Effects of JTV-519 on stretch-induced manifestations of mechanoelectric feedback

JTV-519 is a 1,4-benzothiazepine derivative with multichannel effects that inhibits Ca2+ release from the sarcoplasmic reticulum and stabilizes the closed state of the ryanodine receptor, preventing myocardial damage and the induction of arrhythmias during Ca2+ overload. Mechanical stretch increases cellular Na+ inflow, activates the reverse mode of the Na+/Ca2+ exchanger, and modifies Ca2+ handling and myocardial electrophysiology, favoring arrhythmogenesis. This study aims to determine whether JTV-519 modifies the stretch-induced manifestations of mechanoelectric feedback. The ventricular fibrillation (VF) modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=9) or during JTV-519 perfusion: 0.1 μM (n=9) and 1 μM (n=9). Spectral and mapping techniques were used to establish the baseline, stretch and post-stretch VF characteristics. JTV-519 slowed baseline VF and decreased activation complexity. These effects were dose-dependent (baseline VF dominant frequency: control=13.9±2.2 Hz; JTV 0.1 μM=11.1±1.1 Hz, p<0.01; JTV 1 μM=6.6±1.1 Hz, p<0.0001). The stretch-induced acceleration of VF (control=38.8%) was significantly reduced by JTV-519 0.1 μM (19.8%) and abolished by JTV 1 μM (-1.5%). During stretch, the VF activation complexity index was reduced in both JTV-519 series (control=1.60±0.15; JTV 0.1 μM=1.13±0.3, p<0.0001; JTV 1 μM=0.57±0.21, p<0.0001), and was independently related to VF dominant frequency (R=0.82; p<0.0001). The fifth percentile of the VF activation intervals, conduction velocity and wavelength entered the multiple linear regression model using dominant frequency as the dependent variable (R=-0.84; p<0.0001). In conclusion, JTV-519 slowed and simplified the baseline VF activation patterns and abolished the stretch-induced manifestations of mechanoelectric feedback. This article is protected by copyright. All rights reserved.