Kristin M. Burns

The Congenital Heart Disease Genetic Network Study Rationale, Design, and Early Results

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community’s use of Pediatric Cardiac Genomics Consortium resources is welcome.

Expansion of the mycobacterial “PUPylome”

Selective degradation of cellular proteins offers an important mechanism to coordinate cellular processes including cell differentiation, defense, metabolic control, signal transduction and proliferation. While much is known about eukaryotic ubiquitination, we know little about the recently discovered ubiquitin-like protein in prokaryotes (PUP). Through expression of His(7) tagged PUP and exploitation of the characteristic +243 Da mass shift attributed to trypsinized PUPylated peptides, a global pull-down of protein targets for PUPylation in Mycobacterium smegmatis revealed 103 candidate PUPylation targets and 52 confirmed targets. Similar to eukaryotic ubiquitination, further analysis of these targets revealed neither primary sequence nor secondary structure homology at the point of attachment. Pathways containing PUPylated proteins include many central to rapid cell growth, such as glycolysis, gluconeogenesis, amino acid and mycolic acid metabolism and biosynthesis, as well as translation. Seventeen of the 29 nitrosylated protein targets previously identified in Mycobacterium tuberculosis were also identified as PUPylation candidates indicating a connection between PUP-mediated remodeling of critical metabolic pathways and the mycobacterial response to exogenous stress.

Emerging Research Directions in Adult Congenital Heart Disease: A Report From an NHLBI/ACHA Working Group.

Congenital heart disease (CHD) is the most common birth defect, affecting about 0.8% of live births. Advances in recent decades have allowed >85% of children with CHD to survive to adulthood, creating a growing population of adults with CHD. Little information exists regarding survival, demographics, late outcomes, and comorbidities in this emerging group, and multiple barriers impede research in adult CHD. The National Heart, Lung, and Blood Institute and the Adult Congenital Heart Association convened a multidisciplinary working group to identify high-impact research questions in adult CHD. This report summarizes the meeting discussions in the broad areas of CHD-related heart failure, vascular disease, and multisystem complications. High-priority subtopics identified included heart failure in tetralogy of Fallot, mechanical circulatory support/transplantation, sudden cardiac death, vascular outcomes in coarctation of the aorta, late outcomes in single-ventricle disease, cognitive and psychiatric issues, and pregnancy.

New Mechanistic and Therapeutic Targets for Pediatric Heart Failure Report From a National Heart, Lung, and Blood Institute Working Group

Pediatric heart failure (HF) is the inability of the heart of an infant, child, or adolescent to meet the body’s metabolic demands. It involves circulatory, neurohumoral, and molecular abnormalities that manifest as edema, respiratory distress, growth failure, and exercise intolerance. The myriad causes include inherited and acquired myocardial anomalies (cardiomyopathy [CM]), volume overload (intracardiac shunts, valvular regurgitation), and the unique hemodynamics predicated by a functional single ventricle (palliated complex congenital heart disease [CHD]). Although the societal and financial costs of adult HF are well known, the burden of pediatric HF is less familiar, but no less onerous. New-onset HF requiring hospital admission occurs in 0.87 per 100 000 children,1 yet that does not include the growing population with CHD-related HF. In 2006, there were nearly 14 000 pediatric hospitalizations for HF from all causes in the United States.2 The rate of HF-related admissions was nearly 18 per 100 000 children,2 which is comparable to severe sepsis.3 The mortality for pediatric HF hospitalizations is significant. The 7% overall hospital mortality rate exceeds the 4% mortality of adult HF admissions4 and represents a 20-fold increase over children without HF.2 With comorbidities like renal failure, sepsis, or stroke, hospital mortality in pediatric HF can exceed 20%,2 yet the risk does not end with discharge. After an initial HF hospitalization, only 21% of children in 1 study avoided readmission, death, or transplantation.5 Pediatric HF treatment is resource intensive. Although the total healthcare costs for pediatric HF are lower than for adults, per-patient costs are higher. The estimated hospital charge per pediatric HF admission in 2006 was >

Report of the National Heart, Lung, and Blood Institute Working Group: An Integrated Network for Congenital Heart Disease Research.

135 000, with aggregate charges exceeding

Utilizing a Collaborative Learning Model to Promote Early Extubation Following Infant Heart Surgery

1.8 billion.6 Certain subpopulations of pediatric HF incurred disproportionally higher costs. For example, single-ventricle CHD averaged >

Transplant-Free Survival and Interventions at 6 Years in the SVR Trial

200 000 per hospitalization,7 whereas adult …

Perspective on Congenital Heart Disease Research

The National Heart, Lung, and Blood Institute convened a working group in January 2015 to explore issues related to an integrated data network for congenital heart disease research. The overall goal was to develop a common vision for how the rapidly increasing volumes of data captured across numerous sources can be managed, integrated, and analyzed to improve care and outcomes. This report summarizes the current landscape of congenital heart disease data, data integration methodologies used across other fields, key considerations for data integration models in congenital heart disease, and the short- and long-term vision and recommendations made by the working group.

Opportunities and Challenges in Chronic Chagas Cardiomyopathy

Objective: To determine whether a collaborative learning strategy-derived clinical practice guideline can reduce the duration of endotracheal intubation following infant heart surgery. Design: Prospective and retrospective data collected from the Pediatric Heart Network in the 12 months pre- and post-clinical practice guideline implementation at the four sites participating in the collaborative (active sites) compared with data from five Pediatric Heart Network centers not participating in collaborative learning (control sites). Setting: Ten children’s hospitals. Patients: Data were collected for infants following two-index operations: 1) repair of isolated coarctation of the aorta (birth to 365 d) and 2) repair of tetralogy of Fallot (29–365 d). There were 240 subjects eligible for the clinical practice guideline at active sites and 259 subjects at control sites. Interventions: Development and application of early extubation clinical practice guideline. Measurements and Main Results: After clinical practice guideline implementation, the rate of early extubation at active sites increased significantly from 11.7% to 66.9% (p < 0.001) with no increase in reintubation rate. The median duration of postoperative intubation among active sites decreased from 21.2 to 4.5 hours (p < 0.001). No statistically significant change in early extubation rates was found in the control sites 11.7% to 13.7% (p = 0.63). At active sites, clinical practice guideline implementation had no statistically significant impact on median ICU length of stay (71.9 hr pre- vs 69.2 hr postimplementation; p = 0.29) for the entire cohort. There was a trend toward shorter ICU length of stay in the tetralogy of Fallot subgroup (71.6 hr pre- vs 54.2 hr postimplementation, p = 0.068). Conclusions: A collaborative learning strategy designed clinical practice guideline significantly increased the rate of early extubation with no change in the rate of reintubation. The early extubation clinical practice guideline did not significantly change postoperative ICU length of stay.

Screening in Pediatrics—More Questions than Answers?

Background: In the SVR trial (Single Ventricle Reconstruction), 1-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 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 versus modified Blalock–Taussig shunt groups did not differ at 6 years (64% versus 59%, P=0.25) or with all available follow-up of 7.1±1.6 years (log-rank P=0.13). The RVPAS versus modified Blalock–Taussig shunt treatment effect had nonproportional hazards (P=0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before stage II surgery (HR, 0.66; 95% confidence interval, 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% confidence interval, 0.86–2.17; P=0.17) or after the Fontan procedure (HR, 0.76; 95% confidence interval, 0.33–1.74; P=0.52). By 6 years, patients with RVPAS had a higher incidence of catheter interventions (0.38 versus 0.23/patient-year, P<0.001), primarily because of more interventions between the stage II and Fontan procedures (HR, 1.72; 95% confidence interval, 1.00–3.03). Complications did not differ by shunt type; by 6 years, 1 in 5 patients had had a thrombotic event, and 1 in 6 had had seizures. Conclusions: By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS versus modified Blalock–Taussig shunt 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: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00115934.