Does the inhibition of late INa and CaMKII suppress beta-adrenergic activation-induced atrial fibrillation in rabbit models?
Inhibition of late sodium current and CaMKII exerts synergistic anti-arrhythmic effects against catecholaminergic activation-induced atrial fibrillation in preclinical models.
Atrial fibrillation (AF) is frequently associated with β-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was to determine the synergism of late sodium current (late I Na ) and Ca 2+ /calmodulin-dependent protein kinase (CaMKII)-mediated arrhythmogenic activities in β-adrenergic overactivation-associated AF. Monophasic action potential, conduction properties, protein phosphorylation, ion currents and cellular trigger activities were measured from rabbit-isolated hearts, atrial tissue and atrial myocytes, respectively. Isoproterenol (ISO, 1–15 nM) increased atrial conduction inhomogeneity index, phospho-Na v 1.5 and phospho-CaMKII protein levels and late I Na by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied ( p < 0.05). Sea anemone toxin II (ATX-II, 2 nM) was insufficient to induce any atrial arrhythmias, whereas the propensities of AF were greater in hearts treated with a combination of ATX-II and ISO. Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Na v 1.5 and CaMKII, and reversed the increase of late I Na ( p < 0.05) in a synergistic mode. Overall, late I Na in association with the activation of CaMKII potentiates β-adrenergic stimulation-induced AF and the inhibition of both late I Na and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
Liu et al. (Mon,) studied this question.