Abstract 4359996: Systemic Neutralization of Granulocyte-Macrophage Colony-Stimulating Factor Attenuates Stellate Ganglion Neuroinflammation and Cardiac Sympathetic Overactivation in Chronic Heart Failure

Background: Chronic heart failure (CHF) is marked by cardiac sympathetic overactivation, a critical driver for ventricular arrhythmogenesis and sudden cardiac death. Much evidence suggests that macrophage-mediated neuroinflammation in stellate ganglia (SG) fuels cardiac sympathetic overdrive in CHF. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotent cytokine involved in M1 (pro inflammatory) macrophage polarization in-vivo. In patients with CHF, serum levels of GM-CSF correlate with disease severity and neurohormonal activation. Hypothesis: We hypothesize that systemic perfusion of GM-CSF neutralizing antibody reduces macrophage-induced neuroinflammation and cardiac sympathetic overactivation in SG. Methods: CHF was induced by surgical ligation of the left coronary artery in rats. Echocardiography was conducted 16 to 18 weeks after surgical ligation. Then a mini osmotic pump was subcutaneously implanted, and GM-CSF neutralizing antibody was perfused for two weeks. Serum GM-CSF levels were measured by ELISA. Protein expression of IBA1 (activated macrophage marker), TNF-a, and IL-1b in SG was measured using western blotting. Whole-cell patch-clamp was used to measure action potentials (AP) of SG neurons. Cardiac sympathetic nerve activity and left ventricular pressure were also recorded by general electrophysiological technique and a Millar pressure transducer. Results: Perfusion of GM-CSF antibody reduced circulating levels of GM-CSF elevated in CHF rats (8.9±1.6 to 3.3±0.5 pg/ml; p<0.01). GM-CSF neutralization also decreased protein expression of IBA1 (0.81±0.12; p<0.01), TNF-a (0.74±0.08; p<0.05) and Il-1b (0.03±0.02; p<0.01), compared to CHF controls (1.98±0.1, 1.13±0.003, and 0.67±0.05, respectively). These molecular changes were accompanied by reduced cell excitability of SG neurons, as evidenced by lower AP spikes in the rats with GM-CSF antibody perfusion (17.5±1.7 vs. 25.1±1.4 spikes/sec; p<0.01). Additionally, GM-CSF neutralization significantly attenuated the CHF-induced elevations in cardiac sympathetic nerve activity and left ventricular diastolic pressure (p<0.05). Conclusion: GM-CSF neutralization mitigates CHF-induced sympathetic overactivation, mechanistically linked to a reduction in macrophage-mediated neuroinflammation and neuronal excitability in SG. These data highlight GM-CSF as a critical mediator of cardiac autonomic dysfunction, presenting a promising avenue for restoring cardiac autonomic balance in CHF.