The Current Status Of Neuroprotection in Congenital Heart Disease Part 2

3. Maternal Neuroprotection-Preclinical Studies for Future Translation

Tetrahydrobiopterin

Tetrahydrobiopterin (BH4) is a key component of neuronal NO synthase function. During cerebral hypoxia, BH4 levels are depleted, leading to neuronal NO synthase uncoupling and a subsequent shift in production from NO to peroxynitrite [59,60]. 

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Research shows that tetrahydrobiopterin can improve memory by increasing acetylcholine levels in the brain. Acetylcholine is a neurotransmitter that plays an important role in normal brain function and memory maintenance. As we age, acetylcholine levels in the body gradually decrease, leading to weakened memory. Tetrahydrobiopterin can help replenish and maintain acetylcholine levels in the brain, thereby enhancing memory.

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The ensuing damage generated by peroxynitrite interaction with DNA and the increased production of reactive oxygen species escalates apoptotic and necrotic cell death, ultimately culminating in neurological injury [61]. 

As such, addressing the exhaustion of BH4 could be advantageous in protecting against WMI injury in the context of hypoxia. A recent study from Romanowicz et al. tested this hypothesis in a hypoxic rat model mimicking 3rd trimester human development [62]. 

In their experiment, they revealed that BH4 treatment prevented chronic hypoxia-associated delayed myelination and diminished mature oligodendrocyte populations while broadly decreasing apoptosis, although not specifically in oligodendrocytes. Crucially, BH4-treated mice showed protected motor-sensory coordination compared to control mice. These data are promising, suggesting possible auxiliary use of an FDA-approved agent for prenatal neuroprotective therapy.

4. Peri-Operative Neuroprotection-Clinical Studies

4.1. Corticosteroids

Corticosteroids have been used in cardiac surgery for more than 60 years. Mechanisms of action include modulation of CPB-associated systemic inflammatory response [63] and possible counteraction of surgery-related relative adrenal insufficiency [64]. 

Several randomized controlled studies have shown that perioperative steroids reduce post-CPB inflammatory markers [65–67] However, the intraoperative use of corticosteroids in corrective congenital cardiac surgery is a highly debated topic [68]. Notwithstanding the numerous trials conducted, the long-term neurological effects of corticosteroids have yet to be studied [69,70]. Recently, a secondary analysis of a two-center, double-blind, randomized, placebo-controlled trial by Zyblewski et al. finally offered a glimpse into the neuroprotective effects of methylprednisolone [71]. 

They found that no significant difference was present in 12-month Bayley-III Developmental scores and post-operative brain injury biomarker levels between patients who received intra-operative methylprednisolone or placebo. Currently, a phase 3 trial investigating the safety and efficacy of methylprednisolone in infants undergoing heart surgery with CPB is ongoing. 

The trial, when completed, will be one of the largest trials ever and will hopefully provide some clear answers regarding the use of corticosteroids for congenital heart surgery. (https://clinicaltrials.gov/ct2/show/NCT03229538, accessed on 3 November 2021).

4.2. Remote Ischemic Preconditioning

Ischemic preconditioning is a protective strategy against ischemia-reperfusion brain injury and is defined as the introduction of transient periods of ischemia before a prolonged period of ischemia such as hypothermic circulatory arrest [72]. The concept of remote ischemic preconditioning (RIPC) is similar but is distinguished by its ability to protect organs separate from the organ being exposed to transient ischemia [72]. 

Several animal studies have demonstrated the effects of RIPC in the protection of cerebral injury from stroke and hypothermic circulatory arrest [72–74]. As a result, numerous clinical trials have been launched to translate these results to the clinical setting. Gaynor et al. recently published a randomized control trial evaluating RIPC and sham interventions in neonates before CPB commencement [75]. 

They identified no significant difference in WMI incidence or change in WMI volume change between groups. Another trial reported a similar lack of difference in neurodevelopmental outcomes when measuring post-operative neuron-specific enolase (NSE) and S100B levels [76]. However, they did observe cardioprotective effects with a decrease in post-operative Troponin1 and Creatine Kinase-MB levels in patients who received RIPC. 

Although these studies provide a greater understanding of the immediate post-operative effects of RIPC, a clinical trial underway in the United States will elaborate on RIPC in a longer-term setting by being the first trial to report 12-month Bayley Developmental Scores in patients with CHD (https://clinicaltrials.gov/ct2/show/NCT01835392, accessed on 3 November 2021).

4.3. Mesenchymal Stromal Cells

Mesenchymal stromal cells (MSC) are a potential therapeutic agent for hypoxic brain injury due to their immunomodulatory and regenerative properties [77]. Various studies have shown that MSCs accelerate white matter remyelination through the activation of endogenous oligodendrocyte progenitors, promote neurogenesis from subventricular zone neural progenitors, and regulate microglia activation after hypoxic-ischemic brain insults [78,79]. 

A recent laboratory study showed that MSC delivery through CPB has the potential to mitigate the effects of CPB on neural stem/progenitor cells and to promote the migration of neuroblasts in the subventricular zone [79]. In that study, MSCs were delivered intraoperatively rather than preoperatively because cardiac surgery's use of CPB provides arterial access which prevents loss of MSCs in the lungs observed during venous injection. The practicality of this method of delivery was recently assessed in an ex vivo CPB model. 

The study found that MSC delivery does not interfere with oxygenator function and does not elicit an immunogenic response in the host [80]. Together these findings have culminated in the initiation of a phase 1 prospective, open-label, single-center study which will determine the safety and feasibility of delivering MSCs in patients with CHD as well as any neurodevelopmental, neuroimaging, and postoperative inflammatory differences (https://clinicaltrials.gov/ct2/show/NCT04236479, accessed on 3 November 2021).

4.4. Erythropoietin

Erythropoietin (EPO) has been investigated as a potential neuroprotective pharmacologic intervention in neonates [81]. Although a previous meta-analysis of four randomized trials by Hendrik et al. demonstrated EPO reduced the risk of neurodevelopmental impairment as measured by the Mental Developmental Index score at an age of 18 to 24 months [82], a recent randomized trial by Juul et al. showed high-dose EPO administration to extremely preterm infants did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age [83]. 

In addition a clinical trial specifically focusing on intraoperative and peri-operative effects of EPO administration failed to show significant neurodevelopment outcome improvement at 1 year of life in neonates who underwent surgery for D-transposition of the great vessels, hypoplastic left heart syndrome, or aortic arch reconstruction, albeit with a small sample size [84]. 

Nevertheless, this study showed that the studied doses of EPO were safe in the neonate and will require future appropriately powered studies to elucidate the true effects of EPO on neurodevelopment in CHD patients following neonatal corrective surgery.

4.5. Dexmedetomidine
Prolonged and repeated use of anesthetics results in an important risk of developmental neurotoxicity in patients with CHD [85,86]. Dexmedetomidine, an α2 adrenergic receptor agonist, has been explored in several studies to test its neuroprotective properties in a CHD population [87–89]. 

Results have demonstrated an association between Dexmedetomidine administration and reduced levels of biomarkers of neurological injury, NES and S-100B, and have led to the initiation of ongoing clinical trials in CHD patient populations (https://clinicaltrials.gov/ct2/show/NCT02492269, accessed on 3 November 2021). 

Additionally other investigations into the utilization of Sevoflurane and specific anesthetic strategies have joined Dexmedetomidine in the clinical trial phase and may produce valuable insights as to how to better promote preservation of neurologic function in CHD patients undergoing cardiac surgery (https://clinicaltrials.gov/ct2/show/NCT03882788, accessed on 3 November 2021, https://clinicaltrials.gov/ct2/show/NCT02492269, accessed on 3 November 2021, https://clinicaltrials.gov/ct2/show/NCT03366597, accessed on 3 November 2021, https://clinicaltrials.gov\protect\leavevmode@ifvmode\kern.5em{}/ct2 /show/NCT04484922, accessed on 3 November 2021). 

Despite the safety and effectiveness of dexmedetomidine, it is known to have cardiac toxicities including bradycardia and hypotension. Dose adjustments should be considered especially with neonates who have reduced clearance [90]

4.6. Tight Glycemic Control

Neurodevelopment has been assessed within the context of perioperative glycemic control. Studies linking neonatal hypoglycemia with adverse neurodevelopmental outcomes and hyperglycemia with microglial activation and neuronal damage to the hippocampal and frontal cortex have established the importance of maintaining a euglycemic state in neonates [91,92]. 

This has led to the idea that there may be a role for tight glycemic control in the care of neonates with CHD. In 2016, Sadhwani et al. reported the results of a two-center, prospective, randomized trial assessing infant neurodevelopment in CHD patients randomized to tight glycemic control or standard care post-operatively, ultimately finding no differences in neurodevelopmental scores at 1 year of age between groups [93]. 

Furthermore, a study and its post hoc analysis by Agus et al. revealed that while infections were reduced in infants greater than 60 days old within the tight glycemic control group, tight glycemic control did not lead to a difference in mortality, length of stay, or overall infection rates [94].

4.7. Allopurinol

Xanthine oxidase is a potent source of free oxygen radicals, especially superoxide. Allopurinol is a xanthine oxidase inhibitor, which reduces the production of oxygen radicals [95]. In a rodent model of acute hypoxia-ischemic brain injury, allopurinol was shown to decrease brain injury through its antioxidant properties grounded in its ability to chelate unbound iron and scavenge free hydroxyl radicals [96]. 

Several clinical studies demonstrated a possible neuroprotective effect in neonates with HIE. Gunes et al. later found in a small randomized clinical trial of neonates with HIE that allopurinol treatment was associated with better developmental outcomes compared with placebo at one year of age [97]. Four to five-year follow-ups of a separate trial of asphyxiated patients broadly showed no difference in mortality or adverse developmental outcomes [98]. 

However, the sub-group analysis revealed a decrease in severe adverse outcomes defined as mortality or severe disability in neonates with moderate HIE who received allopurinol. While the effects of allopurinol in the context of CHD are unknown, these studies have demonstrated potential benefits in animal models and neonates with encephalopathy. 

A prospective randomized phase 3 trial currently taking place in the Netherlands is studying the perioperative and postnatal administration of allopurinol in CHD patients (https://clinicaltrials.gov/ct2/show/NCT04217421, accessed on 3 November 2021).

5. Peri-Operative Neuroprotection-Preclinical Studies for Future Translation

5.1. Inhaled H2

H2 gas is a potential agent capable of addressing CPB-associated neurological injury. It is known that the generation of superoxide anions and subsequent production of toxic hydroxyl radicals occurs in neurodegenerative and neuroinflammatory disorders [99]. Without an endogenous detoxification mechanism to neutralize these hydroxyl radicals, humans are susceptible to cellular injury and increased apoptosis that takes place when reactive oxygen species (ROS) interact with cellular components [100]. H2 gas may be able to fill this deficit through its role as a reducing agent [101]. 

Indeed, improved neurological scores, myocardial function, and survival have been associated with H2 gas treatment in a study comparing H2-treated rodents to rodents treated with only therapeutic hypothermia after 5 min of asphyxia-induced cardiac arrest [102]. These results paired with CPB's association with cerebral hypoxia have led to further study in CPB models. Recently Cole et al. studied continuous pre- and post-operative administration of 2.4% H2 gas in a neonatal swine model of CPB-induced cerebral hypoxic-ischemic injury [103]. 

They found that H2 gas administration led to greater rates of neurologically intact survival, improved neurologic deficit scores, and lower volumes of WMI both by MRI and histological analysis. The positive results of this study have led the authors to suggest possible applications of H2 in CHD heart surgery as well as in the settings of extracorporeal membrane oxygenation, myocardial infarction, and stroke.

5.2. Inhaled Nitric Oxide

In addition to CPB, deep hypothermic circulatory arrest (DHCA) potentiates the development of neurological injury in CHD patients. One of the causes is the disruption of nitric oxide (NO) regulated processes including ischemia/reperfusion, cerebral blood flow autoregulation, and microglial activation [104]. Inhaled NO (iNO) use during pediatric CPB has become popular and several trials have been reported [105,106]. 

These studies demonstrate improvement in postoperative outcomes determined by the anti-inflammatory effects of NO but are not specific to neuronal protection. The use of iNO requires further studies. iNO exerts its neuroprotective effects by preserving cerebral autoregulation, an important factor in preserving oxygen delivery to the brain. This mechanism was better defined in a porcine model of TBI which showed that protection of cerebral autoregulation and subsequent decrease in hippocampal injury can be attributed to inhibition of Endothelin 1 (ET-1) and Extracellular Signal-Regulated Kinase (ERK)/Mitogen-Activated Protein Kinase (MAPK) and simultaneous IL-6 upregulation [107]. 

The translation of these findings to models of cardiac surgery is reasonable as TBI and cardiac surgery share sequelae of impaired cerebral autoregulation and neuronal damage. Kajimoto et al. recently investigated the anti-inflammatory effects of inhaled Nitric Oxide in porcine models specifically in the setting of heart surgery with DHCA [104]. The study showed that iNO-treated pigs had less neuronal degeneration, smaller microglial cell body volume, longer dendrite process length, and a larger quantity of branch segments and terminal branch points. 

Altogether these findings are suggestive of decreased microglial activation and maintain consistency with previous studies of iNO's neuroprotective mechanisms. These results from basic research will likely lead to future clinical studies to determine the effectiveness of iNO in mitigating the deleterious effects of CPB and cardiac surgery on neuronal development.

5.3. Whole Body Periodic Acceleration

The suggested neuroprotective effects of whole-body periodic acceleration (pGz) are also based on its potential to modulate NO-regulated pathways. Defined as a rhythmic pattern of acceleration and deceleration along the head-to-foot axis akin to the motion generated when pushing a stroller back and forth, pGz has been hypothesized to activate endothelial Nitric Oxide Synthase (eNOS) pathways via pulsatile shear stress generation [108]. 

Upregulation of these pathways, in turn, promotes cardiac and neuroprotective effects through their anti-inflammatory and anti-apoptotic properties [109]. A porcine model was used to investigate pGz preconditioning as a strategy for neuroprotection in cardiac surgery and found expected activation of eNOS and increased activation of anti-apoptotic p-Akt/Akt and Bcl/Bax signaling [110].

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