Physiologic and Genetic Contributions of Impaired Fetal Brain Development in Congenital Heart Disease

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PROJECT SUMMARY Congenital heart disease (CHD) is the most common birth defect and, as survival has improved for patients with moderate-severe CHD, adults now outnumber children with this diagnosis. This reduction in mortality has shifted research focus to improving long-term outcomes and quality of life. The most common adverse outcome is neurodevelopmental impairment and occurs in 50% of patients with moderate-severe CHD. While postnatally measured medical and surgical factors play a crucial role in the care and outcomes of these infants, brain magnetic resonance imaging (MRI) studies have identified impaired brain development even before cardiac surgery and have emphasized the fetal period as a time when these abnormalities are evolving. These data suggest fetal interventions may be an important aspect of improving the high rates of neurodevelopmental impairments in CHD. The National Heart, Lung, and Blood Institute has highlighted a need for research focused on preventive and therapeutic strategies for reducing neurodevelopmental deficits in CHD. This Mentored Patient-Oriented Career Development Award aligns well with this need by aiming to characterize the trajectory of disrupted cortical brain development in fetuses with moderate-severe CHD and to understand mechanistic interactions between physiologic and genetic variation that underlie brain disruption in this population. These data will assist in identifying the timing and population of CHD fetuses that may benefit from fetal neuroprotective interventions and will inform risk prediction for patient counseling. This Award will provide the candidate the education, training, and mentoring necessary to successfully undertake this proposal and to develop the skills required to become an independent clinician scientist focused on improving neurodevelopmental outcomes in patients with CHD. Dr. Ortinau has already developed expertise in MR analysis techniques. Thus, the training and mentorship for this award will focus on: 1) enhancing knowledge of fetal cardiac physiology and developing expertise in the association of cardiac physiology with cerebral hemodynamics and fetal brain development; and 2) gaining knowledge and experience in genetic and genomic research to understand the contribution of genetic variation to cerebral cortical development. The unique environment at Washington University School of Medicine provides the opportunity to train in these key areas using the infrastructure, resources, and mentorship outlined in the candidate’s Career Development Plan. These research activities will provide the preliminary data necessary for development of an hypothesis-driven R01 application in Year 2 of this Award, aimed at understanding mechanistic interactions between physiologic and genetic pathways that may underlie disruption of brain development in moderate-severe CHD.