**5. Probucol**

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 pacing, and markedly reduces the promotion and maintenance of AF. Also, probucol signifi‐ cantly reduces atrial oxidative stress and increases total antioxidant capacity [55]. A further study from this group suggested that probucol attenuates structural remodeling and preventes atrial apoptosis, decreasing the left atrial MDA content in paced dogs [56]. Very recently, we investigated the effects of probucol on atrial structural and electrical remodeling in alloxaninduced diabetic rabbits [57]. After treatment for 8 weeks, the diabetic rabbits on probucol exhibited alleviation of oxidative stress displayed as decreased plasma MDA and increased plasma SOD levels compared with diabetic controls, while probucol significantly reduced left atrial interstitial fibrosis and AF inducibility [57]. Therefore, it seems reasonable to speculate that the antioxidant effects of probucol may favorably affect atrial autonomic and structural remodeling.

(SNP), as a NO donor, in the prevention of POAF [70]. Specifically, 100 consecutive patients undergoing CABG surgery were randomized to receive SNP (0.5 μg /Kg.min) or placebo (dextrose 5% in water) during the rewarming period. The occurrence of AF was significantly lower in the SNP group (*P*<0.005). Furthermore, the inflammatory biomarker CRP was higher postoperatively in the control group compared to the SNP group (*P*<0.05). However, a recent study didn't find any association between the use of sodium nitroprusside during cardio‐ thoracic surgery and POAF in a retrospective cohort of 1025 patients undergoing bypass surgery [71]. Therefore, anti-inflammatory and antioxidant effects of NO may have beneficial effects on the prevention of POAF. Further randomized controlled studies are urgently needed

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

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

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NADPH oxidases (NOXs) have been investigated as a key enzymatic source of ROS and seem to play an important role in the pathogenesis of hypertension, atherosclerosis, and heart failure [72-74]. NOXs are multi-subunit transmembrane enzymes that utilize NADPH as an electron donor to reduce oxygen to superoxide anion and hydrogen peroxide. NOX2 and NOX4 are

Recent evidence indicates that NOX-derived ROS plays a pivotal role in the development and maintenance of AF. Dudley et al. [75] showed reduced NO and increased superoxide produc‐ tion production in the left atrial appendage (LAA), which was related to increased NADPH oxidase activity in an experimental model of atrial tachy-pacing. Of note, the NADPH oxidase inhibitor apocynin reduced the superoxide production by 91%. In addition, Kim et al. [76] investigated the sources of superoxide production from the right atrial appendage (RAA) of patients undergoing cardiac surgery. They indicated that the membrane-bound subunit gp91phox (NOX2) containing NADPH oxidase was the main source of atrial superoxide production in human atrial myocytes during sinus rhythm and AF. Also, NADPH-stimulated superoxide release from RAA homogenates was significantly increased in patients with AF. In a subsequent study, they measured atrial NADPH oxidase activity in RAA samples from 170 consecutive patients undergoing coronary artery bypass surgery. The multivariate analysis showed that atrial NADPH oxidase activity was the strongest independent risk factor for the development of POAF [77]. Remarkably, recent clinical evidence [78] suggests that the behaviour of NADPH oxidase is related to the type of AF. Cangemi et al. demonstrated that NOX2 was upregulated in patients with paroxysmal/persistent AF compared with those with permanent AF and controls [78]. Also, NOX4-derived hydrogen peroxide production is markedly increased in the LAA tissues of AF patients. Moreover, treatment of HL-1 atrial cells with angiotensin II, resulted in upregulation of NOX4 and H2O2 production [79]. Bearing in mind the potent NADPH oxidase inhibitors such as NOX2 inhibitors and apocynin [80] may

to clarify the role of NO and its donor or precursor on the AF prevention.

be served as potential candidate for the novel preventive agents on AF.

**7. NADPH oxidases inhibitors**

the most abundant NOX subtypes in cardiomyocytes.

Succinobucol (AGI-1067), a derivative of probucol, is a metabolically stable compound that has greater intracellular antioxidant efficacy in vitro than probucol without causing a signifi‐ cant prolongation of the QT interval [58]. Surprisingly, the ARISE study [59] showed that use of succinobucol was associated with increased incidence of new-onset AF in patients with an acute coronary syndrome. Our previous meta-analysis suggested that increased CRP levels are associated with greater risk of immediate and short-term AF recurrence following electrical cardioversion [60, 61]. In this context, although succinobucol have potent antioxidant effects, its unfavourable influence on CRP levels may be a possible potential explanation for this undesirable effect [62, 63]. Undoubtedly, further studies are needed to elucidate the precise role of probucol and succinobucol in atrial remodeling and their clinical impact on AF.
