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Antioxidants for prevention of atrial fibrillation: a potentially useful future therapeutic approach? A review of the literature and meta-analysis

Francesco Violi, Daniele Pastori, Pasquale Pignatelli, Lorenzo Loffredo
DOI: http://dx.doi.org/10.1093/europace/euu040 1107-1116 First published online: 4 April 2014


Atrial fibrillation (AF) is a self-perpetuating arrhythmia which is dependent upon structural and functional changes elicited by atrial high rate activity. Shortening of atrial effective refractory period is the earliest functional change which characterizes atrial remodelling. Studies in humans demonstrated oxidant species overproduction in the cardiac specimens from patients with AF and a significant association between reactive oxidant species (ROS) formation and risk of AF. Also, there is experimental evidence to suggest that ROS may be implicated not only in promoting AF but also in maintaining atrial arrhythmia. Several enzymatic pathways seem to be implicated in ROS overproduction, which ultimately leads to enhanced vulnerability to AF; they include myeloperoxidase, Nicotinamide adenine dinucleotide phosphate oxidase, and uncoupled nitric oxide synthase enzymes. To explore if ROS are implicated in promoting AF experimental studies with antioxidants, prevalently antioxidant vitamins such as ascorbic acid and vitamin E, have been planned. Furthermore, interventional trials have been carried out with antioxidants in clinical settings characterized by enhanced risk of AF. This review reports on experimental and clinical studies exploring the role of ROS in eliciting the occurrence or recurrence of AF and the potential efficacy of a treatment by antioxidant vitamins; furthermore, we performed a meta-analysis of the interventional trials in patients at risk of AF to see if antioxidant treatment is able to reduce the AF occurrence.

  • Antioxidant
  • Atrial fibrillation
  • Reactive oxygen species
  • NADPH oxidase
  • MPO


Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population and in patients undergoing cardiac surgery.1 As prevalence of AF increases with advancing age, its social impact is becoming most relevant because of the associated high risk of cardiovascular events and increased morbidity and mortality.2 Furthermore, clinical characteristics of ischaemic stroke from AF are increasingly severe and thromboembolism is considered the most important cause.3 Ischaemic stroke is, in fact, deemed to stem from thrombus formation generated in the left atrial appendage with ensuing embolism in the cerebral circulation.4 Lowering the negative clinical impact of AF, particularly in the elderly population, represents an important goal mainly in the western countries whose ageing population is quite numerous.5 Thus, it has become crucial to better understand the underlying mechanism of AF to plan appropriate therapeutic intervention.

Atrial fibrillation is a self-perpetuating arrhythmia which is facilitated by structural and functional changes elicited by atrial high rate activity. Shortening of atrial effective refractory period (ERP) is the earliest functional change that characterizes atrial remodelling.6 Loss of rate adaptation and prolongation of atrial conduction are other factors concurring to AF self-maintenance.7 Overload of calcium in the cardiomyocytes of AF has been suggested to be a key step in atrial electrical remodelling,8 but the underlying mechanism is still elusive. Among the recognized triggers of AF, there is evidence that some specialized cardiac cells located in the context of the pulmonary veins are capable of pacemaking activity in the animals and humans.9 Zhou et al.10 demonstrated that in dogs such focal activity may be enhanced in persistent AF, suggesting that pulmonary veins may also be important in sustaining reentry mechanisms. Left atrial ablation combined with pulmonary vein isolation targeting AF triggers, is effective in the treatment of most paroxysmal AF.11

Studies in humans demonstrated oxidant species overproduction in the cardiac specimens from patients with AF.12 Mihm et al.13 found, for instance, the accumulation of nitrotyrosine in the atrial appendage of AF patients suggesting a potential relationship between oxidative stress and AF perpetuation. Thus, there is experimental evidence to suggest that reactive oxidant species (ROS) may be implicated not only in promoting AF but also in maintaining atrial arrhythmia.12,13 Furthermore, trials with antioxidant treatments have been planned to explore if blunting ROS activity may result in halting AF recurrence in experimental and clinical studies.

The aim of this review is to examine if a causal relationship between oxidative stress and AF is supported by experimental studies and if antioxidant treatment may represent an interesting option to halt or retard the occurrence of AF.

Oxidative stress and atrial fibrillation

Experimental and clinical studies suggest that ROS may have a role not only as trigger of AF but also as a factor maintaining cardiac arrhythmia once AF is developed.1416 Experimental studies specifically addressed this issue by analysing if myeloperoxidase (MPO) may favour the occurrence of AF in animals that were rendered susceptible to AF.17 Myeloperoxidase is an enzyme of leucocytes with oxidant property via the formation of hypochlorous acid (HOCL). As a consequence of this property, MPO activates enzymes such as metalloproteinases which are implicated in the turnover of extracellular matrix and likely linked to atrial remodelling.18,19 The experimental model consisted a 2-week infusion of angiotensin II (Ang-II), which is known to elicit atrial remodelling and fibrosis.20 Infusion of Ang-II was associated with the accumulation in the atria of 3-chlorotyrosine, a specific marker of MPO-dependent HOCL formation, and atrial fibrosis, two effects which were significantly attenuated in animals knockout for MPO. These data suggested that Ang-II elicits atrial fibrosis via activation of MPO.20 In addition to structural remodelling MPO was also implicated in functional remodelling. This was suggested by increased electrical instability and higher vulnerability for the development of AF in animals treated with MPO, an effect that was not observed in animal knockout for the enzyme.17 Several experiments were also performed to see the transferability of these findings to human AF. First, the study showed MPO over-expression in specimens taken from right atrial appendages of patients with AF compared with patients on sinus rhythm. Secondly, higher serum levels of MPO was found in a small cohort of patients developing AF after cardiac surgery.17 These findings, taken together, lead to hypothesize that Ang-II exerted its pro-arrhythmic effect prevalently via the oxidant activity of MPO released by activated leucocytes. However, it remains to be established that the intrinsic mechanism by which Ang-II elicits the release of MPO by leucocytes and the intracellular pathway implicated in Ang-II- induced MPO activation. Nonetheless, MPO does not seem the only enzymatic pathway contributing to oxidative stress in the atria and eventually to AF. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH) is the most important cellular producer of ROS and, as MPO, plays a crucial role in the activity of the innate immune system; hereditary deficiency of NADPH oxidase is, in fact, associated with life-threatening infections.21 Dudley et al.22 measured oxidative stress in left atrium or left atrium appendage after 1 week of AF induced by pacing in pigs. The study showed that, compared with controls, pigs with sustained AF have enhanced oxidative stress, which was dependent upon activation of NADPH oxidase. Kim et al.12 demonstrated, indeed, that NADPH oxidase was the main source of ROS in atrial myocytes and was functionally up-regulated in atrial homogenates and myocytes taken from the right atrial appendage of patients with AF compared with those in sinus rhythm. Such up-regulation was also associated with nitric oxide synthase (NOS) ‘uncoupling’ suggesting that both NADPH oxidase activation and dysfunctional NOS contribute to structural and functional remodelling in AF.12 In accordance with these findings, our group recently demonstrated that patients with paroxysmal/persistent AF had enhanced urinary excretion of isoprostanes, a marker of oxidative stress, and up-regulation of NOX2, one isoform of NADPH oxidase, compared with patients with permanent AF suggesting a role for NOX2 as a trigger of AF.23 Further study from Kim et al.24 evaluated if NADPH oxidase has a role in the pathogenesis of human AF. They analysed the behaviour of the enzyme in a clinical setting, i.e. cardiac surgery, which is characterized by a high rate of AF after the intervention. They found that NADPH oxidase-stimulated ROS production in the right atrial appendage from 170 patients undergoing coronary artery bypass surgery was up-regulated in patients who developed AF after surgery compared with those who remained in sinus rhythm.24 Multivariate analysis demonstrated that atrial activity of NADPH oxidase was the strongest independent predictor of post-surgery AF. However, other NOX isoforms may be involved in the pathogenesis of AF. In particular, NOX4 has been found to be over-expressed in the left atrium appendage cells of patients affected by AF compared with controls and to be associated with increased H2O2 production.25

The interplay between ROS formation and AF was supported and extended by Reilly et al.,26 who found the up-regulation of different pathways generating ROS according to the AF duration in animals undergoing atrial pacing. In particular, they found that short-lasting AF (2 weeks) was associated with over-expression of NOX2 and gp22phox, the two membrane-bound sub-units of NADPH oxidase, which accounted for NADPH oxidase-mediated oxidative stress in the left atrium.26 Conversely, in longstanding AF ‘uncoupled’ NOS, secondary to lowered tetrahydrobiopetrin (BH4), a cofactor of NOS, and increased mitochondrial oxidases were implicated in enhancing oxidative stress.

In accordance with this finding Goette et al.15 detected an increased serum levels of asymmetric dimethylarginine (ADMA), an inhibitor of NOS synthase, in patients with AF. In keeping with these results was an experimental study in pigs in which atrial tachypacing was associated with increased serum levels of ADMA. Of note, the serum levels of ADMA significantly decreased after cardioversion suggesting that AF per se may down-regulate NOS and in turn sustain cardiac arrhythmia with an oxidative stress-mediated mechanism. This hypothesis has been formulated by Goette et al.14 who suggested AF-induced ischaemia as a mechanism producing ROS and ultimately AF maintenance. This hypothesis has been investigated in a prospective study that included 144 patients with paroxysmal/persistent AF undergoing electrical cardioversion. During a 3-month follow-up, recurrence was more frequent in patients who showed, at baseline, enhanced NOX2 and lower serum levels of vitamin E, an antioxidant which inhibits lipid peroxidation,27 suggesting a role for oxidative stress in sustaining AF.

Together the data suggest that at least three enzymatic pathways generating ROS, namely MPO, NADPH oxidase, and uncoupled NOS, may be implicated in triggering and maintaining AF in the experimental and clinical models. The association between MPO and AF reinforces the concept that atrial inflammation plays a role in initiating AF as MPO is a leucocyte enzyme which is released upon cell activation. The fact that Ang-II is able to elicit MPO release from leucocytes is of particular relevance taking into account that hypertension, which is a classic atherosclerotic risk factor, is detected in the majority of AF patients. It is, therefore, arguable that hypertension may favour the occurrence of AF via an inflammatory process involving MPO release from leucocytes. Up-regulation of NADPH oxidase and ‘uncoupled’ NOS in the atria of patients prone to AF could also reflect a process of systemic inflammation related to the atherosclerotic process occurring in AF.12 Thus, atherosclerosis is suggested to gradually reduce blood supply to myocardial tissue and cause atrium damage, which eventually leads to premature myocytes apoptosis, fibrotic replacement, and electrical changes associated with reentry processes.28 Up-regulation of NADPH has been documented in several clinical settings characterized by accelerated atherosclerosis. Patients with peripheral artery disease, which is a classic hallmark of systemic atherosclerosis, disclosed up-regulation of NOX2 from blood cells including leucocytes with a significant association between NOX2 expression and intima media thickness.29 Similar findings have been found in diabetic patients in whom NOX2 over-expression was also detected in platelets suggesting a possible implication of the enzyme in the thrombotic process.30 Uncoupled NOS with ensuing overproduction of ROS, which is one of the major determinants of endothelial dysfunction, is typically associated with atherosclerosis risk factors such as diabetes.31 Furthermore, two prospective studies investigated if patients with or at risk of atherosclerosis are more prone to experiencing AF.32,33 The results of these studies suggested that patients with sub-clinical atherosclerosis and no overt manifestation of cardiovascular disease are more prone to developing AF and that atherosclerosis may favour the occurrence of AF. Based on this it is possible to postulate that up-regulation of MPO and NADPH oxidase in the atria of patients prone to AF may reflect a systemic/local inflammatory process involving leucocyte activation with ensuing release of MPO and/or atrial up-regulation of enzymes regulating ROS production such as NADPH oxidase. Classic atherosclerotic risk factors such as hypertension, diabetes, dyslipidaemia, and smoking may contribute to up-regulate these two enzymes hence favouring structural and functional remodelling that ultimately lead to atria fibrosis and changes in electrical atrium excitability (Figure 1).

Figure 1

Oxidative stress as mechanism promoting and perpetuating AF.

Antioxidants in experimental models of atrial fibrillation

In several experimental models of atrial pacing, an enhanced production of ROS has been detected in cardiac tissues, suggesting a potential interplay between ROS formation and atrial electrical changes which ultimately lead to AF. Experimental studies investigated if oxidative stress may be implicated in perpetuating AF by interventional trials with antioxidants. Two studies have specifically addressed this issue in a similar model of tachypacing-induced atrial excitability and vulnerability to AF.34,35 Animals were given ascorbic acid, an antioxidant which scavenges oxygen radicals,34 alone or in combination with vitamin E.35 In both studies, animals were loaded with 500–1000 mg ascorbic acid beginning the night or the day before the tachypacing and continued with a dosage of 1 or 2 g ascorbic acid throughout the study period. The results of the studies were divergent as Carnes et al.36 showed that antioxidant treatment reduced ERP shortening elicited by atrial pacing while Shiroshita-Takeshita et al.35 found no effect of ascorbic acid alone or in combination with vitamin E in reducing atrial excitability or vulnerability to AF. The reason for this divergence, despite the similarity in the study protocol, is not easy to explain. It is of note, however, that Carnes et al.36 used higher dosage of vitamin C during the study period and supported the ascorbic acid antioxidant property by showing increased pacing-induced atrial content of 3-nitrotyrosine, a marker of oxidative stress, and its reduction in ascorbic acid-treated animals. Conversely, no data concerning the antioxidant effect of ascorbic acid in the study period was provided by the other studies. Carnes et al.36 also investigated if ascorbic acid was effective in preventing AF occurring after cardiac surgery. For this purpose, 50 patients undergoing cardiac surgery were treated with 500 mg ascorbic acid the night before surgery and 500 mg twice daily for 5 days after surgery. A group undergoing the same cardiac surgery but not treated with ascorbic acid was used as the control. Even if the study showed that ascorbic acid significantly reduced the occurrence of post-surgery AF compared with the control group, these findings must be wisely considered because of small sample size and non-randomized study.

Consistent with the positive effects of antioxidants in lowering pacing-induced atrial remodelling are the results of an experimental study with probucol, an antioxidant which scavenges oxygen free radicals.37 The experiments consisted in evaluating atrial structural remodelling in animals undergoing tachypacing, which were treated or not with probucol; also in this experiment antioxidant treatment was given 1 week before tachypacing. The study showed that probucol significantly reduced myocardial damage, as assessed by cardiomyocytes myolysis, coincidentally with lower oxidation of left atrium compared with the controls, suggesting a cause effect relationship between oxidative stress and pacing-induced structural atrial remodelling.38 This finding is consistent with a novel model of AF in which experimentally induced chronic kidney disease is associated with atrial fibrosis, up-regulation of NADPH oxidase, and vulnerability to electrical induction of AF. Treatment of animals with another antioxidant down-regulated NADPH oxidase simultaneously with the reduction of atrial fibrosis and AF occurrence.39

In another interesting model of atrial tachypacing, the effect of an imbalance between oxidative stress and nitric oxide (NO), an antioxidant molecule with vasodilator and antiaggregating properties, was tested.40 The model consisted in inducing heart failure in dogs by atrial pacing for a period of 4 months. For the last 6 weeks of the study period, dogs were randomized to placebo or BH4, and l-arginine, a substrate of NOS. The study showed that heart failure was associated with enhanced left atrial formation of superoxide anion along with NO activity lowering. As heart failure was associated with reduced atrial BH4 and up-regulation of inducible NOS2, this finding suggested that up-regulation of ROS formation was dependent upon uncoupling NOS.40 Interestingly, treatment with BH4 and l-arginine rebalanced this phenomenon by normalizing NO and superoxide formation; this change was associated with the attenuation of pacing-induced ERP shortening and vulnerability to AF reinforcing the concept of a potential cause–effect relationship between oxidative stress and AF.41

Antioxidants in human atrial fibrillation: meta-analysis

To investigate if antioxidants are of potential usefulness for preventing post-operative AF (PO-AF) in human, we performed a meta-analysis of interventional trials. The search with relevant keywords as ‘antioxidant’, ‘vitamin’, ‘ascorbic acid’, ‘tocopherol’, ‘N-acetylcysteine’, and ‘atrial fibrillation’ was carried out until December 2012. Methodology to perform meta-analysis is reported in supplemental data. Fifteen studies, including 1738 subjects, assessed the combined effect of all antioxidants on PO-AF. Characteristics of the study populations are illustrated in Tables 1 and 2. The following trials with antioxidants have been included in the meta-analysis: four with ascorbic acid,36,42,44,46,56 eight with N-acetylcysteine (NAC),4855 and three with multivitamins [omega-3 polyunsaturated fatty acid (PUFA) + ascorbic acid + tocopherol].43,45,47,54

View this table:
Table 1

Interventional studies with ascorbic acid, tocopherol, and vitamin complex

DrugYearStudy/AuthorTypeSettingNo. of patientsDoseEndpointResultsJadad score
Ascorbic acid2001Carnes et al.36Pilot trialCABGIntervention: 43
Control: 43
2 g the night before, then 500 mg twice daily for the 5 daysPO-AF16.3% in ascorbate group and
34.9% in control
(P < 0.05)
Ascorbic acid2007Eslami et al.45RCTCABGIntervention: 50
Control: 50
2 g orally on the night before surgery, then 1 g doses twice daily for 5 daysPO-AF4% in ascorbic acid group and
26% in control
OR: 0.119
P = 0.002
Ascorbic acid + tocopherol + PUFA2011Castillo et al.43RCTCABG
Valve surgery
Intervention: 48
Control: 47
2 g/day PUFAs for 7 days before, 2 days before, vitamin C (1 g/day) plus vitamin E
(400 IU/day) were added
PO-AF15 in control vs. 11 in intervention group
P = 0.32
Ascorbic acid2011Papoulidis et al.44RCTCABGIntervention: 85
Control: 85
2 g 3 h before surgery, then 500 mg twice a day for 5 daysPO-AF61.2% control vs. 44.7% in vitamin C group
P = 0.041
Ascorbic acid + tocopherol + PUFA2012Rodrigo et al.45RCTCardiac surgeryIntervention: 77
Placebo: 75
2 g/d PUFAs at start. Vitamin C (1 g/day) plus Vitamin E (400 IU/day) 2 days before surgeryPO-AF28.5% in placebo vs. 5.4% in treated group
(P = 0.0076)
Ascorbic acid2012Bjordahl et al.46RCTCABGIntervention: 89
Placebo: 96
2 g of oral ascorbic acid the evening before surgery, then 1 g twice daily for 5 daysPO-AF27% in ascorbic group vs. 29% in control group
(P = 0.985)
Ascorbic acid + tocopherol + PUFA2013Rodrigo et al.47RCTCardiac surgeryIntervention: 103
Placebo: 100
2 g/day PUFA at random. Two days before surgery, vitamin C (1 g/day) plus vitamin E (400 IU/day) were addedPO-AF9.7% of the treated
group vs. 32% in placebo
(P < 0.001)
  • OR, odds ratio.

View this table:
Table 2

Interventional studies with NAC

DrugYearStudy/AuthorTypeClinical SettingNo. of patientsDoseEndpointResultsJadad score
NAC2003Eren et al.48RCTCABGNAC: 10
Control: 10
100 mg/kg IV before CPB, 40 mg/kg IV for 24 hPO-AF1 in Group I (10%) and 2 in Group II (20%)2
NAC2006Orhan et al.49RCTCABGNAC: 10
Control: 10
50 mg/kg IV at anaesthesia induction for 30 minPO-AF1 in controls and none in NAC group
(P = NS)
NAC2007El-Hamamsy et al.50RCTCABGNAC: 50
Control: 50
600 mg oral the day before and the morning of the CABG
150 mg/kg IV at start of surgery, 12.5 mg/kg IV for 24 h
PO-AFNo statistical differences between the two groups2
NAC2007Haase et al.51RCTCABG, Valve,
NAC: 31
Control: 30
150 mg/kg IV at start of surgery, 50 mg/kg over 4 h, 100 mg/kg for 20 hPO-AF13 PO-AF in NAC group and 9 PO-AF in placebo group
(P = 0.42)
NAC2007Wijeysundera et al.52RCTCABG, ValveNAC: 88
Control: 87
100 mg/kg IV after induction of anaesthesia, 20 mg/kg/h IV after CPB for 4 hPO-AFPO-AF reduced in NAC group but not statistically significant (57 vs. 67%, P = 0.21, OR 0.66)4
NAC2008Ozaydin et al.53RCTCABG, ValveNAC: 58
Control: 57
50 mg/kg IV for 1 h before surgery, 50 mg/kg/day IV for 48 hPO-AF3 PO-AF in NAC group vs. 12 PO-AF in control group
(P = 0.01)
NAC2011Kim et al.54RCTCABGNAC: 24
Control: 24
100 mg/kg of IV NAC at anaesthesia induction, then IV infusion at 40 mg/kg/day for 24 hPO-AF8 PO-AF in control group vs. 4 PO-AF in NAC group
(P = 0.182)
NAC2013Ozaydin et al.55RCTCABGMetoprolol: 103
Carvedilol: 104
Carvedilol + NAC: 104
50 mg/kg IV for 1 h before operation and at the same dose for 48 h after the procedurePO-AF9 in carvedilol + NAC group vs. 37 in metoprolol group (P < 0.0001) or vs. 25 in carvedilol group (P = 0.03)3
  • IV, intravenous; OR, odds ratio; CPB, Cardiopulmonary bypass.

Compared with the control, patients treated with antioxidants showed a significant reduction of PO-AF (34 vs. 21%) [fixed effects: relative risk (RR): 0.696; 95% confidence interval (CI): 0.60–0.80; P < 0.001; random effects RR: 0.582; 95% CI: 0.45–0.76; P < 0.001] (Figure 2A) with absolute risk reduction (ARR) of 13%.

Figure 2

Meta-analysis of interventional trials on the effect of antioxidants (A) and ascorbic acid and NAC (B) on post-operative AF.

In subgroup meta-analysis, we separately analysed the effect of single antioxidant on PO-AF. Four trials with ascorbic acid were selected,36,42,44,46,56 ranging in size from 86 to 185 patients for a total of 541 patients (Table 1). These studies reported PO-AF after cardiac surgery [coronary artery bypass grafting (CABG) or valve replacement] as the principal outcome.36,42,44,46 Ascorbic acid was usually given before the procedure and up to a maximum of 7 days thereafter. Atrial fibrillation occurred in 71 of 267 (26.59%) patients treated with ascorbic acid and in 108 of 274 (39.41%) controls. Compared with the controls, ascorbic acid significantly reduced AF (fixed effects: RR: 0.716; 95% CI: 0.56–0.90; P = 0.005; random effects RR: 0.641; 95% CI: 0.41–0.99; P = 0.04) (Figure 2B) with an ARR of 12.8%. This effect was confirmed also when we separately analysed CABG interventions trials;36,42,44,46 thus, supplementation with ascorbic acid significantly reduced AF (fixed effects: RR: 0.716; 95% CI: 0.57–0.90; P = 0.005; random effects RR: 0.641; 95% CI: 0.41–0.99; P = 0.04).

Eight RCT4855 with NAC including 375 patients were selected. These studies ranged in size from 20 to 208 patients for a total of 747 patients (Table 2). All of these studies evaluated the onset of PO-AF. N-acetylcysteine was given intravenously48,5055 or by mouth (per os)49 before surgery with dosage almost variable among the trials. N-acetylcysteine was continued for 4 h or till 24–48 h after cardiac surgery. Post-operative AF occurred in 84 of 375 (22.4%) patients treated with NAC and in 121 of 372 (32.5%) controls. Compared with the controls, NAC significantly reduced PO-AF (fixed effects: RR: 0.775; 95% CI: 0.63–0.94; P = 0.013; random effects RR: 0.643; 95% CI: 0.42–0.97; P = 0.03) (Figure 2B) with an ARR of 10%. This effect was confirmed also when we separately analysed CABG interventions trials;4850,54,55 thus, supplementation with NAC significantly reduced AF (fixed and random effects: RR: 0.440; 95% CI: 0.27–0.73; P = 0.002).

Future perspectives and conclusions

The data, herewith reported, suggest a role of oxidative stress in eliciting and perpetuating AF. Oxidative stress seems to promote AF through functional and structural remodeling. This remodelling ultimately leads to electrical abnormalities. Thus, oxidative stress seems to promote functional and structural remodelling by enhancing atrial vulnerability to AF and atrial fibrosis but the underlying mechanism must be further elucidated. At least three enzymatic pathways are involved in up-regulating the production of ROS, namely MPO, NADPH oxidase, and uncoupled NOS; over-expression of these enzymes has been detected in the atria in experimental and clinical models of AF. A cause–effect relationship between oxidative stress and AF has been investigated with interventional trials with antioxidants. Meta-analysis of these trials provided evidence that antioxidant treatment is able to reduce the risk of PO-AF; however, sub-analysis of specific antioxidant showed that such beneficial effect was restricted to NAC and ascorbic acid. No significant benefit was, however, observed in trials in which ascorbic acid was combined with other vitamins or in trials where vitamin E was employed. Both NAC and ascorbic acid are recognized as ROS scavengers;57 however, there is experimental evidence that NAC may interfere directly with NADPH oxidase activation by down-regulation of p22phox.58

The positive results achieved with NAC and ascorbic acid are, however, flawed by low qualities of the studies, by the small sample size and lack of evidence that these molecules actually exerted an antioxidant effect in vivo. A reason of concern is, for example, that ascorbic acid is a weak antioxidant when given ‘per os’ but a strong antioxidant when administered intravenously;36,42,44,46,56 regarding this, it should be underscored that in almost all trials ascorbic acid was given per ‘os’. This concern is in accordance with a previous report underscoring the uncertain role of ascorbic acid therapy as a tool to prevent PO-AF.59

To overcome this issue, future trials should include a larger number of patients and provide evidence that vitamins, with putative antioxidant property, actually exert such activity when administered to humans. Among the scavengers molecules MitoTEMPO should be considered in addition to the other already known antioxidants. Thus, MitoTEMPO prevents mitochondrial dysfunction elicited by ROS.60

Another perspective is the use of drugs that limit the activity of MPO, NADPH oxidase, or ‘uncoupled’ NOS to reduce or prevent AF (Figure 1). To the best of our knowledge, apocynin is the only drug which has been used for experimental purposes to inhibit NADPH oxidase.61 Apocynin is an extract from several plant sources that has been shown to possess antiatherosclerotic properties via inhibition of p47phox assembly to the core of NADPH oxidase.61,62 It should be underscored, however, that inhibition of NADPH oxidase might have potentially deleterious effects as its down-regulation could negatively influence the activity of the innate immune system hence predisposing to infections. Thus, extension to which NADPH oxidase may be reduced without interfering with the activity of innate immune system is a critical issue that should be taken into account.

In conclusion, the experimental and clinical studies suggest a causal interplay between oxidative stress and AF. Oxidative stress may contribute to functional and structural remodelling that favour the occurrence of AF; in this context, at least three enzymatic pathways, namely MPO, NADPH oxidase, or ‘uncoupled’ NOS, seem to be implicated in up-regulating ROS production. Atrial fibrillation became a cardiac pathology with enormous social impact because of its increasing prevalence in general population and its frequent association with cerebral and cardiac atherothromboembolism.28 Despite many efforts having been done to therapeutically prevent or limit AF occurrence and/or recurrence, the results with several antiarrhythmic drugs are disappointing. As shown by Figure 1, scavenging ROS overproduction or down-regulating MPO, NADPH oxidase, or ‘uncoupled’ NOS could be investigated to see if this may represent a novel therapeutic approach to limit or prevent AF occurrence.


Conflict of interest: none declared.


  • These two authors declare joint seniorship.


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