Abstract 16371: High Levels of Tumor Necrosis Factor-α in Patients With Continuous-Flow Left Ventricular Assist Devices Mediate Altered Vessel Growth and Are Associated With Higher Non-Surgical Bleeding

Background: Angiodysplasia is common in patients with LVADs. Thrombin-induced expression of Angiopoietin-2 (Ang-2) in LVAD patients leads to altered angiogenesis and is associated with loss of Angiopoietin-1 (Ang-1). However, Ang-2 alone is insufficient to induce angiogenesis, suggesting involvement of other factors. The reason for decreased Ang-1 expression in LVAD patients is also not known. We hypothesized that high levels of Tumor Necrosis Factor-α (TNF-α) in LVAD patients regulate angiogenesis, downregulate Ang-1 expression, induce pericyte apoptosis, and induce Tissue Factor (TF) expression. Methods: TNF-α and TF levels were measured by ELISA in blood from 101 patients with heart failure (HF), LVAD, or orthotopic heart transplant (OHT). Cultured endothelial cells were incubated on Matrigel with serum from each patient with or without TNF-α-blocking antibody and tube formation was measured by microscopy. Then, cultured pericytes were incubated with serum from each patient with or without TNF-α blockade. Ang-1 expression was measured by RT-PCR and pericyte death was measured by fluorescent live/dead stain. Finally, TF gene expression was measured by RT-PCR in cultured endothelial cells incubated with plasma from each patient with or without TNF-α inhibitor. TF expression in endothelial biopsy samples from these patients was measured by quantitative immunofluorescence. Results: Compared with HF or OHT, levels of TNF-α were higher in LVAD patients. This corresponded with increased angiogenic potential of serum from patients with LVADs, which was normalized with TNF-α blockade. Serum from LVAD patients reduced Ang-1 expression and induced more pericyte cell death than serum from HF or OHT patients and this effect was blunted by TNF-α blockade. Further, plasma from LVAD patients induced more TF expression in endothelial cells than plasma from HF or OHT patients and this effect was reduced with TNF-α blockade. Compared with HF or OHT patients, plasma and endothelial cells from LVAD patients contained higher amounts of TF. Conclusions: Elevated TNF-α in LVAD patients is a central regulator of altered angiogenesis, pericyte apoptosis, and expression of thrombotic factors. Blockade of TNF-α may decrease vascular complications in LVAD patients.