Brain injury with systemic inflammation in newborns with congenital heart disease undergoing heart surgery

Abstract

The potential role of systemic inflammation on brain injury in newborns with congenital heart disease (CHD) was assessed by measuring levels of central nervous system (CNS)-derived proteins in serum prior to and following cardiac surgery. A total of 23 newborns (gestational age, 39±1 weeks) with a diagnosis of CHD that required cardiac surgery with cardiopulmonary bypass (CPB) were enrolled in the current study. Serum samples were collected immediately prior to surgery and 2, 24 and 48 h following CPB, and serum levels of phosphorylated neurofilament-heavy subunit (pNF-H), neuron-specific enolase (NSE) and S100B were analyzed. Systemic inflammation was assessed by measuring serum concentrations of complement C5a and complement sC5b9, and the following cytokines: Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL12p70, interferon γ and tumor necrosis factor (TNF)-α. Analysis of cord blood from normal term deliveries (n=26) provided surrogate normative values for newborns. pNF-H and S100B were 2.4- to 2.8-fold higher (P<0.0001) in patient sera than in cord blood prior to surgery and remained elevated following CPB. Pre-surgical serum pNF-H and S100B levels directly correlated with interleukin (IL)-12p70 (ρ=0.442, P<0.05). pNF-H was inversely correlated with arterial pO2 prior to surgery (ρ=−0.493, P=0.01) and directly correlated with arterial pCO2 post-CPB (ρ=0.426, P<0.05), suggesting that tissue hypoxia and inflammation contribute to blood brain barrier (BBB) dysfunction and neuronal injury. Serum IL12p70, IL-6, IL-8, IL-10 and TNF-α levels were significantly higher in patients than in normal cord blood and levels of these cytokines increased following CPB (P<0.001). Activation of complement was observed in all patients prior to surgery, and serum C5a and sC5b9 remained elevated up to 48 h post-surgery. Furthermore, they were correlated (P<0.05) with low arterial pO2, high pCO2 and elevated arterial pressure in the postoperative period. Length of mechanical ventilation was associated directly with post-surgery serum IL-12p70 and IL-8 concentrations (P<0.05). Elevated serum concentrations of pNF-H and S100B in neonates with CHD suggest BBB dysfunction and CNS injury, with concurrent hypoxemia and an activated inflammatory response potentiating this effect.

Antenatal and Perioperative Mechanisms of Global Neurological Injury in Congenital Heart Disease

“…While surgery by itself causes a systemic inflammatory response, exposure of blood cells to the circuit surface during CPB initiates an even stronger systemic inflammatory reaction, which worsens HI reperfusion injury [ 132 , 137 – 139 ]. Infants with CHD have a preoperative increase in neuron-specific marker phosphorylated neurofilament heavy and the calcium-binding protein S100B, and detectable levels of neuron-specific enolase (NSE) in their plasma, which suggest a compromised blood–brain barrier.…”

“…Although S100B is not exclusively a neuronal marker, neuronal damage is the most likely source of elevated plasma S100B levels. Elevated S100B release from other sources such as adipose tissues is unlikely because the adipose marker adiponectin remains constant in the perioperative period [ 137 , 140 , 141 ]. CHD also increases serum levels of the complement proteins C5a and sC5b9 and the inflammatory cytokines IL-12p70, IL‑6, IL‑8, IL‑10 and TNF‑α levels preoperatively.…”

“…CHD also increases serum levels of the complement proteins C5a and sC5b9 and the inflammatory cytokines IL-12p70, IL‑6, IL‑8, IL‑10 and TNF‑α levels preoperatively. CPB further increases cytokine levels and complement remains activated after surgery [ 137 ]. The use of modified ultrafiltration during CPB reduces inflammation and morbidity after surgery [ 132 ].…”

Shear stress associated with cardiopulmonary bypass induces expression of inflammatory cytokines and necroptosis in monocytes

“…Systemic inflammation has been tied to longer intensive care unit and hospital stays ( 9 ), as well as postoperative complications such as organ damage and dysfunction ( 10 ). Specifically, elevated IL-8 levels in neonatal patients were associated with prolonged hospital stay ( 9 ), myocardial injury ( 8 , 11 ), and length of mechanical ventilation ( 12 ). High levels of TNF-α after CPB are associated with reduced glomerular filtration rate and renal insufficiency ( 13 ).…”

MEF2C loss-of-function mutation contributes to congenital heart defects

“…As a group of structural abnormalities of the heart, CHD is usually classified into 25 different clinical types, including ventricular septal defect (VSD), atrial septal defect, atrioventricular canal defect, patent ductus arteriosus (PDA), tetralogy of Fallot, double outlet right ventricle, transposition of the great arteries, interrupted aortic arch, aortic stenosis, truncus arteriosus, coarctation of the aorta, tricuspid atresia, pulmonary stenosis (PS), pulmonary atresia, hypoplastic left heart, single ventricle, and abnormal pulmonary venous connection 1 . Although mild cardiovascular anomalies can resolve spontaneously 1 , major defects may require timely surgical treatment and otherwise can result in degraded health-related quality of life 4 , reduced exercise performance 5 , retarded central neural development and brain injury 6 - 9 , cerebral and pulmonary thromboembolism 10 , 11 , infective endocarditis 12 - 16 , pulmonary arterial hypertension 17 - 22 , chronic heart failure 23 - 26 , supraventricular and ventricular arrhythmias 27 - 31 and sudden cardiac death 32 - 37 . Therefore, CHD represents the most prevalent cause of infant birth defect-related demises, with roughly 24% of infants who died of a birth defect having a cardiovascular deformity 1 .…”