Predominance of fatty acid metabolic genes – genesis of NICM might be metabolic in nature
Predominance of abnormalities in catalytic activity with ICM (serine proteinase inhibitors)
TNFRSF11B (member of TNF receptor subfamily) is significantly downregulated in ICM
Experimental Procedure for Data that We are Using
Collected myocardial samples from patients undergoing cardiac transplantation whose failure arises from ischemic cardiomyopathy and from "normal" organ donors whose hearts cannot be used for transplants
The transcriptional profile of the mRNA in these samples was measured with gene array technology.
Changes in transcriptional profiles can be correlated with the physiologic profile of heart-failure hearts acquired at the time of transplantation.
To identify as many differentially expressed genes as possible, while incurring a relatively low proportion of false positives.
H 0 : No differential gene expression (between Ischemic and normal group)
Large multiplicity problem: more than fifty thousand hypotheses are tested simultaneously.
How can we control the false positive rate genomewide? –FDR or pFDR.
Table1. Possible outcomes from thresholding m genes for significance (m p-values with some cutoff point applied). m m - S S (# of sign. features) Total m 1 m 1 - F T (# of true positives) True alternative ( H a is true) m 0 m 0 - F F (# of false positives) True null ( H 0 is true) Total Called not significant (accept H 0 ) Called significant (reject H 0 )
Differentially Expressed Genes to ISC-Normal Comparisons
Among the 100 genes that are differentially expressed between ischemic and normal, the majority fell into cell adhesion, cell growth and maintenance, signal transduction, muscle contraction and development, immune response and regulation of transcription.
Most of the genes are up-regulated in above process except one or two genes in the process of cell growth and maintenance and cell adhesion.
Few genes belong to metabolism, inflammatory response, acute phase response and oncogenesis.
Serine proteinase inhibitors has an anti-ischemic protective effect and has been previously observed in pigs subject to experimentally induced myocardial ischemia (Khan 2004): “Aprotinin reduces reperfusion injury after regional ischemia and cardioplegic arrest. Protease inhibition may represent a molecular strategy to prevent postoperative myocardial injury after surgical revascularization with cardiopulmonary bypass”.
It was hypothesized to ben an important gene in Kittleson’s paper (Physiol. Genomics, 2004).
The gene differentiation analysis find out the genes that either up-regulated or down-regulated in ischemic patients, which can correlated with clinical parameters in heart failure patients and supported ongoing efforts to incorporate expression profiling-based biomarkers in determining prognosis and response to therapy in heart failure.
Because circumstances causing a donor heart to be ineligible for cardiac transplantation, such as infection or prolonged hypotension, can also affect gene expression, a normal functional unused donor heart is not the same as a normal heart.