Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices

Abstract

Background Cytokine activation in the myocardium of deteriorating patients with heart failure who undergo left ventricular assist-device (LVAD) implantation has been documented, but the underlying mechanisms remain poorly understood. We hypothesized the innate immune system is activated with expression of Toll-like receptor 4 (TLR4), leading to cytokine activation in these patients. Methods We used quantitative real-time reverse-transcriptase polymerase chain reaction to measure TLR4, interleukin-1 (IL-1) receptor, IL-1β, IL-6, and tumor necrosis factor α (TNF-α) mRNA expression in myocardial samples from 36 patients. We compared 18 patients who underwent LVAD implantation with 18 patients with less severe heart failure who underwent elective heart transplantation. Results Toll-like receptor 4 expression was 1.69-fold greater ( p < 0.05) and IL-1 receptor expression was 3.64–fold greater ( p < 0.0001) in the deteriorating patients who required LVADs. Myocardial TNF-α (1.71-fold, p < 0.05), IL-6 (2.57-fold, p < 0.005), and IL-1β (9.78-fold, p < 0.001) also were increased in the LVAD candidates. Toll-like receptor 4 expression correlated strongly with IL-1 receptor expression ( r= 0.75, p < 0.0001) and with IL-1 β expression in individual patients ( r = 0.7, p < 0.0001). Interleukin-1 receptor expression also correlated with IL-1β expression ( r = 0.78, p < 0.0001) within patients. We found no correlation between TLR4 and either TNF-α or IL-6 expression. Conclusions Patients who required LVAD support showed evidence of innate immune system activation, indicated by an increase in the key effector molecule TLR4 associated with a specific pattern of cytokine expression in the myocardium.