optocardiography-electrophysiology-studies-ex-vivo-langendorff

Optocardiography and Electrophysiology Studies of Ex Vivo Langendorff-perfused Hearts

Small animal models are most commonly used in cardiovascular research due to the availability of genetically modified species and lower cost compared to ...

Children's National Hospital

White matter (WM) injury is common after neonatal cardiopulmonary bypass (CPB). We have demonstrated that the inflammatory response to CPB is an important mechanism of WM injury. Microglia are brain-specific immune cells that respond to inflammation and can exacerbate injury. We hypothesized that microglia activation contributes to WM injury caused by CPB.

Prolonged White Matter Inflammation After Cardiopulmonary Bypass and Circulatory Arrest in a Juvenile Porcine Model.

White-matter injury after surgery is common in neonates with cerebral immaturity secondary to in utero hypoxia. Astrocytes play a central role in brain protection; however, the reaction of astrocytes to hypothermic circulatory arrest (HCA) remains unknown. We investigated the role of astrocytes in white-matter injury after HCA and determined the effects of preoperative hypoxia on this role, using a novel mouse model.

Hypoxia diminishes the protective function of white-matter astrocytes in the developing brain.

Anomalies of Ventriculoarterial Connections and Immature Brain Development.

Long-term neurological deficits due to immature cortical development are emerging as a major challenge in congenital heart disease (CHD). However, cellular mechanisms underlying dysregulation of perinatal corticogenesis in CHD remain elusive. The subventricular zone (SVZ) represents the largest postnatal niche of neural stem/progenitor cells (NSPCs). We show that the piglet SVZ resembles its human counterpart and displays robust postnatal neurogenesis. We present evidence that SVZ NSPCs migrate to the frontal cortex and differentiate into interneurons in a region-specific manner. Hypoxic exposure of the gyrencephalic piglet brain recapitulates CHD-induced impaired cortical development. Hypoxia reduces proliferation and neurogenesis in the SVZ, which is accompanied by reduced cortical growth. We demonstrate a similar reduction in neuroblasts within the SVZ of human infants born with CHD. Our findings demonstrate that SVZ NSPCs contribute to perinatal corticogenesis and suggest that restoration of SVZ NSPCs' neurogenic potential is a candidate therapeutic target for improving cortical growth in CHD.

Abnormal neurogenesis and cortical growth in congenital heart disease.

In the past 2 decades, it has become evident that individuals born with congenital heart disease (CHD) are at risk of developing life-long neurological deficits. Multifactorial risk factors contributing to neurodevelopmental abnormalities associated with CHD have been identified; however, the underlying causes remain largely unknown, and efforts to address this issue have only recently begun. There has been a dramatic shift in focus from newly acquired brain injuries associated with corrective and palliative heart surgery to antenatal and preoperative factors governing altered brain maturation in CHD. In this review, we describe key time windows of development during which the immature brain is vulnerable to injury. Special emphasis is placed on the dynamic nature of cellular events and how CHD may adversely impact the cellular units and networks necessary for proper cognitive and motor function. In addition, we describe current gaps in knowledge and offer perspectives about what can be done to improve our understanding of neurological deficits in CHD. Ultimately, a multidisciplinary approach will be essential to prevent or improve adverse neurodevelopmental outcomes in individuals surviving CHD.

Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation.

Newly developed white matter (WM) injury is common after cardiopulmonary bypass (CPB) in severe/complex congenital heart disease. Fractional anisotropy (FA) allows measurement of macroscopic organization of WM pathology but has rarely been applied after CPB. The aims of our animal study were to define CPB-induced FA alterations and to determine correlations between these changes and cellular events after congenital heart disease surgery.

Microstructural Alterations and Oligodendrocyte Dysmaturation in White Matter After Cardiopulmonary Bypass in a Juvenile Porcine Model.

Congenital heart disease (CHD) is among the most common birth defects. Children with CHD frequently display long-term intellectual and behavioral disability. Emerging evidence indicates that cardiac anomalies lead to a reduction in cerebral oxygenation, which appears to profoundly impact on the maturation of cerebral regions responsible for higher-order cognitive functions. In this review we focus on the potential mechanisms by which dysregulation of cortical neuronal development during early life may lead to the significant cognitive impairments that commonly occur in children with CHD. Further understanding of the mechanisms underlying cortical dysmaturation due to CHD will be necessary to identify strategies for neonatal neuroprotection and for mitigating developmental delays in this patient population.

Article	Year
Prolonged White Matter Inflammation After Cardiopulmonary Bypass and Circulatory Arrest in a Juvenile Porcine Model. The Annals of thoracic surgery\| PubMed ID: 26228605	2015
Hypoxia diminishes the protective function of white-matter astrocytes in the developing brain. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 26412317	2016
Anomalies of Ventriculoarterial Connections and Immature Brain Development. World journal for pediatric & congenital heart surgery\| PubMed ID: 27587497	2016
Abnormal neurogenesis and cortical growth in congenital heart disease. Science translational medicine\| PubMed ID: 28123074	2017
Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation. Circulation research\| PubMed ID: 28302742	2017
Microstructural Alterations and Oligodendrocyte Dysmaturation in White Matter After Cardiopulmonary Bypass in a Juvenile Porcine Model. Journal of the American Heart Association\| PubMed ID: 28862938	2017
Cortical Dysmaturation in Congenital Heart Disease. Trends in neurosciences\| PubMed ID: 30616953	2019

Nobuyuki Ishibashi

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