OBJECTIVE: To investigate the possible molecular mechanisms of radiofrequency ablation (RFA) for treating atrial fi brillation (AF) and the microRNA (miRNA) target for intervention in the future. METHODS: We examined the changes in miRNAs regulating the atrial ion-channel proteins across the whole genome. We compared fi ndings from 90 AF patients with those from 90 healthy subjects before RFA and three months after RFA. RESULT: Twenty-one miRNAs regulating ion-channel proteins were differentially expressed more than tenfold, and the fi ndings were completely reversed after RFA as compared with the pre-RFA results. The colonial regulating effects of miRNAs regulating the outward K + current channels such as those for the ultra-rapid delayed rectifi er potassium current (Ikur), voltage-dependent delayed rectifi er potassium current (Ikr), and delayed rectifi er potassium channel current (Iks) were more unanimous and stronger, while this was not the case for miRNAs regulating the L-type Ca 2+ current and INa current channels. Generally, miR-1266 levels were increased in the blood but down-regulated in the rheumatic atrial tissue, while a dual luciferase test indicated that SCN5A was the direct target gene of miR-1266. CONCLUSION: Using RFA to treat AF may have an impact via reversing the changes in miRNAs regulating the ion-channel proteins, especially for outward K+ current channels such as Ikur, Ikr, and Iks, which may play a major role in electrical remodeling in AF. It may be that miR-1266 is an antiarrhythmic miRNA and an AF intervention target in the future (Tab. 2, Fig. 4, Ref. 46).