production. 3,4 Furthermore, it has been documented that cardiac mast cell density is higher in the failing myocardium and that mast cells degranulate and release preformed tumor necrosis factor-α (TNF-α), initiating cytokine cascade contributing to myocardial damage. 5 Other authors hypothesize that the increased produc- tion of cytokines in patients with CHF may be the con- sequence of bacterial or endotoxin translocation from the bowel into the blood stream. 6 Endotoxin is bound by a serum protein termed lipopolysaccharide-binding protein and interacts with the CD14 membrane protein on monocytes and tissue macrophages to start a signal- ing cascade that leads to increased cytokine produc- tion. The purpose of this study was to measure the circulat- ing levels of cytokines and their soluble receptors in patients with CHF and various degrees of ventricular dysfunction and to correlate the plasma levels with the hemodynamic parameters. Furthermore, to determine whether increased levels of cytokines derive from the heart or from the splanch- nic area, we measured cytokine concentrations in the coronary sinus, inferior vena cava, hepatic vein, and ascending aorta. Accumulating evidence indicates that cytokines may play an important role in modulating the left ventricular dysfunction that supervenes in many pathophysiologic contexts. 1 Studies performed to analyze the complexity of the cytokine network in chronic heart failure (CHF) demonstrate a shift toward enhanced levels of proin- flammatory mediators combined with inadequately raised or even decreased levels of anti-inflammatory mediators. 2 Despite the repeated observations of elevated levels of cytokines in patients with CHF, the stimulus and the site of production of cytokines are as yet unknown. Some studies propose that the failing myocardium itself might contribute to the increased cytokine concentra- tion as a consequence of an overexpression of cytokine From the a Department of Internal Medicine, Cardiology, and Heart Surgery, and the b Department of Clinical Biochemistry, University of Naples “Federico II,” Italy; and the c Institute of Internal Medicine, Second University of Naples. Submitted May 16, 2000; accepted August 16, 2000. Reprint requests: Domenico Bonaduce, MD, Via A. Falcone 394, 80127 Napoli, Italy. E-mail: bonaduce@unina.it Copyright © 2000 by Mosby, Inc. 0002-8703/2000/$12.00 + 0 4/90/110935 doi:10.1067/mhj.2000.110935 Circulating levels of cytokines and their site of production in patients with mild to severe chronic heart failure Mario Petretta, MD,a Gian L. Condorelli, MD,c Letizia Spinelli, MD,a Francesco Scopacasa, MD,b Maurizio de Caterina, MD,b Dario Leosco, MD,a Maria L.E. Vicario, MD,a and Domenico Bonaduce, MDa Naples, Italy Background Patients with chronic heart failure have elevated levels of proinflammatory cytokines; however, the mech- anism for their increased expression and the site of their production are unknown. Methods Twenty-two patients with heart failure, New York Heart Association functional class II to IV, underwent hemo- dynamic evaluation and echocardiographic study. Blood samples for cytokine evaluation were performed in the ascending aorta, coronary sinus, inferior vena cava, and hepatic vein. Levels of tumor necrosis factor-α (TNF-α), its soluble receptors sTNF-RI and sTNF-RII, interleukin-6 (IL-6), IL-6 soluble receptor, soluble gp130, interleukin-2 soluble receptor, and soluble Fas were measured with enzyme-linked immunosorbent assay kits. Results IL-6 concentrations were higher in class IV patients than in class III patients, which in turn were higher than those in class II. TNF-α, sTNF-RI, and sTNF-RII were higher in class IV patients than in class III and II patients. Significant correla- tions were found between IL-6 concentrations and left ventricular end-systolic volume (r = 0.64; P < .001), pulmonary wedge pressure (r = 0.56; P < .01), and left ventricular ejection fraction (r = –0.56; P < .01). No correlation was found between TNF-α and its soluble receptors and left ventricular volumes or hemodynamic measures. Finally, no difference in cytokine concentrations was found among the different sample sites. Conclusions Among inflammatory cytokines, IL-6 concentrations better reflect the hemodynamic derangement in patients with heart failure. No cardiac or gut production of cytokines occurs in patients with mild to severe heart failure. (Am Heart J 2000;140:e28.)