Interleukin-6 Spillover in the Peripheral Circulation Increases With the Severity of Heart Failure, and the High Plasm Level of Interleukin-6 Is an Important Prognostic Predictor in Patients With Congestive Heart Failure

Objectives. We 1) evaluated whether interleukin-6 (IL-6) is produced in the peripheral circulation in patients with congestive heart failure (CHF), 2) estimated the factors for increased IL-6, and 3) clarified the prognostic role of high plasm levels of IL-6 in patients with CHF. Background. Although plasm levels of IL-6 have been reported to increase in patients with CHF, and production of IL-6 in endothelial cells and vascular smooth muscle cells has been postulated from in vitro studies, the origin of the increase of IL-6 in CHF remains unknown. Moreover, the prognostic value of high plasm level of IL-6, independent of classic neurohumoral factors, remains to be elucidated. Methods. comparison was made of the plasm levels of IL-6 between the femoral artery and the femoral vein in 13 normal subjects and in 80 patients with CHF. In another study, we measured plasm IL-6 in 100 patients with CHF and follow-up data. Results. Plasm IL-6 levels increased significantly from the femoral artery to the femoral vein in normal subjects and in patients with CHF. Arteriovenous IL-6 spillover in the leg increased with the severity of CHF. Among the hemodynamic variables and the various neurohumoral factors, the plasm norepinephrine (NE) level showed an independent and significant positive relation with the plasm IL-6 level in patients with CHF. Moreover, treatment with beta-adrenergic blocking agents showed an independent and significant negative relation with plasm IL-6 levels. In 100 patients, plasm IL-6 (p < 0.0001), NE (p = 0.0004) and left ventricular ejection fraction (0.015) were significant independent prognostic predictors by Cox proportional hazards analysis. Conclusions. Our findings indicate that the IL-6 spillover in the peripheral circulation increases with the severity of CHF and that the increase in plasm IL-6 is mainly associated with the activation of the sympathetic nervous system. High plasm levels of IL-6 can provide prognostic information in patients with CHF, independent of left ventricular ejection fraction and plasm NE, suggesting an important role for IL-6 in the pathophysiology of CHF.