TUMOR-NECROSIS-FACTOR CHALLENGES IN CANINES - PATTERNS OF CARDIOVASCULAR DYSFUNCTION

Three groups of conscious canines were given different intravenous doses of human recombinant tumor necrosis factor (TNF) over 1 h, and the resulting cardiovascular abnormalities were examined for 10 days. As TNF dose increased [0 (controls), 30, 60, and 120 mug/kg body wt], the number of deaths increased (P < 0.025; 0 of 6, 1 of 8, 1 of 8, 4 of 8, number of deaths in each group, respectively). In all three groups receiving TNF, the mean left ventricular ejection fraction (LVEF) at 2 h after infusion decreased (P < 0.003) compared with controls. The group receiving the highest dose of TNF (1 20 mug/kg body wt) had the greatest decrease (P < 0.05) in LVEF from 0 to 2 h. At 8 h, all three groups receiving TNF had similar LVEF. In these three groups, other multiple measures of LV function at 8 h showed significant and similar decreases in cardiac contractility compared with controls. From 24 to 240 h, however, the time required for cardiac performance (LVEF) to return to normal was dose dependent (30 < 60 < 120 mug/kg body wt; P < 0.05). Canines receiving the lowest dose of TNF had near normal cardiac function (LVEF) at 24 h, whereas canines receiving the highest dose had persistent cardiac abnormalities at 240 h. Thus, at 8 h, the severity of cardiac dysfunction is independent of TNF dose, but the rate of onset and the duration of cardiac abnormality are markedly dependent of dose. These data show TNF decreases cardiac contractility within hours, and TNF dose is important in the timing and extent of cardiovascular changes and lethality.