Can Erythropoietin Reduce Hypoxemic Neurological Damages in Neonates With Congenital Heart Defects?

Abstract

Congenital heart defects (CHD), the most common cause of birth defects with increasing birth prevalence, affect nearly 1% of live births worldwide. Cyanotic CHD are characterized by hypoxemia, with subsequent reduced oxygen delivery to the brain, especially critical during brain development, beginning in the fetus and continuing through the neonatal period. Therefore, neonates with CHD carry a high risk for neurological comorbidities, even more frequently when there are associated underlying genetic disorders. We review the currently available knowledge on potential prevention strategies to reduce brain damage induced by hypoxemia during fetal development and immediately after birth, and the role of erythropoietin (EPO) as a potential adjunctive treatment. Maternal hyper-oxygenation had been studied as a potential therapeutic to improve fetal oxygenation. Despite demonstrating some effectiveness, maternal hyper-oxygenation has proven to be impractical for extensive clinical application, thus prompting the investigation of specific pathways for pharmacological intervention. Among those, the role of antioxidant pathways and Hypoxia Inducible Factors (HIF) have been studied for their involvement in the protective response to hypoxic injury. One of the proteins induced by HIF, EPO, has properties of being anti-apoptotic, antioxidant, and protective for neurons, astrocytes, and oligodendrocytes. In human trials, EPO administration in neonates with hypoxic ischemic encephalopathy (HIE) significantly reduced the neurological hypoxemic damages in several reported studies. Currently, it is unknown if the mechanisms of pathophysiology of cyanotic CHD are like HIE. Neonates with cyanotic CHD are exposed to both chronic hypoxemia and episodes of acute ischemia-reperfusion injury when undergo cardiopulmonary bypass surgery requiring aortic cross-clamp and general anesthesia. Our review supports future trials to evaluate the potential efficiency of EPO in reducing the hypoxemic neurologic damages in neonates with CHD. Furthermore, it suggests the need to identify early biomarkers of hypoxia-induced neurological damage, which must be sensitive to the neuroprotective effects of EPO.

The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia

“…In summary, the bioenergetic changes associated with hypoxia, the logical consequences of the aerobic-to-anaerobic switch, may favor hypoxia adaptation, but the unavailability of methods to directly measure the O 2 delivery in vivo at the mitochondrial level without the use of indirect mathematical calculations prevents an appreciation of how the bioenergetic changes may impact hypoxia adaptation. In addition, the role of pleiotropic factors that may modulate aerobic and anaerobic energy production, such as EPO, although already hypothesized [ 90 ], is still to be worked out.…”

Role of hypoxia-inducible factor in postoperative delirium of aged patients: A review

“…[16] A novel HIF stabilizer, FG4592 (Roxadustat), enhanced renal vascular regeneration, possibly via activating the HIF-1α/VEGFA/ VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). [68][69][70]…”

“…Acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. [69] Disrupted brain energy metabolism may be associated with postoperative delirium. [70][71][72][73][74] HIF-1 plays a very important role in energy metabolism.…”