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

Zhong Gao, Andreas S. Barth, Deborah DiSilvestre, Fadi G. Akar, Yanli Tian, Antti Tanskanen, David A. Kass, Raimond L. Winslow, Gordon F. Tomaselli

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)222-230
Number of pages9
JournalPhysiological Genomics
Volume35
Issue number3
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

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Gene Regulatory Networks
Heart Failure
Gene Expression
Action Potentials
Canidae
Myocardium
Atrial Remodeling
Gene Ontology
Oxidative Phosphorylation
Left Ventricular Dysfunction
Oligonucleotide Array Sequence Analysis
Transcriptome
Left Ventricular Function
Tachycardia
Extracellular Matrix
Mammals
Adenosine Triphosphate
Hemodynamics
Blood Pressure
Morbidity

Keywords

  • Action potential
  • Microarray
  • Oxidative phosphorylation
  • Transcriptional remodeling

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling. / Gao, Zhong; Barth, Andreas S.; DiSilvestre, Deborah; Akar, Fadi G.; Tian, Yanli; Tanskanen, Antti; Kass, David A.; Winslow, Raimond L.; Tomaselli, Gordon F.

In: Physiological Genomics, Vol. 35, No. 3, 01.11.2008, p. 222-230.

Research output: Contribution to journalArticle

Gao, Zhong ; Barth, Andreas S. ; DiSilvestre, Deborah ; Akar, Fadi G. ; Tian, Yanli ; Tanskanen, Antti ; Kass, David A. ; Winslow, Raimond L. ; Tomaselli, Gordon F. / Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling. In: Physiological Genomics. 2008 ; Vol. 35, No. 3. pp. 222-230.
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