Abstract 2459: A Potentially Novel Role Of The Follistatin-activin Pathway In Heart Failure And Myocardial Recovery Following Lvad Combination Therapy
Background - Recent evidence suggests that the activin pathway may play an important role in the pathogenesis of heart failure. Follistatins are potent inhibitors of activin signalling but their role in the heart is unknown. The purpose of this study was to investigate myocardial expression of follistatin (FST) and follistatin-like (FSTL1 and FSTL3) in heart failure and following recovery in patients who received combined mechanical unloading using left ventricular assist device (LVAD) and pharmacologic therapy.
Methods and results - Real time quantitative PCR was used to examine gene expression in myocardial samples from donors (n=9), end-stage heart failure patients (n=27) and patients who recovered from heart failure sampled at the time of LVAD implant, at the time of LVAD removal following recovery, and one year post explant. Both FSTL1 and FSTL3 were elevated in heart failure (1.51 and 2.50 fold respectively p<0.005) with expression returning to normal following recovery. Whereas FSTL3 correlated with molecular markers of disease severity, FSTL1 showed negative correlation with skeletal α-actin and positive correlation with the endothelial cell marker CD31, suggesting a potential link with extent of vascularization. FSTL1 expression levels at LVAD implant also correlated with significantly higher ejection fraction following recovery suggesting initial levels may have an influence on long term outcome. Immunohistochemical analysis showed that FST was localised in fibroblasts and endothelium, FSTL1 in myocytes, endothelium and smooth muscle cells, and FSLT3 in myocytes and endothelium. Microarray analysis showed that FST and FSTL1 expression correlate with extracellular matrix-related and calcium binding proteins, whereas FSTL3 is associated with cell signalling and transcription.
Conclusion - These data show for the first time that elevated myocardial expression of follistatin-like genes is a feature of heart failure and that this may be linked both to disease severity and to mechanisms underlying recovery thereby revealing new insight into the pathogenesis of heart failure and offering novel therapeutic targets.