3-nitrotyrosine and Atrial-Fibrillation

Catheter ablation (CA) is a procedure commonly used to restore sinus rhythm in patients with atrial fibrillation (AF). However, AF recurrence after CA remains a relevant clinical issue. We tested the effects of an oral antioxidant treatment (alpha lipoic acid [ALA]) on AF recurrence post-CA. Patients with paroxysmal AF have been enrolled in a randomized, prospective, double-blind, controlled placebo trial. After CA, patients have been randomly assigned to receive ALA oral supplementation (ALA group) or placebo (control group) and evaluated at baseline and after a 12-month follow-up: 73 patients completed the 12-month follow-up (ALA: 33 and control: 40). No significant difference has been detected between the 2 groups at baseline. Strikingly, 1 year after CA, ALA therapy significantly reduced serum markers of inflammation. However, there was no significant difference in AF recurrence events at follow-up comparing ALA with placebo group. Multivariate analysis revealed that the only independent prognostic risk factor for AF recurrence after CA is age. In conclusion, ALA therapy reduces serum levels of common markers of inflammation in ablated patients. Nevertheless, ALA does not prevent AF recurrence after an ablative treatment.

Topics: Aged; Antioxidants; Atrial Fibrillation; Biomarkers; Blood Glucose; C-Reactive Protein; Catheter Ablation; Cholesterol, HDL; Cholesterol, LDL; Cytokines; Double-Blind Method; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peroxynitrous Acid; Postoperative Care; Recurrence; Thioctic Acid; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha; Tyrosine

Atrial fibrillation (AF), the most common chronic arrhythmia, increases the risk of stroke and is an independent predictor of mortality. Available pharmacological treatments have limited efficacy. Once initiated, AF tends to self-perpetuate, owing in part to electrophysiological remodeling in the atria; however, the fundamental mechanisms underlying this process are still unclear. We have recently demonstrated that chronic human AF is associated with increased atrial oxidative stress and peroxynitrite formation; we have now tested the hypothesis that these events participate in both pacing-induced atrial electrophysiological remodeling and in the occurrence of AF following cardiac surgery. In chronically instrumented dogs, we found that rapid (400 min(-1)) atrial pacing was associated with attenuation of the atrial effective refractory period (ERP). Treatment with ascorbate, an antioxidant and peroxynitrite decomposition catalyst, did not directly modify the ERP, but attenuated the pacing-induced atrial ERP shortening following 24 to 48 hours of pacing. Biochemical studies revealed that pacing was associated with decreased tissue ascorbate levels and increased protein nitration (a biomarker of peroxynitrite formation). Oral ascorbate supplementation attenuated both of these changes. To evaluate the clinical significance of these observations, supplemental ascorbate was given to 43 patients before, and for 5 days following, cardiac bypass graft surgery. Patients receiving ascorbate had a 16.3% incidence of postoperative AF, compared with 34.9% in control subjects. In combination, these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insight into the etiology and potential treatment of an enigmatic and difficult to control arrhythmia. The full text of this article is available at http://www.circresaha.org.

Topics: Aged; Animals; Antioxidants; Ascorbic Acid; Atrial Fibrillation; Cardiac Pacing, Artificial; Coronary Artery Bypass; Dogs; Electrophysiology; Female; Heart Atria; Humans; Male; Middle Aged; Multivariate Analysis; Nitrates; Time Factors; Treatment Outcome; Tyrosine

Atrial fibrillation (AF) is the most common cardiac arrhythmia. However, the current drug interference of antiarrhythmia has limited efficacy and off-target effects. Accumulating evidence has implicated a potential role of nitration stress in the pathogenesis of AF. The aim of the study was to determine whether TPEN provided antinitration effects on atrial myocytes during AF, especially under circumstances of nitration stress.. We utilized a rapid paced HL-1 cells model for AF. The changes of electrophysiological characteristics and structure of paced HL-1 cells were determined by a patch clamp and a TEM method. The effects of TPEN on pacing and ONOO(-) pretreated HL-1 cells were examined using MTT assay, TUNEL technique, confocal microscope experiment, and Western blot analysis.. The results revealed that ONOO(-) reduced the viability of HL-1 cells in a dose-dependent manner, and 1 μmol/L TPEN significantly ameliorated the damage caused by 50 μmol/L ONOO(-) (P < 0.05). Pacing and/or ONOO(-) -induced marked shortening of APD, myolysis, and nuclear condensation. TPEN inhibited the Ca(2+) overload induced by rapid pacing (P < 0.05) and ONOO(-) stimulation (P < 0.05). The application of TPEN significantly prevented the protein nitration caused by pacing or pacing plus ONOO(-) (P < 0.05). Additionally, pacing in combination with ONOO(-) treatment led to increase in apoptosis in HL-1 cells (P < 0.01), which could be reduced by pretreatment with TPEN (P < 0.05).. TPEN prevents Ca(2+) overload and nitration stress in HL-1 atrial myocytes during rapid pacing and circumstances of nitration stress.

Topics: Animals; Apoptosis; Atrial Fibrillation; Calcium; Cardiac Pacing, Artificial; Cell Line; Cell Survival; Cytoprotection; Dose-Response Relationship, Drug; Ethylamines; Mice; Myocytes, Cardiac; Peroxynitrous Acid; Pyridines; Reactive Nitrogen Species; Signal Transduction; Tyrosine

Congestive heart failure (CHF) is a common cause of atrial fibrillation (AF). Oxidative stress and inflammation (profibrotic) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha, antifibrotic) factors may be involved in CHF-related remodeling. We evaluated the effects of simvastatin (antioxidant, anti-inflammatory) and fenofibrate (PPAR-alpha activator) on CHF-related atrial remodeling.. Dogs were subjected to 2-week ventricular tachypacing (VTP) in the absence and presence of simvastatin (20 or 80 mg/day) or fenofibrate. Induced AF duration (DAF) was increased by VTP from 36+/-14 (non-paced controls) to 1005+/-257 s (p<0.01). Simvastatin prevented VTP-induced DAF increases (147+/-37 and 84+/-37 s at 20 and 80 mg/day, respectively), but fenofibrate did not (1018+/-352 s). Simvastatin also attenuated CHF-induced conduction abnormalities (heterogeneity-index reduced from 1.5+/-0.1 to 1.1+/-0.1 and 1.0+/-0.1 at 20 and 80 mg/day, p<0.01) and atrial fibrosis (from 19.4+/-1.3% to 10.8+/-0.8% and 9.9+/-0.8% at 20 and 80 mg/day, p<0.01), while fenofibrate did not. Simvastatin (but not fenofibrate) also attenuated VTP-induced left-ventricular nitric-oxide synthase and nitrotyrosine increases, along with hemodynamic dysfunction. Atrial fibroblast proliferation increased with 24-h fetal bovine serum (FBS) stimulation from 654+/-153 to 7264+/-1636 DPM (p<0.001). Simvastatin, but not fenofibrate, suppressed fibroblast proliferation (664+/-192 DPM, p<0.001). Simvastatin also significantly attenuated transforming growth factor-beta1-stimulated alpha-smooth muscle actin (alpha-SMA) expression (indicating myofibroblast differentiation) from 1.3+/-0.1 to 1.0+/-0.1 times baseline (p<0.05).. CHF-induced atrial structural remodeling and AF promotion are attenuated by simvastatin, but not fenofibrate. Statin-induced inhibition of profibrotic atrial fibroblast responses and attenuation of left-ventricular dysfunction may contribute to preventing the CHF-induced fibrotic AF substrate.

Topics: Actins; Animals; Anti-Inflammatory Agents; Atrial Fibrillation; Biomarkers; Cardiac Pacing, Artificial; Cell Proliferation; Cells, Cultured; Dogs; Fenofibrate; Fibroblasts; Heart Atria; Heart Failure; Heart Ventricles; Hypolipidemic Agents; Models, Animal; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; PPAR alpha; Refractory Period, Electrophysiological; Simvastatin; Tyrosine; Ventricular Remodeling

Atrial fibrillation (AF) is associated with severe contractile dysfunction and structural and electrophysiological remodeling. Mechanisms responsible for impaired contractility are undefined, and current therapies do not address this dysfunction. We have found that myofibrillar creatine kinase (MM-CK), an important controller of myocyte contractility, is highly sensitive to oxidative injury, and we hypothesized that increased oxidative stress and energetic impairment during AF could contribute to contractile dysfunction. Methods and Results-- Right atrial appendages were obtained from AF patients undergoing the Maze procedure and from control patients who were in normal sinus rhythm and undergoing cardiac surgery. MM-CK activity was reduced in AF patients compared with controls (25.4+/-3.4 versus 18.2+/-3.8 micromol/mg of myofibrillar protein per minute; control versus AF; P<0.05). No reduction in total CK activity or myosin ATPase activity was detected. This selective reduction in MM-CK activity was associated with increased relative expression of the beta-myosin isoform (25+/-6 versus 63+/-5%beta, CTRL versus AF; P<0.05). Western blotting of AF myofibrillar isolates demonstrated no changes in protein composition but showed increased prevalence of protein oxidation as detected by Western blotting for 3-nitrotyrosine (peroxynitrite biomarker) and protein carbonyls (hydroxyl radical biomarker; P<0.05). Patterns of these oxidative markers were distinct, which suggests discrete chemical events and differential protein vulnerabilities in vivo. MM-CK inhibition was statistically correlated to extent of nitration (P<0.01) but not to carbonyl presence.. The present results provide novel evidence of oxidative damage in human AF that altered myofibrillar energetics may contribute to atrial contractile dysfunction and that protein nitration may be an important participant in this condition.

Topics: Aged; Atrial Appendage; Atrial Fibrillation; Biomarkers; Blotting, Western; Chronic Disease; Creatine Kinase; Creatine Kinase, MB Form; DNA; Electrophoresis, Polyacrylamide Gel; Energy Metabolism; Female; Humans; Hydroxyl Radical; Isoenzymes; Male; Middle Aged; Myocardial Contraction; Myocardium; Myofibrils; Myosins; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Protein Isoforms; Proteins; Tyrosine