Abstract 4121234: Macrophage activation in aorticorenal ganglion as a potential trigger to induce renal sympathetic overactivation-related ventricular arrhythmias after acute myocardial infarction

Background: Ischemia-related ventricular arrhythmia is the leading cause of death in patients after acute myocardial infarction (AMI). Although the therapeutic potential of renal denervation (RDN) for ventricular arrhythmias has been reported, RDN-induced adverse complications partially limit its use in the clinic. Since neuroinflammation has recently emerged as a key factor for sympathetic overactivation in the central and peripheral nervous systems, this study aims to test if macrophage activation in renal sympathetic postganglionic (RSP) neurons located in the aorticorenal ganglion (ARG) contributes to renal sympathetic overactivation-related ventricular arrhythmogenesis post-AMI. Methods and Results: AMI was induced by surgical ligation of the left anterior descending artery in rats. Data from immunofluorescence staining showed that the expression of Iba1, TNF-α, and IL-1β was increased in ARGs at 3 days post-AMI rats compared with sham rats, suggesting that macrophage activation and neuroinflammation occurred in the ARG at an early stage after AMI. Direct recording of renal sympathetic nerve activity (RSNA) found that the RSNA was much higher in the 3 days post-AMI rats than in sham rats. To validate the contribution of macrophage activation to AMI-elevated RSNA, we depleted macrophages in ARGs by local microinjection of clodronate liposomes (CL) into ARGs. Immunofluorescence staining data showed that microinjection of CL into ARGs attenuated the AMI-induced macrophage activation (Iba1) and neuroinflammation (TNF-α and IL-1β) in ARGs. Flow cytometry data also confirmed that macrophage depletion in ARGs reduced the AMI-elevated macrophage infiltration in ARGs, which was accompanied by a significant decrease in RSNA in CL-treated AMI rats. To test the ventricular arrhythmogenesis post-AMI, we measured ventricular tachycardia/fibrillation (VT/VF) from 24-hour telemetry ECG recording in conscious rats. Our data showed that macrophage depletion in ARGs alleviated AMI-induced ventricular arrhythmogenesis, as evidenced by a significant reduction in the occurrence of VT/VF in CL-treated AMI rats. Conclusion: These data suggest that macrophage activation and neuroinflammation in the ARG might be critical factors responsible for the renal sympathetic overactivation-related ventricular arrhythmia post-AMI. Inhibiting macrophage activation and neuroinflammation in the ARG could be an effective strategy to achieve the antiarrhythmic effect of RDN after AMI.