Abstract
BackgroundMechanical 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 INaL current and Ca2+ overload.ObjectiveThis study investigates the effects of mechanical stretch on activation patterns in atrial cell monolayers and its pharmacological response to ranolazine.MethodsConfluent 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.ResultsHL-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).ConclusionRanolazine attenuates the modifications of activation patterns induced by mechanical stretch in atrial myocyte monolayers.
Highlights
Mechanical stretch is an arrhythmogenic factor in different cardiovascular disorders such as arterial hypertension, mitral valve disease, and congestive heart failure, as well as in acute clinical scenarios such as pulmonary embolism, acute heart failure, acute valve regurgitation, hypertensive crises, or the initial moments of tachyarrhythmia (Ravelli and Allessie, 1997; De Jong et al, 2011; Jalife, 2011; Strege et al, 2012)
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
Ranolazine attenuates the modifications of activation patterns induced by mechanical stretch in atrial myocyte monolayers
Summary
Mechanical stretch is an arrhythmogenic factor in different cardiovascular disorders such as arterial hypertension, mitral valve disease, and congestive heart failure, as well as in acute clinical scenarios such as pulmonary embolism, acute heart failure, acute valve regurgitation, hypertensive crises, or the initial moments of tachyarrhythmia (Ravelli and Allessie, 1997; De Jong et al, 2011; Jalife, 2011; Strege et al, 2012). The augmentation of late sodium current prolongs repolarization and facilitates the appearance of early after depolarizations, and the consequent Na+ overload is capable of causing delayed after depolarizations in atrial myocytes. Kinases such as Ca2+/calmodulin-dependent protein kinase (CaMKII), whose activity is enhanced by the stretch-induced increase in intracellular Ca2+, could modulate Nav1.5 channels (Ma et al, 2012; Shryock et al, 2013). 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 INaL current and Ca2+ overload
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