Late sodium current in synergism with Ca <sup>2+</sup> /calmodulin-dependent protein kinase II contributes to β-adrenergic activation-induced atrial fibrillation
Xiaoyan Liu, Lu Ren, Shandong Yu, Gang Li, Pengkang He, Qiaomei Yang, Xiao‐Hong Wei, Phung N. Thai, Lin Wu, Yong Huo
Abstract
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’.