Abstract 2415: Intra-ischemic Hypothermia During Hemorrhagic Shock Improves Outcomes and Reverses Cardiac Transcriptional Stress Response
OBJECTIVE: To study the effect of hemorrhagic shock (HS) and induced hypothermia (HT) on cardiac genomic transcription, hemodynamics and outcome in HS.
METHODS: Female mice (30 ± 2g) were bled to a mean arterial pressure (MAP) = 35 mmHg and maintained for 90 min (S90). At S90 animals were resuscitated with shed blood plus L-lactated Ringer’s. After 30 min of shock, animals were randomly assigned to HT (33±0.3°C, n=26) or continued normothermia (NT 37±0.4°C, n=26) until 60 min following resuscitation (R60) and then monitored for 180 min. In a separate study, genomic expression profiling was performed on whole heart tissue RNA in NT and HT groups at S90 (n=5 each) and at baseline (n=5) using Affymetrix mouse 430 2.0 microarrays.
RESULTS: HT significantly improved 3-hour survival rates (23/26 vs. 13/26). By S90, HT significantly lowered heart rate (331 ±71 vs. 508 ±69 bpm, p<0.01) and end-tidal CO2 (30 ± 3 vs. 40± 6 mmHg, p<0.01). At R60, HT increased MAP (57 ± 9 mmHg vs. 43 ± 13, p<0.01), decreased heart rate (342 ±66 vs. 533 ±88 bpm, p<0.01) and decreased ETCO2 (32 ±4 vs. 37 ±5 mmHg, p<0.01) relative to NT. At S90, HT hearts displayed greater than 4.5 times the number of significant cardiac gene expression changes (3276 genes, > 1.2 fold change relative to baseline, p < 0.05) than the NT group (897 genes) of which only 6.6% (276/4173) were common to both groups. Transcription increased relative to baseline in 21% (HT, 691/3276) and 28% (NT, 251/897) of these significant genes. In 191 of these genes, HT reversed transcription changes (> 1.2 fold change relative to NT, p < 0.05) induced at S90 in NT animals. Functional analysis of this gene list suggests that HT reverses changes in several canonical pathways including those involved in leukocyte extravasation, protein ubiquitination and NF-kB signaling.
CONCLUSION: In the heart, significant gene transcription changes are rapidly triggered during HS prior to resuscitation. Intra-ischemic HT modulates this response and may reverse changes across several important canonical pathways. The induction of hypothermia during shock improves survival and hemodynamic parameters in a mouse model of pressure-controlled HS.