In vitro endothelial cell activation and inflammatory responses in end-stage heart failure

Background: vascular endothelial cell activation and dysfunction are observed in patients with severe heart failure and may contribute to systemic manifestations of this syndrome. It remains unknown whether inflammatory activation of these cells occurs in these patients because of increased circulating proinflammatory mediators. Aim: to determine whether the serum from patients with heart failure possesses a net proinflammatory bioactivity to active proinflammatory pathways in cultured endothelial cells. Methods: serum was obtained from stable patients with end-stage heart failure undergoing elective cardiac transplantation (Tx) and severely decompensated patients with heart failure requiring emergency left ventricular assist device (LVAD) implantation. Net proinflammatory bioactivity of serum was investigated by monitoring IκBα degradation and E-selectin expression in cultured human pulmonary artery endothelial cells (HPAEC) following incubation with serum samples. Serum cytokine concentrations were measured by ELISA and neutralizing antibodies were used to determine the role of specific factors in the observed bioactivity. Result: serum from both patient groups induced HPAEC IκBα degradation. Low basal HPAEC E-selectin expression significantly increased following treatment with Tx but not LVAD serum. Serum tumor necrosis factor-α (TNF-α) and IL-10 concentrations were higher in patients with LVAD than those with Tx, and soluble TNF-α receptor expression was high in both groups. Neither TNF-α nor IL-10 blocking experiments altered either bioassay result. Conclusion: activation of a specific profile of pro- and anti-inflammatory mediators is associated with heart failure resulting in HPAEC nuclear factor (NF)-κB activation. However, E-selectin expression is further regulated by unidentified factors. TNF-α is upregulated but appears to play no part in NFκB activation in these patients. These findings could have important therapeutic implications.