Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

Autores de INCLIVA

• Irene Del Canto Serrano

  Autor

• 

  Luis Such Belenguer

  Autor

• 

  Francisco Javier Chorro Gascó

  Autor

Participantes ajenos a INCLIVA

• Gomez-Cid, L
• Hernandez-Romero, I
• Guillem, MS
• Fernandez-Santos, ME
• Atienza, F
• Fernandez-Aviles, F
• Climent, AM

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Electrofisiología cardiaca experimental

  

  Leading Researcher

  Antonio M. Alberola Aguilar

Abstract

Background Mechanical stretch increases Na(+)inflow into myocytes, related to mechanisms including stretch-activated channels or Na+/H(+)exchanger activation, involving Ca(2+)increase that leads to changes in electrophysiological properties favoring arrhythmia induction. Ranolazine is an antianginal drug with confirmed beneficial effects against cardiac arrhythmias associated with the augmentation ofI(NaL)current and Ca(2+)overload. Objective This study investigates the effects of mechanical stretch on activation patterns in atrial cell monolayers and its pharmacological response to ranolazine. Methods Confluent HL-1 cells were cultured in silicone membrane plates and were stretched to 110% of original length. The characteristics ofin vitrofibrillation (dominant frequency, regularity index, density of phase singularities, rotor meandering, and rotor curvature) were analyzed using optical mapping in order to study the mechanoelectric response to stretch under control conditions and ranolazine action. Results HL-1 cell stretch increased fibrillatory dominant frequency (3.65 +/- 0.69 vs. 4.35 +/- 0.74 Hz,p< 0.01) and activation complexity (1.97 +/- 0.45 vs. 2.66 +/- 0.58 PS/cm(2),p< 0.01) under control conditions. These effects were related to stretch-induced changes affecting the reentrant patterns, comprising a decrease in rotor meandering (0.72 +/- 0.12 vs. 0.62 +/- 0.12 cm/s,p< 0.001) and an increase in wavefront curvature (4.90 +/- 0.42 vs. 5.68 +/- 0.40 rad/cm,p< 0.001). Ranolazine reduced stretch-induced effects, attenuating the activation rate increment (12.8% vs. 19.7%,p< 0.01) and maintaining activation complexity-both parameters being lower during stretch than under control conditions. Moreover, under baseline conditions, ranolazine slowed and regularized the activation patterns (3.04 +/- 0.61 vs. 3.65 +/- 0.69 Hz,p< 0.01). Conclusion Ranolazine attenuates the modifications of activation patterns induced by mechanical stretch in atrial myocyte monolayers.

© 2020 Del-Canto, Gómez-Cid, Hernández-Romero, Guillem, FernándezSantos, Atienza, Such, Fernández-Avilés, Chorro and Climent. 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) and the copyright owner(s) 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

Keywords

• mechanical stretch; mechanoelectric feedback; fibrillatory patterns; ranolazine; optical mapping; rotor dynamic analysis; HL-1 cell