Pathophysiological correlates of increased serum tumor necrosis factor in patients with congestive heart failure: Relation to nitric oxide-dependent vasodilation in the forearm circulation

Background: Tumor necrosis factor-α (TNFα), which we and others have shown to be elevated in patients with severe congestive heart failure (CHF), is involved in the regulation of nitric oxide metabolism. Whether increased concentrations of TNFα affect nitric oxide-mediated vasodilation in patients with CHF has not been studied previously. Methods and Results: Serum concentrations of TNFα, interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined in venous blood (pg/mL) from 17 patients with stable New York Heart Association classes II and III CHF (mean age, 58±11 years; mean left ventricular ejection fraction, 19.5±7.3) and 17 age- matched normal subjects with enzyme-linked immunosorbent assays (detection limit of assays, 20 pg/mL). Forearm blood flows were determined with plethysmography (mL/min per 100 mL) in 17 patients and 7 normal subjects in response to brachial artery administration of graded concentrations of acetylcholine (10^-6 mol/L and 10^-5 mol/L) and nitroglycerin (10^-7 mol/L and 10^-6 mol/L). Serum concentrations of TNFα were above the detection limits of the assay in 10 of 17 patients with CHF (mean serum concentration, 39.4±3.8 pg/mL). Forearm blood flow responses to acetylcholine and nitroglycerin were significantly greater in these 10 patients than in the 7 patients without detectable serum TNFα and were closely correlated with TNFα serum concentrations (r≥.81, P<.01 and r≥.65, P<.05 respectively). In 1 of 17 normal subjects, the serum concentration of TNFα was just above the detection limit of the assay. Serum concentrations of IL-2 were above the detection limit of the assay in 14 of 17 patients with CHF (mean serum concentration, 112±19 pg/mL). IL-2 was not detected in the serum of normal subjects. Serum concentrations of IL-1 and IL-6 were below the detection limit of the assays in all patients and normal subjects assayed. Conclusions: Increased TNFα concentrations are closely correlated with forearm blood flow responses to regional administration of acetylcholine and nitroglycerin. The significant correlation between serum concentrations of TNFα and forearm blood flow responses to acetylcholine and nitroglycerin suggests that both the inducible and the constitutive forms of nitric oxide synthase are involved in the regulation of peripheral vasomotor tone in patients with CHF.