Congenital heart disease (CHD) affects ~1% of all live births in the United States. Over 85% of individuals with CHD now live well into adulthood1?4, exposing a burden of non-cardiac disabilities, such as neurodevelopmental disabilities. In fact, over half of all children with moderate or complex CHD suffer from neuropsychological deficits, with impaired executive functions (EF) the most common. EF are critical higher-order neurocognitive functions important for independent living and mental health. However, predicting who will be more impaired and in need of intervention is challenging, as routinely measured patient and medical factors explain only one-third of the variance in outcomes. Because impaired EF is particularly amenable to treatment, better predictors of EF are needed to appropriately allocate services and improve outcomes. To develop such methods, we first focus on dextro-transposition of the great arteries (d-TGA). Among the severe forms of CHD, d-TGA is the more common, occurring in 3/10,000 live births. d-TGA leads to severe in utero hypoxia that is corrected soon after birth with an arterial switch operation. Additional surgery and cardiovascular sequelae are rare. Thus d-TGA patients have the most uniform postnatal course of all CHDs but, like other CHDs, is associated with hypoxia and has significant yet variable impairment in EF. This project leverages adult d-TGA subjects being studied under R01HL135061 and d-TGA patients involved in prior Boston trials to create the largest, best characterized d-TGA cohort to date. We propose to perform sophisticated image analysis on brain MRI data and add genetic testing focused on neuroresilience and hypoxia response genes. First, we will employ our sulcal pattern analysis to determine the extent of in utero alterations in brain development, as sulcal patterns are determined prenatally and remain stable into adult life. Second, we will explore the rich club structural and functional networks to separate highly connected central hubs (rich club) that form early in life from less connected peripheral regions which are thought to be adaptive. The overarching goal of this study is to use novel MRI analyses to determine the brain organizational changes associated with altered EF and the modulating role of neuroresilience and hypoxia response genes in adults with d-TGA. Toward these ends, we propose the following specific aims:
Aim 1. Determine the relationship between sulcal patterns and executive function in adults with d-TGA and if this relationship is modified by (a) presence of neuro-resilience gene ApoE ?2 or ?4 alleles, or (b) variants in hypoxia response genes.
Aim 2 /3. Determine the relationship between structural/functional connectivity using rich club and executive function in adults with d-TGA and if this relationship is modified by (a) presence of neuro-resilience gene ApoE ?2 or ?4 alleles or (b) variants in hypoxia response genes. Successful completion would help determine brain changes associated with altered EF and the potential modulating role of neuroresilience and hypoxia response genes as well as inform the balance of in utero versus adaptive changes. This knowledge is relevant to the larger CHD group and will inform the need for prenatal versus postnatal interventions.

Public Health Relevance

This proposal creates the largest, best-characterized adult cohort of d-transposition of the great arteries to date in order to explore the structural and functional brain MRI features associated with adult executive function and the potential modulating effects of common genetic variants in neuroresilience and hypoxia genes. Successful completion of this study would be relevant to patients with many types of congenital heart diseases and increase our understanding of prenatal versus adaptive changes associated with altered executive function and may help identify potential pathways for protective versus modifying therapeutic interventions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Burns, Kristin
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston Children's Hospital
United States
Zip Code