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(Circulation. 2009;119:1263-1271.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Reciprocal Regulation of Myocardial microRNAs and Messenger RNA in Human Cardiomyopathy and Reversal of the microRNA Signature by Biomechanical Support

Scot J. Matkovich, PhD; Derek J. Van Booven, BS; Keith A. Youker, PhD; Guillermo Torre-Amione, MD, PhD; Abhinav Diwan, MD; William H. Eschenbacher; Lisa E. Dorn; Mark A. Watson, MD, PhD; Kenneth B. Margulies, MD; Gerald W. Dorn, II, MD

From the Center for Pharmacogenomics, Washington University, St Louis, Mo (S.J.M., D.J.V.B., A.D., W.H.E., L.E.D., G.W.D.); Department of Cardiology, Methodist Hospital and Methodist DeBakey Heart Center, Houston, Tex (K.A.Y., G.T.-A.); Department of Pathology and Immunology, Washington University, St Louis, Mo (M.A.W.); and Cardiovascular Research Institute, University of Pennsylvania School of Medicine, Philadelphia (K.B.M.).

Correspondence to Gerald W. Dorn II, MD, Washington University in St Louis, Center for Pharmacogenomics, 660 S Euclid Ave, Campus Box 8086, St Louis, MO 63110. E-mail gdorn{at}dom.wustl.edu

Received August 8, 2008; accepted December 19, 2008.

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).

Methods and 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 119: 1177-1179. [Extract] [Full Text]

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