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.

Figure 1

ANP transcriptional profiles, * = p < .05 vs nonfailing

Figure 2

Transcriptional Profiles of Contractile Genes, * = p<.05 vs nonfailing, # = p<.1

Figure 3

Transcriptional Profiles of Metabolic Genes, * = p<.05, # = p<.1

Figure 4

Western blot of HIF 1α (NF= non-failing, F= Failing, Fp=Failing post LVAD human heart tissue)