**2. Vitamin C and E**

Recently, antioxidant vitamins C and E have been tested in the prevention of AF, especially postoperative AF (POAF) [11-14]. These dietary vitamin supplementations have been proven to protect against the development and progression of AF in experimental models [15, 16]. Vitamin C is a potent water-soluble antioxidant that protects against oxidative stress derived

© 2013 Liu et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 should be tested in future clinical trials.

antioxidant interventions may be improved with aging. In a recent meta-analysis including five randomized controlled trials with 567 patients, Harling et al. [13] showed that the prophylactic use of vitamins C and E significantly reduced the incidence of POAF (OR: 0.43, 95% CI: 0.21 to 0.89) as well as the all-cause arrhythmia (OR: 0.54, 95% CI: 0.29 to 0.99) following cardiac surgery. However, the overall quality of enrolled studies was relatively poor. Un‐ doubtedly, further well-designed studies with enough sample size are warranted in order to

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

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

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The clinical evidence relating to the potential role of antioxidant vitamins for secondary prevention of AF is sparse. Korantzopoulos et al. [21] prospectively studied 44 patients following successful electrical cardioversion of persistent AF. The patients randomized into Vitamin C group and control group. Within one week, AF recurred in 4.5% of patients in the vitamin C group and in 36.3% of patients in the control group (P=0.024). Moreover, inflam‐ matory biomarkers decreased after cardioversion in patients receiving vitamin C. Another recently published study evaluated whether serum Vitamin E level was related to AF recur‐ rence in patients undergoing electrical cardioversion (EC) [22]. One hundred fourty four consecutive patients who underwent successful EC were prospectively enrolled and followed for 3 months. It was indicated that low serum Vitamin E level is an independent predictor for the AF recurrence. Further studies are needed in order to examine the efficacy of antioxidant

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

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

to clarify this issue.

vitamin E in AF prevention.

**3. Thiazolidinediones**

superoxide dismutase (Cu/Zn SOD) [28].

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 incidence.

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 AF into sinus rhythm.

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 antioxidant interventions may be improved with aging. In a recent meta-analysis including five randomized controlled trials with 567 patients, Harling et al. [13] showed that the prophylactic use of vitamins C and E significantly reduced the incidence of POAF (OR: 0.43, 95% CI: 0.21 to 0.89) as well as the all-cause arrhythmia (OR: 0.54, 95% CI: 0.29 to 0.99) following cardiac surgery. However, the overall quality of enrolled studies was relatively poor. Un‐ doubtedly, further well-designed studies with enough sample size are warranted in order to to clarify this issue.

The clinical evidence relating to the potential role of antioxidant vitamins for secondary prevention of AF is sparse. Korantzopoulos et al. [21] prospectively studied 44 patients following successful electrical cardioversion of persistent AF. The patients randomized into Vitamin C group and control group. Within one week, AF recurred in 4.5% of patients in the vitamin C group and in 36.3% of patients in the control group (P=0.024). Moreover, inflam‐ matory biomarkers decreased after cardioversion in patients receiving vitamin C. Another recently published study evaluated whether serum Vitamin E level was related to AF recur‐ rence in patients undergoing electrical cardioversion (EC) [22]. One hundred fourty four consecutive patients who underwent successful EC were prospectively enrolled and followed for 3 months. It was indicated that low serum Vitamin E level is an independent predictor for the AF recurrence. Further studies are needed in order to examine the efficacy of antioxidant vitamin E in AF prevention.
