Abstract 17051: Oxytocin Receptor in the Spinal Neuraxial Modulation of Ventricular Excitability

Abstract

Introduction: Cardiac sympathoexcitation is a major contributor to the pathogenesis of ventricular tachyarrhymias (VTs) during ischemia reperfusion (I/R) and chronic myocardial infarction (MI). Afferent network connections in the intermediolateral cell column (IML) and dorsal horn (DH) control sympathetic output to the heart. Our team reported spinal cord stimulation (SCS), decreased cardiac sympathoexcitation and reduced VTs during ischemia. Oxytocin (OXT) is a known neuromodulator; however, whether OXT signaling can modulate the cardiospinal neural network is unknown. Hypothesis: SCS neuromodulation is reducing sympathoexcitation and VTs through OXT signaling pathways. Methods: Two models of cardiac ischemia were used in Yorkshire domestic swine. In acute I/R, a suture was placed around the left anterior descending (LAD) coronary artery, after sternotomy. Chronic infarction (MI) was created by accessing the femoral with fluoroscopy guidance. Polystyrene microspheres (1ml) were injected via a 3mm angioplasty balloon catheter to the LAD. Animals then recovered post-MI for 6-8wk. SCS treatment was delivered through a four-pole lead which was inserted in the epidural space (T1-T4)(50Hz, 0.4ms pulse duration). T2-T4 spinal cord was collected postmortem for molecular analysis. Fluorescence in situ hybridization (FISH) protocol for RNAscope Fluorescent v2 Assay (ACD) was followed. Cell counts represented as 3 puncta or more centered around DAPI. Results: We report that OXT receptor positive cells significantly decreased as a result of I/R and MI (p<0.001, two-way ANOVA n=4-5 animals, average of 2-3 slices per animal). Within the DH the majority of OXT positive cells were inhibitory GABAergic neurons. Within the IML, a majority of the cells regulated by I/R and MI were microglia, and both an inhibitory and excitatory population contributed to the onset of ischemia. SCS treatment after I/R and MI resulted in the recovery of this OXT receptor cell population. Conclusions: By evaluating the role of OXT in reducing cardiac sympathoexcitation at the level of the spinal cord, we provide new insights into optimizing current neuromodulation approaches and developing new pharmacologic therapies.