Intracellular Monocyte Cytokine Production and CD14 Expression Are Up-Regulated in Severe vs Mild Chronic Heart Failure Viviane M. Conraads, MD, PhD, a Johan M. Bosmans, MD, PhD, a Annemie J. Schuerwegh, MD, PhD, b Inge Goovaerts, MT, a Luc S. De Clerck, MD, PhD, b Wim J. Stevens, MD, PhD, b Chris H. Bridts, MT, b and Christiaan J. Vrints, MD, PhD a Background: The role of circulating monocytes in the process of low-grade inflammation, characteristic of chronic heart failure (CHF), has recently been questioned. Lipopolysaccharide (LPS) desensitization has been proposed to mediate reduced monocyte cytokine elaboration in patients with severe CHF. Methods: Intracellular monocyte production of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF)-, and monocyte CD14 expression were measured flow-cytometrically without and after 8-hour LPS stimulation in 46 patients with CHF and in a healthy control group. Results: Basal cytokine concentrations were similar for the control and the mild CHF groups (New York Heart Association [NYHA] Class I or II). After LPS stimulation, IL-6 (p = 0.002) and TNF- levels (p = 0.001) were lower in the latter group, whereas IL-1 production was comparable. For the moderate–severe CHF patients, unstimulated IL-1 (p = 0.04) was higher, whereas IL-6 (p = 0.2) and TNF- (p = 0.1) levels were not different from the controls. Measurement of LPS-stimulated cytokine production showed no differences between the control group and patients with moderate–severe CHF (all p  0.5). Upon comparing mild vs moderate–severe CHF patients, higher levels of unstimulated cytokine production (IL-1, p = 0.002; IL-6, p = 0.01; TNF-, p = 0.003), stimulated IL-1 (p = 0.002) and IL-6 (p = 0.008) were found in the latter patients. CD14 expression in the moderate–severe CHF group was higher than in the mild-CHF group (p = 0.03) and was strongly related to stimulated IL-1 (r = 0.62, p  0.0001), IL-6 (r = 0.56, p = 0.0002) and TNF- (r = 0.41, p = 0.006) production. Conclusions: CD14 expression and monocyte cytokine production, both unstimulated and after LPS stimulation, are increased in moderate–severe CHF when compared with mild CHF. These data suggest that circulating monocytes, possibly via increased CD14 expression, may play a significant role in the immunologic dysbalance observed in advanced CHF. J Heart Lung Transplant 2005;24:854 –9. Copyright © 2005 by the International Society for Heart and Lung Transplantation. Immunologic dysbalance with systemic inflammation plays an important role in chronic heart failure (CHF). Overexpression of interleukin-6 (IL-6), tumor necrosis factor (TNF)- and soluble TNF receptors correlates with severity of heart failure. 1–4 Moreover, extensive data have shown the prognostic relevance of pro- inflammatory cytokines and, more so, of both soluble TNF receptors in these patients. 1,3,4 The question of how and why this immunologic dysbalance arises, however, remains to be answered. Possible sources include cytokine production by car- diac myocytes 5 and cardiac non-myocyte cells, 6 and spillover in the peripheral circulation due to tissue hypoxia and hypoperfusion. 7 Although circulating monocytes have a pivotal function in the production of pro-inflammatory cytokines in physiologic circum- stances, controversy has recently arisen concerning their potential role in the activated cytokine network of CHF patients. Tran et al 8 measured markers of mono- cyte activation in patients with CHF. They found that reactive oxygen intermediates, cell surface expression of CD11b, CD14 and CD49e as well as intracellular levels of IL-1 and TNF- release were not different from an age-matched control group. Others investiga- tors observed a differential cytokine-generating capacity according to heart failure severity, whereby monocytes of patients with severe disease, characterized by the highest circulating cytokine levels, were rather desen- sitized to LPS stimulation. 9,10 The objectives of this study were to address the elaboration of pro-inflammatory cytokines in CHF by From the Departments of a Cardiology and b Immunology, University Hospital Antwerp (UIA), Antwerp, Belgium. Received October 8, 2003; revised March 23, 2004; accepted April 12, 2004. Reprint requests: Viviane Conraads, MD, Department of Cardi- ology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. Telephone: 32-3821-4672. Fax: 32-3825-0848. E-mail: viviane.conraads@uza.be Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2004.04.017 854 FAILING HEART— BASIC SCIENCE