Fluvastatin reduces increased blood monocyte Toll-like receptor 4 expression in whole blood from patients with chronic heart failure

Background: Innate immune activation mediated by myocardial Toll-like receptors (TLRs) is involved in cardiovascular disease. The function and role of TLRs on peripheral leukocytes in human chronic heart failure (CHF) are not known. Methods: We measured whole blood TLR4 and TLR2 expressions in 28 patients with CHF (64 2 years, New York Heart Association [NYHA] functional class 2.2 +/- 0.1, left ventricular (LV) ejection fraction 32 +/- 2%) and 13 healthy subjects of similar age and gender. Results: As assessed by flow cytometry, TLR4 and TLR2 were detected on CD14+ monocytes. Unstimulated monocyte TLR4 expression was significantly higher in CHF patients compared to controls (mean fluorescence intensity, 3.57 +/- 0.57 vs. 1.72 +/- 0.32, p < 0.05). TLR2 expressions were similar in CHF patients and control subjects (p=0.5). TLR4 levels correlated with the severity of CHF (NYHA class I/II: 2.66 +/- 0.40, and NYHA class III/IV: 5.08 +/- 1.24, p < 0.01) and with serum lipid levels (total cholesterol, r= - 0.44, p < 0.01 and high-density lipoprotein, r=-0.68, p < 0.001). After stimulation of monocytes by lipopolysaccharide (LPS, 10 ng/ml, 3 h), activated TLR4 was higher in CHF patients (p < 0.05). Pre-incubation with fluvastatin for 24 h inhibited dose-dependently ex vivo monocyte TLR4 and TLR2 expressions (P < 0.001). Conclusions: This study suggests that upregulation of monocyte TLR4 may contribute to the pathophysiology of chronic heart failure. Fluvastatin may prevent excessive innate immune response in vitro in chronic heart failure by inhibition of monocyte Toll-like receptor signaling. (C) 2007 Elsevier Ireland Ltd. All rights reserved.