Abstract P1091: Granulocyte-Macrophage Colony-Stimulating Factor Signaling Pathway And Antiarrhythmic Effect Of Renal Denervation In Chronic Heart Failure

Abstract

Renal denervation (RDN) is widely investigated in multiple studies of sympathetically driven cardiovascular diseases. While the therapeutic potential of RDN for ventricular arrhythmia has been reported, the mechanisms responsible for the antiarrhythmic effect of RDN are poorly understood. Our recent study showed that macrophage expansion-induced neuroinflammation in the stellate ganglion (SG) was a critical factor for cardiac sympathetic overactivation and ventricular arrhythmogenesis in chronic heart failure (CHF). This study aims to investigate if and how RDN decreases ventricular arrhythmias through attenuating neuroinflammation in cardiac sympathetic postganglionic (CSP) neurons in CHF. CHF was induced by acute surgical ligation of the left coronary artery in rats. Completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein and followed by application of 70% ethanol around the vessels. Using immunofluorescence staining and Western blot analysis, we found that expression of granulocyte-macrophage colony-stimulating factor receptor-α subunit (GM-CSFRα), and Iba1 (an activated macrophage marker) in macrophages from the SG were increased in 16-week CHF rats, compared with age matched sham rats. In the ELISA experiment, we observed high levels of GM-CSF in kidney, serum, and SG in CHF rats, which were markedly reduced at 3 weeks after RDN. CHF-elevated macrophage activation and expression of GM-CSFRα in the SG were decreased by RDN. Flow cytometry data confirmed that CHF-increased percentage of macrophages in the SG was reduced at 3 weeks after RDN. Patch-clamp data found that RDN reduced the N-type Ca 2+ currents in CSP neurons from CHF rats (50.5+3.3 pA/pF in CHF rats vs. 28.6+2.2 pA/pF in CHF+RDN rats, P<0.05). RDN attenuated CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-hour continuous telemetry recording in conscious rats revealed that RDN decreased the incidence and duration of spontaneous ventricular tachyarrhythmias in CHF rats. Based on these data, we confirm that RDN inhibits cardiac sympathetic overactivation and ventricular arrhythmogenesis through GM-CSF-macrophage activation-neuroinflammation-N-type Ca 2+ channel signaling axis in CHF.