Single ventricle lesions comprise 10-15% of all congenital heart disease (CHD), but consume 25% of CHD health care resources. Striking improvement in the survival of patients with single ventricle, treated with staged palliation culminating in the Fontan operation (""""""""Fontan patients""""""""), has revealed that this population harbors a high prevalence of neurologic and developmental abnormalities. Furthermore, most patients after Fontan now survive to adulthood, when consequences of neurodevelopmental impairment may affect employability and mental health. We propose to evaluate 155 Fontan patients at ages 13 through 17 years, compared to 50 adolescents in the general population of similar age and gender.
In Aim 1, Fontan and control groups will be compared on Magnetic Resonance Imaging (MRI) measures of brain structure. Using quantitative volumetric MRI imaging, the primary outcome will be the segmented volume of total cortical gray matter. Secondary outcomes will comprise other segmented volumes: cortical and subcortical gray matter, white matter, cerebrospinal fluid (CSF), total intracranial volume (cortical gray matter + subcortical gray matter + white matter + CSF), and parcellated regional brain volumes. Using diffusion tensor MRI imaging, the primary outcome will be regional white matter microstructure, as measured by fractional anisotropy. Secondary outcomes will be regional apparent diffusion coefficients.
Aim 2 will compare the Fontan and control groups on MRI measures of brain function. The primary outcomes for executive function and visual-spatial function will be regional functional MRI (fMRI) activation derived from performance of a Stroop paradigm and a visual closure paradigm, respectively.
Aim 3 will evaluate the relationship of brain MRI measures to academic achievement, cognition, and behavior. The primary neurocognitive outcome will be the Total Composite score on the Wechsler Individual Achievement Test-II. Secondary outcomes will include measures of ability (IQ), learning disability, neuropsychological function (i.e., language, memory, attention, executive functions, and visual-spatial/motor integration), and mental health, including quality-of-life and global emotional functioning, as well as specific psychiatric diagnoses including mood, anxiety, attention-deficit/disruptive behavior, and psychotic disorders.
Aim 4 will explore the relationship of brain MRI measures to genetic and medical factors. Fontan patients will be assessed by a clinical geneticist, undergo chromosomal microarray, and have the opportunity to provide a sample for a DNA biorepository. We will use correlation and regression methods to analyze associations of MRI measures with genetic and medical factors. We will explore whether these factors modify the relationship between MRI findings and cognition through interaction models. These studies will establish, with greater clarity and specificity, the nature and basis of neurodevelopmental sequelae of single ventricle patients following Fontan palliation.

Public Health Relevance

Patients with single ventricle who have undergone the Fontan procedure have a high risk of neurologic, developmental, and behavioral disorders that are important barriers to learning and development;interfere with the acquisition of academic, vocational, and social skills;and negatively affect adult adjustment. The proposed assessment offers an opportunity to address important questions of broad biologic significance regarding the relationships of measures of brain structure and function with neurodevelopment, as well as their association with genetic and medical factors. Improved understanding of these interrelationships may facilitate the design and implementation of interventions to target specific central nervous system deficits and thereby maximize adult neuropsychological function in the growing post-Fontan population.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Kaltman, Jonathan R
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Children's Hospital Boston
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Cassidy, Adam R; Bernstein, Jane Holmes; Bellinger, David C et al. (2018) Visual-spatial processing style is associated with psychopathology in adolescents with critical congenital heart disease. Clin Neuropsychol :1-19
Bean Jaworski, Jessica L; White, Matthew T; DeMaso, David R et al. (2018) Visuospatial processing in adolescents with critical congenital heart disease: Organization, integration, and implications for academic achievement. Child Neuropsychol 24:451-468
DeMaso, David R; Calderon, Johanna; Taylor, George A et al. (2017) Psychiatric Disorders in Adolescents With Single Ventricle Congenital Heart Disease. Pediatrics 139:
Bellinger, David C; Watson, Christopher G; Rivkin, Michael J et al. (2015) Neuropsychological Status and Structural Brain Imaging in Adolescents With Single Ventricle Who Underwent the Fontan Procedure. J Am Heart Assoc 4:
Cassidy, Adam R; White, Matthew T; DeMaso, David R et al. (2015) Executive Function in Children and Adolescents with Critical Cyanotic Congenital Heart Disease. J Int Neuropsychol Soc 21:34-49