Prenatal hypoxemia alters microglial morphology in fetal sheep

Lawrence, Kendall M.; McGovern, Patrick E.; Mejaddam, Ali Y.; Rossidis, Avery C.; Baumgarten, Heron D.; Kim, Aimee G.; Grinspan, Judith B.; Licht, Daniel J.; Radælli, Enrico; Rychik, Jack; Peranteau, William H.; Davey, Mary‐Ann; Flake, Alan W.; Gaynor, J. William

doi:10.1016/j.jtcvs.2019.06.102

Cited by 20 publications

(36 citation statements)

References 33 publications

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“…6 A recent fetal sheep hypoxia model also found reduced neuronal density, myelination, and abnormal microglial morphology after prolonged fetal cerebral hypoxia. 9,42 Fetal brain MRI cannot discern these neural components at the cellular level and lacks resolution to distinguish the subventricular zone from the surrounding intermediate and ventricular zones. However, our findings are consistent with the hypothesis that subplate neurons, premyelinating oligodendrocytes, and neural progenitor cells are selectively vulnerable to substrate-deficiency in fetal CHD.…”

Section: Discussionmentioning

confidence: 99%

Regional Brain Growth Trajectories in Fetuses with Congenital Heart Disease

Rollins

Ortinau

Stopp

et al. 2020

Annals of Neurology

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Objective Congenital heart disease (CHD) is associated with abnormal brain development in utero. We applied innovative fetal magnetic resonance imaging (MRI) techniques to determine whether reduced fetal cerebral substrate delivery impacts the brain globally, or in a region‐specific pattern. Our novel design included two control groups, one with and the other without a family history of CHD, to explore the contribution of shared genes and/or fetal environment to brain development. Methods From 2014 to 2018, we enrolled 179 pregnant women into 4 groups: “HLHS/TGA” fetuses with hypoplastic left heart syndrome (HLHS) or transposition of the great arteries (TGA), diagnoses with lowest fetal cerebral substrate delivery; “CHD‐other,” with other CHD diagnoses; “CHD‐related,” healthy with a CHD family history; and “optimal control,” healthy without a family history. Two MRIs were obtained between 18 and 40 weeks gestation. Random effect regression models assessed group differences in brain volumes and relationships to hemodynamic variables. Results HLHS/TGA (n = 24), CHD‐other (50), and CHD‐related (34) groups each had generally smaller brain volumes than the optimal controls (71). Compared with CHD‐related, the HLHS/TGA group had smaller subplate (−13.3% [standard error = 4.3%], p < 0.01) and intermediate (−13.7% [4.3%], p < 0.01) zones, with a similar trend in ventricular zone (−7.1% [1.9%], p = 0.07). These volumetric reductions were associated with lower cerebral substrate delivery. Interpretation Fetuses with CHD, especially those with lowest cerebral substrate delivery, show a region‐specific pattern of small brain volumes and impaired brain growth before 32 weeks gestation. The brains of fetuses with CHD were more similar to those of CHD‐related than optimal controls, suggesting genetic or environmental factors also contribute. ANN NEUROL 2021;89:143–157

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Section: Discussionmentioning

confidence: 99%

Regional Brain Growth Trajectories in Fetuses with Congenital Heart Disease

Rollins

Ortinau

Stopp

et al. 2020

Annals of Neurology

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“…Hopefully, the knowledge gained will lead to treatment to protect immature brains during pediatric cardiac surgery. As the present report and recent studies indicate, 8,9 animal studies show great promise in elucidating the cellular etiologies of disturbed brain development in the CHD population and establishing new approaches for improvement of neurologic development. Animal studies are elucidating cellular mechanisms causing disturbed brain development in children with congenital heart disease, leading to new therapies, including application of nitric oxide.…”

mentioning

confidence: 57%

“…7 Alterations in fetal cerebral oxygen delivery cause immature and delayed brain development before birth and before surgery. Lawrence and colleagues 8 recently demonstrated with a unique ''artificial womb'' system that prenatal and preoperative chronic hypoxemia result in similar alterations in microglial morphology in fetal sheep. Several clinical studies demonstrate that further brain damage commonly occurs postoperatively in the individual who has brain immaturity due to fetal hypoxia.…”

mentioning

confidence: 99%

Commentary: Nitric oxide: An important contributor to neuroprotection during pediatric cardiac surgery

Ishibashi

Jonas

2021

The Journal of Thoracic and Cardiovascular Surgery

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Microglia are the resident immune cells of the brain. They play a central role in neural immune function in reacting to a wide variety of brain insults. In addition, recent findings in developmental neuroscience highlight the importance of microglia for maturation and normal function of the central nervous system. 1 We have previously shown that cardiopulmonary bypass (CPB) and hypothermic circulatory arrest cause prolonged microglia expansion. 2 The article by Kajimoto and colleagues 3 from Seattle Children's Hospital in this issue of the Journal describes an interesting laboratory study using a translational piglet model. Study animals were ventilated with 20 parts per million of nitric oxide during reperfusion for approximately 3 hours before sacrifice. Subsequent morphologic analysis suggests that inhaled nitric oxide reduced microglial activation after CPB in the hippocampus.Nitric oxide use during infant and pediatric CPB has become increasingly popular clinically following publication of a large prospective randomized clinical trial. 4 The beneficial effects of nitric oxide were particularly apparent in patients younger than 6 weeks of age, who had significantly reduced length of intensive care unit stay and low cardiac output syndrome. In another clinical study, 5 there was improved myocardial protection, improved fluid balance, and improved postoperative intensive care unit course consistent with a general anti-inflammatory effect of nitric oxide that mitigates the systemic inflammatory response to CPB. We have also demonstrated a neuroprotective effect of nitric oxide during CPB and deep hypothermic circulatory arrest using magnetic resonance spectroscopy. 6 The present report further supports the notion that nitric oxide can be an important contributor to protect neurons and glial cells from insults associated with CPB and deep hypothermic circulatory arrest.It is now clear that the etiology of neurologic deficits in children with congenital heart disease (CHD) is cumulative and multifactorial. 7 Alterations in fetal cerebral oxygen delivery cause immature and delayed brain development before birth and before surgery. Lawrence and colleagues 8 recently demonstrated with a unique ''artificial womb'' system that prenatal and preoperative chronic hypoxemia result in similar alterations in microglial morphology in fetal sheep. Several clinical studies demonstrate that further brain damage commonly occurs postoperatively in the individual who has brain immaturity due to fetal hypoxia. Therefore, future studies will be required to determine the effects of cardiac surgery on the brain that contains microglia that are already activated and toxic to develop the optimal regimen of nitric oxide for neuroprotection.

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“…We congratulate Lawrence and colleagues 7 for their contributions in their effort to find causal factors for wellproven neurodevelopmental delay in patients with congenital heart disease.…”

Section: Lok Sinha MD Nobuyuki Ishibashi Md and Can Yerebakan Mdmentioning

confidence: 99%