Oxidative Stress In Atrial Fibrillation Research Articles

B-PO02-029 REDUCED ATRIAL FIBRILLATION DRIVERS IN RESPONSE TO REACTIVE OXYGEN SCAVENGING - A NOVEL THERAPEUTIC TARGET IN ATRIAL FIBRILLATION?

Oxidative Stress (OS) is thought to be a mediator of atrial fibrillation (AF), but the precise role of OS in AF is unknown. We assessed reactive oxygen species (ROS) scavenging on slow conduction and maintenance of rotational drivers. We hypothesized that ROS are dynamically involved in a vulnerable substrate and that ROS scavenging reduces AF drivers and arrhythmogenic slow conduction zones. AF was induced in 48 dogs by rapid atrial pacing (RAP) for 3-14 weeks. Epicardial high-density mapping was performed (130 electrodes, dist. 2.5mm) in the atrial regions: posterior left atrium (PLA), left atrial free wall (LAFW), left atrial appendage (LAA), posterior right atrium (PRA), right atrial free wall (RAFW), right atrial appendage (RAA). N-acetylcysteine (NAC) was given intravenously (100mg/kg) in 15 AF dogs. We mapped all atrial regions pre and post NAC. We detected rotational activity in activation time maps and quantified slow conduction as activation delay in neighboring electrodes. We detected rotational activity in all regions (Figure A) with the stability of 376±255ms in the LAA, 422±174ms in the PLA, and 317±174ms in the LAFW (Figure B). The cycle length of rotational activity was shorter in the PLA (CL 94±7 ms) compared to other regions (P<0.05) (Figure C) and increased in remote regions with increasing distance to the PLA (Figure D). After providing NAC, rotational activities reduced in the left atrium by 40% in the LAFW, by 39% in the PLA, and by 12% in the LAFW (Figure E). Acute scavenging of ROS reduces arrhythmogenic slow conduction and AF triggers. These results show that ROS is dynamically involved in the maintenance of AF.

Urinary Biomarkers of Oxidative Stress in Atrial Fibrillation

There is increasing evidence from molecular studies to support the role of inflammation and increased oxidative stress that produce structural and electrical atrial remodeling to produce Atrial Fbrillation (AF). Oxidative damage to cardiomyocytes yields chemical substances that are secreted in urine. These substances can serve as biomarkers that can be measured, potentially allowing clinicians to quantify oxidative damage to the heart.

Mechanisms and Treatments of Oxidative Stress in Atrial Fibrillation.

Atrial fibrillation (AF) is a frequent cardiac arrhythmia. It is a common major cause of serious diseases and is an increasing health-care burden. AF is associated with an excess amount of reactive oxygen species. In this review, we summarize several possible reactive oxygen species pathways that induce AF based on atrial electrical and structural remodeling data. The sources and factors implicated in AF-related oxidative stress include NADPH oxidase activation, calcium overloading and mitochondrial damage, angiotensin system activation, nitric oxide synthase uncoupling, and xanthine oxidase activation-associated cardiovascular conditions. Scavenging oxidative stress markers and related substances are essential aspects of these molecular mechanisms, and may be a therapeutic target in AF.

Urinary biomarkers of oxidative stress in atrial fibrillation

Urinary biomarkers of oxidative stress in atrial fibrillation

Abstract 270: Peroxisome Proliferator Activated Receptor- α is a Connecting Link Between Cardiac Fibrosis and Oxidative Stress in Atrial Fibrillation

Background: AF, a common sustained arrhythmia that predisposes heart failure and stroke, is associated with cardiac fibrosis and oxidative stress. Peroxisome proliferator-activated receptor (PPAR)-α, important for ROS and lipid degradation, is reported to negatively correlate with kidney, liver, and lung fibrosis, but its role in cardiac fibrosis is less clear. We hypothesize that reduced expression of PPARα in AF contributes to oxidative stress and interferes with TGFβ signaling, a cytokine implicated in cardiac fibrosis. Methods: Myocardial fibrosis was detected (Masson trichrome) in right atrial appendages of AF and non-AF patients. Levels of 4-hydroxynonenal (4-HNE) (ELISA) and superoxide production (MitoSOX) were assayed in patients’ atrial tissue homogenates and cardiac myofibers respectively. Using atrial fibroblasts (hAF) from AF and non-AF patients, α-SMA, COL1A1 and c-Jun/c-Fos expressions were determined (RT-PCR and/or Western Blot) in the absence and presence of TGF-β (5 ng) with or without ciprofibrate (200 μM), a PPARα agonist. Results: Increased atrial fibrosis, levels of 4-HNE (101.7 vs 7.4 ng/mg protein; p=0.02(n=6)) and oxidative stress (8.7 fold; p=0.04) correlated with reduced PPAR-α mRNA (2.1 fold; p&lt;0.01) in AF patients. Activation of PPARα by ciprofibrate reduced TGFβ1-induced increased expression of α-SMA and COL1A1 by repressing AP-1 signaling in hAF. Conclusion: Reduced expression of PPARα is associated with impaired cardiac mitochondrial metabolism and promotes TGFβ-induced profibrotic pathway. Preliminary data suggest PPARα agonist might confer therapeutic benefits for patients with cardiac fibrosis and oxidative stress in AF.

Comparison of Serum Uric Acid Concentrations in Subjects With and Without Atrial Fibrillation

Background: Uric acid, a product of purine degradation, is a risk factor for cardiovascular disease. Studies have demonstrated a relationship between uric acid and increased inflammatory and oxidative stress in the general population. Recent studies also confirmed the role of inflammatory factors and oxidative stress in atrial fibrillation (AF). Objectives: The purpose of this study was to investigate the relationship between serum uric acid levels and the risk of AF. Patients and Methods: This case-control study consisted of 32 patients with AF and 32 healthy controls. Both groups were matched by age, sex, and underlying disease. The diagnosis of AF was based on an electrocardiogram and confirmed by a cardiologist. Patients with heart failure, coronary artery disease, recent infection, renal failure, thyroid disorders and malignancy or who were treated with drugs affecting serum uric acid were excluded. The uric acid levels in both groups were measured using an enzymatic method. The mean serum uric acid of the two groups was compared with a t-test and SPSS software. Results: The female to male ratio in the two groups was 1.28. The mean age of the patients in the AF group and control group was 69.12 ± 11.8 and 67.75 ± 14.8, respectively. There were no significant differences in the age and sex of the two groups. The mean serum uric acid in the AF group and control group was significantly different (5.79 ± 1.19 mg/dL and 4.81 ± 1.26 mg/dL, respectively; P = 0.002). Conclusions: The results suggest that serum uric acid can be considered a risk factor for AF. Further studies are recommended to investigate the role of uric acid reduction in the prevention and treatment of AF.

Does Mediterranean Diet Reduce Cardiovascular Events and Oxidative Stress in Atrial Fibrillation?

Atrial fibrillation (AF) is characterized by enhanced oxidative stress and is complicated by cardiovascular events (CVEs), which are only partially prevented by anticoagulant treatment. The Mediterranean diet (Med-Diet) has a positive effect on atherosclerotic progression. In a prospective cohort of 709 anticoagulated AF patients, adherence to Med-Diet was assessed to investigate whether Med-Diet may reduce CVEs by lowering oxidative stress. The cohort was divided into three groups according to the Med-Diet score: low (0-3 points), medium (4-6 points), and high (7-9 points) adherence. During a mean follow-up of 39.9 months (2604.8 patients/year), we registered 72 (2.8%/year) CVEs: 23.4% in the low-adherence group, 8.4% in the intermediate-adherence group, and 5.3% in the high-adherence group (p<0.001). There were no differences in time in the therapeutic range among groups. The Med-Diet score was inversely correlated with sNOX2-dp (soluble NOX2-derived peptide; Rs: -0.297, p<0.001) and F2-isoprostanes (F2-IsoP; Rs: -0.411, p<0.001). Median values of sNOX2-dp (p<0.001) and F2-IsoP progressively decreased across groups (p<0.001). A Cox regression analysis showed that the Med-Diet score (HR: 0.771, p=0.001), F2-IsoP (HR: 1.002, p=0.004), and heart failure (HR: 1.876, p=0.024) predicted CVEs. In conclusion, these findings raise the hypothesis that adherence to Med-Diet could be associated with a reduction of CVEs, through an antioxidant effect, as shown by a concomitant downregulation of Nox2 and decreased excretion of F2-IsoP.

Defining the role of oxidative stress in atrial fibrillation and diabetes.

Defining the role of oxidative stress in atrial fibrillation and diabetes.

Oral direct renin inhibitor aliskiren reduces in vivo oxidative stress and serum matrix metalloproteinase-2 levels in patients with permanent atrial fibrillation

We aimed to determine the effects of the oral direct renin inhibitor aliskiren on in vivo oxidative stress in atrial fibrillation (AF) patients. In this study, 150mg oral direct renin inhibitor aliskiren was administered once daily to 12 permanent AF patients. Aliskiren significantly reduced urinary excretion of the oxidative stress biomarker 8-iso-prostglandin F2α and serum levels of matrix metalloproteinase-2(MMP-2). We concluded that aliskiren reduces in vivo oxidative stress and serum MMP-2 levels in patients with permanent AF.

Ceruloplasmin dysfunction: a key factor in the pathophysiology of atrial fibrillation?

Ceruloplasmin dysfunction: a key factor in the pathophysiology of atrial fibrillation?

Targeting Inflammation and Oxidative Stress in Atrial Fibrillation: Role of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibition with Statins

Atrial fibrillation (AF) is a burgeoning health-care problem, and the currently available therapeutic armamentarium is barely efficient. Experimental and clinical evidence implicates inflammation and myocardial oxidative stress in the pathogenesis of AF. Local and systemic inflammation has been found to both precede and follow the new onset of AF, and NOX2-dependent generation of reactive oxygen species in human right atrial samples has been independently associated with the occurrence of AF in the postoperative period in patients undergoing cardiac surgery. Anti-inflammatory and antioxidant agents can prevent atrial electrical remodeling in animal models of atrial tachypacing and the new onset of AF after cardiac surgery, suggesting a causal relationship between inflammation/oxidative stress and the atrial substrate that supports AF. Statin therapy, by redressing the myocardial nitroso-redox balance and reducing inflammation, has emerged as a potentially effective strategy for the prevention of AF. Evidence indicates that statins prevent AF-induced electrical remodeling in animal models of atrial tachypacing and may reduce the new onset of AF after cardiac surgery. However, whether statins have antiarrhythmic properties in humans has yet to be conclusively demonstrated, as data from randomized controlled trials specifically addressing the relevance of statin therapy for the primary and secondary prevention of AF remain scanty. A better understanding of the mechanisms underpinning the putative antiarrhythmic effects of statins may afford tailoring AF treatment to specific clinical settings and patient's subgroups. Large-scale randomized clinical trials are needed to support the indication of statin therapy solely on the basis of AF prevention.

Markers of Oxidative Stress and Inflammation Correlate with CHADS-2 Risk Stratification Score in Persistent Atrial Fibrillation

Background: Inflammation has been linked to the pathogenesis of atrial fibrillation (AF). Recent evidence also suggests the role of oxidative stress in AF. CHADS-2 scoring system is a risk stratification schema well validated to determine outcome in AF. We evaluated the correlation of oxidative stress and inflammatory markers with CHADS-2 score in persistent AF.

Role of inflammation and oxidative stress in atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice. Increasing evidence indicates that inflammation and oxidative stress contribute to the pathogenesis of AF, but their role remains poorly defined. In addition, whether inflammation and oxidative stress are associated with particular types of AF is unclear. The purpose of this study was to define the role of inflammation and oxidative stress in AF. Using a case-control study design, 305 patients with AF were compared with 150 control patients. AF was categorized into lone and typical AF and further subcategorized as paroxysmal, persistent, or permanent AF. Serum concentrations of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, vascular endothelial growth factor (VEGF), N-terminal pro-brain (B-type) natriuretic peptide (NTpBNP), and urinary F(2)-isoprostanes, a measure of oxidative stress, were measured. IL-6, IL-8, IL-10, TNF-alpha, MCP1, VEGF, and NTpBNP concentrations were independently associated with AF (all P <.05). However, F(2)-isoprostane excretion was not elevated (P = .50). Graded increases in TNF-alpha [median (interquartile range) 6.8 (3.4-11.3), 8.0 (5.6-10.9), 10.1 (5.7-12.4) pg/mL, P <.05] and NTpBNP [170.6 (67.3-481.9), 681.39 (310.3-1,439.0), 1,179.9 (653.1-2,096.0) pg/mL, P <.001] were seen among the subgroups of paroxysmal, persistent, and permanent AF, respectively. Inflammatory biomarkers were significantly increased in patients with AF, supporting a strong association between inflammation and AF. Surprisingly, urinary F(2)-isoprostanes, a sensitive index of systemic oxidative stress in vivo, were not increased in AF overall or in different subtypes of AF.

Endothelial dysfunction and pathophysiological correlates in atrial fibrillation

Endothelial dysfunction (ED) increases oxidative stress and proinflammatory agents, and impairs nitric oxide (NO)-dependent vasorelaxation. Atrial fibrillation (AF) is a risk factor for ED as documented by (1) impaired acetylcholine-mediated...

A Myocardial Nox2 Containing NAD(P)H Oxidase Contributes to Oxidative Stress in Human Atrial Fibrillation

Human atrial fibrillation (AF) has been associated with increased atrial oxidative stress. In animal models, inhibition of reactive oxygen species prevents atrial remodeling induced by rapid pacing, suggesting that oxidative stress may play an important role in the pathophysiology of AF. NAD(P)H oxidase is a major source of superoxide in the cardiovascular system; however, whether this enzyme contributes to atrial oxidative stress in AF remains to be elucidated. We investigated the sources of superoxide production (using inhibitors and substrates of a range of oxidases, RT-PCR, immunofluorescence, and immunoblotting) in tissue homogenates and isolated atrial myocytes from the right atrial appendage (RAA) of patients undergoing cardiac surgery (n=54 in sinus rhythm [SR] and 15 in AF). A membrane-bound gp91phox containing NAD(P)H oxidase in atrial myocytes was the main source of atrial superoxide production in SR and in AF. NADPH-stimulated superoxide release from RAA homogenates was significantly increased in patients with AF in the absence of changes in mRNA expression of the p22phox and gp91phox subunits of the NAD(P)H oxidase. In contrast with findings in SR patients, NO synthases (NOSs) contributed significantly to atrial superoxide production in fibrillating atria, suggesting that increased oxidative stress in AF may lead to NOS "uncoupling." These findings indicate that a myocardial NAD(P)H oxidase and, to a lesser extent, dysfunctional NOS contribute significantly to superoxide production in the fibrillating human atrial myocardium and may play an important role in the atrial oxidative injury and electrophysiological remodeling observed in patients with AF.