Cynthia Ortinau, MD

Neurological and neurodevelopmental consequences of congenital heart disease (CHD)

My research program studies the neurological and neurodevelopmental consequences of congenital heart disease (CHD). Advances in surgical and medical care for CHD have improved survival for these children, which has shifted research and clinical focus to the long-term morbidities they face. The most common adverse outcome is neurodevelopmental impairment, and underlying alterations in brain development have been identified as an important contributor. The overarching goal of my research program is to define the nature and timing of altered brain development in children with CHD using advanced magnetic resonance imaging (MRI) methods, determine the underlying mechanisms of these alterations, and ultimately design neuroprotective strategies for improving outcomes. Our early work, in collaboration with investigators from New Zealand, identified that CHD infants have reductions in brain size, altered cerebral white matter microstructure, and abnormal cerebral cortical development before cardiac surgery, typically in the first week of life. The identification of early neonatal, preoperative abnormalities led my team to focus on the in utero environment as a primary period of vulnerability. We applied novel fetal MRI methods to CHD and healthy fetuses and  performed serial imaging after birth. We identified a slower rate of total brain growth from the prenatal to postnatal environment in the CHD population, with the cerebral cortex, subcortical gray matter structures, and cerebellum displaying the greatest deficits. With co-investigators at Boston Children’s Hospital, we have also discovered differences in left hemisphere sulcation patterns before 30 weeks gestation that involve the Sylvian Fissure and early emerging sulci. Together, our findings suggest that abnormalities in brain development begin early in pregnancy, affect multiple tissues and regions of the brain, and result in an altered trajectory of brain development during infancy. Our current work takes a multidisciplinary collaborative approach to extend these findings to the timing and trajectory of structure- and region-specific vulnerability of the developing brain by applying volumetric and surface-based methods to serial fetal MRI. We have also begun to study two primary pathways by which prenatal brain development may be disrupted, fetal CHD-related hypoxia and genetic variants affecting both heart and brain development. We  are using novel fetal MRI methods to measure placental and cerebral oxygenation, alongside fetal brain development measures, and collecting trio blood samples after infant birth for whole exome sequencing. Finally, we are also investigating the association of fetal and infant brain imaging with neurodevelopmental outcomes in early-mid childhood. Our hope is that these collaborative clinical investigations will inform future preclinical and clinical studies that target specific mechanistic pathways for neuroprotection. This is directly in line with the Hope Center’s mission to discover fundamental mechanisms that will translate to new understanding and cures for people living with neurological disorders.

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