Atrial fibrillation (AF) is the most common persistent arrhythmia in clinical practice, and AF can increase the risk of thromboembolism and increase overall mortality. Epidemiological data show that there are about 10 million patients with atrial fibrillation in China, which seriously endangers people’s health. However, the etiology of atrial fibrillation is diverse and the pathogenesis is very complex, and the overall treatment effect is not yet very satisfactory. Although significant progress has been made in recent years in catheter ablation treatment of atrial fibrillation, its long-term effect is not yet satisfactory, and antiarrhythmic drugs are still the cornerstone of atrial fibrillation treatment, and there is an urgent need to explore new methods and measures for the prevention and treatment of atrial fibrillation. With the increasing understanding of the mechanisms of AF occurrence, it has been found that non-antiarrhythmic drugs in the traditional sense, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARBs), statins, polyunsaturated fatty acids, and aldosterone receptor antagonists, may prevent the occurrence and progression of AF, i.e., the upstream treatment of AF. Recent studies suggest that oxidative stress is involved in the development of AF, and some non-antiarrhythmic drugs with antioxidant effects such as vitamin C, statins, probucol, and thiazolidinediones may contribute to the prevention and treatment of AF and are expected to be an important component of the upstream treatment of AF. In this paper, we will discuss the use of antioxidants in the prevention and treatment of AF by combining our previous work and the latest literature published in recent years. In this paper, we will discuss the progress of the application of antioxidants in the prevention and treatment of atrial fibrillation, taking into account our previous work and recent literature. I. Oxidative stress and atrial fibrillation Recent studies have shown that oxidative stress plays an important role in the development of cardiovascular disease, and the oxidative stress state refers to the imbalance of pro-oxidants and antioxidants in the body, with pro-oxidants dominating. The oxidative stress state in the body is mainly associated with excessive reactive oxygen species (ROS) production, which can directly lead to DNA damage, apoptosis and cardiomyocyte hypertrophic fibrosis, while the main sources of ROS in the cardiovascular system are nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neutrophils, endothelial cells, vascular smooth muscle cells and cardiomyocytes, and another source is nitric oxide In addition, xanthine oxidase also plays a role in the production of ROS. Recent studies suggest that oxidative stress is involved in the development of atrial fibrillation and leads to electrical and structural remodeling of the atria. Inhibitors of these two enzymes down-regulated their expression and reduced their superoxide anion content. Subsequently, a study by Neuman et al. found that plasma oxidative stress indicators, including reactive oxygen metabolite derivatives and isoprostane, were significantly elevated in patients with atrial fibrillation. In addition, patients with atrial fibrillation occurring after cardiac surgery had increased NADPH oxidase activity in right atrial myocardial tissue and a loss of NOS coupling. Uric acid, the end product of purine metabolism in vivo, correlates with xanthine oxidase activity, which reflects the level of oxidative stress in vivo, and can lead to endothelial damage, cell proliferation, and increased angiotensin II production. Our previous study suggested that elevated plasma uric acid levels are an independent predictor of atrial fibrillation in hypertensive patients. In addition, inflammation and oxidative stress are interrelated, in which the nuclear transcription factor NF-κB plays an important role. Intracellular oxidative stress injury can activate NF-κB and promote gene transcription of multiple inflammation-related factors, which in turn synthesize multiple inflammatory factors. The pathophysiological link between oxidative stress and atrial fibrillation is still not well understood. Possible mechanisms include: (1) oxidative stress directly modifies atrial ion channels, especially the oxidation of various intracellular calcium regulatory proteins, leading to intracellular calcium overload and delayed post-depolarization, and atrial electrical remodeling; (2) under oxidative stress, NADPH oxidase-induced ROS and various inflammatory factors promote fibroblast proliferation, migration and differentiation into myofibroblasts, secretion of matrix metalloproteinase (MMP), increased collagen synthesis, and promotion of atrial myocardial fibrosis, leading to structural remodeling of the atria. Second, antioxidants against atrial fibrillation 1, vitamins C and E Vitamin C is the most important antioxidant in plasma, which can effectively remove superoxide anion and peroxynitrite. Animal experiments suggest that oral administration of vitamin C can prevent the occurrence of atrial electrical remodeling in dogs with rapid atrial pacing and inhibit the production of nitrosotyrosine in atrial tissue. lin et al. evaluated the direct electrophysiological effects of vitamin C on isolated rabbit pulmonary vein tissue and showed that vitamin C reduced the spontaneous electrical activity of pulmonary veins and reversed the arrhythmogenic effects of hydrogen peroxide. Therefore, whether vitamin C can prevent the recurrence of atrial fibrillation after pulmonary vein electrical isolation needs to be further investigated. Clinical evidence for the preventive effect of vitamins C and E on atrial fibrillation comes mainly from the prevention of atrial fibrillation after cardiac surgery. A recent meta-analysis enrolled 567 patients in 5 randomized controlled clinical trials and suggested that prophylactic use of vitamins C and E before cardiac surgical bypass was effective in preventing postoperative atrial fibrillation (OR 0.43, 95% CI 0.21-0.89) and all-cause arrhythmias (OR 0.54, 95% CI 0.29-0.99). However, due to the small number of cases in their sample, the reliability of their results needs to be further confirmed. The use of vitamin C in secondary prevention of atrial fibrillation has been less studied, but Korantzopoulos et al. enrolled 44 patients with persistent atrial fibrillation who underwent successful conversion, and oral vitamin C resulted in a significant reduction in the recurrence rate of atrial fibrillation (4.5% vs 36.3%, P=0.024), as well as a significant reduction in plasma CRP levels, while no significant change was observed in the control group. Another recent study suggested that serum vitamin E levels were associated with recurrence after electrical conversion of AF. 144 patients who underwent electrical conversion of AF were enrolled in this study with a mean follow-up of 3 months. 2, statins Recent studies have shown that statins have anti-inflammatory and antioxidant effects and can reduce the level of C-reactive protein (CRP). Foreign scholars analyzed right atrial muscle specimens from patients with atrial fibrillation who underwent cardiac surgery and found that the preoperative application of atorvastatin decreased atrial NADPH oxidase activity in patients with new-onset atrial fibrillation after surgery, but had no significant effect on NADPH oxidase activity and NO synthase loss coupling in patients with preoperative permanent atrial fibrillation, suggesting that the antioxidant effect of statins on atrial muscle is related to the type and duration of atrial fibrillation. This suggests that the antioxidant effect of statins on atrial muscle is related to the type and duration of AF, suggesting that their effect on primary prevention of AF may be better than secondary prevention. Several clinical studies have evaluated the role of statins in the prevention of atrial fibrillation, with varying results. We conducted a meta-analysis of clinical studies published in recent years on the role of statins in the prevention of atrial fibrillation, and the results suggest that the application of statins may contribute to the prevention of atrial fibrillation, especially for patients after cardiac surgery. 3. Probucol Probucol, chemically known as propofol, was first marketed in the United States in the 1970s as a lipid-lowering drug and used in clinical practice, and its main effect was thought to be to lower serum cholesterol. In recent years, with the increasing understanding of its pharmacological effects, researchers have discovered its pleiotropic effects such as antioxidant, endothelial function protection and anti-atherosclerosis. Probucol is an antioxidant that easily crosses cell membranes and can scavenge oxygen free radicals formed inside cells. Animal experiments suggest that probucol can reverse atrial structural remodeling and fibrosis, reduce the excessive oxidative state of atrial muscle, prevent the occurrence of apoptosis, and also improve atrial autonomic remodeling in dogs with atrial fibrillation in a rapid pacing atrial fibrillation model. We evaluated the effects of probucol on diabetic atrial remodeling by establishing a tetraoxacillin-induced diabetic model in rabbits, and the results suggest that probucol attenuates diabetes-induced atrial myocyte hypertrophy and atrial stromal fibrosis by inhibiting the TNF-α/NF-κB/TGF-β signaling pathway, decreases effective atrial nonresponse dispersion, and leads to a reduction in the occurrence of atrial fibrillation in diabetic rabbits, while plasma inflammation and It was hypothesized that its antioxidant effect was the possible reason for the reversal of diabetic atrial remodeling and atrial fibrillation by probucol. AGI-1067, a derivative of probucol, has stronger antioxidant properties compared with probucol and does not prolong the QT interval. However, some studies have shown that AGI-1067 increases CRP levels and may increase the risk of developing atrial fibrillation. Therefore, the effects of probucol and AGI-1067 on atrial remodeling and the prevention and treatment of atrial fibrillation still need to be studied in depth. 4, thiazolidinediones Thiazolidinediones (TZDs) are currently used as insulin sensitizers in the treatment of type 2 diabetes. These drugs mainly act on peroxisome proliferator-activated receptor γ (PPARγ). In addition to their insulin-sensitizing effects, these drugs also have some pleiotropic effects such as anti-inflammatory and antioxidant, and improve endothelial function, which may contribute to the prevention of atrial fibrillation. In animal studies, pioglitazone was shown to improve atrial structural remodeling, reduce transforming growth factor-β1 (TGF-β1) and TNF-α protein expression, and decrease the occurrence of atrial fibrillation in rabbits with rapid pacing heart failure. The expression of the antioxidant molecule superoxide dismutase (SOD) was upregulated and the expression of the subunits of NADPH oxidase p22phox and gp91phox was downregulated after pioglitazone treatment in aged rats, suggesting that the mechanism of atrial fibrillation prevention by TZDs may be related to its activation of antioxidant molecules and inhibition of NADPH oxidase-induced ROS production. Our study also suggests that pioglitazone can prevent the development of diabetic atrial electrical remodeling and ion channel remodeling, attenuate atrial fibrosis, and prevent the development of atrial fibrillation, while inhibiting inflammation and oxidative stress-related proteins TNF-α, NF-κB, and heat shock protein 70 (HSP70) expression. There are few studies on the effects of rosiglitazone on atrial remodeling, and our work shows that rosiglitazone has a significant antagonistic effect on oxidative stress alterations and atrial myocardial fibrosis in diabetic rabbits, while shortening interatrial conduction time and atrial validity dispersion and reducing the incidence of atrial fibrillation. A recent cohort study enrolling 12,605 patients with type 2 diabetes suggested that thiazolidinediones prevented the development of new-onset atrial fibrillation during a 5-year follow-up period. In addition, pioglitazone may prevent recurrence of atrial fibrillation after radiofrequency ablation of atrial fibrillation. 5. Others Foreign scholars evaluated the preventive effect of sodium nitroprusside (nitric oxide donor) on new-onset atrial fibrillation after coronary artery bypass grafting. The results showed that the incidence of postoperative atrial fibrillation was significantly lower in the sodium nitroprusside group compared with the placebo group (12% vs 27%, P<0.05< span="">), and the duration of atrial fibrillation was significantly shorter. The authors speculate that the anti-inflammatory and antioxidant effects of sodium nitroprusside may be related to its reduction in the occurrence of atrial fibrillation. In addition, the antioxidant N-acetylcysteine was shown to reduce the incidence of atrial fibrillation after cardiac surgery. Our recent study also suggested that the NADPH oxidase inhibitor enthesopine could inhibit high glucose and oxidative stress-induced left atrial fibroblast proliferation and MAPK/MMP9 signaling pathway mediating atrial fibrosis in rabbits, which is expected to be one of the antioxidants to improve atrial remodeling. III. SUMMARY AND PROSPECTS In recent years, with the in-depth research related to oxidative stress and atrial fibrillation, it has been recognized that a variety of antioxidant drugs, such as vitamin C, statins, probucol, thiazolidinediones, N-acetylcysteine and NADPH oxidase inhibitors may play a role in the prevention and treatment of atrial fibrillation and are expected to be a new strategy for controlling atrial fibrillation.