Effect of Short-Term Treatment With Pravastatin on Cytokines and Cytokine Receptors in Patients With Chronic Heart Failure Due to Ischemic and Nonischemic Disease Viviane M. Conraads, MD, PhD, a Johan M. Bosmans, MD, PhD, a Annemie J. Schuerwegh, MD, PhD, b Luc S. De Clerck, MD, PhD, b Chris H. Bridts, MT, b Floris L. Wuyts, PhD, c Wim J. Stevens, MD, PhD, b and Christiaan J. Vrints, MD, PhD a The antiinflammatory effect of lipoproteins through neutralization of circulating endotoxin has questioned the safety of lipid-lowering drugs in chronic heart failure (CHF). We measured serum levels of interleukin-6, tumor necrosis factor (TNF)–, and soluble TNF- receptors 1 and 2 before and after 1-month treatment with pravastatin 40 mg in 58 patients with CHF. Short-term treatment with pravastatin attenuated the immune response in patients with CHF due to ischemic or nonischemic etiology. J Heart Lung Transplant 2005;24:1114 –7. Copyright © 2005 by the International Society for Heart and Lung Transplantation. There is strong evidence for an independent prognostic role for low cholesterol levels in the setting of chronic heart failure (CHF). 1,2 The fact that lower levels of lipoproteins in these investigations are accompanied by elevated proinflammatory cytokine concentrations has led to the endotoxin-lipoprotein hypothesis. 3 Experi- mental and clinical situations accompanied with endo- toxemia (ie, sepsis) suggest that detoxification of endo- toxin or lipopolysaccharide by lipoproteins has an antiinflammatory effect. 4 Increased concentrations of endotoxin, probably derived from the outer membrane of gram-negative intestinal bacteria, have been docu- mented in patients with CHF 5 and are related to im- mune activation. Interventions that reduce endotoxin levels, such as diuretic recompensation 5 and selective bowel decontamination, 6 can abrogate this inflamma- tory process. Assuming that the antiinflammatory effect of lipoproteins is relevant in CHF, cholesterol lowering could have deleterious consequences. However, we recently showed in a cross-sectional study that an atherogenic lipoprotein profile favored the inflamma- tory process in patients with CHF due to coronary artery disease (CAD). 7 No relation was seen between lipoproteins and cytokines in case of dilated cardiomy- opathy (DCMP). On the basis of these differences according to disease etiology, we aimed to investigate the effect of pravastatin on cytokine and cytokine receptor levels in CHF patients with CAD vs nonisch- emic patients. MATERIAL AND METHODS Subjects Out of the 71 patients enrolled into the initial cohort, 7 60 patients agreed to participate in this nonrandomized, non–placebo-controlled trial and to take pravastatin 40 mg during 1 month. Two patients withdrew because of side effects. Symptoms and therapy were stable for at least 1 month. Exclusion criteria included infection, allergy, rheu- matoid disease, cancer, treatment with antiinflammatory drugs, and creatinine 2 mg/dl. Patients had never been treated with fibrates or statins before inclusion. The study was approved by the local ethical committee. All patients gave written informed consent. Laboratory Measurements Fasting blood samples were collected between 8 and 9 AM into ethylenediaminetetraacetic acid tubes (Vacu- tainer; Becton-Dickinson, Meylan, France). Plasma was separated by centrifugation, and aliquots were stored at -20°C. Blood sampling was repeated after 4 weeks of treatment. Concentrations of interleukin (IL)– 6, tumor necrosis factor (TNF)–, and soluble TNF- receptors 1 and 2 (sTNFR1 and sTNFR2) were measured with an enzyme-linked immunosorbent assay according to the manufacturer’s specifications (Quantikine; R&D Sys- tems, Minneapolis, MN; sensitivity 0.7 pg/ml for IL-6, 1.5 pg/ml for sTNFR1, 1 pg/ml for sTNFR2). A high- sensitivity kit (Quantikine HS; R&D Systems; sensitivity 0.18 pg/ml) was used to measure TNF-. All samples were run in duplicate. Total cholesterol (CHOL) and triglycerides were quantified by reflometry with Vitros 750 assays by means of dry slide technology (Ortho From the a Departments of Cardiology, b Immunology, and c Medical Statistics, University Hospital, Antwerp, Belgium. Submitted May 7, 2004; revised August 19, 2004. Reprint requests: Viviane Conraads, MD, PhD, Department of Cardiology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. Telephone: 32 3 821 46 72. Fax: 32 3 825 08 48. 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.2004.08.021 1114