Abstract 4142346: EPAC2-expressing neurons within the stellate ganglia are responsible for cardiac sympathetic innervation

Background: Neurons located in the stellate ganglia (SG) are responsible for providing sympathetic nerve supply to the heart. This innervation plays a role in cardiac sympathetic overactivity, which can lead to malignant ventricular arrhythmias and chronic cardiac remodeling during disease processes. However, the specifics of how SG contributes to cardiac innervation are still not well understood. Methods: We used retrograde neuroanatomical tracing and immunofluorescence assays to confirm the presence of cardiac-innervating neurons, specifically the exchange protein directly activated by cAMP 2 positive (EPAC2+) neurons in the SG. Subsequently, single nucleus RNA sequencing was performed to determine the transcriptional profiles of SG cells, including EPAC2+ neurons. Additionally, we evaluated the physiological function of EPAC2+ neurons in healthy dogs and in an acute myocardial infarction (MI) model induced by occlusion of the left anterior descending artery. To explore the pathological role of EPAC2+ neurons in cardiac remodeling, we used a chronic MI model with neuron-specific adeno-associated virus (AAV). Results: We identified EPAC2+ neurons within the SG that specifically innervate the heart. These EPAC2+ neurons exhibited a unique transcriptional profile compared to EPAC- neurons, with a notable enrichment in genes involved in the calcium signaling pathway, including calcium channels and adenylyl cyclases 8 and 9 (AC8 and AC9). Functionally, activation of EPAC2 in the SG led to increased sympathetic activity. Inhibition of EPAC2 specifically reduced SG nerve activity and prevented ventricular arrhythmias following acute myocardial infarction. Moreover, targeted knockdown of EPAC2 in neurons diminished SG hyperactivity, enhanced cardiac function, reduced sympathetic nerve sprouting at the infarct border zones, and decreased ventricular remodeling after MI, while reversing the phosphorylation of MEK1/2 and ERK1/2. Conclusions: The results indicate that EPAC2+ neurons in the SG play a crucial role in heart innervation. This research enhances our understanding of cardiac sympathetic innervation and could lead to new therapeutic approaches.