Visual Abstract - Neuronal Na+ Channels Are Integral Components of Pro-Arrhythmic Na+/Ca2+ Signaling Nanodomain That Promotes Cardiac Arrhythmias During β-Adrenergic Stimulation: 10.1016/j.jacbts.2016.04.004

• CPVT is often caused by increased levels of circulating catecholamines; however, the mechanistic link between β-AR stimulation and the subcellular/molecular arrhythmogenic trigger(s) is unclear.

• In both CPVT and wild type mice, a subpopulation of Na+ channels (nNav) colocalize with RyR2 and NCX.

• Augmented Na+ entry via nNav and enhanced SR Ca2+-ATPase (SERCA)-mediated SR Ca2+ refill are both essential and necessary for CPVT.

• Augmentation of Na+ entry involves β-AR–mediated activation of Ca2+/CAMKII.

• Selective pharmacological blockade as well as silencing of Nav1.6 inhibit myocyte arrhythmic potential and prevent arrhythmias in vivo.