Renal denervation achieves its antiarrhythmic effect through attenuating macrophage activation and neuroinflammation in stellate ganglia in chronic heart failure.

aimsRenal 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 its antiarrhythmic effect 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 investigates if and how RDN decreases ventricular arrhythmias by attenuating neuroinflammation in cardiac sympathetic post-ganglionic (CSP) neurons in CHF. METHODS AND

resultsRat CHF was induced by surgical ligation of the left anterior descending (LAD) coronary artery. At 12 weeks after LAD ligation, completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein, followed by applying 70% ethanol around the vessels. Immunofluorescence staining and western blot data showed that expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor-α subunit in SGs was increased in CHF rats. RDN not only reduced CHF-elevated GM-CSF levels in kidney, serum, and SGs but also attenuated macrophage expansion and neuroinflammation in SGs from CHF rats. Using flow cytometry, we confirmed that RDN reduced the percentage of macrophages in SGs, which is pathologically increased in CHF. RDN also decreased CHF-enhanced N-type Ca2+ currents in CSP neurons and attenuated CHF-elevated cardiac sympathetic nerve activity. Electrocardiogram data from 24-h continuous telemetry recording in conscious rats revealed that RDN improved CHF-induced heterogeneity of ventricular electrical activities and reduced the duration of spontaneous ventricular tachyarrhythmias in CHF rats.

conclusionRDN alleviates cardiac sympathetic overactivation and ventricular arrhythmogenesis through attenuating GM-CSF-induced macrophage activation and neuroinflammation within SGs in CHF. This suggests that manipulation of the GM-CSF signalling pathway could be a novel strategy for achieving the antiarrhythmic effect of RDN in CHF.