Cardiac afferent signaling partially underlies premature ventricular contraction-induced cardiomyopathy.

Abstract

The mechanisms underlying premature ventricular contraction (PVC)-induced cardiomyopathy (PIC) remain unknown. Transient receptor potential vanilloid-1 (TRPV1) afferent fibers are implicated in the reflex processing of cardiac stress. The purpose of this study was to determine whether cardiac TRPV1 afferent signaling promote PIC. A PIC 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 control (n = 6). We examined early-stage (4 weeks after implantation; n = 5) and late-stage PIC (8 weeks after implantation; n = 6). At terminal experimentation, animals underwent echocardiography, serum sampling, and physiological and autonomic reflex testing. Depletion of cardiac TRPV1 afferents by RTX treatment was confirmed by absent sensory fibers and absent functional responses to TRPV1 activators. Left ventricular ejection fraction was worse in late-stage than early-stage PIC (P <.01). At 4 weeks (early stage), left ventricular ejection fraction was higher in PVC+RTX vs PVC animals (51.7% ± 1.6% vs 45.0% ± 2.1%; P = .030), whereas 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 = .020), suggesting that RTX mitigated profibrotic pathways induced by persistent PVCs. TRPV1 afferent depletion alleviates left ventricular dysfunction in early- but not late-stage PIC. This temporal effect suggests that multiple pathways promote PIC, of which TRPV1 afferents are a part.