Genetics dictating therapeutic decisions in pediatric pulmonary hypertension? A case report suggesting we are getting closer.

Despite therapeutic advances over the past decades, pulmonary arterial hypertension (PAH) and related pulmonary vascular diseases continue to cause significant morbidity and mortality in neonates, infants, and children. Unfortunately, an adequate understanding of underlying biology is lacking. There has been a growing interest in the role that genetic factors influence pulmonary vascular disease, with the hope that genetic information may aid in identifying disease etiologies, guide therapeutic decisions, and ultimately identify novel therapeutic targets. In fact, current data suggest that genetic factors contribute to ~42% of pediatric-onset PH compared to ~12.5% of adult-onset PAH. We report a case in which the knowledge that biallelic ATP13A3 mutations are associated with malignant progression of PAH in young childhood, led us to alter our traditional treatment plan for a 21-month-old PAH patient. In this case, we elected to perform a historically high-risk Potts shunt before expected rapid deterioration. Short-term follow-up is encouraging, and the patient remains the only known surviving pediatric PAH patient with an associated biallelic ATP13A3 mutation in the literature. We speculate that an increased use of comprehensive genetic testing can aid in identifying the underlying pathobiology and the expected natural history, and guide treatment plans among PAH patients.

Association between Z-score for birth weight and postoperative outcomes in neonates and infants with congenital heart disease.

OBJECTIVE: We hypothesized that infants with fetal growth restrictions have increased mortality and morbidity after congenital heart disease surgery. METHODS: The study included patients in The Society of Thoracic Surgeons Congenital Heart Surgery Database (2010-2016) who underwent cardiac surgery at a corrected gestational age of ≤44 weeks. Patients were classified as severely (birth weight Z-score -4 to -2), moderately (Z-score -2 to -1), and mildly growth restricted (Z-score -1.0 to -0.5) and compared with a reference population (Z-score 0-0.5). Multivariable logistic regression clustering on center was used to evaluate the association of birth weight Z-score with operative mortality and postoperative complications and its interaction with gestational age was assessed. RESULTS: In 25,244 patients, operative mortality was 8.6% and major complications occurred in 19.4%. Compared with the reference group, the adjusted odds ratio (AOR) of mortality was increased in infants with severe (AOR, 2.4; 95% confidence interval [CI], 2.0-3.0), moderate (AOR, 1.7; 95% CI, 1.4-2.0), and mild growth restriction (AOR, 1.4; 95% CI, 1.2-1.6). The AOR for major postoperative complications was increased for severe (AOR, 1.4; 95% CI, 1.2-1.7) and moderate growth restriction (AOR, 1.2; 95% CI, 1.1-1.4). There was significant interaction between birth weight Z-score and gestational age (P = .007). CONCLUSIONS: Even birth weight Z-scores slightly below average are independent risk factors for mortality and morbidity in infants who undergo cardiac surgery. The strongest association between poor fetal growth and operative mortality exists in early-term infants. These novel findings might account for some of the previously unexplained variation in cardiac surgical outcomes.

Usp16 contributes to somatic stem-cell defects in Down's syndrome.

Down's syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.

Modified and conventional ultrafiltration during pediatric cardiac surgery: clinical outcomes compared.

OBJECTIVE: This prospective study compared clinical outcomes after heart surgery between three groups of infants with congenital heart disease. One group received dilutional conventional ultrafiltration (group D), another received modified ultrafiltration (group M), and a third group received both dilutional conventional and modified ultrafiltration (group B). We hypothesized that group B patients would have the best clinical outcome. METHODS: Children younger than 1 year undergoing heart surgery for biventricular repair by the same surgeon were randomly allocated to one of the three study groups. Patient management was standardized, and intensive care staff were blinded to group allocation. Primary outcome measure was duration of postoperative mechanical ventilation. Other outcome measures recorded included total blood products transfused, duration of chest tube in situ, chest tube output, and stays in intensive care and in the hospital. RESULTS: Sixty infants completed study protocol. Mean age and weight were as follows: group D (n = 19), 61 days, 4.3 kg; group M (n = 20), 64 days, 4.5 kg; and group B (n = 21), 86 days, 4.4 kg. Preoperative and intraoperative characteristics were similar between groups. Ultrafiltrate volumes obtained were 196 +/- 93 mL/kg in group D, 105 +/- 33 mL/kg in group M, and 261 +/- 113 mL/kg in group B. There were no significant differences between groups for any outcome variable. Technical difficulties prevented completion of modified ultrafiltration in 2 of 41 infants. CONCLUSION: There was no clinical advantage in combining conventional and modified ultrafiltration. Because clinical outcomes were similar across groups, relative risks of the ultrafiltration strategies may influence choice.

Robotically assisted perventricular closure of perimembranous ventricular septal defects: preliminary results in Yucatan pigs.

OBJECTIVE: Robotic systems allow surgeons to perform minimally invasive cardiac surgery in adults. Experience in the pediatric population, however, is limited. Perventricular closure of muscular ventricular septal defects has been reported in humans but requires a median sternotomy. The objective of this study was to assess the feasibility of robotically assisted closure of perimembranous ventricular septal defects by using the perventricular approach. METHODS: The procedure was attempted in 7 pigs with naturally occurring perimembranous ventricular septal defects. Echocardiography was performed to confirm the presence and assess the size of the defect. A 3-armed da Vinci system consisting of two 8-mm instrument ports and a 12-mm endoscopy port was used. A pericardiotomy was performed, and the right ventricular free wall was visualized. A spinal needle was advanced into the right ventricular cavity. By using echocardiographic guidance, a glide wire was advanced through the angiocatheter and manipulated through the defect into the left ventricle or the ascending aorta. A delivery sheath was advanced over the wire. An appropriately sized Amplatzer device was deployed through the sheath. RESULTS: The procedure was successful in 5 pigs. One device was removed because it was smaller than the defect and an appropriately sized device was not available. The placement failed in the second pig in the series. Four pigs were followed up for 1 to 4 months. Angiograms performed before the pigs were killed documented complete occlusion in 3 and mild-to-moderate shunt in 1. CONCLUSIONS: Robotically assisted perventricular closure with the Amplatzer Membranous VSD Occluder is feasible. This approach avoids the associated morbidities of cardiopulmonary bypass and median sternotomy. Further investigation and refinements are needed, however, before application of this approach in humans.