**4. N-acetylcysteine**

stress, and hypertrophic signaling pathways involved in atrial remodeling [29]. Very recently, Kume et al. showed that pioglitazone reduced inflammatory atrial fibrosis and vulnerability to AF in a pressure overload rat model of AF, possibly via the suppression of MCP-1–mediated inflammatory profibrotic processes [30]. In an in vivo rat model, Xu et al. [31] reported pioglitazone inhibited age-related atrial structural remodeling and AF susceptibility via its antioxidant and anti-apoptotic effects. Gene and protein expression levels of antioxidant molecules such as Mn superoxide dismutase (MnSOD) and heat shock protein (HSP) 70 were significantly enhanced, whereas NADPH oxidase subunits p22phox and gp91phox were significantly reduced in aged rats treated with pioglitazone. Therefore, activation of antioxi‐ dant molecules and inhibition of NADPH-derived ROS production may be the mechanisms underlying the favorable effects of TZDs on aging-related atrial remodeling and AF promotion. However, experimental data on the effects rosiglitazone on atrial remodeling in the setting of diabetes is lacking. We have shown that rosiglitazone attenuates atrial structural remodeling reducing the interatrial activation time and the atrial interstitial fibrosis in alloxan-induced diabetic rabbits [31].. Also, rosiglitazone treatment increased plasma antioxidant enzyme superoxide dismutase (SOD) activity and decreased oxidant stress and inflammatory markers

32 Atrial Fibrillation - Mechanisms and Treatment

including malondialdehyde (MDA), C-reactive protein (CRP), and TNF-α levels. [32]

We have previously described two patients with diabetes who experienced a remarkable improvement in their paroxysmal AF episodes following treatment with rosiglitazone [33]. However, two large RCTs, namely RECORD [34] and PROactive [35] which enrolled high-risk patients with type 2 diabetes failed to demonstrate a significant reduction of AF risk from TZDs compared with controls. The potential explanations were: firstly, AF was not a predefined endpoint and reported as an adverse event; secondly, there was a very low AF incidence in both treatment and control groups (1.5-2%). Also, another case-control study showed that preoperative use of TZDs in diabetic patients undergoing cardiac surgery was associated with a non-statistically significant 20% reduction of POAF [36]. In a prospective cohort study including 150 diabetic patients undergoing catheter ablation for AF, Gu et al. showed that previous pioglitazone use was independently associated with a lower recurrence of atrial tachyarrhythmias during a follow-up period of 23 months [37]. Interestingly, in a recent observational study Chao et al. [38] investigated the possible association between TZDs use and development of new-onset AF in 12,605 patients with Type 2 diabetes. During a followup of 5 years, TZDs decreased the risk of new-onset AF by 31% after adjustment for age, underlying diseases and baseline medications. Although growing evidence suggests TZDs use prevents the development and recurrence of AF in diabetic patients, the cardiovascular safety considerations on rosiglitazone recently prompted the European Medicines Agency (EMA) to suspended this drug from the European market and patients taking rosiglitazone were advised to discuss alternative options with their physicians [39]. Since November 18, 2011 the FDA does not allow rosiglitazone to be sold without a prescription from certified doctors. Patients are required to be informed of the risks associated with the use of rosiglitazone. Therefore, it is very hard for rosiglitazone to gain a therapeutic indication for AF in the future [40]. Given the favorable cardiovascular effects of pioglitazone from a recent meta-analysis of 19 RCTs (including PROactive study) enrolling 16,390 patients [41], further large-scale randomized, controlled trials with long-term follow-up or a post hoc analysis from previous trials are still

N-acetylcysteine (NAC) is a precursor of l-cysteine and glutathione. As a source of sulfhydryl groups in cells, it may act as a scavenger of free radicals [44]. In clinical practice, NAC is used as an antioxidant, mucolytic agent widely prescribed in chronic pulmonary disease. Carnes et al. [45] showed that atrial myocytes from AF patients incubated with NAC lead to a significant increase in the density of ICa,L. This observation suggests NAC may possibly attenuates atrial electrophysiological remodeling caused by rapid atrial activation. In a randomized study including 115 patients undergoing CABG or valve surgery, Ozaydin et al. [46] demonstrated that NAC markedly reduces the incidence of POAF lasting more than 5 minutes. A previous meta-analysis [47] evaluated potential beneficial effects of perioperative NAC on the preven‐ tion of complications after cardiothoracic surgery. In the sub-group analysis of six trials which reported POAF as study endpoints, the use of NAC significantly lowered the risk of developing POAF by 36%. In a more recent meta-analysis, Gu et al. [48] included 8 randomized trials incorporating 578 patients, and indicated that NAC significantly reduces the incidence of POAF by 38% (OR: 0.62, 95% CI: 0.41- 0.93; P =0.021) compared with controls. It is worth mentioning that only one trial [46] included in this meta-analysis had specified POAF as a primary endpoint. The remaining seven studies reported POAF as a secondary endpoint. Therefore, future large-scale randomized studies with an adequate power are urgently in demand.
