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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 35/3/222    most recent 00100.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gao, Z. Articles by Tomaselli, G. F. PubMed PubMed Citation Articles by Gao, Z. Articles by Tomaselli, G. F.

Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling

¹ The Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland
² Division of Cardiology, The Johns Hopkins University, Baltimore, Maryland

Heart failure (HF) is the leading cause of morbidity and mortality in the industrialized world. While the transcriptomic changes in end-stage failing myocardium have received much attention, no information is available on the gene expression patterns associated with the development of HF in large mammals. Therefore, we used a well-controlled canine model of tachycardia-induced HF to examine global gene expression in left ventricular myocardium with Affymetrix canine oligonucleotide arrays at various stages after initiation of rapid ventricular pacing (days 3, 7, 14, and 21). The gene expression data were complemented with measurements of action potential duration, conduction velocity, and left ventricular end diastolic pressure, and dP/dt(max) over the time course of rapid ventricular pacing. As a result, we present a phenotype-centered gene association network, defining molecular systems that correspond temporally to hemodynamic and electrical remodeling processes. Gene Ontology analysis revealed an orchestrated regulation of oxidative phosphorylation, ATP synthesis, cell signaling pathways, and extracellular matrix components, which occurred as early as 3 days after the initiation of ventricular pacing, coinciding with the early decline in left ventricular pump function and prolongation of action potential duration. The development of clinically overt left ventricular dysfunction was associated with few additional changes in the myocardial transcriptome. We conclude that the majority of tachypacing-induced transcriptional changes occur early after initiation of rapid ventricular pacing. As the transition to overt HF is characterized by few additional transcriptional changes, posttranscriptional modifications may be more critical in regulating myocardial structure and function during later stages of HF.

transcriptional remodeling; microarray; oxidative phosphorylation; action potential