Abstract Body (Do not enter title and authors here): Background: Ventricular arrhythmia is the leading cause of death in patients after acute myocardial infarction (AMI). Although the blunted baroreflex sensitivity (BRS) is an important predictor of sudden cardiac death after AMI, the mechanisms underlying AMI-depressed BRS remain unclear. Since macrophage activation has emerged as a critical factor for neuronal dysfunction in the central and peripheral nervous systems, our study aims to investigate whether AMI-initiated macrophage activation contributes to ventricular arrhythmogenesis by inducing baroreflex dysfunction after AMI.
Methods and Results: AMI was induced by surgical ligation of the left anterior descending artery in rats. BRS was tested from the aortic depressor nerve activity, heart rate, and renal sympathetic nerve activity in response to phenylephrine-induced blood pressure elevation. Our data showed that BRS was blunted as early as 3 days post-AMI. IF staining data illustrated that macrophage activation (expression of Iba1) in the aortic depressor nerve endings reached the highest level at 3 days post-AMI. To explore the mechanisms of AMI-blunted BRS, we tested the expression of the PIEZO channel, a mechanosensitive ion channel that plays a crucial role in maintaining baroreflex function, in the nodose ganglion (NG). IF staining showed that expression of PIEZO2 was reduced, which was accompanied by a significant macrophage activation in the NG at 3 days post-AMI. Data from flow cytometry confirmed that macrophage infiltration (defined as CD45⁺ & CD68⁺ cells) in baroreceptor neurons was markedly elevated at 3 days post-AMI, compared with sham rats. To validate the contribution of macrophage activation to AMI-depressed BRS, we depleted macrophages by local microinjection of clodronate liposomes around aortic baroreceptor nerve endings immediately after AMI. Our data found that macrophage depletion partially improved AMI-blunted BSR. Data from 24-hour ECG telemetry recording demonstrated that macrophage depletion in baroreceptor nerve endings reduced the cumulative duration of ventricular tachycardia/fibrillation within 3 days post-AMI.
Conclusion: These data suggested that macrophage infiltration in baroreceptor neurons might contribute to ventricular arrhythmogenesis by inducing baroreflex dysfunction after AMI. Our ongoing study is addressing whether reduced expression of PIEZO channels in baroreceptor neurons is responsible for macrophage infiltration-blunted baroreflex function after AMI.