre-Fontan RVEF was lower in the RVPAS vs. MBTS group (41.7±5.1% vs. 44.7±6.0%, P=.007), and RVEF deteriorated in RVPAS (P=.004) but not MBTS subjects (P=.40) (pre-Fontan minus 14-month mean −3.25±8.24% vs. 0.99±8.80%, P=.009). The RVPAS vs. MBTS treatment effect had non-proportional hazards (P=.004); the hazard ratio (HR) favored the RVPAS before 5 months (HR=0.63; 95% CI 0.45–0.88), but the MBTS beyond one year (HR=2.22; 95% CI 1.07–4.62). By 3 years, RVPAS subjects had a higher incidence of catheter interventions (P<.001), with an increasing HR over time (P=0.005): <5 months HR= 1.14 (95% CI, 0.81–1.60); 5 months-1 year HR=1.94 (1.02–3.69), and >1 year HR=2.48 (1.28–4.80). Conclusions By 3 years, the Norwood procedure with RVPAS, compared with MBTS, was no longer associated with superior transplant-free survival. Moreover, RVPAS subjects had slightly worse RVEF and underwent more catheter interventions, with increasing hazard ratio over time. Clinical Trial Registration Information clinicaltrials.gov. Identifier: NCT00115934.

Prenatal diagnosis of congenital heart disease (CHD) is increasingly common. However, the current impact of prenatal diagnosis on neonatal outcomes is unclear. Between January 2004 and January 2008, a retrospective chart review of infants who underwent surgical repair of CHD before discharge at our institution was conducted. Obstetric and perioperative variables were recorded. Of 439 neonates, 294 (67%) were diagnosed prenatally (PREdx). Infants with PREdx had a lower mean birth weight (3.0 ± 0.6 vs. 3.1 ± 0.6 kg, p = 0.002) and gestational age (37.9 ± 2.1 vs. 38.6 ± 2.4 wk, p < 0.001) than those with postnatal diagnosis (POSTdx). Severe lesions were more likely to be PREdx:Correspondence to: Allison Levey, ap465@columbia.edu. NIH Public Access Author ManuscriptPediatr Cardiol. Author manuscript; available in PMC 2011 July 1. Many infants with complex CHD require surgical intervention before hospital discharge. Previous studies investigating whether prenatal diagnosis of CHD favorably impacts survival have demonstrated inconsistent findings [9,15]. Likewise, the impact on morbidity has been variably reported [3,4,16]. In light of these mixed reports, and with the knowledge that prenatal diagnosis is now more common than postnatal diagnosis, we sought to reassess the relations between prenatal diagnosis and various neonatal outcomes. First, we evaluated the effect of prenatal diagnosis on birth characteristics, such as gestational age (GA) and birth weight (BW). Second, the differences in anatomic cardiac diagnoses between PREdx and postnatally diagnosed (POSTdx) infants were investigated. Third, we assessed the impact of prenatal diagnosis on neonatal morbidity, including the need for more aggressive preoperative measures, day of life (DOL) of surgery, and hospital length of stay (LOS). Fourth, the effect of prenatal diagnosis on mortality was determined. Finally, we investigated the trends in prenatal diagnosis and the impact of prenatal diagnosis on DOL of surgery and hospital LOS at our institution during the course of the study period. Methods Study Design and ProceduresA retrospective chart review of infants who underwent repair of CHD before hospital discharge between Univariate descriptive statistics are summarized as means and SDs for normal distributions and as medians and interquartile ranges (IQR) for nonparametric distributions. Differences in proportions between groups were analyzed using 2 × 2 tables and Pearson's χ 2 test statistic. Univariate relations were explored using Kaplan-Meier, and differences in medians were assessed using the log-rank test. In an effort to evaluate more fully the associations between prenatal diagnosis and DOL of surgery, hospital LOS, and neonatal mortality, multivariate models were constructed using both binary logistic regression and the Cox Proportional Hazards technique. Subject characteristics that showed a univariable association with DOL of surgery, hospital LOS, and mortality at the 0.1 level were eligible for inclusion in the multivariable models. All ...

Background In the Single Ventricle Reconstruction (SVR) trial, one-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt (MBTS) in patients with hypoplastic left heart and related syndromes. At 6 years, we compared transplant-free survival and other outcomes between the groups. Methods Medical history was collected annually using medical record review, telephone interviews, and the death index. The cohort included 549 patients randomized and treated in the SVR trial. Results Transplant-free survival for the RVPAS vs. MBTS groups did not differ at 6 years (64% vs. 59%, P=0.25) or with all available follow-up of 7.1±1.6 years (log-rank P=0.13). The RVPAS vs. MBTS treatment effect had non-proportional hazards (P=0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before Stage II surgery (HR=0.66; 95% CI 0.48–0.92). The effect of shunt type on death or transplant was not statistically significant between Stage II to Fontan surgery (HR 1.36, 95% CI 0.86–2.17, p=0.17) or after the Fontan procedure (HR 0.76, 95% CI 0.33–1.74, p=0.52). By 6 years, RVPAS patients had a higher incidence of catheter interventions (0.38 vs. 0.23/patient-year, P<0.001), primarily due to more interventions between the Stage II and Fontan procedures (HR=1.72, 95% CI 1.00–3.03). Complications did not differ by shunt type; by 6 years, one in five patients had had a thrombotic event and one in six, seizures. Conclusions By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS vs. MBTS groups. Children assigned to the RVPAS group had 5% higher transplant-free survival but the difference did not reach statistical significance, and they required more catheter interventions. Both treatment groups have accrued important complications. Clinical Trial Registration Registered with ClinicalTrials.gov number, NCT00115934 URL: http://clinicaltrials.gov/show/NCT00115934