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.

Background-Atrial fibrillation (AF) may persist due to structural changes in the atria that are promoted by inflammation.C-reactive protein (CRP), a marker of systemic inflammation, predicts cardiovascular events and stroke, a common sequela of AF. We hypothesized that CRP is elevated in patients with atrial arrhythmias. Methods and Results-Using a case-control study design, CRP in 131 patients with atrial arrhythmias was compared with CRP in 71 control patients. Among arrhythmia patients, 6 had frequent atrial ectopy or tachycardia, 86 had paroxysmal AF, 39 had persistent AF lasting Ͼ30 days, and 70 had lone arrhythmias. CRP was higher in arrhythmia than in control patients (median, 0.21 versus 0.096 mg/dL; PϽ0.001). Arrhythmia patients in AF within 24 hours before sampling had higher CRP than those in sinus rhythm (0.30 versus 0.15 mg/dL; PϽ0.001). CRP in controls was not different than in patients with atrial ectopy or tachycardia. Lone arrhythmia patients had a CRP of 0.21 mg/dL, which was not significantly lower than arrhythmia patients with structural heart disease (CRP, 0.23 mg/dL) but higher than controls (Pϭ0.002). Persistent AF patients had a higher CRP (0.34 mg/dL) than paroxysmal AF patients (0.18 mg/dL; Pϭ0.008); both groups had higher CRP levels than controls (PՅ0.005). Conclusions-CRP is elevated in AF patients. This study is the first to document elevated CRP in non-postoperative arrhythmia patients. These findings are reinforced by stepwise CRP elevation with higher AF burden. Although the cause of elevated CRP levels in AF patients remains unknown, elevated CRP may reflect an inflammatory state that promotes the persistence of AF.

Abstract-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 Ϫ1) 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. (Circ Res. 2001;89:e32-e38.) Key Words: atrial fibrillation Ⅲ antioxidant Ⅲ ascorbate Ⅲ oxidative stress Ⅲ cardiac surgery A trial fibrillation (AF) is self-perpetuating 1 because of the combined effects of rate-induced electrophysiological and structural remodeling. 2 The earliest observed change in AF is an abbreviation of the atrial effective refractory period (ERP). The mechanisms by which high-rate activity results in electrophysiological remodeling are poorly understood. AF is also a frequent postoperative complication of cardiac surgery, with a reported incidence of 20% to 50%, increasing the risk of stroke. 3 Before arrhythmia onset, patients who experience postoperative AF exhibit increased atrial ectopy, abbreviation of monophasic action potential duration, and increased heart rate. 4 Evidence from animal models of atrial fibrillation, 5-7 as well as our studies of patients with postoperative AF, 8 supports a prominent role for myocyte calcium overload in initiating the process of atrial electrophysiological remodeling. We have documented both significant electrophysiological remodeling 8,9 and biochemical evidence of oxidative stress...

Abnormal cardiac ryanodine receptor (RyR2) function is recognized as an important factor in the pathogenesis of heart failure (HF). However, the specific molecular causes underlying RyR2 defects in HF remain poorly understood. In the present study, we used a canine model of chronic HF to test the hypothesis that the HF-related alterations in RyR2 function are caused by posttranslational modification by reactive oxygen species generated in the failing heart. Experimental approaches included imaging of cytosolic ([Ca2+]c) and sarcoplasmic reticulum (SR) luminal Ca2+ ([Ca2+]SR) in isolated intact and permeabilized ventricular myocytes and single RyR2 channel recording using the planar lipid bilayer technique. The ratio of reduced to oxidized glutathione, as well as the level of free thiols on RyR2 decreased markedly in failing versus control hearts consistent with increased oxidative stress in HF. RyR2-mediated SR Ca2+ leak was significantly enhanced in permeabilized myocytes, resulting in reduced [Ca2+]SR in HF compared to control cells. Both SR Ca2+ leak and [Ca2+]SR were partially normalized by treating HF myocytes with reducing agents. Conversely, oxidizing agents accelerated SR Ca2+ leak and decreased [Ca2+]SR in cells from normal hearts. Moreover, exposure to antioxidants significantly improved intracellular Ca2+-handling parameters in intact HF myocytes. Single RyR2 channel activity was significantly higher in HF versus control because of increased sensitivity to activation by luminal Ca2+ and was partially normalized by reducing agents through restoring luminal Ca2+ sensitivity oxidation of control RyR2s enhanced their luminal Ca2+ sensitivity, thus reproducing the HF phenotype. These findings suggest that redox modification contributes to abnormal function of RyR2s in HF, presenting a potential therapeutic target for treating HF.