The main findings of this study are (i) β-adrenergic activation caused AF and abnormal atrial electrical activity, and late INa enhancer ATX-II promoted proarrhythmic activities of ISO in atria; (ii) the underlying mechanisms of ISO-induced AF may be attributed, at least in part, to augmentation of late INa by phosphorylation of NaV1.5 and CaMKII-δ, and (iii) low concentrations of a late INa inhibitor (either RAN or ELEC) with a CaMKII inhibitor, KN-93, synergistically exerted anti-arrhythmic effects. The gene discussed is SCN5A; the disease is atrial fibrillation.