The role of damage-associated molecular patterns in perioperative morbidities and mortalities of pediatric congenital heart diseases

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Project Summary Although the mortality of congenital heart disease (CHD) has been reduced significantly, neonates and infants undergoing cardiac surgery are still at a high risk of morbidity and mortality due to multiple organ injury/failure. In the Kids’ Inpatient Database, neonates and infants occupied about 57% of all the pediatric population undergoing congenital heart surgery and carried significantly higher in-hospital mortality rate (6.9%) compared to other age groups. Delineation of the cause and mechanism of their organ injury/dysfunction would provide an opportunity to modify our clinical approach and develop therapeutic intervention. Damage-associated molecular patterns (DAMPs) are endogenous nuclear, mitochondrial, or cytosolic molecules that have physiological functions inside the cell. However, upon tissue injury, DAMPs are released into the blood stream by injured cells, and recognized by pattern recognition receptors (PRRs) on neutrophils and platelets. DAMPs can cause organ injury by inducing systemic inflammatory responses (SIRS) and hypercoagulable state resulting in thrombosis. The circulating levels of DAMPs correlated to the SIRS and multiple organ injury in patients with trauma and sepsis. Ischemia-reperfusion injury associated with cardiopulmonary bypass (CPB) and subsequent organ injury/dysfunction has been well described. In the majority of cardiac surgical cases for older children and adults, organs other than heart and lung are continuously perfused during CPB, but in complex neonatal and infant surgery, it is not rare to have surgical repair done under complete circulatory arrest or regional perfusion only to the brain, suggesting that multiple organs may be subjected to ischemia- reperfusion injury. Blood transfusion can induce organ injury and is almost always required in neonates and infants due to their small body size relative to the volume of CPB circuit. Our preliminary study showed that the circulating levels of DAMPs interacting with Toll-like receptor (TLR)2/4/9 were elevated after CPB separation in infants and neonates. We hypothesize that 1) in congenital cardiac surgery in neonates and infants, higher DAMP levels are associated with hypercoagulability (thrombosis) as well as greater organ injury/ dysfunction, and 2) DAMPs induce more NETs-mediated thrombosis and organ injury in infants via TLRs that in adults. In Aim 1, we will examine the 1st hypothesis by performing profiling of DAMPs specific to Toll-like receptor (TLR)2, TLR4 and TLR9 and DAMPs for an aggregate of PRRs, and examine the relationship between DAMPs and systemic inflammation, neutrophil signature, coagulation, as well as postoperative outcomes of neonates and infants undergoing surgical repair. In Aim 2, we will test the 2nd hypothesis using human blood in vitro as well as in vivo mouse model. The goals of this proposal are to 1) establish the correlation between the type and levels of DAMPs and postoperative organ dysfunction/ outcomes, and 2) to determine responses to DAMPs including TLR2/4/9 functions in young age. Once we establish the correlation, we will plan to apply an intervention to reduce DAMP loads or therapeutically target responsible PRRs to mitigate organ injury.