The Current Status Of Neuroprotection in Congenital Heart Disease Part 1

Abstract: 

Neurological deficits are a serious and common sequelae of congenital heart disease (CHD). While their underlying mechanisms have not been fully characterized, their manifestations are well-known and understood to persist through adulthood.

There is a certain relationship between neurological deficits and memory, but not all neurological deficits will hurt memory. Some individuals with neurological deficits can avoid or reduce memory problems through active coping and appropriate treatment.

For some memory impairments caused by neurological deficits, such as Alzheimer's disease, Parkinson's disease, etc., although they will lead to a severe decline in cognitive function, they can still be restored through some effective pharmacological treatments, cognitive training, and rehabilitation treatments. It can greatly reduce patients' symptoms and improve their quality of life.

In addition, some positive behaviors and methods can also help us improve memory, such as good sleeping habits, healthy eating, appropriate exercise, and maintaining an optimistic attitude. These can all be changed and improved through your efforts.

In short, although there is a certain relationship between neurological deficits and memory, as long as we actively respond and treat appropriately, and adopt a positive lifestyle, we can improve our memory and quality of life and welcome a better future. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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The development of therapies to address or prevent these deficits is critical to attenuate future morbidity and improve quality of life. In this review, we aim to summarize the current status of neuroprotective therapy in CHD. 

Through an exploration of present research in the pre-operative, intra-operative, and post-operative phases of patient management, we will describe existing clinical and bench efforts as well as current endeavors underway within this research area.

Keywords: congenital heart disease; neuroprotection; brain; cardiac anomalies; neurological deficit.

1. Introduction

Congenital Heart Disease (CHD) is the leading cause of death in infancy out of all known birth defects, occurring in 8 out of 1000 live births [1,2]. However, the mortality of CHD has trended downward as a result of improved diagnostic modalities, better surgical techniques, and advances in intensive care [3,4]. 

Now, most children affected by CHD will reach adulthood evidenced by the over 50% increase in adult prevalence rates from the years 2000 to 2010 [3]. This increase in survival rates has led to a corresponding shift in research focus from short-term survival to long-term morbidity and quality of life outcomes [5,6]. 

Neurodevelopmental deficits are a common and crucial sequela in patients with critical CHD, contributing to long-term morbidity that starts in infancy and persists into adulthood [3,6–10]. The prevalence and severity of such deficits are correlated with greater complexity of CHD and are estimated to reach an incidence of approximately 50% in infants [6,11]. 

Specifically, manifestations of neurodevelopmental deficits include impaired cognition, gross and fine motor skills, social interaction, communication, and executive function as well as impulsive behavior and inattention [6,12–14] as presented in the following clinical studies.

1.1. Boston Circulatory Arrest Trial

Longitudinal studies following patients with CHD throughout childhood have delivered valuable information about neurodevelopment. The Boston Circulatory Arrest Trial was a single-center longitudinal study that followed a cohort of patients with retrotransposition of the great arteries (d-TGA) who underwent the arterial switch operation (NCT03073122) [10,15,16]. 

In their patients' infancy, Bellinger et al. reported numerous neurodevelopmental challenges including lower than normal scores on the Bayley Scales of Infant Development and substandard expressive language capabilities [17]. Childhood years continued this pattern of abnormal neurodevelopment evident in observations of lower intelligence quotient (IQ), worse mathematics and reading scores, poorer memory scores, attenuated visual-spatial skills, increased prevalence of behavioral problems, and immature motor function. 

Importantly noted was the finding that over a third of the cohort had received remedial services in school [13,14]. Age 16 follow-up demonstrated similar findings with persistent neuro-deficits and impaired psychosocial, physical, and emotional health [10,18]. 

Another study conducted at Boston Children's Hospital observed similar neurodevelopmental outcomes in a cohort of 156 patients who had undergone Fontan procedures for single ventricle pathophysiology. Lower IQ scores, individual achievement, memory, and executive function as well as an increased incidence of attention deficit hyperactivity disorder (ADHD), anxiety disorders, and MRI abnormalities paralleled the d-TGA cohort's findings [19,20].

1.2. Single Ventricle Reconstruction Trial

Results consistent with these were also observed in the Single Ventricle Reconstruction (SVR) trial (NCT02692443). Recently published 6-year outcome data from the SVR trial revealed impairments in adaptive behavior, quality of life, functional status, and adaptive skills within a cohort of newborns with single right ventricular anomalies [21,22]. 

The incidence of these deficits surpasses that of the normal population with mild and severe motor disabilities occurring at 6 and 11 times the normal incidence rate respectively while the odds ratio for parent-reported executive function impairment has been reported to be 4.37 when compared to normative controls [23,24].
These reports are supported by several other studies describing similar results for cognitive, motor, and behavioral aspects of neurodevelopment [25–30]. Indeed, these deficits are common and are not specific to a single CHD subtype.

1.3. Risk Factors Associated with Neurological Deficits in Children with CHD

The causes of neurodevelopmental deficits associated with CHD are cumulative, multifactorial, and synergistic (Figure 1) [5]. Genetic components are unquestionably a broad underlying factor in the development of CHD and also a key contributor to a patient's vulnerability to neurologic injury [5,31,32]. 

Additionally in the in utero phase, chronic fetal hypoxia resulting from abnormal physiology and altered regulatory pathways is largely responsible for immature brain development [33,34]. 

The establishment of a link between cerebral hypoxia and reduced brain volumes as well as poorer neurodevelopmental outcomes in CHD patients has been a crucial element in the push to develop pre-operative neuroprotective treatment aimed at addressing insufficient oxygen delivery to the fetus (Figure 2) [34,35].

Approximately 25% of neonates with CHD will require corrective cardiac surgery within their first year of life and will be at risk for neurological injury associated with cardiac surgery particularly when cardiopulmonary bypass (CPB) is required [36–38]. 

CPB causes systemic inflammatory response syndrome, ischemia-reperfusion, and reoxygenation injury as well as subsequent microglia-mediated inflammation and enhanced oxidative stress, all of which contribute to the high incidence of white matter injury (WMI) observed in neonates and infants with CHD after surgery [39,40]. Although yet to be clearly defined, the mechanisms behind WMI are potential targets for neuroprotective therapy. Post-operatively, factors contributing to neurodevelopmental delay are more broad. 

Environment, socioeconomic status, and incidence of infections are factors that influence the maturation and growth of all infants, not only those with CHD [5,41–44]. Nonetheless, their significance in a patient population already at risk of neurodevelopmental deficits is elevated and must be explored to determine optimal methods of promoting healthy growth.

The gravity and prevalence of neurodevelopmental deficits within the CHD population necessitate therapies at each phase of patient management to prevent neurological injury and promote neurodevelopment. Here, we review recent studies that illustrate the current status of neuroprotective treatment within CHD through analysis of existing strategies within the maternal, peri-operative, and post-operative stages of patient care (Table 1, Figure 3).

2. Maternal Neuroprotection-Clinical Studies

2.1. Maternal Hyperoxia

Chronic hypoxia is a key disruptor of fetal neurodevelopment in CHD. Recently, Lawrence et al. elucidated the role of chronic hypoxia in neurological injury by employing a fetal sheep model. 

They showed that chronic hypoxia in their artificial womb model reduced neuronal density and impaired myelination in the fetus resembling similar findings observed in neonates with CHD [45]. 

These neurological insults may be attenuated by supplementing the oxygen supply. Previous studies have investigated the possibility of increasing oxygen levels in the fetus through maternal hyperoxygenation and have confirmed its feasibility through observed resultant increases in fetal oxygenation [46,47]. 

One clinical study in Canada has recently been initiated to investigate the effects of supplemental maternal oxygen during the 3rd trimester in mothers whose fetuses have been identified as having some form of CHD (https://clinicaltrials.gov/\protect\leavevmode@ifvmode\ kern.5em{}ct2/show/NCT03944837, accessed on 3 November 2021). 10 to 15 L/min of oxygen by mask is given which briefly increases fetal oxygen levels to those reached in the newborn with spontaneous breathing. 

Although neurodevelopment is not directly defined as an endpoint, outcome measures of cerebral oxygen delivery, cerebral oxygen consumption, oximetry of major vessels, fetal brain volumetry, and brain size will provide valuable information about the physiological effects of maternal hyperoxygenation.

2.2. Progesterone

Although its exact cellular mechanism is still unknown, several animal studies have suggested that progesterone and its metabolites have a neuroprotective role in the developing brain [48]. In an acute hypoxia sheep model, allopregnanolone, a metabolite of progesterone through the enzymatic action of 5α-reductase, was found to be upregulated and correlated with an observed neuroprotective response after the introduction of acute brain hypoxia [49]. 

A separate experiment confirmed this observation by observing a subsequent increase in neurological injury after inhibition of 5α-reductase via finasteride [50]. In addition, the same group also showed no increase in the fetal sheep brain allopregnanolone concentration after 20 days of chronic hypoxia created with a model of placental insufficiency in pregnant sheep, indicating a possible beneficial effect of allopregnanolone usage even in a chronic hypoxic state [51]. 

Investigation of WMI and brain immaturity in a neonatal rat model of chronic hypoxia, applied to mimic infants with cyanotic CHD, yielded similarly positive results. Notably, an increase in brain weights and greater motor and coordination abilities were observed in the progesterone-treated group compared to controls [48]. Furthermore, progesterone has been implicated in oligodendrocyte maturation, oligodendrocyte progenitor cell proliferation, and myelination promotion through direct interaction with progesterone receptors [52]. 

As these effects of progesterone address cellular mechanisms of neurological injury observed in CHD, clinical translation of these studies has been pursued. Currently, a randomized phase 2 trial is underway in the USA to evaluate 3rd-trimester Progesterone administration to a mother carrying a fetus with CHD (https://clinicaltrials.gov/ct2/show/NCT02133573, accessed on 3 November 2021). 

With endpoints specifically studying neurodevelopmental scores and brain maturation via MRI, a more thorough understanding of progesterone's effects on neuroprotection will be achieved at its conclusion.

2.3. Topiramate Prophylaxis

Topiramate is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist approved for the treatment of partial and generalized epileptic seizures. Recently it has been shown that Topiramate offers a potential therapy for hypoxic-ischemic encephalopathy by reducing underlying over-excitatory mechanisms of neural injury through increased gamma butyric acid activity (GABA) and decreased glutamate activity to address excessive glutamate production in the brain [53]. 

Combining study results that have demonstrated its neuroprotective capacity and ability to preserve oligodendrocytes in traumatic brain injury (TBI), stroke, epilepsy, and periventricular leukomalacia models with reports of improved long-term cognition, memory, and attenuated WMI when used in tandem with therapeutic hypothermia has propelled Topiramate to the clinical trial phase [54–57]. 

Filippi et al. recently reported the results of a phase 2 multi-center randomized control trial evaluating topiramate in neonates with hypoxic-ischemic encephalopathy (HIE) [58]. In their study, they observed a non-significant downward trend in rates of epilepsy development in the topiramate-treated group compared to controls but no significant difference in mortality and severe neurodevelopmental disability. 

However, this study was limited by its small number in the original cohort and the one-third reduction in sample size due to incorrect randomization. 

A separate study completed in 2017 studying the effects of topiramate prophylaxis in infants with CHD undergoing cardiac surgery will provide more information about the applicability of topiramate specifically in CHD as well as the future direction of this intervention (https://clinicaltrials.gov/ct2/show/NCT01426542, accessed on 3 November 2021).

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