In animals and patients with severe heart failure (HF), the serum tumor necrosis factor-α (TNF-α) concentration is increased. It is, however, still controversial whether or not such increased serum TNF-α originates from the heart itself or is of peripheral origin secondary to gastrointestinal congestion and increased endotoxin concentration. We therefore now examined TNF-α in serum, myocardium, and liver of sham-operated and HF rabbits. In nine rabbits in which HF was induced by left ventricular (LV) pacing at 400 beats/min for 3 wk, LV end-diastolic diameter was increased and systolic shortening fraction (9.4 ± 1.0 vs. 28.5 ± 1.3%, echocardiography, P < 0.05) was reduced. Serum TNF-α was higher in HF than in sham-operated rabbits (240 ± 24 vs. 150 ± 22 U/ml, WEHI-cell assay, P < 0.05). In the heart, TNF-α was located mainly in the vascular endothelium (immunohistochemistry), and TNF-α protein (920 ± 160 vs. 900 ± 95 U/g) did not differ between groups. In the liver of HF rabbits, hepatocytes expressed TNF-α, and TNF-α protein was increased compared with sham-operated rabbits (2,390 ± 310 vs. 1,220 ± 135 U/g, P < 0.05) and correlated to the number of hepatic leukocytes ( r = 0.85) and serum TNF-α ( r = 0.69). The intestinal endotoxin concentration was 24.5 ± 1.2 vs. 17.0 ± 3.1 endotoxin units/g wet wt ( P < 0.05) in HF compared with sham-operated rabbits. In this HF model, serum but not myocardial TNF-α is increased. The increased serum TNF-α originates from peripheral sources.
Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-α, in Patients With Moderate-to-Severe Heart Failure
