Genomic expression pathways associated with brain injury after cardiopulmonary bypass

Abstract

Neurologic injury after cardiac surgery, often manifested as neurocognitive decline, is a common postoperative complication without clear cause. We studied acute variations in gene-expression profiles of patients with neurocognitive decline (NCD group) compared with those without neurocognitive decline (NORM group) after cardiopulmonary bypass. Forty-two patients undergoing coronary artery bypass grafting, valve procedures, or both by using cardiopulmonary bypass were administered a validated neurocognitive battery preoperatively and postoperatively at day 4. Neurocognitive decline was defined as 1 standard deviation from baseline on 25% or greater of tasks. Whole-blood mRNA was isolated preoperatively and at 6 hours after surgical intervention for fold-change calculation. Relative gene expression in the NCD versus the NORM group was assessed by using Affymetrix GeneChip U133 Plus 2.0 (>40,000 genes) from mRNA samples collected. Differential expression, clustering, gene ontology, and canonical pathway analysis were performed. Validation of microarray gene expression was performed with SYBR Green real-time polymerase chain reaction. Patients with neurocognitive decline (17/42 [40.5%] patients) were associated with a significantly different gene-expression response compared with that of healthy patients. Compared with preoperative samples, 6-hour samples had 531 upregulated and 670 downregulated genes uniquely in the NCD group compared with 2214 upregulated and 558 downregulated genes uniquely in the NORM group (P < .001; lower confidence bound, > or =1.2). Compared with patients in the NORM group, patients with neurocognitive decline had significantly different gene-expression pathways involving inflammation (including FAS, IL2RB, and CD59), antigen presentation (including HLA-DQ1, TAP1, and TAP2), and cellular adhesion (including ICAM2, ICAM3, and CAD7) among others. Patients with neurocognitive decline have inherently different genetic responses to cardiopulmonary bypass compared with those of patients without neurocognitive decline Genetic variations in inflammatory, cell adhesion, and apoptotic pathways might be important contributors to the pathophysiology of neurologic injury after cardiopulmonary bypass and could become a target for prevention and risk stratification.