Left superior cervical ganglia lymph node mimicry and its role in rat ventricular arrhythmias following myocardial infarction

Aim: Sympathetic overactivation may lead to severe ventricular arrhythmias (VAs) post-myocardial infarction (MI). The superior cervical ganglion (SCG) is an extracardiac sympathetic ganglion which regulates cardiac autonomic tone. We aimed to investigate the characteristics and functional significance of SCG on neuro-cardiac communication post-MI.

Methods: Constructed MI rat model by left anterior descending coronary artery ligation, and electrophysiological, SCG sympathetic nerve activity testing, echocardiography and histology study were performed. The proteins and gene expression were detected using RNA-seq, spatial transcriptomics, quantitative PCR, and western blotting.

Results: The SCG neuronal remodeling was recognized by significant increase in adrenergic tyrosine hydroxylase (TH) (+) neurons and decrease in neuronal size. Top differentially expressed genes enriched in pro-inflammatory profile and nerve regulatory factor in left SCG (LSCG) post-MI. Interleukin (IL)-1β and IL-6 increased significantly at Day 3, ahead of nerve growth factor (NGF) which peaked at Day 7 post-MI. Spatial transcriptomics further identified the relativity of TH enrichment with macrophages and cytokines. Therapeutic LSCG-ectomy successfully triggered cardiac denervation and improved VA vulnerability. Eventually, cardiac denervation attenuated macrophage/mast cell infiltration at para-infarct regions, thus improved cardiac dysfunction. Mechanism study revealed that genetic knockdown of NGF receptor trkA in LSCG reversed sympathetic remodeling and cardiac inflammation, which may be partially mediated by substance P and calcitonin gene-related peptide (CGRP).

Conclusion: Extracardiac sympathetic LSCG remodeling participated in arrhythmogenesis and cardiac inflammation/function post-MI. NGF bridged neuro-immune crosstalk between pro-inflammatory shifting and sympathetic overdrive. Targeting LSCG modification facilitated cardiac protection and prevented VAs post-MI.