Selective inhibition of IL-6 trans-signaling by sgp130Fc dose-dependently reduced POAF incidence in a murine CABG model, achieving significance at 1 mg/kg (P=0.021 vs. control).
RCT
randomly assigned
Does selective inhibition of IL-6 trans-signaling with sgp130Fc reduce the incidence of postoperative atrial fibrillation in a murine CABG model?
Inhibition of the IL-6 trans-signaling pathway reduces postoperative atrial fibrillation in a murine model, highlighting a potential novel therapeutic target.
p-value: p=0.021
Abstract Background Cumulative evidence suggests that interleukin-6 (IL-6) in the atrium may significantly contribute to the pathogenesis of postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass grafting (CABG). While our previous studies demonstrated a causal relationship between IL-6 and POAF, the specific signaling pathway(classical vs. trans-signaling) mediating this arrhythmogenic effect remains undetermined. Purpose To investigate whether IL-6 induces POAF via activation of the trans-signaling pathway while relatively suppressing the classical pathway. Methods Atrial myocytes (AM), ventricular myocytes (VM), and fibroblasts (FB) were isolated, cultured, and analyzed for IL-6R and glycoprotein 130 (gp130) expression using immunofluorescence and ELISA. Mice were randomly assigned to receive intraperitoneal injections of sgp130Fc (0.1, 0.5, 1 mg/kg), anti-IL-6 antibody (0.08, 0.4, 0.8 mg/kg), or vehicle 24 hours prior to simulated CABG. POAF was monitored for 7 days using an implanted telemetry device. Action potentials (APs), transient outward potassium current (Ito), and inward rectifier potassium current (Ik1) in AM were recorded under control, IL-6 (100 ng/mL), and IL-6 combined with sgp130Fc (0.1, 1, 10 μg/mL) conditions. Results IL-6R protein is expressed on mouse cardiomyocytes (Figures 1A), a finding essential for classical IL-6 signaling initiation and previously unreported. Notably, IL-6R and gp130 levels in AM lysates were lower than in VM and FB, while soluble forms (sIL-6R and sgp130) were significantly higher in AM supernatants (Figures 1C-D), indicating that AM preferentially drives cardiac inflammation through trans-signaling, while showing limited involvement in regeneration and repair via the classical pathway. In Figure 2A, selective inhibition of IL-6 trans-signaling by sgp130Fc dose-dependently reduced POAF incidence, achieving significance at 1 mg/kg (P = 0.021 vs. control), whereas complete IL-6 pathway blockade with anti-IL-6 antibody showed only a non-significant dose-dependent trend. Electrophysiological analysis revealed that IL-6 significantly shortened APD compared to controls, with significant reductions in APD90 and APD50. APD90 increased significantly in the IL-6 + sgp130Fc 10 μg/mL group compared to the IL-6 group and IL-6 + sgp130Fc 1 μg/mL group (Figure 2B). IL-6-treated AM showed reduced Ito current density compared to the control, particularly at voltages from -10 mV to +70 mV and at -40 mV. Conversely, sgp130Fc dose-dependently increased Ito current density from -40 mV to +70 mV (Figure 2C). No significant changes were observed in Ik1 current density with IL-6 or sgp130Fc treatment (Figure 2D). Conclusion IL-6 in cardiac tissue may play a major mechanistic role in the occurrence and maintenance of POAF through activing trans-signaling pathways, and inhibiting the IL-6 trans-signaling pathway may represent a potential novel strategy for preventing POAF.
Wu et al. (Sat,) conducted a rct in Postoperative atrial fibrillation (POAF). sgp130Fc vs. vehicle was evaluated on POAF incidence (p=0.021). Selective inhibition of IL-6 trans-signaling by sgp130Fc dose-dependently reduced POAF incidence in a murine CABG model, achieving significance at 1 mg/kg (P=0.021 vs. control).