Left ventricular unloading alters receptor tyrosine kinase expression in the failing human heart.
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BACKGROUND: Experimental and clinical data suggest that the loss of membrane receptor tyrosine kinase (RTK) activity in cardiac myocytes results in increased frequency of apoptotic cell death and progression of heart failure. The goal of our study was to examine the expression characteristics of RTKs in ventricular myocardium obtained from patients before and after mechanical unloading. METHODS: We extracted RNA from paired formalin-fixed, paraffin-embedded left ventricular tissue blocks obtained at the time of left ventricular assist device (LVAD) implantation and explantation from a cohort of 36 patients (median age 51 years). The duration of LVAD support ranged from 1 to 314 days (median 95 days), 17 patients had ischemic and 19 non-ischemic cardiomyopathy at the time of LVAD implantation. Using real-time reverse transcription-polymerase chain reaction (RT-PCR) we quantitated transcripts for atrial natriuretic factor (ANF) and tumor necrosis factor-alpha (TNF-alpha), markers of heart failure, and the RTKs Her2/neu, Her4 and gp130, regulators of cardiac cell survival. RESULTS: In patients undergoing mechanical unloading, ANF and TNF-alpha mRNA levels were independently suppressed. Her2/neu, along with Her4 was upregulated, mostly in cases of ischemic cardiomyopathy, whereas gp130 levels decreased. Post-LVAD transcript levels of Her2 correlated tightly with gp130 in patients with non-pathologic entry values of gp130. Duration of treatment and age were also determining factors in the change of expression of these genes. CONCLUSION: Real-time quantitative (Q)-RT-PCR can be used to quantitate gene expression in archival myocardial tissue blocks. Mechanical unloading leads to a re-adjustment of RTK transcript levels, but not their reverting to control values in heart failure patients.
