Gene Set Enrichment Analysis of Hyperbilirubinemia-Associated Leukocyte Expression Profiles Following Mechanical Circulatory Support Device Implantation

Introduction: The implantation of mechanical circulatory support devices (MCSD) is frequently associated with hyperbilirubinemia, despite the rapid normalization of right heart failure after surgery. We hypothesized that, by characterizing the temporal dynamics of leukocyte expression profiles during MCSD-implantation using high-throughput microarray transcriptome analysis as markers of the Systemic Inflammatory Response Syndrome (SIRS) to open-heart surgery, signatures associated with hyperbilirubinemia might be identified. Methods: Twelve patients with end-stage heart failure requiring MCSD-implantation were enrolled into this non-randomized, double-blinded prospective observational study from March 2004 to February 2006. Blood was drawn 24 hr before (Day 0) and 24 h after (Day 1) MCSD implantation. Total serum bilirubin levels were measured in all patients for these time points. Peripheral blood mononuclear cells (PBMC) were isolated from 8 mL of venous blood, RNA was extracted and hybridized (Agilent Whole Human Genome CGH Microarray 44 K). Array data were analyzed using Feature Extraction, Gene Spring 9.0 and Gene Set Enrichment Analysis software. Results: The Day 0 and Day 1 bilirubin levels were found to be 1.25±0.52 (0.7 – 2.4) and 2.77±0.92 (1.4 – 4.4) respectively. A significant correlation was found between gene expression profiles and bilirubin levels and a list of 100 most closely correlated genes was generated as shown in Figure 1.Conclusion: We conclude that the MCSD-implantation is associated with hyperbilirubinemia which correlates with inflammatory peripheral leukocyte gene expression profiles. The resulting hypothesis that the SIRS-mediating leukocyte signatures causes hyperbilirubinemia needs to be further explored.