**3. Thiazolidinediones**

by reactive oxygen and nitrogen species. In a canine model of AF, Carnes et al. [15] were the first to demonstrate that ascorbate attenuates the pacing-induced atrial remodeling and atrial peroxynitrite production. However, Shiroshita-Takeshita [16] and colleagues did not confirm the protective effects of Vitamin C and E against AF in their study. Additionaly, tachypacinginduced atrial effective refractory period shortening and AF promotion were not influenced by antioxidant vitamins, whereas simvastatin attenuated atrial remodeling and prevented AF. Recently, Lin et al. [17] investigated whether Vitamin C has direct electrophysiological effects on isolated rabbit pulmonary vein (PV) preparations. They demonstrated that ascorbic acid decreases PV spontaneous activity and attenuates the arrhythmogenic effects of hydrogen peroxide (H2O2). Given that PVs represent major sources of ectopic beats that trigger parox‐ ysmal AF, the potential preventive effects of vitamin C on AF recurrence after PV isolation

The clinical evidence regarding Vitamin C and E on AF prophylaxis is mainly limited in the setting of POAF prevention. In a retrospective observational study, Carnes et al. [15] evaluated the effects of supplemental ascorbate on POAF prevention. A series of 43 consecutive patients scheduled for coronary artery bypass graft (CABG) surgery were given 2 g ascorbic acid the night before surgery, followed by 500mg doses twice daily for the 5 days following CABG. Patients receiving ascorbate had a 16.3% incidence of POAF, in contrast to 34.9% in the control group (P=0.048). However, multivariate analysis after adjusting for other confounding factors demonstrated that β-blockers use exhibits the most protective effect (84% risk reduction, *P*=0.007) and ascorbate alone was not an independent protector for POAF. In particular, the two groups were not ideally matched regarding all risk factors for AF, and the incidence of diabetes, hypertension, and previous history of AF was higher in the control group compared to the treatment group. Finally, this study may not have enough power to evaluate POAF

Eslami et al [18] examined the effects of ascorbic acid as an adjunct to β-blockers in a prospec‐ tive, randomized trial. One hundred patients undergoing CABG surgery were randomized to the ascorbic acid or to the control group. All patients had been treated with β-blockers for at least for one week. Patients in the ascorbic acid group received 2 g of ascorbic acid on the night before the surgery and 1 g twice daily for 5 days following surgery. Patients in the control group did not receive ascorbic acid. Patients in both groups continued to receive β-blockers postoperatively. The incidence of POAF was 4% in the Vitamin C group and 26% in the control group (P=0.002). The authors concluded that ascorbic acid can be prescribed as an adjunctive therapy to β-blockers for the prophylaxis of POAF. Finally, Papoulidis et al. [19] evaluated the preventive effects of Vitamin C on POAF incidence in 170 patients undergoing isolated onpump CABG. Importantly, all the patients were under β-blockers therapy preoperatively. The incidence of POAF was 44.7% in the Vitamin C group and 61.2% in the control group (*P*=0.041). Notably, patients with Vitmain C had a shorter hospital stay as well as conversion time from

Very recently, in another randomized clinical trial (RCT) [20] which enrolled 152 patients scheduled for cardiac surgery, the combination of vitamin C (1 g/d) plus vitamin E (400 IU/d) reduced the risk of POAF in patients aged over 60 years indicating that the efficacy of the

should be tested in future clinical trials.

30 Atrial Fibrillation - Mechanisms and Treatment

incidence.

AF into sinus rhythm.

Thiazolidinediones (TZDs) represent a class of insulin-sensiting agents with peroxisome proliferator-activated receptor-γ (PPAR-γ) activation effects, used to improve insulin resist‐ ance in patients with type 2 diabetes [23, 24]. Troglitazone, the first drug developed and used clinically, has been withdrawn from the market due to its liver toxicity. Pioglitazone and rosiglitazone are the only compounds that are available for clinical use now. Apart from their insulin-sensitizing effects, TZDs have several pleiotropic properties including anti-inflamma‐ tory and antioxidant [25, 26]. It has been demonstrated that PPAR-γ ligands inhibit the expression of inducible nitric oxide synthase (iNOS) and peroxynitrite production in mesan‐ gial cells and in cerebellar granule cells [27]. Also, TZDs enhance endothelial nitric oxide (NO) bioavailability, reducing nicotinamide adenine dinucleotide phosphate (NADPH) oxidasedependent superoxide production, while they induce antioxidant enzymes such as Cu/Zn superoxide dismutase (Cu/Zn SOD) [28].

Recent experimental evidence indicates that TZDs, especially pioglitazone, prevent atrial electrical and structural remodeling through their anti-inflammatory and antioxidant proper‐ ties. In a rabbit model of congestive heart failure, pioglitazone attenuated atrial structural remodeling and inhibited AF promotion, at the same degree as candesartan. Furthermore, the PPAR-γ activator suppressed transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α) and extracellular signal-regulated kinase (ERK) expression in atrial tissue. Therefore, the authors proposed that pioglitazone may inhibit AF by modulating inflammatory, oxidative 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 including malondialdehyde (MDA), C-reactive protein (CRP), and TNF-α levels. [32]

needed to evaluate the potential role of pioglitazone, as an upstream therapy for AF prevention

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

http://dx.doi.org/10.5772/53408

33

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

Probucol is a lipid-lowering agent with potent anti-oxidant and anti-inflammatory effects. It has been used in clinical practice during the past two decades to decrease atherosclerosis and prevent restenosiss following stent implantation. However, the potential side effects including decreasing serum high-density lipoprotein cholesterol level and QT prolongation have limited the probucol's worldwide clinical use [49, 50]. As a potent antioxidant, it may reduce the production of oxygen free radicals and act as a direct superoxide anion scavenger. In an isolated perfused rat model, probucol increased the expression of an important myocardial antioxidant enzyme, namely glutathione peroxidase, and prevented lipid peroxidation following ischemia reperfusion injury [51]. Moreover, probucol inhibited NADPH oxidase activity in the aorta from cholesterol-fed rabbits [52]. Our previous studies suggested that prophylactic treatment with probucol during the periprocedural period in patients undergo‐ ing coronary intervention protects against contrast-induced acute kidney injury [53, 54]. However, experimental studies regarding the possible benefits of probucol on atrial remod‐ eling and AF prevention are lacking. Gong et al. showed that probucol attenuates atrial nerve sprouting and heterogeneous sympathetic hyperinnervation induced by rapid right atrial

in patients with diabetes [42, 43].

**4. N-acetylcysteine**

demand.

**5. Probucol**

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 needed to evaluate the potential role of pioglitazone, as an upstream therapy for AF prevention in patients with diabetes [42, 43].
