Gene expression profiles in children undergoing cardiac surgery for right heart obstructive lesions.
BACKGROUND
The global myocardial stress response during cardiac surgery has not been systematically studied, nor is it known whether the response of the neonatal myocardium is intrinsically different from that of older children. To determine the age-related molecular basis of this response, we conducted microarray-based differential gene expression profiling on right ventricular tissue samples acquired in patients of varying ages with right ventricular outflow tract obstruction.


METHODS
We studied gene expression profiles in 24 patients during operations for lesions involving right ventricular outflow tract obstruction age stratified into group I (7 patients, aged 5 to 66 days; mean, 30 days) and group II (17 patients, aged 4 months to 12.5 years; mean, 2.8 years). Myocardial samples were taken from the right ventricular outflow tract after aortic occlusion and archived in liquid nitrogen. RNA isolation, fluorescence labeling of complementary DNA, hybridization to spotted arrays containing 19,008 characterized or unknown human complementary DNAs, and quantitative fluorescence scanning of gene-expression intensity were performed at the University of Toronto Health Network Microarray Centre. Data were analyzed with the Significance Analysis for Microarrays program. Minimum Information About Microarray Experiments-compliant, log2-normalized data sets were compared to ascertain potential statistical differences in gene expression between patient groups.


RESULTS
There were no hospital deaths or major postoperative morbid events. We identified 50 transcripts differentially expressed in the neonatal group (the predicted false discovery rate was <0.8 transcripts). The neonatal pattern of gene expression (group I) was dominated by genes with literature-validated cardioprotective, antihypertrophic, and antiproliferative properties, including increases in atrial natriuretic peptide, protein phosphatase 2A, small GTPase rap1, and protein inhibitor of activated STAT protein, PIASy. Several transcripts have not been previously reported in heart.


CONCLUSIONS
Neonatal myocardium has a unique pattern of gene expression, which may result from developmental (age-related) differences or reflect a more severe disease phenotype independent of age effects per se. The neonatal transcript profile seems to reflect a stress-induced protective program composed of genes with functions diametrically opposed to those expected to be related to the pathogenesis of critical right ventricular outflow tract obstruction, thus revealing a novel and compensatory antidisease transcriptional response in the neonatal heart.
Division of Cardiovascular Surgery, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
Igor E
IE
Konstantinov
John G
JG
Coles
Cathy
C
Boscarino
Mark
M
Takahashi
Jason
J
Goncalves
Julia
J
Ritter
Glen S
GS
Van Arsdell
D009320:Atrial Natriuretic Factor / Q000235:genetics; D006348:Cardiac Surgical Procedures; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009206:Myocardium / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D016133:Polymerase Chain Reaction; D050828:Protein Inhibitors of Activated STAT; D054648:Protein Phosphatase 2; D012333:RNA, Messenger / Q000032:analysis; D025841:Small Ubiquitin-Related Modifier Proteins; D014694:Ventricular Outflow Obstruction / Q000235:genetics* / Q000601:surgery*
D002352:Carrier Proteins; D018076:DNA, Complementary; C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; D012333:RNA, Messenger; D025841:Small Ubiquitin-Related Modifier Proteins; D009320:Atrial Natriuretic Factor; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2