Abstract 12757: Competing Neurotrophic and Anti-Neurotrophic Remodeling Processes in PVC-Induced Cardiomyopathy

Abstract

Introduction: We previously demonstrated evidence of pro-arrhythmic sympathetic hyperinnervation and hyperactivity of the stellate ganglia in Premature Ventricular Contraction-induced Cardiomyopathy (PVC-CM). However, the presence of neural remodeling within the myocardium remains unclear. Methods: In a canine model of PVC-CM induced by a novel premature pacing algorithm with 12-weeks of bigeminal short-coupled (200ms) PVC exposure, we performed ELISA of serial plasma norepinephrine levels at baseline vs PVC-CM (N=7), and western blotting of neural proteins and beta-adrenoreceptors using snap-frozen left ventricular free wall myocardium in 6 sham controls and 7 PVC-CM hearts. Results: We found increased trans-cardiac norepinephrine (NE) levels in PVC-CM vs controls (Fig. 1A), increased LV myocardial sympathetic nerve protein Tyrosine Hydroxylase (TH) (Fig.1B) but interestingly, decreased Growth Associated Protein (GAP) 43 (Fig.1C), a marker of sprouting nerve cones. There was no change in synaptophysin (SYN), a neural synapse protein, or Choline acetyltransferase (ChAT), a parasympathetic nerve marker (Fig.1D). Further downstream, we found reduced ß-1 receptor levels similar to other forms of heart failure but markedly increased ß-2 receptor levels (Fig.1E), a finding unique to PVC-CM. Functionally, ß-2 effects are known to oppose the ß-1 inotropic and pro-apoptotic effects in the human myocardium Conclusions: There are competing neurotrophic vs anti-neurotrophic processes occurring within the LV myocardium, along with downstream beta-receptor changes. We hypothesize that these changes are a chronic adaptive response to PVC-induced chronic sympathetic surge, that ultimately protect against sympathetic excess and its consequent downstream effects on myocardial calcium handling and inotropy. These changes may have implications for the pathogenesis of PVC-CM and its pro-arrhythmic consequences. !