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ORIGINAL RESEARCH article

Front. Physiol.
Sec. Cardiac Electrophysiology
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1525836

Effects of Eleclazine (GS6615) on the proarrhythmic electrophysiological changes induced by myocardial stretch

Provisionally accepted
Francisco J Chorro Francisco J Chorro 1,2,3*Luis Such-Miquel Luis Such-Miquel 4,5Samuel Cuñat Samuel Cuñat 6Oscar Arias-Mutis Oscar Arias-Mutis 3,4Patricia Genovés Patricia Genovés 3,4Manuel Zarzoso Manuel Zarzoso 3,4,5Antonio Alberola Antonio Alberola 3,4,6Luis Such-Belenguer Luis Such-Belenguer 4,6Irene Del Canto Irene Del Canto 4,7*
  • 1 Department of Medicine, University of Valencia., Valencia, Spain
  • 2 - Carlos III Health Institute, Biomedical Research Center Network Cardiovascular Diseases (CIBERCV), Madrid, Spain
  • 3 Research Institute, Valencia Clinic Hospital (INCLIVA), Valencia, Spain
  • 4 Biomedical Research Center Network - Cardiovascular Diseases (CIBERCV). Carlos III Health Institute, Madrid, Spain
  • 5 Department of Physiotherapy, University of Valencia, Valencia, Spain
  • 6 Department of Physiology, University of Valencia, Valencia, Spain
  • 7 Departament of Electronic Engineering, School of Engineering, University of Valencia, Burjassot, Valencia, Spain

The final, formatted version of the article will be published soon.

    Purpose: Myocardial stretch is a proarrhythmic factor. Eleclazine (GS6615) is a late sodium current (INaL) inhibitor that has shown protective effects against arrhythmias in various experimental models. Data on its effects during myocardial stretch are lacking. The aim of this study was to investigate the electrophysiological modifications induced by eleclazine basally and during acute ventricular stretch.Methods: Left ventricular stretch was induced at baseline and during perfusion with eleclazine in 26 Langendorff rabbit heart preparations. Programmed stimulation and high-resolution mapping techniques were applied using multiple epicardial electrodes. Results: At baseline, both the ventricular refractory period measured at a fixed cycle length (250 ms) and its surrogate obtained during ventricular fibrillation (VF) decreased significantly during stretch (baseline 128±15 vs. stretch 110±14ms; n=15; p<0.001, and baseline 52±14 vs. stretch 44±10 ms; n=11;p<0.05), while the VF dominant frequency (DF) increased significantly (DF baseline 13±3 vs. stretch 17±5Hz; n=11;p<0.01). Eleclazine 1.4 μM prolonged refractoriness, diminished both DF and conduction velocity during the arrhythmia, and avoided the stretch induced variations in refractoriness (baseline 148±19 vs. stretch 150±23ms; n=15;ns, and baseline 73±16 vs. stretch 77±16ms; n=11;ns) and in DF (baseline 12±5 vs. stretch 12±3Hz;ns). The VF complexity index was inversely related to refractoriness (r= -0.64; p<0.001). Under eleclazine perfusion, the VF activation patterns were less complex, and the arrhythmia stopped in 6 out of 11 experiments (55%; p<0.05 vs. baseline). Conclusions: Eleclazine (GS6615) reduced the proarrhythmic electrophysiological changes induced by myocardial stretch and slowed and simplified activation patterns during VF in the experimental model used.

    Keywords: arrhythmias, myocardia stretch, eleclazine (GS6615), Ventricular Fibrillation, Cardiac mapping

    Received: 10 Nov 2024; Accepted: 10 Jan 2025.

    Copyright: © 2025 Chorro, Such-Miquel, Cuñat, Arias-Mutis, Genovés, Zarzoso, Alberola, Such-Belenguer and Del Canto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Francisco J Chorro, Department of Medicine, University of Valencia., Valencia, Spain
    Irene Del Canto, Biomedical Research Center Network - Cardiovascular Diseases (CIBERCV). Carlos III Health Institute, Madrid, Spain

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