With dramatic improvement in survival of patients with hypoplastic left heart syndrome and related forms of single right ventricle undergoing staged palliation to the Fontan operation, a high prevalence of neurodevelopment abnormalities has been exposed. The NHBLI-funded Pediatric Heart Network (PHN) Single Ventricle Reconstruction (SVR) III study, Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type, is a prospective follow-up study of an existing cohort of children with HLHS and other single RV anomalies who were enrolled in early infancy in a randomized clinical trial of the modified Blalock-Taussig shunt (MBTS) versus right ventricular to pulmonary artery shunt (RVPAS). The parent SVR III study seeks to determine if the shunt assignment at the time of the Norwood operation is associated with cardiac function, transplant-free survival, exercise function, and neurodevelopmental outcomes. We here propose a neuroimaging ancillary study to the parent SVR III study that leverages the neurodevelopmental follow-up of the SVR cohort at age 11 years. We will combine state-of-the-art brain imaging techniques (Resting-BOLD and Diffusion Tensor Imaging) in 140 SVR III patients and 100 referent subjects with innovative brain connectome' or graph analyses to determine if brain connectivity graph measurements will provide novel neuroimaging biomarkers for neurodevelopmental disabilities and improve our understanding of their inciting mechanisms in the SVR survivors.
Our specific aims are: 1. To characterize the global brain network topology of the SVR III cohort; 2. To determine which neurocognitive and behavioral outcomes are predicted by global brain network topology in the SVR III cohort. 3. To determine which patient factors (e.g., birth weight, gestational age, maternal education) and medical factors (e.g., intraoperative conduct during Norwood procedure, hemodynamic complications, types and number of interventions, and measures of global morbidity) predict global brain network topology in the SVRIII cohort. 4. To precisely characterize the specific relationships between global brain network topology, specific patient/medical factors, and adverse neurocognitive/behavioral outcomes in the SVRIII cohort. We will use linear regression and mediation statistical methods to analyze associations of MRI graph measures with SVRIII neurodevelopmental measures and surgical/non-surgical clinical independent risk factors. Upon successful completion, these studies will elucidate the nature and basis of neurodevelopmental disability in single ventricle patients following Fontan palliation. This research will also contribute a novel and robust set of clinical/research tools in the form of neuroimaging biomarkers that can be used to help classify and predict outcomes in complex congenital heart disease.

Public Health Relevance

Patients with hypoplastic left heart syndrome and other single right ventricle lesions who have undergone the Fontan procedure have a high risk of neurodevelopmental disorders that affect quality of life and adulthood employment. The proposed ancillary study will leverage the ongoing NHLBI-funded Single Ventricle Reconstruction Study by using innovative graph measures of brain connectivity to elucidate how alterations of the 'connectome' in children with critical congenital heart disease are associated with developmental disabilities and their associated clinical risk factors. Improved understanding of these interrelationships may facilitate development of targeted interventions to improve outcome in the soaring population of adult Fontan survivors.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Burns, Kristin
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University of Pittsburgh
Schools of Medicine
United States
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Schmithorst, Vincent J; Votava-Smith, Jodie K; Tran, Nhu et al. (2018) Structural network topology correlates of microstructural brain dysmaturation in term infants with congenital heart disease. Hum Brain Mapp 39:4593-4610
Gertsvolf, Nina; Votava-Smith, Jodie K; Ceschin, Rafael et al. (2018) Association between Subcortical Morphology and Cerebral White Matter Energy Metabolism in Neonates with Congenital Heart Disease. Sci Rep 8:14057