scholarly journals Delayed maturation of the structural brain connectome in neonates with congenital heart disease

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Maria Feldmann ◽  
Ting Guo ◽  
Steven P Miller ◽  
Walter Knirsch ◽  
Raimund Kottke ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
White Matter ◽  
Congenital Heart ◽  
White Matter Injury ◽  
Network Development ◽  
Brain Connectome ◽  
Structural Network ◽  
Term Newborns ◽  
Structural Brain

Abstract There is emerging evidence for delayed brain development in neonates with congenital heart disease. We hypothesize that the perioperative development of the structural brain connectome is a proxy to such delays. Therefore, we set out to quantify the alterations and longitudinal pre- to post-operative changes in the connectome in congenital heart disease neonates relative to healthy term newborns and assess factors contributing to disturbed perioperative network development. In this prospective cohort study, 114 term neonates with congenital heart disease underwent cardiac surgery at the University Children’s Hospital Zurich. Forty-six healthy term newborns were included as controls. Pre- and post-operative structural connectomes were derived from mean fractional anisotropy values of fibre pathways traced using diffusion MR tractography. Graph theory parameters calculated across a proportional cost threshold range were compared between groups by multi-threshold permutation correction adjusting for confounders. Network-based statistic was calculated for edgewise network comparison. White-matter injury volume was quantified on 3D T1-weighted images. Random coefficient mixed models with interaction terms of (i) cardiac subtype and (ii) injury volume with post-menstrual age at MRI, respectively, were built to assess modifying effects on network development. Pre- and post-operatively, at the global level, efficiency, indicative of network integration, was lower in heart disease neonates than controls. In contrast, local efficiency and transitivity, indicative of network segregation, were higher compared to controls (all P < 0.025 for one-sided t-tests). Pre-operatively, these group differences were also found across multiple widespread nodes (all P < 0.025, accounting for multiple comparison), whereas post-operatively nodal differences were not evident. At the edge-level, the majority of weaker connections in heart disease neonates compared to controls involved inter-hemispheric connections (66.7% pre-operatively; 54.5% post-operatively). A trend showing a more rapid pre- to post-operative decrease in local efficiency was found in class I cardiac sub-type (biventricular defect without aortic arch obstruction) compared to controls. In congenital heart disease neonates, larger white-matter injury volume was associated with lower strength (P = 0.0026) and global efficiency (P = 0.0097). The maturation of the structural connectome is delayed in congenital heart disease neonates, with a pattern of lower structural integration and higher segregation compared to controls. Trend-level evidence indicated that normalized post-operative cardiac physiology in class I sub-types might improve structural network topology. In contrast, the burden of white-matter injury negatively impacts network strength and integration. Further research is needed to elucidate how aberrant structural network development in congenital heart disease represents neural correlates of later neurodevelopmental impairments.

scholarly journals Delayed maturation of the structural brain connectome in neonates with congenital heart disease

2020 ◽  
Author(s):  
Maria Feldmann ◽  
Ting Guo ◽  
Steven P. Miller ◽  
Walter Knirsch ◽  
Raimund Kottke ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Class I ◽  
Network Development ◽  
Local Efficiency ◽  
Brain Connectome ◽  
Structural Network ◽  
Term Newborns ◽  
Structural Brain

There is emerging evidence for delayed brain development in neonates with congenital heart disease (CHD). We hypothesize that the perioperative development of the structural brain connectome is a proxy to such delays. Therefore, we set out to quantify the alterations and longitudinal pre- to postoperative changes in the connectome in CHD neonates and assess risk factors for disturbed perioperative network development relative to healthy term newborns. In this prospective cohort study, 114 term neonates with CHD underwent cardiac surgery at the University Children’s Hospital Zurich. Forty-six healthy term newborns were included as controls. Pre- and postoperative structural connectomes were derived from mean fractional anisotropy values of fibre pathways traced using diffusion tractography. Graph theory parameters calculated across a range of proportional cost thresholds were compared between groups by multi-threshold permutation correction adjusting for con-founders. Network based statistic was calculated for edgewise network comparison. White matter injury (WMI) volume was quantified on 3D T1-weighted images. Random coefficient mixed models with interaction terms of (i) CHD subtype and (ii) WMI volume with postmenstrual age at MRI respectively were built to assess modifying effects on network development. Pre- and postoperatively, at the global level, efficiency, indicative of network integration, was higher in controls compared to CHD neonates. In contrast, local efficiency and transitivity, indicative of network segregation, were higher in CHD neonates compared to controls (all p<0.025 for one-sided t-tests). Preoperatively these group differences were also found across multiple widespread nodes (all p<0.025, accounting for multiple comparison), whereas postoperatively nodal differences were not evident. At the edge-level, the majority of weaker connections in CHD neonates compared to controls involved interhemispheric connections (66.7% preoperatively; 54.5% postoperatively). A trend showing a more rapid pre- to postoperative decrease in local efficiency was found in class I CHD neonates compared to controls. In CHD neonates, larger WMI volume was associated with lower strength (p=0.0026) and global efficiency (p=0.0097). The maturation of the structural connectome is delayed in neonates with CHD, with a pattern of lower structural integration and higher segregation compared to healthy controls. Trend-level evidence indicated that normalized postoperative cardiac physiology in class I CHD neonates might improve structural network topology. In contrast, the degree of WMI burden negatively impacts network strength and integration. Further research is needed to elucidate how aberrant structural network development in CHD represents neural correlates of later neurodevelopmental impairments.

Abstract 19890: Pre-operative Cerebral Hemodynamics From Birth Until Surgery in Neonates With Critical Congenital Heart Disease

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jennifer M Lynch ◽  
John J Newland ◽  
Madeline Winters ◽  
David R Busch ◽  
Ann L McCarthy ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
White Matter ◽  
Congenital Heart ◽  
White Matter Injury ◽  
Therapeutic Interventions ◽  
Metabolic Demand ◽  
Critical Congenital Heart Disease ◽  
Therapeutic Algorithms ◽  
Increased Risk

Introduction: Neonates with critical congenital heart disease (CHD) exhibit a high prevalence of white matter injury (WMI). Recent work in neonates with hypoplastic left heart syndrome has shown that a longer wait from birth to surgery was associated with lower cerebral tissue oxygen saturations (StO2) on the morning of surgery and an increased risk for postoperative white matter injury (WMI). Understanding the daily preoperative changes in cerebral physiology during this vulnerable period may lead to new therapeutic algorithms aimed at prevention of WMI. Methods: Term neonates with critical CHD were recruited for this study. Frequency domain diffuse optical spectroscopy was employed to noninvasively quantify StO2. Daily StO2 measurements were made from day of recruitment until the day of surgery. Results: We studied 37 neonates with critical CHD. Operations were performed at 1-8 days of life. Non-elective reasons for timing of surgery resulted only in earlier surgery in this cohort. The subjects were placed in 2 groups depending on if they had a normal arch (N=20) or obstructed arch (N=17). In a linear mixed-effects model, StO2 decreased as a function of time from birth but was not specific to diagnostic group. Conclusions: Observed longitudinal daily decline in StO2 from birth until surgery supports our earlier findings and extends them to other groups of CHD. These results suggest that reported increases in risk for WMI with time-to-surgery could be due to mismatched oxygen delivery to metabolic demand. Therapeutic interventions such as increasing cerebral blood flow or decreasing cerebral oxygen demand may be considered when earlier surgery is not possible.

scholarly journals Neuroimaging findings in newborns with congenital heart disease prior to surgery: an observational study

2019 ◽  
Vol 104 (11) ◽  
pp. 1042-1048 ◽  
Author(s):  
Christopher J Kelly ◽  
Sophie Arulkumaran ◽  
Catarina Tristão Pereira ◽  
Lucilio Cordero-Grande ◽  
Emer J Hughes ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
White Matter ◽  
Observational Study ◽  
Congenital Heart ◽  
Brain Mri ◽  
Brain Lesions ◽  
Cerebral Injury ◽  
White Matter Injury ◽  
Cerebellar Haemorrhage

ObjectivesNeurodevelopmental impairment has become the most important comorbidity in infants with congenital heart disease (CHD). We aimed to (1) investigate the burden of brain lesions in infants with CHD prior to surgery and (2) explore clinical factors associated with injury.Study designProspective observational study.SettingSingle centre UK tertiary neonatal intensive care unit.Patients70 newborn infants with critical or serious CHD underwent brain MRI prior to surgery.Main outcome measuresPrevalence of cerebral injury including arterial ischaemic strokes (AIS), white matter injury (WMI) and intracranial haemorrhage.ResultsBrain lesions were observed in 39% of subjects (95% CI 28% to 50%). WMI was identified in 33% (95% CI 23% to 45%), subdural haemorrhage without mass effect in 33% (95% CI 23% to 45%), cerebellar haemorrhage in 9% (95% CI 4% to 18%) and AIS in 4% (95% CI 1.5% to 12%). WMI was distributed widely throughout the brain, particularly involving the frontal white matter, optic radiations and corona radiata. WMI exhibited restricted diffusion in 48% of cases. AIS was only observed in infants with transposition of the great arteries (TGA) who had previously undergone balloon atrial septostomy (BAS). AIS was identified in 23% (95% CI 8% to 50%) of infants with TGA who underwent BAS, compared with 0% (95% CI 0% to 20%) who did not.ConclusionsCerebral injury in newborns with CHD prior to surgery is common.

scholarly journals White Matter Injury in Newborns With Congenital Heart Disease: A Diffusion Tensor Imaging Study

2014 ◽  
Vol 51 (3) ◽  
pp. 377-383 ◽  
Author(s):  
Sarah B. Mulkey ◽  
Xiawei Ou ◽  
Raghu H. Ramakrishnaiah ◽  
Charles M. Glasier ◽  
Christopher J. Swearingen ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Diffusion Tensor Imaging ◽  
White Matter ◽  
Congenital Heart ◽  
Diffusion Tensor ◽  
Imaging Study ◽  
White Matter Injury ◽  
Diffusion Tensor Imaging Study

scholarly journals Association between Subcortical Morphology and Cerebral White Matter Energy Metabolism in Neonates with Congenital Heart Disease

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Nina Gertsvolf ◽  
Jodie K. Votava-Smith ◽  
Rafael Ceschin ◽  
Sylvia del Castillo ◽  
Vince Lee ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Energy Metabolism ◽  
White Matter ◽  
Congenital Heart ◽  
Cerebral White Matter ◽  
Matter Energy

TREATMENT WITH TETRAHYDROBIOPTERIN ACCELERATES WHITE MATTER MATURATION IN A MOUSE MODEL OF PRENATAL HYPOXIA SIMULATING CONGENITAL HEART DISEASE

2018 ◽  
Vol 71 (11) ◽  
pp. A586
Author(s):  
Jennifer Romanowicz ◽  
Ludmila Korotcova ◽  
Shruti D. Ramachandra ◽  
Paul D. Morton ◽  
Amrita Cheema ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
White Matter ◽  
Mouse Model ◽  
Congenital Heart ◽  
Prenatal Hypoxia ◽  
White Matter Maturation

Abstract 18446: Treatment With Tetrahydrobiopterin Decreases White Matter Injury in a Mouse Model for In Utero Hypoxia in Congenital Heart Disease

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jennifer Romanowicz ◽  
Ludmila Korotcova ◽  
Paul Morton ◽  
Amrita Cheema ◽  
Vittorio Gallo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
White Matter ◽  
Nitric Oxide Synthase ◽  
Congenital Heart ◽  
In Utero ◽  
Complex Congenital Heart Disease ◽  
Brain White Matter ◽  
Oxide Synthase

Introduction: Reduced oxygen delivery in complex congenital heart disease (CHD) can lead to brain white matter (WM) injury in utero. Currently, no treatment exists. Tetrahydrobiopterin (BH4) is a cofactor for neuronal nitric oxide synthase, and in its absence, toxic peroxynitrite production is favored. Hypoxia activates nitric oxide synthase, which reduces BH4 availability. Hypothesis: Decreased BH4 levels underlie WM injury in the fetus with CHD, and treatment with BH4 will reduce this injury. Methods: Mice were divided into three groups: normoxic controls (Nx), hypoxic (Hx), and hypoxic with BH4 treatment (Hx-BH4). Hx and Hx-BH4 mice were kept at 10.5% FiO2 from postnatal day 3 to 11--a period of WM development equivalent to the 3rd trimester in humans. Brain BH4 levels were quantified and compared between Nx (n=11) and Hx (n=12). Densities of cells expressing CNP (marker of oligodendrocytes--cells responsible for myelination) and Caspase3 (apoptosis marker) were quantified in three WM regions and compared between groups (n=3-6 each). Western blot detected myelin basic protein (myelin marker). Results: Brain BH4 levels were depleted in Hx compared to Nx (-38.4%, p=0.02). CNP+ oligodendrocytes increased after Hx compared to Nx (Fig.1a), consistent with hypoxia-induced proliferation seen previously. BH4 treatment did not limit this proliferation (Fig.1a). Hx had increased WM apoptosis (Fig.1b), which decreased with BH4 treatment (Fig.1b). Remarkably, there was no difference in WM caspase3+ cells between Nx and Hx-BH4 (Fig.1b). There was no difference in effect across WM region. Finally, loss of myelin with hypoxia was mitigated by BH4 treatment (Fig.1c). Conclusions: Our results show that suboptimal BH4 levels influence hypoxic WM injury. BH4 treatment of phenylketonuria is safe during pregnancy, thus maternal BH4 therapy is feasible. Our data demonstrate that repurposing BH4 for use during fetal brain development has potential to limit WM injury in CHD.

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