Reciprocal regulation of myocardial microRNAs and messenger RNA in human cardiomyopathy and reversal of the microRNA signature by biomechanical support.
BACKGROUND
Much has been learned about transcriptional control of cardiac gene expression in clinical and experimental congestive heart failure (CHF), but less is known about dynamic regulation of microRNAs (miRs) in CHF and during CHF treatment. We performed comprehensive microarray profiling of miRs and messenger RNAs (mRNAs) in myocardial specimens from human CHF with (n=10) or without (n=17) biomechanical support from left ventricular assist devices in comparison to nonfailing hearts (n=11).


RESULTS
Twenty-eight miRs were upregulated >2.0-fold (P<0.001) in CHF, with nearly complete normalization of the heart failure miR signature by left ventricular assist device treatment. In contrast, of 444 mRNAs that were altered by >1.3-fold in failing hearts, only 29 mRNAs normalized by as much as 25% in post-left ventricular assist device hearts. Unsupervised hierarchical clustering of upregulated miRs and mRNAs with nearest centroid analysis and leave-1-out cross-validation revealed that combining the miR and mRNA signatures increased the ability of RNA profiling to serve as a clinical biomarker of diagnostic group and functional class.


CONCLUSIONS
These results show that miRs are more sensitive than mRNAs to the acute functional status of end-stage heart failure, consistent with important functions for regulated miRs in the myocardial response to stress. Combined miR and mRNA profiling may have superior potential as a diagnostic and prognostic test in end-stage cardiomyopathy.
Matkovich
Scot J
SJ
Center for Pharmacogenomics, Washington University, St Louis, MO 63110, USA.
Van Booven
Derek J
DJ
Youker
Keith A
KA
Torre-Amione
Guillermo
G
Diwan
Abhinav
A
Eschenbacher
William H
WH
Dorn
Lisa E
LE
Watson
Mark A
MA
Margulies
Kenneth B
KB
Dorn
Gerald W
GW
D009202:Cardiomyopathies / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006333:Heart Failure / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009206:Myocardium; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D020127:Recovery of Function / Q000235:genetics
D005819:Genetic Markers; D035683:MicroRNAs; D012333:RNA, Messenger