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

Abstract

JTV-519 is a 1,4-benzothiazepine derivative with multichannel effects that inhibits Ca release from the sarcoplasmic reticulum and stabilizes the closed state of the ryanodine receptor, preventing myocardial damage and the induction of arrhythmias during Ca overload. Mechanical stretch increases cellular Na inflow, activates the reverse mode of the Na /Ca exchanger, and modifies Ca 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 μmol/L (n=9) and 1 μmol/L (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 μmol/L=11.1±1.1 Hz, P<.01; JTV 1 μmol/L=6.6±1.1 Hz, P<.0001). The stretch-induced acceleration of VF (control=38.8%) was significantly reduced by JTV-519 0.1 μmol/L (19.8%) and abolished by JTV 1 μmol/L (-1.5%). During stretch, the VF activation complexity index was reduced in both JTV-519 series (control=1.60±0.15; JTV 0.1 μmol/L=1.13±0.3, P<.0001; JTV 1 μmol/L=0.57±0.21, P<.0001), and was independently related to VF dominant frequency (R=.82; P<.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=-.84; P<.0001). In conclusion, JTV-519 slowed and simplified the baseline VF activation patterns and abolished the stretch-induced manifestations of mechanoelectric feedback.

Ranolazine Attenuates Stretch-induced Modifications of Electrophysiological Characteristics in HL-1 Cells

“…In the present work, as in previous studies on isolated Langendorff-perfused rabbit hearts [9], we found that stretch increased the AF dominant frequency, which can be considered as proarrhythmic.…”

“…Finally, aside from Na v 1.5 and I NaL , ranolazine inhibits other ionic currents as I CaL and I Na-Ca , which are some of the mechanisms involved in the effects of stretch [6,9]. Nevertheless, the inhibition of these currents was weak at atrial level for the concentration used in this work [6].…”