Abstract 11685: Early Myocardial Gene Expression Profiling After Deep Hypothermic Circulatory Arrest Reveals Ontogenetic Adaptive Mechanisms Underlying Ischemia-Reperfusion Tolerance in the Swine

Abstract

Previous studies suggest that immature hearts are more tolerant to ischemia than adult myocardium; whether differences exist during ontogenic development in severity of global myocardial ischemia/reperfusion (I/R) injury associated with cardiac surgery remains unknown. We employed swine models of deep hypothermic circulatory arrest (DHCA) to test the hypothesis that early differential regulation of cardioprotective genes is associated with increased tolerance of neonatal myocardium to surgical I/R. Male neonatal and adult pigs were randomized to DHCA or sham (N=5-14/group). DHCA animals underwent cardiopulmonary bypass (18°C), DHCA 60 min, and were recovered for 3h. Severity of perioperative myocardial injury was determined biochemically (Troponin I) and echocardiographically. Transcript levels were quantified in left ventricular myocardium using Affymetrix Porcine Genome arrays, followed by differential expression and pathway analysis. A 2-fold increase in severity of perioperative myocardial injury was found in adult pigs (Fig.A). Of 596 transcripts differentially expressed in neonates (≥1.5-fold change, DHCA vs. sham, FDR<0.05), 53 were shared with adults (Fig.B). Among them, divergent expression patterns were found for oxysterol binding protein-like 6 (down-regulated in adults up-regulated in neonates) and bromodomain adjacent to zinc finger domain 2B (up-regulated in adults - down-regulated in neonates). Top transcripts uniquely upregulated in neonates but unchanged in adults were the apoptosis inhibitor baculoviral IAP repeat containing 2, and signal transducer and activator of transcription 3. mTOR signaling and p53 signaling were the top canonical pathways deregulated in adults and neonates, respectively. A high resistance to surgical I/R injury in neonatal vs adult swine heart is correlated with robust differences in early transcriptional programs, suggesting the involvement of fundamental adaptive ontogenetic processes.