Neuroimmune modulation mediated by IL-6: A potential target for the treatment of ischemia-induced ventricular arrhythmias

Background Neural remodeling in the left stellate ganglion (LSG), as mediated by neuroimmune reactions, promotes cardiac sympathetic nerve activity (SNA) and thus increases incidence of VAs. Interleukin-6 is an important factor of the neuroimmune interaction. Objective The present study explored the effects of IL-6 on LSG hyperactivity and the incidence of VAs. Methods Eighteen beagles were randomly allocated into a control group (saline with MI, n = 6), AAV group (AAV with MI, n = 6), and IL-6 group (AAV-IL-6 with MI, n = 6). Ambulatory electrocardiography was performed before and 30 days after AAV microinjection into LSG. LSG function and ventricular electrophysiology were assessed at 31 days after the surgery, and a canine MI model was established. The LSGs were collected for immunofluorescence staining and molecular biological evaluation. Blood samples and 24-hour Holter data were obtained from 24 AMI patients on the day after they underwent PCI to assess the correlation between IL-6 and the SNA. Results IL-6 overexpression increased cardiac sympathetic nerve activity and worsened post-infarction VAs. Furthermore, sustained IL-6 overexpression enhanced LSG function, promoted the expression of NGF, c-fos, and fos B within the LSG, and activated the STAT3/RGS4 signaling pathway. Clinical sample analysis revealed a correlation between serum IL-6 levels and HRV frequency domain index, as well as T-wave alternans. Conclusions IL-6 levels are correlated with cardiac SNA. Chronic overexpression of IL-6 mediates LSG neural remodeling through the STAT3/RGS4 signaling pathway, elevating the risk of VA after MI.