title: 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 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 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.
authors: Department of Medicine, Valencia University "Estudi General", Valencia, Spain.
authors: Irene
authors: I
authors: Del Canto
authors: Department of Physiotherapy, Valencia University "Estudi General", Valencia, Spain.
authors: Luis
authors: L
authors: Such-Miquel
authors: Department of Physiology, Valencia University "Estudi General", Valencia, Spain.
authors: Laia
authors: L
authors: Brines
authors: Department of Physiology, Valencia University "Estudi General", Valencia, Spain.
authors: Carlos
authors: C
authors: Soler
authors: Department of Physiotherapy, Valencia University "Estudi General", Valencia, Spain.
authors: Manuel
authors: M
authors: Zarzoso
authors: Department of Electronic Engineering, Valencia Polytechnic University, Valencia, Spain.
authors: Conrado
authors: C
authors: Calvo
authors: Department of Physiology, Valencia University "Estudi General", Valencia, Spain.
authors: Germán
authors: G
authors: Parra
authors: Department of Electronic Engineering, Valencia Polytechnic University, Valencia, Spain.
authors: Álvaro
authors: Á
authors: Tormos
authors: Department of Physiology, Valencia University "Estudi General", Valencia, Spain.
authors: Antonio
authors: A
authors: Alberola
authors: Department of Electronic Engineering, Valencia Polytechnic University, Valencia, Spain.
authors: José
authors: J
authors: Millet
authors: Department of Physiology, Valencia University "Estudi General", Valencia, Spain.
authors: Luis
authors: L
authors: Such
authors: Department of Medicine, Valencia University "Estudi General", Valencia, Spain. Francisco.J.Chorro@uv.es.|Department of Cardiology, Valencia University Clinic Hospital, INCLIVA, Valencia, Spain. Francisco.J.Chorro@uv.es.
authors: Francisco J
authors: FJ
authors: Chorro
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D025461:Feedback, Physiological / Q000187:drug effects* / Q000502:physiology; D011311:Pressoreceptors / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000503:physiopathology*
chemical_list: D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; C109183:K201 compound
keywords: JTV-519; K201; mapping; mechanoelectric feedback; myocardial stretch; ventricular fibrillation