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BS-512-01 PHARMACOLOGICAL SYMPATHETIC REINNERVATION AFTER MYOCARDIAL INFARCTION PREVENTS ARRHYTHMIAS IN THE MOUSE HEART

      Background

      Sympathetic control of the heart plays a key role in modulating cardiac function and electrophysiology. Sympathetic hypo-innervation following myocardial infarction (MI) increases risk for development of ventricular arrhythmias. We have previously shown that chondroitin sulfate proteoglycans (CSPGs) play a role in post-MI hypo-innervation by signaling through the neuronal protein tyrosine phosphatase receptor σ (PTPσ), and that genetic deletion of PTPσ from the sympathetic neurons of mice restores innervation and prevents arrhythmias post-MI.

      Objective

      To investigate the effects of pharmacological modulation of PTPσ by the novel Intracellular Sigma Peptide (ISP) on cardiac sympathetic innervation and electrophysiology in the post-MI mouse heart.

      Methods

      MI was carried out in male and female mice (C57Bl6, 12-18 weeks old) with 45 min of ischemia followed by reperfusion. Blinded treatment with either vehicle (VEH: 5% DMSO/saline IP) or ISP (10mg/kg IP) was administered on days 3-10 post-MI. Hearts were dissected and Langendorff-perfused 14 days post-MI for electrophysiological studies (performed after 15 min of equilibration, N=4/group). Additional hearts (N=5/group) were used for immunohistochemistry studies to assess infarct size and sympathetic innervation (via tyrosine hydroxylase [TH] staining).

      Results

      ISP treatment had no effect on infarct size compared to VEH. VEH-treated hearts showed significant loss of TH+ fibers in the infarct, whereas ISP-treated hearts did not. Ex vivo heart rate was significantly higher in the ISP-treated compared to VEH hearts (300.3±34.9 vs. 180.3±37.7 BPM, p=0.003). Premature ventricular contractions (PVCs) occurred in all 4 VEH-treated hearts; bigeminy and ventricular tachycardia (VT) occurred in 1 VEH heart each. None of the ISP-treated hearts developed any kind of ventricular arrhythmias, resulting in a significantly lower arrhythmia score in ISP compared to VEH (0±0 vs. 1.75±0.96, p=0.01).

      Conclusion

      Pharmacologic intervention by daily injection of ISP post-MI prevents arrhythmias in the mouse heart, despite no change in infarct size. These data suggest that restoring sympathetic innervation to the infarct is anti-arrhythmic.