title: Assist devices fail to reverse patterns of fetal gene expression despite beta-blockers.
abstract: BACKGROUND
  Heart failure is associated with reversal to a fetal gene expression pattern of contractile and metabolic genes. Substantial recovery of ventricular function with assist devices is rare. Our goal was to evaluate the effects of assist devices on fetal gene expression and hypoxia inducible factor-1 alpha (HIF-1 alpha), a transcriptional factor in hypoxic signaling.
  
  
  METHODS
  Human heart tissue was obtained from the left ventricular apex at the time of assist device implantation and again from the left ventricular free wall during cardiac transplantation. Non-failing tissue was obtained from unused hearts from human donors. Gene expression was measured with the Affymetrix 133 plus 2 Array. HIF-1 alpha was measured by Western blotting with commercially available antibodies.
  
  
  RESULTS
  Heart failure was associated with a decrease in alpha-myosin heavy chain and sarcoplasmic reticulum-Ca(2+) adenosine triphosphatase messenger RNA expression along with an increase in skeletal tropomyosin. This pattern persisted after assist device therapy. Heart failure was also associated with abnormalities in regulatory metabolic genes including glucose transporter 1 (GLUT1). These patterns also persisted after assist device therapy despite a reduction in atrial natriuretic peptide expression and normalization of HIF-1 alpha.
  
  
  CONCLUSIONS
  Failure of assist devices to produce sustained recovery of myocardial contractile function may be due in part to persistent fetal transcriptional patterns of contractile and metabolic genes.
authors.affiliation: Division of Cardiology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Brian.Lowes@UCHSC.edu
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lowes
authors.forename: Ronald
authors.initials: R
authors.lastname: Zolty
authors.forename: Simon F
authors.initials: SF
authors.lastname: Shakar
authors.forename: Andreas
authors.initials: A
authors.lastname: Brieke
authors.forename: Norman
authors.initials: N
authors.lastname: Gray
authors.forename: Michael
authors.initials: M
authors.lastname: Reed
authors.forename: Mihail
authors.initials: M
authors.lastname: Calalb
authors.forename: Wayne
authors.initials: W
authors.lastname: Minobe
authors.forename: JoAnn
authors.initials: J
authors.lastname: Lindenfeld
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Wolfel
authors.forename: Mark
authors.initials: M
authors.lastname: Geraci
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
authors.forename: Joseph
authors.initials: J
authors.lastname: Cleveland
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use; D009200:Myocardial Contraction / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000451:Mineralocorticoid Receptor Antagonists; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C495677:SLC2A1 protein, human; D014335:Tropomyosin; D009320:Atrial Natriuretic Factor; D017346:Protein Serine-Threonine Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains