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J Am Coll Cardiol, 2003; 41:1096-1106, doi:10.1016/S0735-1097(03)00043-3
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY

Differential gene expression and genomic patient stratification following left ventricular assist device support

Burns C. Blaxall, PhD*, Bryn M. Tschannen-Moran, BSci*, Carmelo A. Milano, MD* and Walter J. Koch, PhD*,*

* Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA

Manuscript received July 3, 2002; revised manuscript received December 2, 2002, accepted December 4, 2002.

* Reprint requests and correspondence: Dr. Walter J. Koch, Duke University Medical Center, Box 2606, Room 479, MSRB Research Drive, Durham, North Carolina 27710, USA.
koch0002{at}mc.duke.edu

OBJECTIVES: We sought to determine whether mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in significant changes in overall left ventricular gene expression.

BACKGROUND: Mechanical circulatory support by LVAD in end-stage human heart failure (HF) can result in beneficial reverse remodeling of myocardial structure and function. The molecular mechanisms behind this salutary process are not well understood.

METHODS: Left ventricular samples from six male patients were harvested during LVAD placement and subsequently at the time of explantation. Cardiac gene expression was determined using oligonucleotide microarrays.

RESULTS: Paired t test analysis revealed numerous genes that were regulated in a statistically significant fashion, including the downregulation of several previously studied genes. Further statistical analysis revealed that the overall gene expression profiles could significantly distinguish pre- and post-LVAD status. Interestingly, the data also identified two distinct groups among the pre-LVAD failing hearts, in which there was blind segregation of patients based on HF etiology. In addition to the substantial divergence in genomic profiles for these two HF groups, there were significant differences in their corresponding LVAD-mediated regulation of gene expression.

CONCLUSIONS: Support with an LVAD in HF induces significant changes in myocardial gene expression, as pre- and post-LVAD hearts demonstrate significantly distinct genomic footprints. Thus, reverse remodeling is associated with a specific pattern of gene expression. Moreover, we found that deoxyribonucleic acid microarray technology could distinguish, in a blind manner, patients with different HF etiologies. Expansion of this study and further development of these statistical methods may facilitate prognostic prediction of the individual patient response to LVAD support.

Abbreviations and Acronyms
  BNP = brain natriuretic peptide
  DNA = deoxyribonucleic acid
  HF = heart failure
  LV = left ventricle/ventricular
  LVAD = left ventricular assist device
  MDS = multidimensional scaling
  RNA = ribonucleic acid
  rRNA = ribosomal ribonucleic acid




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