Aprotinin Attenuates Genomic Expression Variability Following Cardiac Surgery
Basel Ramlawi2, Hasan Otu1, Sirisha Emani1, Cesario Bianchi1, Frank W. Sellke1; 1Beth Israel Deaconess Medical Center / Harvard Medical School, Boston, MA; 2University of Western Ontario, London, ON, Canada
Comment on this Abstract
Objective: Aprotinin, a commonly used antifibrinolytic agent, was the subject of recent controversy regarding adverse clinical outcomes following cardiac surgery. We compared the role of Aprotinin and ε-aminocaproic acid, on clinical outcomes and the attenuation of the post-cardiopulmonary bypass (CPB) response at the genomic expression and cytokine (protein) level.
Methods: Thirty nine low-risk patients undergoing coronary revascularization (CABG) and/or valve procedures using cardiopulmonary CPB were enrolled into a prospective cohort study. Half-Hammersmith dose Aprotinin (1 x 106 KIU preoperatively) or ε-aminocaproic acid (100 mg/kg load, 5g pump prime and 30 mg/kg/h infusion) was administered to patients. Gene expression was assessed with Affymetrix GeneChip U133 Plus 2.0 (>40,000 genes) from whole blood mRNA samples collected preoperatively (PRE) and 6 hours (6H) postoperatively for fold-change calculation. Differential expression, clustering, gene ontology and canonical pathway analysis was performed. Validation of gene expression was performed with SYBR Green real time PCR. Cytokine values were quantified from serum using high sensitivity immunoassay technique preoperatively and postoperatively at 6h and 4 days (POD4) and analyzed in a blinded fashion using parametric statistics.
Results: Preoperative baseline characteristics were similar in both characteristics with respect to age, sex, re-operative status, type of operation or intraoperative factors (pump time, temperature etc.). Serum inflammatory markers measured did not reveal significant difference between patients receiving Aprotinin (APR) and those receiving ε-aminocaproic acid (Amicar). Compared with PRE samples, 6H samples had 264 up-regulated and 548 down-regulated genes uniquely in the APR group compared to 4826 up-regulated and 1114 down-regulated genes uniquely in the NORM group (p<0.001, Lower confidence bound ≥1.2). Compared to patients in the Amicar group, APR patients had significantly different gene expression pathways involving NF-κbeta regulation, programmed cell death and cell-cell adhesion (table below). None of the patients developed postoperative stroke, myocardial infarction or systemic infections.
Conclusion: APR leads to significantly less genomic expression variability compared to Amicar and has a differential effect on specific genomic pathways.
Differentially Expresed Pathways
| GO Pathway No. | GO Pathway Description | p-value |
| 45012 | MHC class II receptor activity | <0.000001 |
| 43123 | positive regulation of NF-kappaB cascade | 0.000001 |
| 3988 | acetyl-CoA C-acyltransferase activity | 0.001001 |
| 6406 | mRNA export from nucleus | 0.004039 |
| 7259 | JAK-STAT cascade | 0.007447 |
| 12501 | Programmed cell death | 0.010656 |
| 6944 | membrane fusion | 0.016926 |
| 43297 | apical junction assembly | 0.017328 |
| 8080 | N-acetyltransferase activity | 0.027009 |
| 16494 | C-X-C chemokine receptor activity | 0.028045 |
| 6959 | Humoral immune response | 0.030155 |
| 16337 | Cell-cell adhesion | 0.037522 |
GO - Gene Ontology
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