**Acknowledgements**

**8. Xanthine oxidase inhibitors**

36 Atrial Fibrillation - Mechanisms and Treatment

Accumulating evidence suggests that xanthine oxidase (XO) is another important source of ROS and may relate to atrial remodeling and AF [81]. In a pig model of rapid atrial pacing, increased XO activity in LAA and reduced superoxide production by 85% following admin‐ istration of oxypurinol (a XO inhibitor) was demonstrated [75]. However, no significant effect of oxypurinol on superoxide production in human RAA was demonstrated in another study [76]. A potential explanation for this evident difference is that in the porcine model the increased XO activity was located in the LAA, whereas RAA specimens were examined in the human study. Of note, in a similar porcine model, it was demonstrated that after 1 week of rapid atrial pacing NO expression was decreased in the LAA but not in the RAA, indicating

UA is a metabolic product of purine metabolism produced via the action of XO. Therefore, UA represents a marker of oxidative stress and inflammation [83, 84]. There is a positive association between UA levels and AF in different population. In a small observational study, we showed a stepwise increase of UA levels in patients with paroxysmal AF and permanent AF compared to controls [85]. It was also demonstrated that high serum UA levels were independent predictor for AF presence in hypertensive patients [86] and AF recurrence following catheter ablation [87]. In the ARIC study, a large prospective cohort study, elevated serum UA was

No clinical trial to date has examined the effect of allopurinol administration on AF. Only one observational study reported that patients receiving UA lowering agents had decreased AF prevalence [89]. In a very recent experimental study using a dog model of atrial tachypacing, allopurinol suppressed AF promotion by preventing both electrical and structural remodeling, while it also reduced endothelial NOS protein expression without affecting the left ventricular ejection fraction or LA diameter [90]. Finally, there are no data on the cardiovascular effects of

A substantial body of evidence indicates that oxidative stress plays a critical role in the pathophysiology of atrial remodeling. However, the molecular pathways of this pathologic process are complex and depend on different underlying substrates and concomitant diseases. Antioxidant therapy seems to be a promising intervention strategy in the prevention of AF development and perpetuation, at least in the case of POAF. It should be acknowledged that antioxidant substances may be ineffective in many instances since they act at an advanced stage of the oxidative damage cascade. On the other hand, interventions that target early steps

associated with a greater risk of AF development during the follow-up period [88].

that the oxidative stress was enhanced only in the left atrium [82].

the newly released non-purine XO inhibitor febuxostat.

of ROS formation seem to be a more promising strategy.

**9. Conclusion**

This work was supported by grants (30900618, 81270245 to T.L.) from the National Natural Science Foundation of China.
