Hawley H. Seiler Resident Award. Transcriptional profile of brain injury in hypothermic circulatory arrest and cardiopulmonary bypass.
BACKGROUND
Little is known about the molecular mechanisms of neurologic complications after hypothermic circulatory arrest (HCA) with cardiopulmonary bypass (CPB). Canine genome sequencing allows profiling of genomic changes after HCA and CPB alone. We hypothesize that gene regulation will increase with increased severity of injury.


METHODS
Dogs underwent 2-hour HCA at 18 degrees C (n = 10), 1-hour HCA (n = 8), or 2-hour CPB at 32 degrees C alone (n = 8). In each group, half were sacrificed at 8 hours and half at 24 hours after treatment. After neurologic scoring, brains were harvested for genomic analysis. Hippocampal RNA isolates were analyzed using canine oligonucleotide expression arrays containing 42,028 probes.


RESULTS
Consistent with prior work, dogs that underwent 2-hour HCA experienced severe neurologic injury. One hour of HCA caused intermediate clinical damage. Cardiopulmonary bypass alone yielded normal clinical scores. Cardiopulmonary bypass, 1-hour HCA, and 2-hour HCA groups historically demonstrated increasing degrees of histopathologic damage (previously published). Exploratory analysis revealed differences in significantly regulated genes (false discovery rate < 10%, absolute fold change > or = 1.2), with increases in differential gene expression with injury severity. At 8 hours and 24 hours after insult, 2-hour HCA dogs had 502 and 1,057 genes regulated, respectively; 1-hour HCA dogs had 179 and 56 genes regulated; and CPB alone dogs had 5 and 0 genes regulated.


CONCLUSIONS
Our genomic profile of canine brains after HCA and CPB revealed 1-hour and 2-hour HCA induced markedly increased gene regulation, in contrast to the minimal effect of CPB alone. This adds to the body of neurologic literature supporting the safety of CPB alone and the minimal effect of CPB on a normal brain, while illuminating genomic results of both.
Allen
Jeremiah G
JG
Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Weiss
Eric S
ES
Wilson
Mary Ann
MA
Arnaoutakis
George J
GJ
Blue
Mary E
ME
Talbot
C Conover
CC
Jie
Chunfa
C
Lange
Mary S
MS
Troncoso
Juan C
JC
Johnston
Michael V
MV
Baumgartner
William A
WA
D000818:Animals; D001927:Brain Diseases / Q000209:etiology* / Q000235:genetics*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D050792:Circulatory Arrest, Deep Hypothermia Induced / Q000009:adverse effects*; D004285:Dogs; D020869:Gene Expression Profiling; D015601:Injury Severity Score; D008297:Male