Longitudinal Assessment of Growth in Hypoplastic Left Heart Syndrome: Results From the Single Ventricle Reconstruction Trial

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 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

De novo mutations in histone modifying genes in congenital heart disease

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

Risk factors for prolonged length of stay after the stage 2 procedure in the single-ventricle reconstruction trial

BackgroundThe single-ventricle reconstruction trial randomized patients with single right ventricle lesions to a modified Blalock-Taussig or right ventricle-to-pulmonary artery shunt at the Norwood. This analysis describes outcomes at the stage 2 procedure and factors associated with a longer hospital length of stay (LOS).MethodsWe examined the association of shunt type with stage 2 hospital outcomes. Cox regression and bootstrapping were used to evaluate risk factors for longer LOS. We also examined characteristics associated with in-hospital death.ResultsThere were 393 subjects in the analytic cohort. Median stage 2 procedure hospital LOS (8 days; interquartile range [IQR], 6-14 days), hospital mortality (4.3%), transplantation (0.8%), median ventilator time (2 days; IQR, 1-3 days), median intensive care unit LOS (4 days; IQR, 3-7 days), number of additional cardiac procedures or complications, and serious adverse events did not differ by shunt type. Longer LOS was associated (R2 = 0.26) with center, longer post-Norwood LOS (hazard ratio [HR], 1.93 per log day; P < .001), nonelective timing of the stage 2 procedure (HR, 1.78; P < .001), and pulmonary artery (PA) stenosis (HR, 1.56; P < .001). By univariate analysis, nonelective stage 2 (65% vs 32%; P = .009), moderate or greater atrioventricular valve (AVV) regurgitation (75% vs 24%; P < .001), and AVV repair (53% vs 9%; P < .001) were among the risk factors associated with in-hospital death.ConclusionsNorwood LOS, PA stenoses, and nonelective stage 2 procedure, but not shunt type, are independently associated with longer LOS. Nonelective stage 2 procedure, moderate or greater AVV regurgitation, and need for AVV repair are among the risk factors for death