Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

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 of I 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 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/cm 2 , p < 0.01) under control conditions. These effects were related to stretchinduced 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 stretchinduced 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.

Combined atrial fibrillation ablation and balloon mitral commissurotomy in patients with rheumatic mitral stenosis

“…Despite propensity score matching was performed, optimal statistical matching was challenging, and this may influence the outcome, thus results should be taken with caution. The potential benefits of mechanical stretch pharmacologic modifiers were not evaluated 20 . Moreover, the exclusion of patients with non‐inducible AF or severe LA scarring will reduce the potential effects of ablation in this population.…”

“…The potential benefits of mechanical stretch pharmacologic modifiers were not evaluated. 20 Moreover, the exclusion of patients with non-inducible AF or severe LA scarring will reduce the potential effects of ablation in this population.…”

Extracellular vesicles secreted by human cardiosphere-derived cells attenuate electrophysiological remodelling in an in vitro model of atrial fibrillation

“…Recently, Cho et al [471] demonstrated the antiarrhythmic effects of CDCs in rats with This study used HL-1 CM monolayers as models of arrhythmic substrate. Despite being an in vitro cell line capable of presenting a mature cardiac phenotype and being widely used to study cardiac electrophysiology and arrhythmias [477][478][479][480][481][482][483][484][485][486], their use has several limitations that must be taken into account. HL-1 cells, although being mature, are of murine origin and present important electrophysiological differences with adult human cardiac tissue.…”

“…Electrophysiological properties of cell cultures were analyzed by processing CaT recordings as illustrated in Figure 7.1b. with custom software written in MATLAB, quantifying dominant frequency (DF), complexity, curvature, rotor meandering and CV as described by Climent et al [477,478].…”

Fabrication of human myocardium using multidimensional modelling of engineered tissues

“…Custom software written in MATLAB was used to perform optical mapping image processing and analysis [30]. Data was filtered to remove fluorescence noise, applying a spatial Gaussian filter (kernel size = 5) and a temporal smoothing filter (kernel size = 5) as described in previous studies [31]. Finally, CaT signals of each pixel were normalized between 0 and 1 [32].…”