Tumor necrosis factor antagonism with etanercept improves systemic endothelial vasoreactivity in patients with advanced heart failure

Background - Anti-tumor necrosis factor (TNF)-alpha therapy with etanercept, a recombinant TNF receptor that binds to and functionally inactivates TNF-a, was shown to improve the functional status of patients with congestive heart failure (CHF). Because administration of TNF-a has been shown experimentally to depress endothelium-dependent relaxation, we hypothesized that TNF-a antagonism with etanercept might improve the depressed systemic endothelial vasodilator function, which importantly contributes to increased peripheral vascular resistance in patients with advanced CHF. Methods and Results - Endothelium-dependent (acetylcholine, ACH; 10 to 50 mug/min) and endothelium-independent (sodium nitroprusside, SNP; 2 to 8 mug/min) forearm blood flow (FBF) responses were measured by venous occlusion plethysmography in 13 patients with documented CHF (New York Heart Association class III) before, 6 hours after, and 7 days after subcutaneous injection of a single dose of 25 mg etanercept. Maximum ACH-induced FBF increased significantly from 6.9 +/- 1.0 to 13.0 +/- 1.6 mL/min per 100 mL of forearm tissue (P <0.05) 6 hours after administration of etanercept and returned to 7.0 +/- 1.1 mL/min per 100 mL of forearm tissue after 7 days (P=NS), whereas SNP-induced FBF responses were not significantly affected. In contrast, FBF responses were not altered in control CHF patients, who did not receive etanercept (n=5). Etanercept-induced increases in ACH-mediated FBF were closely correlated with baseline TNF-a serum levels (r=0.66; P <0.02). Conclusions - The administration of etanercept profoundly improves systemic endothelial vasodilator capacity in patients with advanced heart failure, suggesting an important role of inflammatory mediators for impaired endothelial vasoreactivity in CHF. Improvement of systemic endothelial function might importantly contribute to the beneficial effects of etanercept on the functional status of patients with CHF.