Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

Irene Del-Canto; Lidia Gómez-Cid; Ismael Hernández-Romero; María S Guillem; María Eugenia Fernández-Santos; Felipe Atienza; Luis Such; Francisco Fernández-Avilés; Francisco J Chorro; Andreu M Climent

doi:10.3389/fphys.2020.00922

Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

Front Physiol. 2020 Aug 4:11:922. doi: 10.3389/fphys.2020.00922. eCollection 2020.

Authors

Affiliations

¹ INCLIVA Health Research Institute, Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Valencia, Spain.
² Department of Electronic Engineering, Universitat Politècnica de València, Valencia, Spain.
³ Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain.
⁴ Department of Signal Theory and Communications, Universidad Rey Juan Carlos, Madrid, Spain.
⁵ ITACA Institute, Universitat Politècnica de València, Valencia, Spain.
⁶ Department of Physiology, Universitat de València Estudi General, Valencia, Spain.
⁷ Department of Cardiology, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain.

Abstract

Background: Mechanical stretch increases Na⁺ inflow into myocytes, related to mechanisms including stretch-activated channels or Na⁺/H⁺ exchanger activation, involving Ca²⁺ 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 of I _NaL current and Ca²⁺ 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 of in vitro fibrillation (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/cm², 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.

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