LAUSR

BACKGROUND The mechanisms underlying premature ventricular contraction (PVC)-induced cardiomyopathy remain unknown. Transient receptor potential vanilloid 1 (TRPV1) afferent fibers are implicated in the reflex processing of cardiac stress. OBJECTIVE We aimed to determine whether cardiac TRPV1 afferent signaling promote PVC-induced cardiomyopathy. METHODS A PVC-induced cardiomyopathy swine model (50% PVC burden) was created via an implanted pacemaker. We selectively depleted cardiac TRPV1 afferent fibers using percutaneous epicardial application of Resiniferatoxin (RTX). Animals were randomized to PVC only (n=11), PVC+RTX (n=11), or controls (n=6). We examined early-stage (4 weeks after implantation, n=5) and late-stage PVC-induced cardiomyopathy (8 weeks after implantation, n= 6). At terminal experimentation, animals underwent echocardiography, serum sampling, physiologic, and autonomic reflex testing. RESULTS Depletion of cardiac TRPV1 afferents by RTX treatment was confirmed by absent sensory fibers, and absent functional responses to TRPV1 activators. LVEF was worse in late-stage PVC-induced cardiomyopathy than early stage (p< 0.01). At 4 weeks (early stage), LVEF was higher in PVC+RTX vs. PVC animals (51.7 ± 1.6% vs. 45.0 ± 2.1%, p= 0.030), while no significant difference between PVC and PVC+RTX was observed at 8 weeks (late stage). Histologic studies demonstrated reduced fibrosis in PVC+RTX vs PVC alone at 4 weeks (2.27 ± 0.14% vs. 3.01 ± 0.21%, p= 0.020), suggesting that RTX mitigated pro-fibrotic pathways induced by persistent PVCs. CONCLUSION TRPV1 afferent depletion alleviates LV dysfunction in early, but not late stage PVC-induced cardiomyopathy. This temporal effect suggests that multiple pathways promote PVC-induced cardiomyopathy, of which TRPV1 afferents are a part.