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

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.