Expression profiling of human idiopathic dilated cardiomyopathy.
OBJECTIVE
To investigate the global changes accompanying human dilated cardiomyopathy (DCM) we performed a large-scale expression screen using myocardial biopsies from a group of DCM patients with moderate heart failure. By hierarchical clustering and functional annotation of the deregulated genes we examined extensive changes in the cellular and molecular processes associated to DCM.


METHODS
The expression profiles were obtained using a whole genome covering library (UniGene RZPD1) comprising 30336 cDNA clones and amplified RNA from myocardiac biopsies from 10 DCM patients in comparison to tissue samples from four non-failing, healthy donors.


RESULTS
By setting stringent selection criteria 364 differentially expressed, sequence-verified non-redundant transcripts were identified with a false discovery rate of <0.001. Numerous genes and ESTs were identified representing previously recognised, as well as novel DCM-associated transcripts. Many of them were found to be upregulated and involved in cardiomyocyte energetics, muscle contraction or signalling. Two hundred and twenty-two deregulated transcripts were functionally annotated and hierarchically clustered providing an insight into the pathophysiology of DCM. Data was validated using the MLP-deficient mouse, in which several differentially expressed transcripts identified in the human DCM biopsies could be confirmed.


CONCLUSIONS
We report the first genome-wide expression profile analysis using cardiac biopsies from DCM patients at various stages of the disease. Although there is a diversity of links between the cytoskeleton and the initiation of DCM, we speculate that genes implicated in intracellular signalling and in muscle contraction are associated with early stages of the disease. Altogether this study represents the most comprehensive and inclusive molecular portrait of human cardiomyopathy to date.
Grzeskowiak
Rafal
R
Max-Planck Institute for Molecular Genetics, Ihnestr. 73, 14195 Berlin, Germany.
Witt
Henning
H
Drungowski
Mario
M
Thermann
Rolf
R
Hennig
Steffen
S
Perrot
Andreas
A
Osterziel
Karl J
KJ
Klingbiel
Dirk
D
Scheid
Stefanie
S
Spang
Rainer
R
Lehrach
Hans
H
Ruiz
Patricia
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D016022:Case-Control Studies; D020869:Gene Expression Profiling; D015723:Gene Library; D006801:Humans; D060588:LIM Domain Proteins; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D023421:Models, Animal; D009124:Muscle Proteins / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3