TNF inhibition at the time of myocardial infarction attenuates the subsequent development of heart failure

Chronic heart failure is associated with a state of immunomodulation. The cause of increased cytokine production and immune cell dysfunction currently remains unknown, endotoxaemia being discussed as a possible trigger. We have studied gene expression in unstimulated peripheral blood mononuclear cells of 38 patients with chronic heart failure and 15 healthy controls using quantitative RT-PCR analysis (Light Cycler). Patients were subgrouped as asymptomatic (New York Heart Association (NYHA) class I, n 8) and mild (NYHA class II, n 17) or moderate (NYHA class III, n 13) heart failure. Gene expression of IL -1 and TNF -a was significantly higher in patients with mild to moderate symptoms compared to asymptomatic patients. Compared to healthy controls, heart failure patients showed elevated levels of IL -1 , IL-1 RA, MCP and ICAM-1 as well as increased levels of the lipopolysaccharide (LPS) receptor CD14 and of the Toll-like receptors (TLR) TLR2 and TLR4. CD14 surface expression measured by FACS analysis was significantly lower in patients compared to healthy controls suggesting increased CD14 cleavage or predominant production of soluble CD14. In conclusion, patients with chronic heart failure have increased gene expression levels of inflammatory cytokines, which correlate with the clinical symptoms. In addition, increased gene expression of the LPS receptor CD14 and its related receptors TLR2 and TLR4 supports a pathogenetic role of endotoxinaemia and/or monocyte activation in chronic heart failure.